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Sample records for bombesin derivative designed

  1. Radiolabeled bombesin derivatives for preclinical oncological imaging

    PubMed Central

    de Aguiar Ferreira, Carolina; Fuscaldi, Leonardo Lima; Townsend, Danyelle M.; Rubello, Domenico; de Barros, André Luís Branco

    2017-01-01

    Despite efforts, cancer is still one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths each year, according to the World Health Organization. Among the strategies to reduce cancer progression and improving its management, implementing early detection technologies is crucial. Based on the fact that several types of cancer cells overexpress surface receptors, small molecule ligands, such as peptides, have been developed to allow tumor identification at earlier stages. Allied with imaging techniques such as PET and SPECT, radiolabeled peptides play a pivotal role in nuclear medicine. Bombesin, a peptide of 14 amino acids, is an amphibian homolog to the mammalian gastrin-releasing peptide (GRP), that has been extensively studied as a targeting ligand for diagnosis and therapy of GRP positive tumors, such as breast, pancreas, lungs and prostate cancers. In this context, herein we provide a review of reported bombesin derivatives radiolabeled with a multitude of radioactive isotopes for diagnostic purposes in the preclinical setting. Moreover, since animal models are highly relevant for assessing the potential of clinical translation of this radiopeptides, a brief report of the currently used GRP-positive tumor-bearing animal models is described. PMID:28040598

  2. Brain RVD-haemopressin, a haemoglobin-derived peptide, inhibits bombesin-induced central activation of adrenomedullary outflow in the rat

    PubMed Central

    Tanaka, Kenjiro; Shimizu, Takahiro; Yanagita, Toshihiko; Nemoto, Takayuki; Nakamura, Kumiko; Taniuchi, Keisuke; Dimitriadis, Fotios; Yokotani, Kunihiko; Saito, Motoaki

    2014-01-01

    BACKGROUND AND PURPOSE Haemopressin and RVD-haemopressin, derived from the haemoglobin α-chain, are bioactive peptides found in brain and are ligands for cannabinoid CB1 receptors. Activation of brain CB1 receptors inhibited the secretion of adrenal catecholamines (noradrenaline and adrenaline) induced by i.c.v. bombesin in the rat. Here, we investigated the effects of two haemoglobin-derived peptides on this bombesin-induced response EXPERIMENTAL APPROACH Anaesthetised male Wistar rats were pretreated with either haemoglobin-derived peptide, given i.c.v., 30 min before i.c.v. bombesin and plasma catecholamines were subsequently measured electrochemically after HPLC. Direct effects of bombesin on secretion of adrenal catecholamines were examined using bovine adrenal chromaffin cells. Furthermore, activation of haemoglobin α-positive spinally projecting neurons in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of central adrenomedullary outflow) after i.c.v. bombesin was assessed by immunohistochemical techniques. KEY RESULTS Bombesin given i.c.v. dose-dependently elevated plasma catecholamines whereas incubation with bombesin had no effect on spontaneous and nicotine-induced secretion of catecholamines from chromaffin cells. The bombesin-induced increase in catecholamines was inhibited by pretreatment with i.c.v. RVD-haemopressin (CB1 receptor agonist) but not after pretreatment with haemopressin (CB1 receptor inverse agonist). Bombesin activated haemoglobin α-positive spinally projecting neurons in the PVN. CONCLUSIONS AND IMPLICATIONS The haemoglobin-derived peptide RVD-haemopressin in the brain plays an inhibitory role in bombesin-induced activation of central adrenomedullary outflow via brain CB1 receptors in the rat. These findings provide basic information for the therapeutic use of haemoglobin-derived peptides in the modulation of central adrenomedullary outflow. PMID:24138638

  3. Comparative in vivo evaluation of two novel 99mTc labelled bombesin derivatives

    NASA Astrophysics Data System (ADS)

    Gourni, Eleni; Bouziotis, Penelope; Zikos, Christos; Loudos, George; Xanthopoulos, Stavros; Fani, Melpomeni; Archimandritis, Spyridon C.; Varvarigou, Alexandra D.

    2006-12-01

    Bombesin (BN), a 14 amino acid peptide, is an analogue of human gastrin-releasing-peptide (GRP) that binds to GRP receptors (GRP-R) with high affinity and specificity. In addition to this physiological role, GRP, through its interaction with GRP-R, promotes tumour growth in a number of human cancer cell lines. The GRP receptors are over-expressed on a variety of human cancer cells. Aim of the present work is the study of two novels BN-like peptides, by investigating the radiochemical and radiopharmacological behaviour of their complexes with metals. The derivatives under study are: Gly-Gly-Cys-Aca-BN [2-14] where Aca: 6-amino-hexanoic acid. Pyroglutamic acid in the bombesin molecule has been replaced by the chemical group Gly-Gly-Cys-Aca, which bears an amino-acid combination capable of complexing a variety of radiometals. The other derivative under study is: Gly-Gly-Cys-Aca-BN [7-14]. This moiety of the peptide has been chosen because it has been proven to be a potent GRP agonist. The peptide derivatives were synthesized by SPPS, according to the Fmoc strategy and were identified by reverse phase high performance liquid chromatography (RP-HPLC). Radiolabelling with 99mTc was performed via the precursor 99mTc-gluconate. The stability of the radiolabelled species was examined with time. In vivo studies of the two 99mTc-labelled derivatives were performed, comparatively, in normal mice, attention being focused on GRP receptor-bearing organs, and in experimentally induced prostate cancer models. Experimental tumours were imaged in a small field-of-view animal gamma camera.

  4. Synthesis and evaluation of bombesin derivatives on the basis of pan-bombesin peptides labeled with indium-111, lutetium-177, and yttrium-90 for targeting bombesin receptor-expressing tumors.

    PubMed

    Zhang, Hanwen; Chen, Jianhua; Waldherr, Christian; Hinni, Karin; Waser, Beatrice; Reubi, Jean Claude; Maecke, Helmut R

    2004-09-15

    Bombesin receptors are overexpressed on a variety of human tumors like prostate, breast, and lung cancer. The aim of this study was to develop radiolabeled (Indium-111, Lutetium-177, and Yttrium-90) bombesin analogues with affinity to the three bombesin receptor subtypes for targeted radiotherapy. The following structures were synthesized: diethylenetriaminepentaacetic acid-gamma-aminobutyric acid-[D-Tyr6, beta-Ala11, Thi13, Nle14] bombesin (6-14) (BZH1) and 1,4,7,10-tetraazacyclododecane-N,N',N",N"' -tetraacetic acid-gamma-aminobutyric acid-[D-Tyr6, beta-Ala11, Thi13, Nle14] bombesin (6-14) (BZH2). [111In]-BZH1 and in particular [90Y]-BZH2 were shown to have high affinity to all three human bombesin receptor subtypes with binding affinities in the nanomolar range. In human serum metabolic cleavage was found between beta-Ala11 and His12 with an approximate half-life of 2 hours. The metabolic breakdown was inhibited by EDTA and beta-Ala11-His12 (carnosine) indicating that carnosinase is the active enzyme. Both 111In-labeled peptides were shown to internalize into gastrin-releasing peptide-receptor-positive AR4-2J and PC-3 cells with similar high rates, which were independent of the radiometal. The biodistribution studies of [111In]-BZH1 and [111In]-BZH2 ([177Lu]-BZH2) in AR4-2J tumor-bearing rats showed specific and high uptake in gastrin-releasing peptide-receptor-positive organs and in the AR4-2J tumor. A fast clearance from blood and all of the nontarget organs except the kidneys was found. These radiopeptides were composed of the first pan-bombesin radioligands, which show great promise for the early diagnosis of tumors bearing not only gastrin-releasing peptide-receptors but also the other two bombesin receptor subtypes and may be of use in targeted radiotherapy of these tumors.

  5. Ca/sup 2 +/-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 mouse cells

    SciTech Connect

    Lopez-Rivas, A.; Mendoza, S.A.; Nanberg, E.; Sinnett-Smith, J.; Rozengurt, E.

    1987-08-01

    Addition of the mitogenic peptides bombesin and vasopressin to quiescent Swiss 3T3 mouse cells increased the cytosolic Ca/sup 2 +/ concentration without any measurable delay. In contrast, there was a significant lag period (16 +/- 1.2 s) before platelet-derived growth factor (PDGF) increased cytosolic Ca/sup 2 +/ concentration. This lag was not diminished at high concentrations of either porcine or human PDGF. Similar results were obtained in 3T3 cells loaded with quin-2 or fura-2. The differences in the effects of bombesin, vasopressin, and PDGF on Ca/sup 2 +/ movements were also substantiated by measurements of /sup 45/Ca/sup 2 +/ efflux and of cellular /sup 45/Ca/sup 2 +/ content. Activation of protein kinase C by phorbol esters inhibited Ca/sup 2 +/ mobilization induced by either bombesin or vasopressin. In contrast, phorbol esters had no effect on PDGF-induced cytosolic Ca/sup 2 +/ concentration increase or acceleration of /sup 45/Ca/sup 2 +/ efflux. Finally, bombesin and vasopressin caused a rapid increase in the production of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate, whereas PDGF, even at a saturating concentration, exerted only a small effect. These results indicate that the signal transduction pathway activated by PDGF that lead to Ca/sup 2 +/ mobilization can be distinguished form those utilized by bombesin and vasopressin.

  6. A Bombesin-Shepherdin Radioconjugate Designed for Combined Extra- and Intracellular Targeting

    PubMed Central

    Fischer, Christiane A.; Vomstein, Sandra; Mindt, Thomas L.

    2014-01-01

    Radiolabeled peptides which target tumor-specific membrane structures of cancer cells represent a promising class of targeted radiopharmaceuticals for the diagnosis and therapy of cancer. A potential drawback of a number of reported radiopeptides is the rapid washout of a substantial fraction of the initially delivered radioactivity from cancer cells and tumors. This renders the initial targeting effort in part futile and results in a lower imaging quality and efficacy of the radiotracer than achievable. We are investigating the combination of internalizing radiopeptides with molecular entities specific for an intracellular target. By enabling intracellular interactions of the radioconjugate, we aim at reducing/decelerating the externalization of radioactivity from cancer cells. Using the “click-to-chelate” approach, the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT) was combined with the binding sequence of bombesin for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r) and peptidic inhibitors of the cytosolic heat shock 90 protein (Hsp90) for intracellular targeting. Receptor-specific uptake of the multifunctional radioconjugate could be confirmed, however, the cellular washout of radioactivity was not improved. We assume that either endosomal trapping or lysosomal degradation of the radioconjugate is accountable for these observations. PMID:24871806

  7. Nicotine, acetylcholine and bombesin are trophic growth factors in neuroendocrine cell lines derived from experimental hamster lung tumors

    SciTech Connect

    Schueller, H.M.; Nylen, E.; Park, P.; Becker, K.L. George Washington Univ., Washington, DC )

    1990-01-01

    Neuroendocrine hamster lung tumors, induced by exposure to 60% hyperoxia and subcutaneous administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) for 12 weeks, were placed in cell culture. By subsequent selective transfer of epithelial cells and maintenance in an atmosphere of 8% CO{sub 2}, cell lines with characteristics of neuroendocrine cells were established. The neuroendocrine markers expressed by these cell lines included electron dense neuroendocrine secretion granules as well as secretion of calcitonin and mammalian bombesin. In keeping with data previously reported for a human neuroendocrine lung tumor cell line, nicotine, acetylcholien, and mammalian bombesin (MB) acted as strongrowth factors in these neuroendocrine hamster tumor lines. The mitogenic effect of nicotine an acetylcholine was abolished by nicotinic receptor inhibition while the effects of mammalian bombesin were inhibited by an antagonist of MB receptors. Our data suggest that a receptor-mediated mitogenic effect of nicotine on neuroendocrine lung cells may be instrumental in the induction of smoking-associated small cell lung cancer.

  8. Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide.

    PubMed Central

    Isacke, C M; Meisenhelder, J; Brown, K D; Gould, K L; Gould, S J; Hunter, T

    1986-01-01

    Bombesin and the related mammalian peptides, such as gastrin-releasing peptide (GRP), are potent mitogens for some fibroblast cell lines. Here we have examined the bombesin- and GRP-mediated changes in the phosphorylation of proteins in Swiss 3T3 cells and compared these to the events observed after platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and tumor promoter treatment. In agreement with previous reports, bombesin, GRP and PDGF, but not EGF, increased the activity of protein kinase C. This was assayed by an inhibition of [125I]EGF binding, stimulation in phosphorylation of pp60c-src on serine 12 and stimulation in phosphorylation of a group of 80 kd proteins. The different phosphorylated forms of the 80 kd proteins were examined by tryptic peptide mapping and shown to contain multiple phosphorylation sites. An investigation of the tyrosine phosphorylation events following mitogen treatment revealed a significant difference between PDGF and the bombesin peptides. PDGF treatment caused a marked increase in total cellular phosphotyrosine levels, and tyrosine phosphorylation both of known substrates and its own receptor. In contrast, bombesin and GRP treatments resulted in only a weak or undetectable increase in tyrosine phosphorylation of total cellular protein or known substrates. In this respect bombesin and GRP were more similar to EGF. The fact that the bombesin peptides do not induce a phosphorylation response identical with either PDGF or EGF suggests that there is not a single common signal pathway which is activated by all these mitogens. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:2431903

  9. Evolution of bombesin conjugates for targeted PET imaging of tumors.

    PubMed

    Zhang, Hanwen; Abiraj, Keelara; Thorek, Daniel L J; Waser, Beatrice; Smith-Jones, Peter M; Honer, Michael; Reubi, Jean Claude; Maecke, Helmut R

    2012-01-01

    Bombesin receptors are under intense investigation as molecular targets since they are overexpressed in several prevalent solid tumors. We rationally designed and synthesized a series of modified bombesin (BN) peptide analogs to study the influence of charge and spacers at the N-terminus, as well as amino acid substitutions, on both receptor binding affinity and pharmacokinetics. This enabled development of a novel (64/67)Cu-labeled BN peptide for PET imaging and targeted radiotherapy of BN receptor-positive tumors. Our results show that N-terminally positively charged peptide ligands had significantly higher affinity to human gastrin releasing peptide receptor (GRPr) than negatively charged or uncharged ligands (IC(50): 3.2±0.5 vs 26.3±3.5 vs 41.5±2.5 nM). The replacement of Nle(14) by Met, and deletion of D-Tyr(6), further resulted in 8-fold higher affinity. Contrary to significant changes to human GRPr binding, modifications at the N-terminal and at the 6(th), 11(th), and 14(th) position of BN induced only slight influences on affinity to mouse GRPr. [Cu(II)]-CPTA-[βAla(11)] BN(7-14) ([Cu(II)]-BZH7) showed the highest internalization rate into PC-3 cells with relatively slow efflux because of its subnanomolar affinity to GRPr. Interestingly, [(64/67)Cu]-BZH7 also displayed similar affinities to the other 2 human BN receptor subtypes. In vivo studies showed that [(64/67)Cu]-BZH7 had a high accumulation in PC-3 xenografts and allowed for clear-cut visualization of the tumor in PET imaging. In addition, a CPTA-glycine derivative, forming a hippurane-type spacer, enhanced kidney clearance of the radiotracer. These data indicate that the species variation of BN receptor plays an important role in screening radiolabeled BN. As well, the positive charge from the metallated complex at the N-terminal significantly increases affinity to human GRPr. Application of these observations enabled the novel ligand [(64/67)Cu]-BZH7 to clearly visualize PC-3 tumors in vivo

  10. Human lung small-cell carcinoma contains bombesin.

    PubMed Central

    Erisman, M D; Linnoila, R I; Hernandez, O; DiAugustine, R P; Lazarus, L H

    1982-01-01

    The presence of immunoreactive bombesin in a human lung small-cell carcinoma grown in nude mice was established by several criteria: (i) Radioimmunoassay of tissue extracts for bombesin revealed approximately 6.5 pmol/g of tissue; (ii) bombesin was found in 12-14% of the tumor cells by immunohistochemical localization; (iii) gel filtration of small-cell carcinoma extract on Sephadex G-75 and Bio-Gel P-4 gave only a single peak of immunoreactivity, which occurred at the elution volume of bombesin; and (iv) reverse-phase HPLC of acid-solubilized extracts separated the immunoreactive material into three discrete peaks, one of which eluted with a retention time identical to that of synthetic bombesin. The presence of bombesin may represent the ectopic expression of this peptide in small-cell carcinoma, because immunoreactive bombesin was found in human fetal and neonatal lung but apparently not in adult lung tissue [Wharton, J., Polak, J. M., Bloom, S. R., Ghatei, M. A., Solcia, E., Brown, M. R. & Pearse, A. G. E. (1978) Nature (London) 273, 769-770]. The immunoreactive bombesin previously found in mammalian tissues is considerably larger than amphibian bombesin; these data substantiate the presence of a mammalian form of bombesin in a human tumor that may have a structure similar to that of the amphibian peptide. Images PMID:6285381

  11. Receptor for bombesin with associated tyrosine kinase activity.

    PubMed Central

    Cirillo, D M; Gaudino, G; Naldini, L; Comoglio, P M

    1986-01-01

    The neuropeptide bombesin is known for its potent mitogenic activity on murine 3T3 fibroblasts and other cells. Recently it has been implicated in the pathogenesis of small cell lung carcinoma, in which it acts through an autocrine loop of growth stimulation. Phosphotyrosine (P-Tyr) antibodies have been successfully used to recognize the autophosphorylated receptors for known growth factors. In Swiss 3T3 fibroblasts, phosphotyrosine antibodies identified a 115,000-Mr cell surface protein (p115) that became phosphorylated on tyrosine as a specific response to bombesin stimulation of quiescent cells. The extent of phosphorylation was dose dependent and correlated with the mitogenic effect induced by bombesin, measured by [3H]thymidine incorporation. Tyrosine phosphorylation of p115 was detectable minutes after the addition of bombesin, and its time course paralleled that described for the binding of bombesin to its receptor. Immunocomplexes of phosphorylated p115 and phosphotyrosine antibodies bound 125I-labeled [Tyr4]bombesin in a specific and saturable manner and displayed an associated tyrosine kinase activity enhanced by bombesin. Furthermore, the 125I-labeled bombesin analog gastrin-releasing peptide, bound to intact live cells, was coprecipitated with p115. These data strongly suggest that p115 participates in the structure and function of the surface receptor for bombesin, a new member of the family of growth factor receptors with associated tyrosine kinase activity. Images PMID:2432404

  12. Role of spinal bombesin-responsive neurons in nonhistaminergic itch

    PubMed Central

    Akiyama, Tasuku; Tominaga, Mitsutoshi; Takamori, Kenji; Carstens, E.

    2014-01-01

    Intrathecal administration of the neurotoxin bombesin-saporin reduces or abolishes pruritogen-evoked scratching behavior. We investigated whether spinal neurons that respond to intradermal (ID) injection of pruritogens also respond to spinal superfusion of bombesin and vice versa. Single-unit recordings were made from superficial lumbar spinal dorsal horn neurons in anesthetized mice. We identified neurons with three search strategies: 1) ID injection of the nonhistaminergic itch mediator chloroquine, 2) spinal superfusion of bombesin, and 3) noxious pinch. All units were tested with an array of itch mediators (chloroquine, histamine, SLIGRL, BAM8-22), algogens [capsaicin, allyl isothiocyanate (AITC)], and physical stimuli (brush, pinch, noxious heat, cooling) applied to the hindlimb receptive field. The vast majority of chloroquine-responsive units also responded to bombesin. Of 26 chloroquine-sensitive units tested, most responded to SLIGRL, half responded to histamine and/or BAM8-22, and most responded to capsaicin and/or AITC as well as noxious thermal and mechanical stimuli. Of 29 bombesin-responsive units, a large majority also responded to other itch mediators as well as AITC, capsaicin, and noxious thermal and mechanical stimuli. Responses to successive applications of bombesin exhibited tachyphylaxis. In contrast, of 36 units responsive to noxious pinch, the majority (67%) did not respond to ID chloroquine or spinal bombesin. It is suggested that chloroquine- and bombesin-sensitive spinal neurons signal itch from the skin. PMID:25122701

  13. Direct subphthalocyanine conjugation to bombesin vs. indirect conjugation to its lipidic nanocarrier.

    PubMed

    Bernhard, Yann; Gigot, Elodie; Goncalves, Victor; Moreau, Mathieu; Sok, Nicolas; Richard, Philippe; Decréau, Richard A

    2016-05-11

    Bombesin (BBN) was covalently bound to graftable subphthalocyanine (SubPc) or to a cholesterol derivative, a component of a liposome that encapsulates non-graftable SubPc. The latter bioconjugation approach was suitable to address the stability of SubPc and was achieved by copper-free click-chemistry on the outer-face of the liposome. Liposomes were purified (FPLC) and then analyzed in size (outer diameter about 60 nm measured by DLS). In vitro binding studies allowed to determine the IC50 13.9 nM for one component of the liposome, cholesterol, conjugated to BBN. Hence, azido- (or alkynyl-) liposomes give fluorophores with no reactive functional group available on their backbone a second chance to be (indirectly) bioconjugated (with bombesin).

  14. Lutetium-177 Labeled Bombesin Peptides for Radionuclide Therapy.

    PubMed

    Reynolds, Tamila Stott; Bandari, Rajendra P; Jiang, Zongrun; Smith, Charles J

    2016-01-01

    The rare-earth radionuclides that decay by beta particle (β-) emission are considered to be ideal in the context of targeted radiotherapy. The rare-earth isotopes exist primarily in the 3+ oxidation state and are considered to be hard metal centers, requiring multidentate, hard donor ligands such as the poly(aminocarboxylates) for in vivo kinetic inertness. 177Lu is a rare-earth radionuclide that is produced in moderate specific activity (740 GBq/mg) by direct neutron capture of enriched 176Lu via the 176Lu(n,γ)177Lu nuclear reaction. 177Lu has a half-life of 6.71 d, decays by beta emission (Ebmax = 0.497 MeV), and emits two imagable photons (113keV, 3% and 208kev, 11%). High specific activity, no-carrier-added 177Lu can also be prepared by an indirect neutron capture nuclear reaction on a 176Yb target. Herein, we report upon bombesin (BBN) peptides radiolabeled with 177Lu. The impetus driving many of the research studies that we have described in this review is that the high-affinity gastrin releasing peptide receptor (GRPR, BBN receptor subtype 2, BB2) has been identified in tissue biopsy samples and immortalized cell lines of many human cancers and is an ideal biomarker for targeting early-stage disease. Early on, the ability of GRPR agonists to be rapidly internalized coupled with a high incidence of GRPR expression on various neoplasias was a driving force for the design and development of new diagnostic and therapeutic agents targeting GRP receptor-positive tumors. Recent reports, however, show compelling evidence that radiopharmaceutical design and development based upon antagonist-type ligand frameworks clearly bears reexamination. Last of all, the ability to target multiple biomarkers simultaneously via a heterodimeric targeting ligand has also provided a new avenue to investigate the dual targeting capacity of bivalent radioligands for improved in vivo molecular imaging and treatment of specific human cancers. In this report, we describe recent advances

  15. Stimulatory effect of bombesin on phosphoinositide metabolism in the rat pineal gland.

    PubMed

    Novotná, R; Novotný, I

    1997-10-03

    The pineal gland is under complex peptidergic nervous control originating from hypothalamic nuclei. The daily rhythm of bombesin-like peptide in the hypothalamus suggests that this neuropeptide, similarly as other neuropeptides, might be involved in modulation of the physiological activity of the pineal gland. In our experiments we studied the mechanism of signal transduction of bombesin in the isolated pineal glands of rats. The phosphoinositide signalling system was examined by measuring 32P-labelling of phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP) and phosphatidylinositol bisphosphate (PIP2), which reflects phosphoinositide cycle activation. Bombesin induced a significant increase in 32P-labelling of PI, PIP and PIP2. The antagonist of this neuropeptide, (D-Phe12-Leu14)-bombesin, suppressed the increase in 32P-labelling of all phosphoinositides. Bombesin was without effect on cAMP dependent protein phosphorylation. The data indicate that bombesin activates the PI signalling system via specific receptors.

  16. The Effect of Central Injection of Ghrelin and Bombesin on Mean Plasma Thyroid Hormones Concentration

    PubMed Central

    Mahmoudi, Fariba; Mohsennezhad, Fatemeh; Khazali, Homayoun; Ehtesham, Haleh

    2011-01-01

    Ghrelin increases food intakes and body weight. Bombesin decreases food intakes and inhibits the stimulatory effect of Ghrelin on food intakes. Thyroid hormones have a crucial role in the regulation of body weight and yet the effect of bombesin on thyroid axis activity is not fully clear. Therefore, the goal of this study was to determine the effect of different doses of Ghrelin or bombesin on mean plasma thyroid-stimulating hormone (TSH), Triiodothyronine (T3) and Thyroxin (T4) concentration and also, the effect of interaction between Ghrelin and bombesin on thyroid axis activity. Forty-nine rats in seven groups received saline or different doses of Ghrelin (4, 10 or 15 nmol) and bombesin ( 2.5, 5 or 10 nmol) and forty-two rats in six groups received simultaneous injection of Ghrelin (10 or 15 nmol) and different doses of bombesin (2.5, 5 or 10 nmol) via lateral cerebral ventricle. Blood samples were collected via decapitation 20 min after the injection and plasma was assayed for plasma TSH, T3 and T4 concentration by Radioimmunoassay (RIA). Ghrelin significantly decreased the concentration of mean plasma thyroid hormones compared to saline. Bombesin did not significantly increase thyroid hormones concentration compared to saline but bombesin blocked the inhibitory effect of Ghrelin on thyroid axis activity. Bombesin may be the antagonist of Ghrelin action. PMID:24250396

  17. Effects of caffeine and Bombesin on ethanol and food intake

    SciTech Connect

    Dietze, M.A.; Kulkosky, P.J. )

    1991-01-01

    The methylxanthine caffeine and ethyl alcohol are widely used and powerful psychotropic drugs, but their interactions are not well understood. Bombesin is a brain-gut neuropeptide which is thought to function as a neurochemical factor in the inhibitory control of voluntary alcohol ingestion. We assessed the effects of combinations of intraperitoneal doses of caffeine and bombesin on 5% w/v ethanol solution and food intake in deprived rats. Deprived male and female Wistar rats received access to 5% ethanol or Purina chow for 30 minutes after i.p. injections. In single doses, CAF and BBS significantly decreased both ethanol and food consumption, at 50 mg/kg and 10 {mu}g/kg, respectively. CAF and BBS combinations produced infra-additive, or less-than-expected inhibitory effects on ethanol intake, but simple additive inhibitory effects on food intake. This experimental evidence suggests a reciprocal blocking of effects of CAF and BBS on ethanol intake but not food intake. Caffeine, when interacting and bombesin, increases alcohol consumption beyond expected values. Caffeine could affect the operation of endogenous satisfy signals for alcohol consumption.

  18. Evaluation of a technetium-99m labeled bombesin homodimer for GRPR imaging in prostate cancer.

    PubMed

    Yu, Zilin; Carlucci, Giuseppe; Ananias, Hildo J K; Dierckx, Rudi A J O; Liu, Shuang; Helfrich, Wijnand; Wang, Fan; de Jong, Igle J; Elsinga, Philip H

    2013-02-01

    Multimerization of peptides can improve the binding characteristics of the tracer by increasing local ligand concentration and decreasing dissociation kinetics. In this study, a new bombesin homodimer was developed based on an ε-aminocaproic acid-bombesin(7-14) (Aca-bombesin(7-14)) fragment, which has been studied for targeting the gastrin-releasing peptide receptor (GRPR) in prostate cancer. The bombesin homodimer was conjugated to 6-hydrazinopyridine-3-carboxylic acid (HYNIC) and labeled with (99m)Tc for SPECT imaging. The in vitro binding affinity to GRPR, cell uptake, internalization and efflux kinetics of the radiolabeled bombesin dimer were investigated in the GRPR-expressing human prostate cancer cell line PC-3. Biodistribution and the GRPR-targeting potential were evaluated in PC-3 tumor-bearing athymic nude mice. When compared with the bombesin monomer, the binding affinity of the bombesin dimer is about ten times lower. However, the (99m)Tc labeled bombesin dimer showed a three times higher cellular uptake at 4 h after incubation, but similar internalization and efflux characters in vitro. Tumor uptake and in vivo pharmacokinetics in PC-3 tumor-bearing mice were comparable. The tumor was visible on the dynamic images in the first hour and could be clearly distinguished from non-targeted tissues on the static images after 4 h. The GRPR-targeting ability of the (99m)Tc labeled bombesin dimer was proven in vitro and in vivo. This bombesin homodimer provides a good starting point for further studies on enhancing the tumor targeting activity of bombesin multimers.

  19. Metabolically Stabilized (68)Ga-NOTA-Bombesin for PET Imaging of Prostate Cancer and Influence of Protease Inhibitor Phosphoramidon.

    PubMed

    Richter, Susan; Wuest, Melinda; Bergman, Cody N; Krieger, Stephanie; Rogers, Buck E; Wuest, Frank

    2016-04-04

    Peptide receptor-based targeted molecular imaging and therapy of cancer is on the current forefront of nuclear medicine preclinical research and clinical practice. The frequent overexpression of gastrin-releasing peptide (GRP) receptors in prostate cancer stimulated the development of radiolabeled bombesin derivatives as high affinity peptide ligands for selective targeting of the GRP receptor. In this study, we have evaluated a novel (68)Ga-labeled bombesin derivative for PET imaging of prostate cancer in vivo. In addition, we were interested in testing the recently proposed "serve-and-protect" strategy to improve metabolic stability of radiolabeled peptides in vivo and to enhance tumor uptake. GRP receptor targeting peptides NOTA-BBN2 and (nat)Ga-NOTA-BBN2 demonstrated a characteristic antagonistic profile and high binding affinity toward the GRP receptor in PC3 cells (IC50 4.6-8.2 nM). Radiolabeled peptide (68)Ga-NOTA-BBN2 was obtained from NOTA-BBN2 in radiochemical yields greater than 62% (decay-corrected). Total synthesis time was 35 min, including purification using solid-phase extraction. (68)Ga-NOTA-BBN2 exhibited favorable resistance against metabolic degradation by peptidases in vivo within the investigated time frame of 60 min. Interestingly, metabolic stability was not further enhanced in the presence of protease inhibitor phosphoramidon. Dynamic PET studies showed high tumor uptake in both PC3- and LNCaP-bearing BALB/c nude mice (SUV5min > 0.6; SUV60min > 0.5). Radiotracer (68)Ga-NOTA-BBN2 represents a novel radiometal-based bombesin derivative suitable for GRP receptor targeting in PC3 and LNCaP mouse xenografts. Further increase of metabolic stability in vivo and enhanced tumor uptake were not observed upon administration of protease inhibitor phosphoramidon. This led to the conclusion that the recently proposed "serve-and-protect" strategy may not be valid for peptides exhibiting favorable intrinsic metabolic stability in vivo.

  20. Neurotensin and bombesin, a relationship between their effects on body temperature and locomotor activity?

    PubMed

    van Wimersma Greidanus, T B; Schijff, J A; Noteboom, J L; Spit, M C; Bruins, L; van Zummeren, B M; Rinkel, G J

    1984-08-01

    Neurotensin and bombesin have been tested for their effects on body temperature and locomotor activity in an open field. Both peptides induce hypothermia and suppress ambulation and rearing. The time curves of the hypothermic effects of both peptides appear to be rather similar, although bombesin is a more potent hypothermic agent than neurotensin. The time curves of the effects on locomotor activity appear to be quite different. The suppressive effect of neurotensin on locomotor activity is relatively short lasting and reaches its maximum at approximately 32 minutes. The effect of bombesin follows a different time curve and shows two peaks, suggesting that two different mechanisms are involved in the suppressive action of bombesin on locomotor activity. Calculation of the correlation coefficients between the effects of neurotensin and of bombesin on body temperature and on locomotor activity (ambulation) suggest that a causal relationship between these two effects is not likely, in particular for neurotensin.

  1. Brain histamine mediates the bombesin-induced central activation of sympatho-adrenomedullary outflow.

    PubMed

    Okuma, Y; Yokotani, K; Murakami, Y; Osumi, Y

    1997-01-01

    Intracerebroventricular (i.c.v.) administration of bombesin (0.3 nmol) increased plasma levels of both adrenaline and noradrenaline in urethane anesthetized rats. These bombesin-induced increases were inhibited by i.c.v. pretreatment with pyrilamine, an H1-receptor antagonist. Ranitidine, an H2-receptor antagonist also inhibited the increase of adrenaline, however, its effective dose was much larger than that of pyrilamine. Furthermore, the bombesin-induced increase of noradrenaline was not effectively inhibited by ranitidine. In the next series, turnover of histamine was assessed by measuring accumulation of tele-methylhistamine (t-MH), a major metabolite of brain histamine. I.c.v. administration of bombesin (0.3-3 nmol) increased turnover of hypothalamic histamine, while its intravenous administration was without effect. The present results suggest that the bombesin-induced central activation of sympatho-adrenomedullary outflow is probably, at least in part, mediated through brain histaminergic neurons.

  2. Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells

    PubMed Central

    Jensen, R. T.; Moody, T.; Pert, C.; Rivier, J. E.; Gardner, J. D.

    1978-01-01

    We have prepared 125I-labeled [Tyr4]bombesin and have examined the kinetics, stoichiometry, and chemical specificity with which the labeled peptide binds to dispersed acini from guinea pig pancreas. Binding of 125I-labeled [Tyr4]-bombesin was saturable, temperature-dependent, and reversible and reflected interaction of the labeled peptide with a single class of binding sites on the plasma membrane of pancreatic acinar cells. Each acinar cell possessed approximately 5000 binding sites, and binding of the tracer to these sites could be inhibited by [Tyr4]bombesin [concentration for half-maximal effect (Kd), 2 nM], bombesin (Kd, 4 nM), or litorin (Kd, 40 nM) but not by eledoisin, physalemin, somatostatin, carbachol, atropine, secretin, vasocative intestinal peptide, neurotensin, or bovine pancreatic polypeptide. At high concentrations (>0.1 μM), cholecystokinin and caerulein each caused a small (15-20%) reduction in binding of lableled [Tyr4]bombesin. With bombesin, litorin, and [Tyr4]bombesin, there was a close correlation between the relative potency for inhibition of binding of labeled [Tyr4]bombesin and that for stimulation of amylase secretion. For a given peptide, however, a 10-fold higher concentration was required for half-maximal inhibition of binding than for half-maximal stimulation of amylase secretion, calcium outflux, or cyclic GMP accumulation. These results indicate that dispersed acini from guinea pig pancreas possess a single class of receptors that interact with [Tyr4]bombesin, bombesin, and litorin and that occupation of 25% of these receptors will cause a maximal biological response. PMID:216015

  3. Wound repair and proliferation of bronchial epithelial cells enhanced by bombesin receptor subtype 3 activation.

    PubMed

    Tan, Yu-Rong; Qi, Ming-Ming; Qin, Xiao-Qun; Xiang, Yang; Li, Xiang; Wang, Yue; Qu, Fei; Liu, Hui-Jun; Zhang, Jian-Song

    2006-07-01

    The present study was designed to investigate the role of bombesin receptor subtype 3 (BRS-3) in airway wound repair. The results showed that: (1) There was few expression of BRS-3 mRNA in the control group. In contrast, the expression of BRS-3 mRNA was gradually increased in the early 2 days, and peaked on the fourth day, and then decreased in the ozone-stressed AHR animal. BRS-3 mRNA was distributed in the ciliated columnar epithelium, monolayer columnar epithelium cells, scattered mesenchymal cells and Type II alveolar cells; (2) The wound repair and proliferation of bronchial epithelial cells (BECs) were accelerated in a concentration-dependent manner by BRS-3 activation with P3513, which could be inhibited by PKA inhibitor H89. The study demostrated that activation of BRS-3 may play an important role in wound repair of AHR.

  4. Insights into Bombesin receptors and ligands: highlighting recent advances

    PubMed Central

    Ramos-Álvarez, Irene; Moreno, Paola; Mantey, Samuel A.; Nakamura, Taichi; Nuche-Berenguer, Bernardo; Moody, Terry W.; Coy, David H.; Jensen, Robert T.

    2015-01-01

    This following article is written for Prof. Abba Kastin’s Festschrift, to add to the tribute to his important role in the advancement of the role of peptides in physiological, as well as pathophysiological processes. There have been many advances during the 35 years of his prominent role in the Peptide field, not only as editor of the journal Peptides, but also as a scientific investigator and editor of two volumes of the Handbook of Biological Active Peptides [146,147]. Similar to the advances with many different peptides, during this 35 year period, there have been much progress made in the understanding of the pharmacology, cell biology and the role of (Bombesin) Bn receptors and their ligands in various disease states, since the original isolation of bombesin from skin of the European frog Bombina bombina in 1970 [76]. This paper will briefly review some of these advances over the time period of Prof Kastin 35 years in the peptide field concentrating on the advances since 2007 when many of the results from earlier studies were summarized [128,129]. It is appropriate to do this because there have been 280 articles published in Peptides during this time on Bombesin-related peptides and it accounts for almost 5% of all publications. Furthermore, 22 Bn publications we have been involved in have been published in either Peptides [14,39,55,58,81,92,93,119,152,216,225,226,231,280,302,309,355,361,362] or in the Prof Kastin’s Handbook of Biological Active Peptides [137,138,331]. PMID:25976083

  5. Characterization of ligand binding and processing by bombesin receptors in an insulin-secreting cell line.

    PubMed Central

    Swope, S L; Schonbrunn, A

    1987-01-01

    Bombesin is a tetradecapeptide which stimulates insulin secretion in vivo by isolated islets and by HIT-T15 cells, a clonal line of hamster pancreatic-islet cells. In the present study we have used [125I-Tyr4]bombesin to characterize bombesin receptors in HIT-T15 cells. [125I-Tyr4]Bombesin binding was time- and temperature-dependent: maximum binding occurred after 45 min, 90 min and 10 h at 37, 22 and 4 degrees C respectively. Thereafter, cell-associated radioactivity declined at 37 degrees C and 22 degrees C but not at 4 degrees C. Scatchard analysis of [125I-Tyr4]bombesin binding measured at 4 degrees C showed that HIT-T15 cells contain a single class of binding sites (approximately equal to 85000/cell) with an apparent Kd of 0.9 +/- 0.11 nM. Structurally unrelated neuropeptides did not compete for [125I-Tyr4]bombesin binding. However, the relative potencies of bombesin and four bombesin analogues in inhibiting the binding of [125I-Tyr4]bombesin correlated with their ability to stimulate insulin release. Receptor-mediated processing of [125I-Tyr4]bombesin was examined by using an acid wash (0.2 M-acetic acid/0.5 M-NaCl, pH 2.5) to dissociate surface-bound peptide from the cells. Following [125I-Tyr4]bombesin binding at 4 degrees C, more than 85% of the cell-associated radioactivity could be released by acid. When the temperature was then increased to 37 degrees C, the bound radioactivity was rapidly (t1/2 less than 3 min) converted into an acid-resistant state. These results indicate that receptor-bound [125I-Tyr4]bombesin is internalized in a temperature-dependent manner. In fact, the entire ligand-receptor complex appeared to be internalized, since pretreatment of cells with 100 nM-bombesin for 90 min at 37 degrees C decreased the subsequent binding of [125I-Tyr4]bombesin by 90%. The chemical nature of the cell-associated radioactivity was determined by reverse-phase chromatography of the material extracted from cells after a 30 min binding incubation at 37

  6. Evaluation of 99mTc-HYNIC-βAla-Bombesin(7-14) as an agent for pancreas tumor detection in mice

    PubMed Central

    Carlesso, F.N.; Fuscaldi, L.L.; Araújo, R.S.; Teixeira, C.S.; Oliveira, M.C.; Fernandes, S.O.A.; Cassali, G.D.; Reis, D.C.; Barros, A.L.B.; Cardoso, V.N.

    2015-01-01

    Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using99mTc-HYNIC-βAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that99mTc-HYNIC-βAla-Bombesin(7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that99mTc-HYNIC-βAla-Bombesin(7-14)may be useful for the detection of pancreatic adenocarcinoma. PMID:26445336

  7. A Stress-Related Peptide Bombesin Centrally Induces Frequent Urination through Brain Bombesin Receptor Types 1 and 2 in the Rat

    PubMed Central

    Shimizu, Shogo; Higashi, Youichirou; Nakamura, Kumiko; Yoshimura, Naoki; Saito, Motoaki

    2016-01-01

    Stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome, but the underlying mechanisms are unknown. Bombesin-like peptides and bombesin receptor types 1 and 2 (BB1 and BB2, respectively) in the brain have been implicated in the mediation/integration of stress responses. In this study, we examined effects of centrally administered bombesin on micturition, focusing on their dependence on 1) the sympathoadrenomedullary system (a representative mechanism activated by stress exposure) and 2) brain BB receptors in urethane-anesthetized (1.0–1.2 g/kg, i.p.) male rats. Intracerebroventricularly administered bombesin significantly shortened intercontraction intervals (ICI) at both doses (0.1 and 1 nmol/animal) without affecting maximal voiding pressure. Bombesin at 1 nmol induced significant increments of plasma noradrenaline and adrenaline levels, which were both abolished by acute bilateral adrenalectomy. On the other hand, adrenalectomy showed no effects on the bombesin-induced shortening of ICI. Much lower doses of bombesin (0.01 and 0.03 nmol/animal, i.c.v.) dose-dependently shortened ICI. Pretreatment with either a BB1 receptor antagonist (BIM-23127; d-Nal-cyclo[Cys-Tyr-d-Trp-Orn-Val-Cys]-Nal-NH2; 3 nmol/animal, i.c.v.) or a BB2 receptor antagonist (BEA; H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; 3 nmol/animal, i.c.v.), respectively, suppressed the BB (0.03 nmol/animal, i.c.v.)–induced shortening of ICI, whereas each antagonist by itself (1 and 3 nmol/animal, i.c.v.) had no significant effects on ICI. Bombesin (0.03 nmol/animal, i.c.v.) significantly reduced voided volume per micturition and bladder capacity without affecting postvoid residual volume or voiding efficiency. These results suggest that brain bombesin and BB receptors are involved in facilitation of the rat micturition reflex to induce bladder overactivity, which is independent of the sympathoadrenomedullary outflow modulation. PMID:26729307

  8. GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness.

    PubMed

    Svendsen, Berit; Pais, Ramona; Engelstoft, Maja S; Milev, Nikolay B; Richards, Paul; Christiansen, Charlotte B; Egerod, Kristoffer L; Jensen, Signe M; Habib, Abdella M; Gribble, Fiona M; Schwartz, Thue W; Reimann, Frank; Holst, Jens J

    2016-01-01

    The incretin hormones glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal endocrine cells, the so-called L- and K-cells. The cells are derived from a common precursor and are highly related, and co-expression of the two hormones in so-called L/K-cells has been reported. To investigate the relationship between the GLP1- and GIP-producing cells more closely, we generated a transgenic mouse model expressing a fluorescent marker in GIP-positive cells. In combination with a mouse strain with fluorescent GLP1 cells, we were able to estimate the overlap between the two cell types. Furthermore, we used primary cultured intestinal cells and isolated perfused mouse intestine to measure the secretion of GIP and GLP1 in response to different stimuli. Overlapping GLP1 and GIP cells were rare (∼5%). KCl, glucose and forskolin+IBMX increased the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between the GLP1-producing 'L-cell' and the GIP-producing 'K-cell'.

  9. Receptors for GRP/bombesin-like peptides in the rat forebrain

    SciTech Connect

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( SVI-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides.

  10. Autoradiographic localization of (/sup 125/I-Tyr4)bombesin-binding sites in rat brain

    SciTech Connect

    Zarbin, M.A.; Kuhar, M.J.; O'Donohue, T.L.; Wolf, S.S.; Moody, T.W.

    1985-02-01

    The binding of (/sup 125/I-Tyr/sub 4/)bombesin to rat brain slices was investigated. Radiolabeled (Tyr/sub 4/)bombesin bound with high affinity (K/sub d/ . 4 nM) to a single class of sites (B/sub max/ . 130 fmol/mg of protein); the ratio of specific to nonspecific binding was 6/1. Also, pharmacology studies indicated that the C-terminal of bombesin was important for the high affinity binding activity. Autoradiographic studies indicated that the (/sup 125/I-Tyr4)bombesin-binding sites were discretely distributed in certain gray but not white matter regions of rat brain. Highest grain densities were present in the olfactory bulb and tubercle, nucleus accumbens, suprachiasmatic and periventricular nuclei of the hypothalamus, central medial thalamic nucleus, medial amygdaloid nucleus, hippocampus, dentate gyrus, subiculum, nucleus of the solitary tract, and substantia gelatinosa. Moderate grain densities were present in the parietal cortex, deep layers of the neocortex, rhinal cortex, caudate putamen, stria terminalis, locus ceruleus, parabrachial nucleus, and facial nucleus. Low grain densities were present in the globus pallidus, lateral thalamus, and midbrain. Negligible grain densities were present in the cerebellum, corpus callosum, and all regions treated with 1 microM unlabeled bombesin. The discrete regional distribution of binding suggests that endogenous bombesin-like peptides may function as important regulatory agents in certain brain loci.

  11. Precise multipass Herriott cell design: Derivation of controlling design equations

    NASA Astrophysics Data System (ADS)

    Engel, Gregory S.; Moyer, Elisabeth J.

    2007-03-01

    Multipass Herriott cells are often designed using the thin lens approximation, which results in approximate dimensions or imperfect patterns due to both spherical aberration and the finite width of the optic. We derive the design equations for exact solutions to the Herriott cell problem. We also show that Herriott cells using spherical mirrors cannot be designed such that multiple concentric beam patterns all meet their reentrant condition. We derive a solution for elliptical mirrors that allows this condition to be met simultaneously for many beams.

  12. JMV641: a potent bombesin receptor antagonist that inhibits Swiss 3T3 cell proliferation.

    PubMed

    Azay, J; Gagne, D; Devin, C; Llinares, M; Fehrentz, J A; Martinez, J

    1996-08-27

    The peptides of the bombesin family are involved in stimulation of mitogenesis in various cell lines, including cancerous cell lines. Bombesin receptor antagonists are of great interest to inhibit this proliferation. We have synthesized a potent bombesin receptor antagonist, e.g., compound JMV641 [H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-*CH[CH2-CH(CH3)2]-**CHOH- (CH2)3-CH3 [*(S); **92% of (S) isomer], in which a pseudopeptide bond mimicking the transition state analogue replaced the peptide bond between the two C-terminal residues. This compound was highly potent to dose-dependently inhibit binding of 125I-GRP to Swiss 3T3 cells (IC50 = 0.85 +/- 0.15 nM) and bombesin-stimulated Swiss 3T3 proliferation (pA2 = 8.78). However, compound JMV641 can inhibit bombesin-induced AP-1 regulated genes that are nuclear messengers mediating the actions of signal transduction pathways stimulated by growth factors.

  13. Requirement of cortical actin organization for bombesin, endothelin, and EGF receptor internalization.

    PubMed

    Lunn, J A; Wong, H; Rozengurt, E; Walsh, J H

    2000-12-01

    The role of actin organization in occupancy-induced receptor internalization remains poorly defined. Here we report that treatment of mouse Swiss 3T3 cells with latrunculin A, a potent inhibitor of actin polymerization (including cortical actin), inhibited the internalization of the endogenous bombesin/gastrin-releasing peptide (GRP) receptor, as judged by uptake of (125)I-labeled GRP or fluorescent Cy3-labeled bombesin. In contrast, cells pretreated with cytochalasin D showed minimal inhibition of bombesin/GRP receptor internalization. Similarly, pretreatment of Swiss 3T3 cells with the potent Rho-kinase inhibitor HA-1077, at concentrations (10-20 microM) that abrogated bombesin-mediated stress fiber formation, did not significantly alter receptor-mediated internalization of (125)I-GRP. These results indicate that bombesin/GRP receptor internalization depends on latrunculin A-sensitive cortical actin rather than on rapidly turning over actin stress fibers that are disrupted by either cytochalasin D or HA-1077. The rates and total levels of internalization of the endogenously expressed endothelin A receptor and epidermal growth factor receptor were also markedly reduced by latrunculin A in Swiss 3T3 cells. The potency of latrunculin A for inhibiting G protein-coupled receptor endocytosis was comparable to that for reducing internalization of the epidermal growth factor tyrosine kinase receptor. We conclude that cortical actin structures, disrupted by latrunculin A, are necessary for occupancy-induced receptor internalization in animal cells.

  14. Activation of the protein-tyrosine kinase associated with the bombesin receptor complex in small cell lung carcinomas.

    PubMed Central

    Gaudino, G; Cirillo, D; Naldini, L; Rossino, P; Comoglio, P M

    1988-01-01

    It has been hypothesized that bombesin-like peptides produced by small cell lung carcinomas may sustain deregulated proliferation through an autocrine mechanism. We have shown that the neuropeptide bombesin leads to the activation of a protein-tyrosine kinase that phosphorylates a 115-kDa protein (p115) associated with the bombesin receptor complex in mouse Swiss 3T3 fibroblasts. We now report that phosphotyrosine antibodies recognize a 115-kDa protein, phosphorylated on tyrosine, in four human small cell lung carcinoma cell lines producing bombesin but not in a nonproducer "variant" line. p115 from detergent-treated small cell lung carcinoma cells binds to bombesin-Sepharose and can be phosphorylated on tyrosine in the presence of radiolabeled ATP and Mn2+. As for the p115 immunoprecipitated from mouse fibroblast, the small cell lung carcinoma p115 can be phosphorylated in an immunocomplex kinase assay. However, the latter does not require the presence of exogenous bombesin for activity. Binding data, obtained by using radiolabeled ligand, suggest receptor occupancy in the cell lines producing bombesin. These observations are consistent with the hypothesis that proliferation in some human small cell lung carcinoma lines is under autocrine control, regulated through activation of bombesin receptors. Images PMID:2451242

  15. Rhodium-105 Bombesin Analogs for Prostate Cancer Radiotherapy

    SciTech Connect

    Silvia S. Jurisson, PhD

    2005-12-31

    Over the period of this grant (11/01/2001 to 12/31/2005), the consistent and reproducible production of Rh-105, synthesis and evaluation of three new chelate systems based on hydroxymethyl phosphines, development of a new non-hydroxymethyl phosphine N{sub 2}P{sub 2} chelate system, conjugation of two of the chelates to the bombesin peptide analog BBN[7-14]NH{sub 2}, evaluation of the bombesin conjugates and their Rh-105 complexes for stability, cell binding affinity, and in vivo biodistribution in normal mice has been developed. The BBN analogs bind to GRP receptors that are overexpressed on PC-3 prostate tumor cells. A dedicated glove box is used for the separation and isolation of {sup 105}Rh from the target ({sup 104}Ru). All tubing/connections/valves from the point of the Cl{sub 2} tank are made of Teflon to minimize/eliminate the introduction of any metal into the process (e.g., iron from stainless steel corrosion). The separation of {sup 105}Rh produced from the enriched {sup 104}Ru target involves oxidation of the enriched {sup 104}Ru metal target to ruthenium tetroxide with chlorine gas and sodium hydroxide solution to generate hypochlorite in situ. The RuO4 is removed by distillation and the {sup 105}Rh remaining in the reaction vial is converted into {sup 105}Rh-chloride by acidification with hydrochloric acid and heating. The {sup 105}Rh production process has become reproducible over the past year to consistently make 10-30 mCi of {sup 105}Rh from 1-3 mg of an enriched (99.21%) {sup 104}Ru target. The process itself involves irradiation of the enriched {sup 104}Ru target in the core of the reactor (University of Missouri Research Reactor (MURR)) for one week to yield 16-40 mCi of {sup 105}Rh. The irradiated target is processed to separate the Rh-105 in high specific activity from the {sup 104}Ru target. The irradiated target is dissolved in NaOH (2M, 3 mL) by bubbling Cl{sub 2} gas through the solution (generating NaOCl in situ) to generate RuO{sub 4

  16. Bombesin stimulates insulin secretion by a pancreatic islet cell line.

    PubMed Central

    Swope, S L; Schonbrunn, A

    1984-01-01

    The amphibian tetradecapeptide, bombesin (BBS) has been shown to stimulate insulin secretion both in vivo and by pancreatic islet cells in vitro. To determine whether BBS can act directly on pancreatic beta cells, we examined its effects on insulin secretion by HIT-T15 cells (HIT cells), a clonal islet cell line. Addition of 100 nM BBS to HIT cells stimulated insulin release 25-fold within 30 sec. The rapid stimulatory effect of BBS on insulin release was short-lived: the secretory rate returned to basal levels after 90 min of BBS treatment. The decrease in the rate of insulin release in the continued presence of BBS was due not to depletion of intracellular insulin stores but to specific desensitization to this peptide. Stimulation of insulin secretion by BBS was dose dependent with an ED50 value (0.51 +/- 0.15 nM) similar to the concentration of BBS-like immunoreactive material in rat plasma. Five BBS analogs, including porcine gastrin-releasing peptide, were as powerful as BBS in stimulating insulin release. The relative potencies of the analogs tested indicated that the COOH-terminal octapeptide sequence in BBS was sufficient for stimulation of release. In contrast, 14 peptides structurally unrelated to BBS did not alter insulin secretion. BBS action was synergistic with that of glucagon; insulin secretion in the presence of maximal concentrations of both peptides was greater than the additive effects of the two peptides added individually. Somatostatin inhibited BBS-stimulated release by 69 +/- 1% with an ID50 value of 3.2 +/- 0.3 nM. These results show that BBS stimulation of insulin secretion by a clonal pancreatic cell line closely parallels its effects in vivo and support the hypothesis that BBS stimulates insulin secretion by a direct effect on the pancreatic beta cell. The clonal HIT cell line provides a homogeneous cell preparation amenable for studies on the biochemical mechanisms of BBS action in the endocrine pancreas. PMID:6143320

  17. Development of a new bombesin analog radiolabeled with lutetium-177: in vivo evaluation of the biological properties in Balb-C mice.

    PubMed

    Pujatti, P B; Santos, J S; Massicano, A V F; Mengatti, J; De Araújo, E B

    2010-05-10

    In this work we describe the first results of radiolabeling with lutetium-177 ((177)Lu) and in vivo biodistribution and pharmacokinetics studies in normal Balb-c mice of a new bombesin analog (BEFG2)--DOTA-Phe-X-BBN(6-14), where X is a spacer of two aminoacids. Bombesin (BBN) is an amphibian analog of human gastrin releasing peptide (GRP). Development of radiolabeled BBN derivatives as agents for diagnostic imaging and systemic radiotherapy has increased considerable because of the observation that GRP receptors (GRPr) are over-expressed in a variety of human tumor cells, such as prostate tumor cells. (177)Lu-labeled peptides are attractive due to the excellent radiophysical properties and commercial availability of the radiometal. BEFG2 was successfully labeled with high yield and kept stable for more than 96 hours at 2-8 degrees C and 1 hour in human plasma. Data analysis obtained from the in vivo studies showed that the amount of BEFG2 present in plasma decreased rapidly and became almost undetectable at 60 min p.i., indicating rapid peptide excretion, which is performed mainly by renal pathway. In addition, biodistribution and single photon emission tomography showed low abdominal accumulation of (177)Lu-DOTA- Phe-X-BBN(6-14), indicating that this analog is a potential candidate for tumors target therapy.

  18. Central bombesin activates adrenal adrenaline- and noradrenaline-containing cells via brain thromboxane A2 in rats.

    PubMed

    Usui, Daisuke; Yamaguchi-Shima, Naoko; Okada, Shoshiro; Shimizu, Takahiro; Wakiguchi, Hiroshi; Yokotani, Kunihiko

    2009-05-11

    The sympathetic nervous system regulates peripheral organs via the adrenal chromaffin cells containing adrenaline (A-cells) or noradrenaline (NA-cells) and the sympathetic ganglia. We examined the effect of intracerebroventricularly administered bombesin on neuronal activities of adrenal A-cells and NA-cells and several kinds of sympathetic ganglia (superior cervical, stellate and celiac ganglia) using c-Fos (a marker for neuronal activation), with regard to brain prostanoid, in anesthetized rats. Bombesin induced c-Fos in both adrenal A-cells and NA-cells, but not in any of the sympathetic ganglia. Central pretreatment with either indomethacin (a cyclooxygenase inhibitor) or furegrelate (a thromboxane A(2) synthase inhibitor) abolished all bombesin-induced responses. These results suggest that bombesin centrally activates adrenal A-cells and NA-cells by brain thromboxane A(2)-mediated mechanisms in rats.

  19. Synthesis of bombesin-functionalized iron oxide nanoparticles and their specific uptake in prostate cancer cells

    NASA Astrophysics Data System (ADS)

    Martin, Amanda L.; Hickey, Jennifer L.; Ablack, Amber L.; Lewis, John D.; Luyt, Leonard G.; Gillies, Elizabeth R.

    2010-06-01

    The imaging of molecular markers associated with disease offers the possibility for earlier detection and improved treatment monitoring. Receptors for gastrin-releasing peptide are overexpressed on prostate cancer cells offering a promising imaging target, and analogs of bombesin, an amphibian tetradecapeptide have been previously demonstrated to target these receptors. Therefore, the pan-bombesin analog [β-Ala11, Phe13, Nle14]bombesin-(7-14) was conjugated through a linker to dye-functionalized superparamagnetic iron oxide nanoparticles for the development of a new potential magnetic resonance imaging probe. The peptide was conjugated via click chemistry, demonstrating a complementary alternative methodology to conventional peptide-nanoparticle conjugation strategies. The peptide-functionalized nanoparticles were then demonstrated to be selectively taken up by PC-3 prostate cancer cells relative to unfunctionalized nanoparticles and this uptake was inhibited by the presence of free peptide, confirming the specificity of the interaction. This study suggests that these nanoparticles have the potential to serve as magnetic resonance imaging probes for the detection of prostate cancer.

  20. Conformational structure of bombesin as studied by vibrational and circular dichroism spectroscopy.

    PubMed

    Carmona, P; Lasagabaster, A; Molina, M

    1995-01-19

    Raman and Fourier transform infrared (FTIR) spectroscopies and circular dichroism (CD) have been applied to investigate the secondary structure of bombesin in the solid state and in phosphate buffer solution (pH 3.8). At concentrations around 10(-5) M, circular dichroism reveals that bombesin exists as an irregular or disordered conformation. However, the secondary structure of the peptide appears to be a mixture of disordered structure and intermolecular beta-sheets in 0.01 M sodium phosphate buffer when the peptide concentrations are higher than around 6.5 mM. The tendency of bombesin to form aggregated beta-sheet species seems to be originated mainly in the sequence of the residues 7-14, as supported by the Raman spectra and beta-sheet propensities (P beta) of the amino-acid residues. It is the hydrophobic force of this amino-acid sequence, and not a salt bridge effect, that is the factor responsible for the formation of peptide aggregates.

  1. Effect of the cholecystokinin-receptor antagonist lorglumide on pancreatic enzyme secretion stimulated by bombesin, food, and caerulein, giving similar plasma cholecystokinin concentrations in the dog.

    PubMed

    de Jong, A J; Singer, M V; Jansen, J B; Niebel, W; Rovati, L C; Lamers, C B

    1991-02-01

    This study was undertaken to determine the role of cholecystokinin in pancreatic enzyme secretion stimulated by bombesin and a meal by (a) comparing the pancreatic enzyme output during bombesin infusion and after a meal to output during caerulein infusion and (b) comparing the inhibitory effect of the cholecystokinin-receptor antagonist lorglumide (CR-1409) on enzyme output in response to bombesin and food with the response to caerulein. Bombesin (90 pmol/kg per h) and caerulein (30 pmol/kg per h) were infused into seven dogs in doses giving similar plasma cholecystokinin peak increments as a meal (mean (SEM) 6.8 (0.8), 6.3 (1.2), and 5.7 (0.8) pM, respectively), together with either saline or 2 mg/kg per h of lorglumide. A background infusion of synthetic secretin 20.5 pmol/kg per h was given in each experiment. In addition, gastric acid secretion was determined in the experiments with bombesin and caerulein infusion. Pancreatic protein responses to bombesin (1231 (247) mg/h) and food (1430 (220) mg/h) were similar to the responses to caerulein (1249 (201) mg/h). Lorglumide inhibited pancreatic protein output during stimulation with bombesin by 60%, after the meal by 45%, and during caerulein infusion by 68%. Pancreatic bicarbonate output by bombesin, caerulein, and food was inhibited by lorglumide by 28%, 40%, and 38%, respectively. In contrast, lorglumide significantly increased gastric acid secretion from 1.12 to 7.98 mmol/h during bombesin infusion and from 0.52 to 7.62 mmol/h during caerulein infusion. In conclusion, cholecystokinin plays an important part in the stimulation of pancreatic enzyme secretion by bombesin and a meal in conscious dogs and it is involved in the regulation of gastric acid during stimulation by infusions of caerulein and bombesin.

  2. Comparative study of in vitro and in vivo activities of bombesin pseudopeptide analogs modified on the C-terminal dipeptide fragment.

    PubMed

    Azay, J; Nagain, C; Llinares, M; Devin, C; Fehrentz, J A; Bernad, N; Roze, C; Martinez, J

    1998-01-01

    Analogs of bombesin in which the peptide bond between the two last amino acid residues were replaced by a pseudopeptide bond mimicking the transition state analog were evaluated. These compounds were able to recognize the bombesin receptor on isolated rat pancreatic acini with high potency (Ki from 0.60 +/- 0.27 nM to 4.3 +/- 2.3 nM). Although they were devoid of agonist activity, they were able to antagonize bombesin-induced amylase secretion in this model, with potencies in accordance with their affinities (IC50 from 1.6 +/- 0.3 nM to 10.0 +/- 1.7 nM). When tested in vivo in the anesthetized rat, these bombesin receptor antagonists exhibited high potency in inhibiting bombesin-induced pancreatic secretion (H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]-CHOH-(CH 2)3-CH3, JMV845, was among the most potent compounds with ED50 of 7.82 +/- 2.89 nM in inhibiting bombesin-induced protein secretion). The results of this study showed that replacing the peptide bond between the two last amino acid residues in bombesin by mimicking the transition state analog resulted in in vitro and in vivo potent bombesin receptor antagonists.

  3. Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse

    PubMed Central

    Akiyama, T.; Nagamine, M.; Davoodi, A.; Iodi Carstens, M.; Cevikbas, F.; Steinhoff, M.

    2015-01-01

    Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml−1·min−1), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans. PMID:26311187

  4. Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse.

    PubMed

    Akiyama, T; Nagamine, M; Davoodi, A; Iodi Carstens, M; Cevikbas, F; Steinhoff, M; Carstens, E

    2015-10-01

    Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml(-1)·min(-1)), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans.

  5. Breast cancer cell-associated endopeptidase EC 24.11 modulates proliferative response to bombesin

    PubMed Central

    Burns, D M; Walker, B; Gray, J; Nelson, J

    1999-01-01

    We have investigated the production, growth and inactivation of gastrin-releasing peptide (GRP)-like peptides in human breast cancer cell lines. Radioimmunoassay detected GRP-like immunoreactivity (GRP-LI) in T47D breast cancer cells but not in the conditioned medium, indicating rapid clearance. No GRP-LI was found in the ZR-75-1 or MDA-MB-436 cells or their conditioned medium. High-performance liquid chromatography (HPLC) analysis of the GRP-LI in the T47D cells revealed a major peak, which co-eluted with GRP18–27, and a minor more hydrophilic peak. In vitro stimulation of T47D cell growth by bombesin (BN) was enhanced to 138% of control levels (bombesin alone) by the addition of the selective endopeptidase EC 3.4.24.11 inhibitor phosphoramidon (0.1 ng ml−;1). Fluorogenic analysis using whole cells confirmed low levels of this phosphoramidon-sensitive enzyme on the T47D cells. This enzyme, previously unreported in human breast cancer cells, significantly modulates both T47D growth and its response to BN-induced growth. © 1999 Cancer Research Campaign PMID:9888460

  6. Modulation of phagocytic function in murine peritoneal macrophages by bombesin, gastrin-releasing peptide and neuromedin C.

    PubMed Central

    De la Fuente, M; Del Rio, M; Ferrandez, M D; Hernanz, A

    1991-01-01

    Bombesin, as well as the two mammalian bombesin-like peptides gastrin-releasing peptide and neuromedin C, have been shown in this study to stimulate in vitro all steps of the phagocytic process in murine peritoneal macrophages: adherence to substrate, chemotaxis, ingestion of cells (Candida albicans) and inert particles (latex beads), and production of superoxide anion as measured by nitroblue tetrazolium reduction. A dose-response relationship was observed, with maximal stimulation of phagocytic process between 10(-12)M and 10(-9)M. Gastrin-releasing peptide (GRP) and neuromedin C caused a higher activation of adherence, chemotaxis and ingestion of C. albicans than bombesin. The three neuropeptides induced in murine macrophages a significant, but transient, increase of inositol 1,4,5-trisphosphate (IP3) levels at 60 seconds. On the contrary, these neuropeptides produced a rapid, transient and significant decrease of cAMP at 30 seconds. These results suggest that there are close relations between IP3 and cAMP messenger systems and the phagocytic process in murine peritoneal macrophages when these cells are incubated in the presence of bombesin, GRP or neuromedin C. PMID:1649124

  7. Evolution of Geometric Sensitivity Derivatives from Computer Aided Design Models

    NASA Technical Reports Server (NTRS)

    Jones, William T.; Lazzara, David; Haimes, Robert

    2010-01-01

    The generation of design parameter sensitivity derivatives is required for gradient-based optimization. Such sensitivity derivatives are elusive at best when working with geometry defined within the solid modeling context of Computer-Aided Design (CAD) systems. Solid modeling CAD systems are often proprietary and always complex, thereby necessitating ad hoc procedures to infer parameter sensitivity. A new perspective is presented that makes direct use of the hierarchical associativity of CAD features to trace their evolution and thereby track design parameter sensitivity. In contrast to ad hoc methods, this method provides a more concise procedure following the model design intent and determining the sensitivity of CAD geometry directly to its respective defining parameters.

  8. "Perfect" designer chromosome V and behavior of a ring derivative.

    PubMed

    Xie, Ze-Xiong; Li, Bing-Zhi; Mitchell, Leslie A; Wu, Yi; Qi, Xin; Jin, Zhu; Jia, Bin; Wang, Xia; Zeng, Bo-Xuan; Liu, Hui-Min; Wu, Xiao-Le; Feng, Qi; Zhang, Wen-Zheng; Liu, Wei; Ding, Ming-Zhu; Li, Xia; Zhao, Guang-Rong; Qiao, Jian-Jun; Cheng, Jing-Sheng; Zhao, Meng; Kuang, Zheng; Wang, Xuya; Martin, J Andrew; Stracquadanio, Giovanni; Yang, Kun; Bai, Xue; Zhao, Juan; Hu, Meng-Long; Lin, Qiu-Hui; Zhang, Wen-Qian; Shen, Ming-Hua; Chen, Si; Su, Wan; Wang, En-Xu; Guo, Rui; Zhai, Fang; Guo, Xue-Jiao; Du, Hao-Xing; Zhu, Jia-Qing; Song, Tian-Qing; Dai, Jun-Jun; Li, Fei-Fei; Jiang, Guo-Zhen; Han, Shi-Lei; Liu, Shi-Yang; Yu, Zhi-Chao; Yang, Xiao-Na; Chen, Ken; Hu, Cheng; Li, Da-Shuai; Jia, Nan; Liu, Yue; Wang, Lin-Ting; Wang, Su; Wei, Xiao-Tong; Fu, Mei-Qing; Qu, Lan-Meng; Xin, Si-Yu; Liu, Ting; Tian, Kai-Ren; Li, Xue-Nan; Zhang, Jin-Hua; Song, Li-Xiang; Liu, Jin-Gui; Lv, Jia-Fei; Xu, Hang; Tao, Ran; Wang, Yan; Zhang, Ting-Ting; Deng, Ye-Xuan; Wang, Yi-Ran; Li, Ting; Ye, Guang-Xin; Xu, Xiao-Ran; Xia, Zheng-Bao; Zhang, Wei; Yang, Shi-Lan; Liu, Yi-Lin; Ding, Wen-Qi; Liu, Zhen-Ning; Zhu, Jun-Qi; Liu, Ning-Zhi; Walker, Roy; Luo, Yisha; Wang, Yun; Shen, Yue; Yang, Huanming; Cai, Yizhi; Ma, Ping-Sheng; Zhang, Chun-Ting; Bader, Joel S; Boeke, Jef D; Yuan, Ying-Jin

    2017-03-10

    Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024-base pair chromosome synV in the "Build-A-Genome China" course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in Saccharomyces cerevisiae under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders.

  9. Design, synthesis and insecticidal activity of novel phenylurea derivatives.

    PubMed

    Sun, Jialong; Zhou, Yuanming

    2015-03-19

    A series of novel phenylurea derivatives were designed and synthesized according to the method of active groups linkage and the principle of aromatic groups bioisosterism in this study. The structures of the novel phenylurea derivatives were confirmed based on ESI-MS, IR and 1H-NMR spectral data. All of the compounds were evaluated for the insecticidal activity against the third instars larvae of Spodoptera exigua Hiibner, Plutella xyllostella Linnaeus, Helicoverpa armigera Hubner and Pieris rapae Linne respectively, at the concentration of 10 mg/L. The results showed that all of the derivatives displayed strong insecticidal activity. Most of the compounds presented higher insecticidal activity against S. exigua than the reference compounds tebufenozide, chlorbenzuron and metaflumizone. Among the synthesized compounds, 3b, 3d, 3f, 4b and 4g displayed broad spectrum insecticidal activity.

  10. Capsaicin treatment differentially affects feeding suppression by bombesin-like peptides.

    PubMed

    Ladenheim, Ellen E; Knipp, Susan

    2007-05-16

    Peripheral administration of bombesin (BN) and the related mammalian peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB), suppress food intake in rats. To examine whether all BN-like peptides utilize the same neural pathways to reduce feeding, rats were treated on postnatal day 2 with the injection vehicle or capsaicin, a neurotoxin that damages a subset of visceral afferent fibers. When rats reached adulthood, we compared the ability of a dose range of systemically administered BN, GRP18-27 and NMB to reduce intake of a 0.5 kcal/ml glucose solution in a short-term feeding test. Our results demonstrate that capsaicin treatment abolished or attenuated the suppression of glucose intake produced by BN and NMB but had no effect on the ability of GRP to reduce feeding. These results suggest that different neural substrates underlie the anorexic effects of peripherally administered BN-like peptides.

  11. A new near-infrared absorption and fluorescent probe based on bombesin for molecular imaging

    NASA Astrophysics Data System (ADS)

    Kujala, Naresh; Zhai, Huifang; Smith, Charles; Prasanphanich, Adam; Sieckman, Gary; Hoffman, Timothy; Volkert, Wynn; Ma, Lixin; Yu, Ping

    2009-02-01

    We have developed a series of new dye bombesin conjugates for site-specific absorption and fluorescence imaging of human prostate and breast cancers. Bombesin (BBN), an amphibian analog to the endogenous ligand, binds to the gastrin releasing peptide (GRP) receptors with high specificity and affinity. Previously, we developed an Alexa Fluor 680-GGG-BBN peptide conjugate which demonstrated high binding affinity and specificity for breast cancer cells in the in vitro and in vivo tests (Ref: Ma et al., Molecular Imaging, vol. 6, no. 3, 2007: 171-180). This probe can not be used as an absorption probe in near-infrared imaging because its absorption peak is in the visible wavelength range. In addition, site specific longer wavelength fluorescent probe is desired for in vivo molecular imaging because long wavelength photons penetrate deeper into tissue. The new absorption and fluorescent probe we developed is based on the last eight-residues of BBN, -Q-W-A-V-G-H-L-M-(NH2), and labeled with AlexaFluor750 through a chemical linker, beta-alanine. The new probe, Alexa Fluor 750-BetaAla-BBN(7-14)NH2, exhibits optimal pharmacokinetics for specific targeting and optical imaging of the GRP receptor over-expressing cancer cells. Absorption spectrum has been measured and showed absorption peaks at 690nm, 720nm and 735nm. Fluorescent band is located at 755nm. In vitro and in vivo investigations have demonstrated the effectiveness of the new conjugates to specifically target human cancer cells overexpressing GRP receptors and tumor xenografts in severely compromised immunodeficient mouse model.

  12. Design, Synthesis, and Antibacterial Activities of Novel Heterocyclic Arylsulphonamide Derivatives.

    PubMed

    Singh, Anuradha; Srivastava, Ritika; Singh, Ramendra K

    2017-02-13

    Design, synthesis, and antibacterial activities of a series of arylsulphonamide derivatives as probable peptide deformylase (PDF) inhibitors have been discussed. Compounds have been designed following Lipinski's rule and after docking into the active site of PDF protein (PDB code: 1G2A) synthesized later on. Furthermore, to assess their antibacterial activity, screening of the compound was done in vitro conditions against Gram-positive and Gram-negative bacterial strains. In silico, studies revealed these compounds as potential antibacterial agents and this fact was also supported by their prominent scoring functions. Antibacterial results indicated that these molecules possessed a significant activity against Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Escherichia coli with MIC values ranging from 0.06 to 0.29 μM. TOPKAT results showed that high LD50 values and the compounds were assumed non-carcinogenic when various animal models were studied computationally.

  13. Designing the microturbine engine for waste-derived fuels.

    PubMed

    Seljak, Tine; Katrašnik, Tomaž

    2016-01-01

    Presented paper deals with adaptation procedure of a microturbine (MGT) for exploitation of refuse derived fuels (RDF). RDF often possess significantly different properties than conventional fuels and usually require at least some adaptations of internal combustion systems to obtain full functionality. With the methodology, developed in the paper it is possible to evaluate the extent of required adaptations by performing a thorough analysis of fuel combustion properties in a dedicated experimental rig suitable for testing of wide-variety of waste and biomass derived fuels. In the first part key turbine components are analyzed followed by cause and effect analysis of interaction between different fuel properties and design parameters of the components. The data are then used to build a dedicated test system where two fuels with diametric physical and chemical properties are tested - liquefied biomass waste (LW) and waste tire pyrolysis oil (TPO). The analysis suggests that exploitation of LW requires higher complexity of target MGT system as stable combustion can be achieved only with regenerative thermodynamic cycle, high fuel preheat temperatures and optimized fuel injection nozzle. Contrary, TPO requires less complex MGT design and sufficient operational stability is achieved already with simple cycle MGT and conventional fuel system. The presented approach of testing can significantly reduce the extent and cost of required adaptations of commercial system as pre-selection procedure of suitable MGT is done in developed test system. The obtained data can at the same time serve as an input for fine-tuning the processes for RDF production.

  14. Glycosaminoglycan derivatives: promising candidates for the design of functional biomaterials.

    PubMed

    Scharnweber, Dieter; Hübner, Linda; Rother, Sandra; Hempel, Ute; Anderegg, Ulf; Samsonov, Sergey A; Pisabarro, M Teresa; Hofbauer, Lorenz; Schnabelrauch, Matthias; Franz, Sandra; Simon, Jan; Hintze, Vera

    2015-09-01

    Numerous biological processes (tissue formation, remodelling and healing) are strongly influenced by the cellular microenvironment. Glycosaminoglycans (GAGs) are important components of the native extracellular matrix (ECM) able to interact with biological mediator proteins. They can be chemically functionalized and thereby modified in their interaction profiles. Thus, they are promising candidates for functional biomaterials to control healing processes in particular in health-compromised patients. Biophysical studies show that the interaction profiles between mediator proteins and GAGs are strongly influenced by (i) sulphation degree, (ii) sulphation pattern, and (iii) composition and structure of the carbohydrate backbone. Hyaluronan derivatives demonstrate a higher binding strength in their interaction with biological mediators than chondroitin sulphate for a comparable sulphation degree. Furthermore sulphated GAG derivatives alter the interaction profile of mediator proteins with their cell receptors or solute native interaction partners. These results are in line with biological effects on cells relevant for wound healing processes. This is valid for solute GAGs as well as those incorporated in collagen-based artificial ECM (aECMs). Prominent effects are (i) anti-inflammatory, immunomodulatory properties towards macrophages/dendritic cells, (ii) enhanced osteogenic differentiation of human mesenchymal stromal cells, (iii) altered differentiation of fibroblasts to myofibroblasts, (iv) reduced osteoclast activity and (v) improved osseointegration of dental implants in minipigs. The findings of our consortium Transregio 67 contribute to an improved understanding of structure-function relationships of GAG derivatives in their interaction with mediator proteins and cells. This will enable the design of bioinspired, functional biomaterials to selectively control and promote bone and skin regeneration.

  15. [Design, synthesis and activities of novel benzothiazole derivatives containing arylpiperazine].

    PubMed

    Liu, Wen-Hu; Chang, Jin-Xia; Liu, Yi; Luo, Jie-Wei; Zhang, Jian-Wu

    2013-08-01

    Twenty-four novel benzothiazole derivatives containing arylpiperazine were designed and synthesized by bioisosterism principle. Anti-proliferative effect of these synthesized compounds against four cancer cell and two normal cell lines were evaluated in vitro by the standard MTT assay. Pharmacological test showed that most of the compounds exhibited potent antitumor activity. Some of the compounds (II2, II3, II6, II7) showed strong anti-proliferation activities against HepG2 and HeLa229 cell lines with the IC 50 values of 1.6-4.5 micromol x L(-1) and 2.5-5.3 micromol x L(-1), respectively, and compounds having cyan in p-substituted benzene ring (I4, I8, I12, II4, II8 and II12) were found to have better antitumor activities against AsPC-1 cell lines with the IC50 values of 5.2-11.3 micromol x L(-1). The structure-activity relationship of benzothiazole derivatives containing arylpiperazine was also discussed preliminarily.

  16. Mechanisms underlying anorexia after microinjection of bombesin into the lateral cerebroventricle.

    PubMed

    Tsushima, Hiromi; Mori, Mayumi

    2005-02-01

    Intracerebroventricular (i.c.v.) injections of bombesin (BN) and gastrin-releasing peptide (GRP) dose-dependently decreased food intake in male Wistar rats fasted for 17 h. Neuromedin B (NMB) did not show any effect on food intake. After BN administration, locomotor activity did not significantly change, compared with a vehicle-injected group. The anorexia induced by BN (0.3 microg) was perfectly inhibited by pretreatment with a GRP-receptor antagonist, [D-Tyr(6)]BN(6-13) methyl ester (10 microg), an NO synthase inhibitor, L-nitro-arginine (30 microg), and a PKG inhibitor, H-9 (2 microg). The cGMP concentration in the hypothalamus increased 1 h after administration when compared with the vehicle-injected group. On the other hand, an NMB-receptor antagonist, BIM23127 (10 microg), and the protein kinase (PK) C inhibitors, chelerythrine (2 microg) and Go6983 (2 microg), inhibited only the late phase of the anorexia. A PKC activator, phorbol 12, 13-dibutyrate (3 microg), injected into the ventricle decreased food intake. These findings suggest that BN suppresses food intake mainly mediated through the GRP receptor and NO-cGMP-PKG pathway, and NMB receptor and PKC is partly involved in the late phase of the anorexia.

  17. Inhibition of serotonin release by bombesin-like peptides in rat hypothalamus in vitro

    SciTech Connect

    Saporito, M.S.; Warwick, R.O. Jr.

    1989-01-01

    We investigated the activity of bombesin (BN), neuromedin-C (NM-C) and neuromedin-B (NM-B) on serotonin (5-HT) release and reuptake in rat hypothalamus (HYP) in vitro. BN and NM-C but not NM-B decreased K/sup +/ evoked /sup 3/H-5-HT release from superfused HYP slices by 25%. Bacitracin, a nonspecific peptidase inhibitor, reversed the inhibitory effect of BN on K/sup +/ evoked /sup 3/H-5-HT release. Phosphoramidon (PAN, 10 /mu/M) an endopeptidase 24.11 inhibitor, abolished the inhibitory effect of BN, but not NM-C, on K/sup +/ evoked /sup 3/H-5-HT release. The peptidyl dipeptidase A inhibitor enalaprilat (ENP, 10 /mu/M), enhanced both BN and NM-C inhibition of /sup 3/H-5-HT release. Bestatin (BST, 10 /mu/M) had no effect on BN or NM-C inhibitory activity on /sup 3/H-5-HT release. Neither BN, NM-C nor NM-B affected reuptake of /sup 3/H-5-HT into HYP synaptosomes alone or in combination with any of the peptidase inhibitors, nor did these peptides alter the ability of fluoxetine to inhibit /sup 3/H-5-HT uptake.

  18. Interaction of bombesin and its fragments with gold nanoparticles analyzed using surface-enhanced Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Tąta, Agnieszka; Szkudlarek, Aleksandra; Kim, Younkyoo; Proniewicz, Edyta

    2017-02-01

    This work demonstrates the application of commercially available stable surface composed of gold nanograins with diameters ranging from 70 to 226 nm deposited onto silicon wafer for surface-enhanced Raman scattering investigations of biologically active compounds, such as bombesin (BN) and its fragments. BN is an important neurotransmitter involved in a complex signaling pathways and biological responses; for instance, hypertensive action, contractive on uterus, colon or ileum, locomotor activity, stimulation of gastric and insulin secretion as well as growth promotion of various tumor cell lines, including: lung, prostate, stomach, colon, and breast. It has also been shown that 8-14 BN C-terminal fragment partially retains the biological activity of BN. The SERS results for BN and its fragment demonstrated that (1) three amino acids from these peptides sequence; i.e., L-histidine, L-methionine, and L-tryptophan, are involved in the interaction with gold coated silicon wafer and (2) the strength of these interactions depends upon the aforementioned amino acids position in the peptide sequence.

  19. Pancreatic endocrine responses to nutrients and bombesin after segmental pancreas autotransplantation in dogs.

    PubMed

    Dupre, J; Grace, D M; McDonald, T J; Inculet, R; Leblanc, B

    1987-01-01

    The capacity of autotransplanted (ATP) distal pancreas segments with systemic venous and peritoneal exocrine drainage to support physiologic control of plasma glucose levels was tested, and compared with the functions of "simulated autotransplants" (SATP) prepared with similar dissection and peritoneal exocrine drainage, but with hepatic portal venous drainage, in dogs. In ATP in the postabsorptive state, plasma levels of glucose, immunoreactive insulin (IRI) and immunoreactive glucagon (IRG1) were normal. Autotransplants resulted in impaired glucose tolerance after meals with impaired early insulin responses, and the normal brisk rise of IRG1 in the plasma was delayed and reduced through the first 30 min of feeding. In ATP, also, the response to bombesin was abnormal; the normal stimulation of release of both IRI and IRG1 was delayed in both cases. In studies of responses to oral and intravenous glucose in ATP and SATP dogs, similar mild degrees of glucose intolerance were found with both routes of administration; however, whereas in ATP dogs increases of IRI were highly exaggerated with both routes of administration of glucose, in SATP dogs plasma IRI rose from subnormal levels in the postabsorptive state through subnormal increments with both routes of administration. Further studies are necessary to determine the relative importance of denervation and reduction of the mass of the pancreas in these effects, and to assess the significance of the differences in blood insulin levels in the two preparations.

  20. Breast cancer photothermal therapy based on gold nanorods targeted by covalently-coupled bombesin peptide

    NASA Astrophysics Data System (ADS)

    Heidari, Zahra; Salouti, Mojtaba; Sariri, Reyhaneh

    2015-05-01

    Photothermal therapy, a minimally invasive treatment method for killing cancers cells, has generated a great deal of interest. In an effort to improve treatment efficacy and reduce side effects, better targeting of photoabsorbers to tumors has become a new concept in the battle against cancer. In this study, a bombesin (BBN) analog that can bind to all gastrin-releasing peptide (GRP) receptor subtypes was bound covalently with gold nanorods (GNRs) using Nanothinks acid as a link. The BBN analog was also coated with poly(ethylene glycol) to increase its stability and biocompatibility. The interactions were confirmed by ultraviolet-visible and Fourier transform infrared spectroscopy. A methylthiazol tetrazolium assay showed no cytotoxicity of the PEGylated GNR-BBN conjugate. The cell binding and internalization studies showed high specificity and uptake of the GNR-BBN-PEG conjugate toward breast cancer cells of the T47D cell line. The in vitro study revealed destruction of the T47D cells exposed to the new photothermal agent combined with continuous-wave near-infrared laser irradiation. The biodistribution study showed significant accumulation of the conjugate in the tumor tissue of mice with breast cancer. The in vivo photothermal therapy showed the complete disappearance of xenographted breast tumors in the mouse model.

  1. Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3.

    PubMed

    Lateef, Dalya M; Abreu-Vieira, Gustavo; Xiao, Cuiying; Reitman, Marc L

    2014-03-01

    Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and β3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

  2. Effects of cholecystokinin and bombesin on the expression of preprosomatostatin-encoding genes in goldfish forebrain.

    PubMed

    Canosa, Luis Fabián; Peter, Richard E

    2004-09-15

    It was previously demonstrated that both cholecystokinin (CCK) and bombesin (BBS) stimulate growth hormone (GH) secretion in goldfish. Both peptides induce satiety and it was speculated that they integrate satiation and the postprandial increase in GH circulating levels. In the present paper we investigated the effects of CCK and BBS on the forebrain expression of the somatostatin gene family in goldfish to analyze if somatostatin peptides may be part of the effector mechanisms of CCK and BBS. We found that peripherally as well as centrally administered CCK decreases mRNA levels of preprosomatostatin (PSS)-I that encodes for SRIF-14, having no effects on PSS-II and PSS-III, which encode for gSRIF-28 and [Pro2] SRIF-14, respectively. In addition, a direct action on the pituitary to stimulate GH release, this inhibition of PSS-I expression provides a possible mechanism for CCK to increase postprandial GH levels. On the other hand, BBS inhibits the forebrain expression of PSS-I and PSS-II but does not affect PSS-III regardless of the route of administration. We conclude that this could be the most likely mechanism of action of BBS to increase GH secretion, since there are few BBS-immunoreactive (IR) fibers and BBS binding sites in the anterior pituitary of goldfish.

  3. Molecular design and screening of energetic nitramine derivatives.

    PubMed

    Devi, Alka; Deswal, Sonal; Dharavath, Srinivas; Ghule, Vikas D

    2015-11-01

    Six nitramines (N1-6) were designed with all possible arrangements of N-NO2 groups on a cyclic skeleton and structural optimization was performed using the density functional theory (DFT). We observed that all nitramines have high positive heats of formation proportionate to the number of N-NO2 groups in their molecular structure. Among the designed nitramines, N5 and N6 have crystal densities of 1.77 and 1.81 g cm(-3), respectively, which lead to reasonable respective detonation velocities (D = 8.70 and 9.07 km s(-1)) and detonation pressures (P = 33.23 and 36.57 GPa) comparable to those of RDX. To understand the relationship between sensitivity and molecular structure, bond dissociation energies, impact sensitivities (h 50), free space in crystal lattice, imbalance between the positive and negative surface potentials and heats of detonation (Q) were investigated. The comparable performance of N5 and N6 with RDX highlights the potential application of these nitramine derivatives as high energy materials and also supports the advantage of N-N bonds in the backbone and substitution of N-NO2 groups. Graphical Abstract Electrostatic potential on the 0.001 electron/bohr(3) molecular surface of N6.

  4. Characterization of a bombesin receptor on Swiss mouse 3T3 cells by affinity cross-linking

    SciTech Connect

    Sinnett-Smith, J.; Zachary, I.; Rozengurt, E.

    1988-12-01

    We have previously identified by chemical cross-linking a cell surface protein in Swiss 3T3 cells of apparent Mr 75,000-85,000, which may represent a major component of the receptor for peptides of the bombesin family in these cells. Because bombesin-like peptides may interact with other cell surface molecules, it was important to establish the correlation between receptor binding and functions of this complex and further characterize the Mr 75,000-85,000 cross-linked protein. Detailed time courses carried out at different temperatures demonstrated that the Mr 75,000-85,000 affinity-labelled band was the earliest cross-linked complex detected in Swiss 3T3 cells incubated with 125I-labelled gastrin-releasing peptide (125I-GRP). Furthermore, the ability of various nonradioactive bombesin agonists and antagonists to block the formation of the Mr 75,000-85,000 cross-linked complex correlated extremely well (r = 0.994) with the relative capacity of these peptides to inhibit 125I-GRP specific binding. Pretreatment with unlabelled GRP for up to 6 h caused only a slight decrease in both specific 125I-GRP binding and the affinity labelling of the Mr 75,000-85,000 protein. We also show that the cross-linked complex is a glycoprotein. First, solubilized affinity labelled Mr 75,000-85,000 complex applied to wheat germ lectin-sepharose columns was eluted by addition of 0.3 M N-acetyl-D-glucosamine. Second, treatment with endo-beta-N-acetylglucosaminidase F reduced the apparent molecular weight of the affinity-labelled band from 75,000-85,000 to 43,000, indicating the presence of N-linked oligosaccharide groups.

  5. Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives.

    PubMed

    El-Gamal, Mohammed I; Khan, Mohammad Ashrafuddin; Tarazi, Hamadeh; Abdel-Maksoud, Mohammed S; Gamal El-Din, Mahmoud M; Yoo, Kyung Ho; Oh, Chang-Hyun

    2017-02-15

    This article describes the design, synthesis, and biological screening of a new series of diarylurea derivatives possessing quinoline nucleus. Nine target compounds were selected by the National Cancer Institute (NCI, Bethesda, Maryland, USA) for in vitro antiproliferative screening against a panel of 58 cancer cell lines of nine cancer types. Following one-dose initial screening, compounds 1d-g and 2b were selected for 5-dose screening in order to calculate their IC50 and total growth inhibition (TGI) values against the cell lines. Compounds 1e and 1g were the most promising analogues. Both compounds showed strong potency and broad-spectrum antiproliferative activity against the different tested cancer types. Their IC50 and TGI values were less than those of the reference drug, sorafenib, against most of the tested cell lines of the nine different cancer types. Furthermore, the most potent compounds 1d-g were tested against C-RAF kinase as a potential molecular target of this series of compounds. All of them showed high potency, and the most potent derivative was compound 1e (IC50 = 0.10 μM). It was further tested against a panel of another twelve kinases, and it showed selectivity against C-RAF kinase. This could be, at least in part, the possible mechanism of antiproliferative action of this series of compounds at molecular level. The binding modes of compounds 1e and 1g were studied by docking studies, which highlighted the importance of the urea linker compared with the amide linker.

  6. Design, synthesis and insecticidal evaluation of aryloxy dihalopropene derivatives.

    PubMed

    Yang, Ji-Chun; Li, Miao; Wu, Qiao; Liu, Chang-Ling; Chang, Xiu-Hui

    2016-02-01

    Plutella xylostella (P. xylostella) is a highly migratory, cosmopolitan species and one of the most important pest of cruciferous crops worldwide. Pyridalyl as a novel class of insecticides has good efficacy against P. xylostella. On the basis of the commercial insecticide pyridalyl, a series of new aryloxy dihalopropene derivatives were designed and synthesized by using Intermediate Derivatization Methods. Their chemical structures were confirmed by (1)H NMR, high-resolution mass spectrum (HRMS), and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds against P. xylostella were evaluated. The results of bioassays indicated that most of the compounds showed moderate to high activities at the tested concentration, especially compounds 10e and 10g displayed more than 75% insecticidal activity against P. xylostella at 6.25mg/L, while pyridalyl showed 50% insecticidal activity at the same concentration. The field trials result of the insecticidal activities showed that compound 10e as a 10% emulsifiable concentrate (EC) was effective in the control of P. xylostella at 75-150g a.i./ha, and the mortality of P. xylostella for treatment with compound 10e at 75g a.i./ha was equivalent to pyridalyl at 105g a.i./ha.

  7. Stress and eating: a dual role for bombesin-like peptides

    PubMed Central

    Merali, Z.; Graitson, S.; MacKay, J. C.; Kent, P.

    2013-01-01

    The current obesity “epidemic” in the developed world is a major health concern; over half of adult Canadians are now classified as overweight or obese. Although the reasons for high obesity rates remain unknown, an important factor appears to be the role stressors play in overconsumption of food and weight gain. In this context, increased stressor exposure and/or perceived stress may influence eating behavior and food choices. Stress-induced anorexia is often noted in rats exposed to chronic stress (e.g., repeated restraint) and access to standard Chow diet; associated reduced consumption and weight loss. However, if a similar stressor exposure takes place in the presence of palatable, calorie dense food, rats often consume an increase proportion of palatable food relative to Chow, leading to weight gain and obesity. In humans, a similar desire to eat palatable or “comfort” foods has been noted under stressful situations; it is thought that this response may potentially be attributable to stress-buffering properties and/or through activation of reward pathways. The complex interplay between stress-induced anorexia and stress-induced obesity is discussed in terms of the overlapping circuitry and neurochemicals that mediate feeding, stress and reward pathways. In particular, this paper draws attention to the bombesin family of peptides (BBs) initially shown to regulate food intake and subsequently shown to mediate stress response as well. Evidence is presented to support the hypothesis that BBs may be involved in stress-induced anorexia under certain conditions, but that the same peptides could also be involved in stress-induced obesity. This hypothesis is based on the unique distribution of BBs in key cortico-limbic brain regions involved in food regulation, reward, incentive salience and motivationally driven behavior. PMID:24298233

  8. Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism.

    PubMed

    Lateef, Dalya M; Xiao, Cuiying; Brychta, Robert J; Diedrich, André; Schnermann, Jurgen; Reitman, Marc L

    2016-04-01

    Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting α2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.

  9. Bombesin receptor subtype-3 is expressed by the enteric nervous system and by interstitial cells of Cajal in the rat gastrointestinal tract.

    PubMed

    Porcher, Christophe; Juhem, Aurélie; Peinnequin, André; Bonaz, Bruno

    2005-04-01

    Bombesin receptor subtype-3 (BRS-3), a G-protein-coupled orphan receptor, shares 47% and 55% homology with other known mammalian bombesin receptors. Despite the molecular characterization of BRS-3, its function remains unclear as a consequence of its low affinity for bombesin and the absence of an identified natural ligand. Although the other mammalian bombesin receptors are widely distributed in the gut and central nervous system, expression of BRS-3 in the gastrointestinal tract has not been previously described. We report the expression of BRS-3 mRNA and protein in the tunica muscularis of the rat gastrointestinal tract. The mRNA expression pattern was studied by reverse transcription followed by quantitative polymerase chain reaction. To identify the cellular sites of expression of BRS-3, we performed immunocytochemistry by using a N-terminus-specific affinity-purified antiserum. BRS-3 was found to be widely expressed in the rat gastrointestinal tract at both the mRNA and protein levels. BRS-3-like immunoreactivity (BRS-3-LI) was localized in neurons of the myenteric and submucosal ganglia, being primarily concentrated near the neuronal plasma membrane, and in fibers distributed in the longitudinal and circular muscle layers. In addition, BRS-3-LI was observed in the cell bodies and processes of c-kit+ interstitial cells of Cajal. These data have functional applications for the effects mediated by the activation of BRS-3 on gut motility through distinct neuronal and non-neuronal pathways.

  10. Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives.

    PubMed

    Li, Wen-Qun; Wang, Xu-Li; Qian, Keduo; Liu, Ying-Qian; Wang, Chih-Ya; Yang, Liu; Tian, Jin; Morris-Natschke, Susan L; Zhou, Xing-Wen; Lee, Kuo-Hsiung

    2013-04-15

    Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 μM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 μM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

  11. On singular cases in the design derivative of Green's functional

    NASA Technical Reports Server (NTRS)

    Reiss, Robert

    1987-01-01

    The author's prior development of a general abstract representation for the design sensitivities of Green's functional for linear structural systems is extended to the case where the structural stiffness vanishes at an internal location. This situation often occurs in the optimal design of structures. Most optimality criteria require that optimally designed beams be statically determinate. For clamped-pinned beams, for example, this is possible only if the flexural stiffness vanishes at some intermediate location. The Green's function for such structures depends upon the stiffness and the location where it vanishes. A precise representation for Green's function's sensitivity to the location of vanishing stiffness is presented for beams and axisymmetric plates.

  12. Design, synthesis and antimicrobial evaluation of novel benzoxazole derivatives.

    PubMed

    Zhang, Wei; Liu, Jingbao; Macho, Jocelyn M; Jiang, Xizhen; Xie, Dongsheng; Jiang, Faqin; Liu, Wenlu; Fu, Lei

    2017-01-27

    The synthesis of (S)-2-(4-tert-butylphenoxy)-3-(benzoxazol-5-yl) propanoic acid derivatives (2a-k) were described and their in vitro antibacterial activities were determined against Gram-negative and -positive bacteria. These compounds were found to exert a broad spectrum of activity against the screened bacteria, but poor MIC values were found for Candida albicans fungi. Compound 2b bearing a hydrophobic aromatic tie was the most active derivative against all bacteria studied with MIC values ranging from 0.098 to 0.78 μg/mL. The activity of 2b against B. subtilis was 2-fold higher than Penicillin, and 8- to 510-fold higher than other control antibiotics.

  13. Rational design of bacitracin A derivatives by incorporating natural product derived heterocycles.

    PubMed

    Wagner, Björn; Schumann, Dirk; Linne, Uwe; Koert, Ulrich; Marahiel, Mohamed A

    2006-08-16

    Heterocycles display common structural motifs in nonribosomally produced peptides with an enormous impact on their bioactivity. In the case of the branched cyclic Bacitracin A, the thiazoline moiety is manufactured during NRPS peptide chain elongation. Here we describe a method to selectively alter the heterocyclic metal binding subunit of Bacitracin A by the synthesis of heterocyclic building blocks that were successfully coupled to the linear decapeptide and subsequently cyclized using the excised bacitracin PCP-TE bidomain. Utilization of this cyclase allowed the first generation of branched cyclic bacitracin derivatives containing thiazole and oxazoles. The generated bacitracin derivatives showed bactericidal activity, indicating the possibility of altering the biological important heterocyclic subunit and overcoming existing limitations for the application of bacitracin.

  14. Proficiency-Based Curriculum Design: Principles Derived from Government Experience.

    ERIC Educational Resources Information Center

    Lowe, Pardee, Jr.

    1985-01-01

    Describes principles for designing a proficiency-based course to prepare students for the ACTFL/ETS Advanced Plus/Superior level according to Interagency Language Roundtable guidelines. Proposes ways to combine grammatical and "functional/notional" syllabuses with a proficiency approach. Examines the implications of these principles for…

  15. Strategies for Vaccine Design Using Phage Display-Derived Peptides.

    PubMed

    Goulart, Luiz R; Santos, Paula de S

    2016-01-01

    Development of peptide vaccines through the phage display technology is a powerful strategy that relies on short peptides expressed in the phage capsid surface to induce highly targeted immune responses. Phage display-derived immunogenic peptides can be used directly as a phage-fused peptide reagent or as a synthetic peptide with specific modifications, according to target molecule and disease pathogen/parasite. Peptides' selection (mimotopes) can be performed against monoclonal or polyclonal antibodies to disclose determinant regions (epitopes) that can induce a neutralizing response. Validations of mimotopes are performed in vitro and in vivo, based on cell culture and animal models, to demonstrate its immunogenic potential for final vaccine formulations with an appropriate adjuvant. Here we present specific methods for the discovery of novel immunogenic peptides based on phage display.

  16. A novel photopolymerizable derivative of hyaluronan for designed hydrogel formation.

    PubMed

    Bobula, Tomáš; Buffa, Radovan; Hermannová, Martina; Kohutová, Lenka; Procházková, Pavlína; Vágnerová, Hana; Čepa, Martin; Wolfová, Lucie; Židek, Ondřej; Velebný, Vladimír

    2017-04-01

    A new photopolymerizable derivative of hyaluronan (methacrylhydrazide-HA, MAHA) was prepared by carbodiimide chemistry. The reaction conditions were optimized for molecular weight (Mw), reaction time and amount of reagents with a degree of methacrylation (DM) ranging from 2% to 58%. Methacrylhydrazide-HA was hydrolytically stable (PBS, 7days, 37°C) in contrast to commonly used methacrylester analoque (23% hydrolyzed). MAHA readily photopolymerized into densely crosslinked hydrogels under physiological conditions. The varied DM, Mw, irradiation time (texp) and macromer concentration in photocrosslinking afforded hydrogels with different physical (swelling ratio, degradation rate) and mechanical properties (stiffness, toughness). Three-dimensional fabrication and surface patterning of MAHA hydrogels were demonstrated by photolithography and light mediated micromolding. A live-dead assay with skin fibroblasts showed convenient biocompatibility of MAHA (16%, 116kDa) for potential scaffolding applications in tissue engineering and regenerative medicine.

  17. Constraining continuous rainfall simulations for derived design flood estimation

    NASA Astrophysics Data System (ADS)

    Woldemeskel, F. M.; Sharma, A.; Mehrotra, R.; Westra, S.

    2016-11-01

    Stochastic rainfall generation is important for a range of hydrologic and water resources applications. Stochastic rainfall can be generated using a number of models; however, preserving relevant attributes of the observed rainfall-including rainfall occurrence, variability and the magnitude of extremes-continues to be difficult. This paper develops an approach to constrain stochastically generated rainfall with an aim of preserving the intensity-durationfrequency (IFD) relationships of the observed data. Two main steps are involved. First, the generated annual maximum rainfall is corrected recursively by matching the generated intensity-frequency relationships to the target (observed) relationships. Second, the remaining (non-annual maximum) rainfall is rescaled such that the mass balance of the generated rain before and after scaling is maintained. The recursive correction is performed at selected storm durations to minimise the dependence between annual maximum values of higher and lower durations for the same year. This ensures that the resulting sequences remain true to the observed rainfall as well as represent the design extremes that may have been developed separately and are needed for compliance reasons. The method is tested on simulated 6 min rainfall series across five Australian stations with different climatic characteristics. The results suggest that the annual maximum and the IFD relationships are well reproduced after constraining the simulated rainfall. While our presentation focusses on the representation of design rainfall attributes (IFDs), the proposed approach can also be easily extended to constrain other attributes of the generated rainfall, providing an effective platform for post-processing of stochastic rainfall generators.

  18. [Bombesin-mediated non-cholinergic late slow excitatory postsynaptic potentials in guinea pig inferior mesenteric ganglion in vitro].

    PubMed

    Kong, De-Hu; Wang, Gang; Wang, Hong-Mei; Ke, Dao-Ping; Hu, Jin-Lan; Zhu, Yan; Huang, Zhen-Xin

    2003-08-25

    The effect of bombesin (BOM) on non-cholinergic excitatory synaptic transmission of the guinea pig inferior mesenteric ganglion (IMG) was investigated by intracellular recording. Repetitive stimulation of the colon nerves (1 ms, 25 Hz, 4 s) elicited a burst of action potentials, which was followed by a long-lasting depolarization in 74.3% (52/70) of the IMG neurons. The depolarization was not blocked by nicotinic (d-tubocurarine, 100 micromol/L) and muscarinic (atropine, 1 micromol/L) antagonists, but was eliminated in a low Ca(2+)/high Mg(2+) Krebs solution, indicating that the depolarization was due to the release of non-cholinergic transmitters. Superfusing the ganglia with BOM (10 micromol/L, 1 min) induced a slow depolarization in 66.5% (109/164) neurons tested. The BOM response was not appreciably changed in low Ca(2+)/high Mg(2+) Krebs solution (n=6, P>0.05), suggesting that BOM depolarized the neurons by acting directly on the postsynaptic membrane rather than via a release of other endogenous depolarizing substances. In a total of 102 cells that exhibited late slow excitatory postsynaptic potential (ls-EPSP), superfusion of the ganglia with BOM produced a membrane depolarization in 82 neurons (80%), while the remaining 20 cells (20%) exhibited no response to BOM. In 18 neurons with ls-EPSP, 4 (22%) neurons were sensitive to both BOM and SP; 6 (33%) and 5 (28%) neurons were only sensitive to BOM and SP, respectively. The remaining 3 (17%) neurons were insensitive to both BOM and SP. Membrane resistance (Rm) had no apparent change in 47.3%, 59.5 % of the neurons tested during the ls-EPSP (n=55) and BOM depolarization (n=84), respectively, but had a marked decrease in 38.2%, 27.4%, and a marked increase in the remaining 14.5%, 13.1% of the neurons. However, when the Rm change accompanying ls-EPSP was compared with that accompanying BOM depolarization (n=20) in the same neuron, the changes in Rm were always parallel. Moreover, ls-EPSP (n=6) and BOM

  19. Design study of RL10 derivatives. Volume 2: Engine design characteristics. [application of rocket engine to space tug propulsion

    NASA Technical Reports Server (NTRS)

    Adams, A.

    1973-01-01

    The design characteristics of the RL-10 rocket engine are discussed. The results from critical elements evaluation, baseline engine design, parametric and special study tasks are presented. Critical element evaluation established the feasibility of various engine features such as tank head idle, pumped idle, autogenous tank pressurization, and two-phase pumping. Three baseline engines, derived from the RL-10 were conceptually designed. Parametric life and performance data were generated. Special studies were conducted to establish the impact on the engine design of environment, safety, interchangeability, and maintenance.

  20. Structure-Based Design of Molecules to Reactivate Tumor Derived p53 Mutations

    DTIC Science & Technology

    2005-06-01

    Tumor suppressor, p53, DNA-Damage, apoptosis, inhibitors, structural 10 biology, x-ray crystallography, structure-based drug design 16. PRICE CODE 77...Compounds that show favorable properties will be structurally characterized for further analysis (Aim 4). The structure-based drug design approach...often called "rational drug design "), which we are using towards the development of small molecule compounds that might restore function to tumor-derived

  1. Bayesian design and analysis of computer experiments: Use of derivatives in surface prediction

    SciTech Connect

    Morris, M.D.; Mitchell, T.J. ); Ylvisaker, D. . Dept. of Mathematics)

    1991-06-01

    The work of Currin et al. and others in developing fast predictive approximations'' of computer models is extended for the case in which derivatives of the output variable of interest with respect to input variables are available. In addition to describing the calculations required for the Bayesian analysis, the issue of experimental design is also discussed, and an algorithm is described for constructing maximin distance'' designs. An example is given based on a demonstration model of eight inputs and one output, in which predictions based on a maximin design, a Latin hypercube design, and two compromise'' designs are evaluated and compared. 12 refs., 2 figs., 6 tabs.

  2. Design, synthesis, cytotoxicities and DNA cleavage activities of dibenzoxepine and isoquinoline derivatives starting from dehydroabietylamine.

    PubMed

    Liu, Chao-Xiang; Lin, Zhong-Xiang; Zhou, Ai-Min

    2016-12-01

    A series of novel hexahydrodibenzoxepine and quinazoline derivatives were designed and synthesized starting from dehydroabietylamine. The cytotoxicities of the compounds against L02 and HepG2 cell lines were investigated. Meanwhile, the plasmid DNA (Escherichia coli) cleavage of several heterocyclic derivatives was studied. These compounds exhibit remarkable activities on plasmid DNA pBR322. Our study provides useful information for developing new and more potent antitumor agents.

  3. The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition

    PubMed Central

    Pierre, Joseph F.; Neuman, Joshua C.; Brill, Allison L.; Brar, Harpreet K.; Thompson, Mary F.; Cadena, Mark T.; Connors, Kelsey M.; Busch, Rebecca A.; Heneghan, Aaron F.; Cham, Candace M.; Jones, Elaina K.; Kibbe, Carly R.; Davis, Dawn B.; Groblewski, Guy E.; Kudsk, Kenneth A.

    2015-01-01

    Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis. PMID:26185331

  4. The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition.

    PubMed

    Pierre, Joseph F; Neuman, Joshua C; Brill, Allison L; Brar, Harpreet K; Thompson, Mary F; Cadena, Mark T; Connors, Kelsey M; Busch, Rebecca A; Heneghan, Aaron F; Cham, Candace M; Jones, Elaina K; Kibbe, Carly R; Davis, Dawn B; Groblewski, Guy E; Kudsk, Kenneth A; Kimple, Michelle E

    2015-09-15

    Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis.

  5. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

    PubMed

    Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

    2013-05-01

    Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

  6. Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

    PubMed

    Sasmal, Sanjita; Balaji, Gade; Kanna Reddy, Hariprasada R; Balasubrahmanyam, D; Srinivas, Gujjary; Kyasa, Shivakumar; Sasmal, Pradip K; Khanna, Ish; Talwar, Rashmi; Suresh, J; Jadhav, Vikram P; Muzeeb, Syed; Shashikumar, Dhanya; Harinder Reddy, K; Sebastian, V J; Frimurer, Thomas M; Rist, Øystein; Elster, Lisbeth; Högberg, Thomas

    2012-05-01

    Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

  7. Design, synthesis, and antibacterial activities of conformationally constrained kanamycin A derivatives.

    PubMed

    Zhang, Wenxuan; Chen, Ying; Liang, Qingzhao; Li, Hui; Jin, Hongwei; Zhang, Liangren; Meng, Xiangbao; Li, Zhongjun

    2013-01-18

    A series of conformationally constrained kanamycin A derivatives with a 2'-hydroxyl group in ring I and a 5-hydroxyl group in ring II tethered by carbon chains were designed and synthesized. Pivotal 5,2'-hydroxyl groups were exposed, and the kanamycin A intermediate was synthesized from 5, 2', 4″, 6″-di-O-benzylidene-protected tetraazidokanamycin A. Cyclic kanamycin A derivatives with intramolecular 8-, 9-, 10-, and 11-membered ethers were then prepared by cesium carbonate mediated Williamson ether synthesis or a ring-closing metathesis reaction. The kanamycin A derivatives were assayed against both susceptible and resistant bacterial strains. Although no derivative showed better antibacterial activities than kanamycin A, the antibacterial activities of these cyclic kanamycin A derivatives indeed varied with the length of the bridge. Moreover, different variations of activities were observed between the susceptible and resistant bacterial strains. More tightly constrained derivative 2 with a one-carbon bridge showed better activity than the others against susceptible strains, but it was much less effective for resistant bacterial strains than derivative 3 with a two-carbon bridge and derivative 6 with an unsaturated four-carbon bridge.

  8. Design of incomplete derivative fuzzy PID control system for fast-steering mirror

    NASA Astrophysics Data System (ADS)

    Ai, Zhiwei; Tan, Yi; Wu, Qiongyan; Ren, Ge; Tan, Yufen; Zhu, Nengbing; Zhu, Fuyin

    2016-10-01

    The structure parameters of fast-steering mirror (FSM) might change with time goes by. In order to reduce the impact of this change on the output performance of FSM system, an incomplete derivative fuzzy PID control system is proposed. This control system can effectively improve the time domain quality of FSM system by optimizing the PID control parameters online. First, the dynamic model of FSM is established. Second, the initial parameters of the incomplete derivative PID control system are designed according to the frequency domain quality of the closed-loop system. Then, the rules and related factors of the fuzzy controller are designed on the basis of the initial parameters. Finally, simulation experiments are carried out. The results show that the incomplete derivative PID control system has shorter adjustment time, less overshoot and lower dependence on the parameters of FSM when compared with the fixed parameters PID control system.

  9. 75 FR 63732 - Requirements for Derivatives Clearing Organizations, Designated Contract Markets, and Swap...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-18

    ...The Commodity Futures Trading Commission (the ``Commission'') hereby proposes rules to implement new statutory provisions enacted by Title VII of the Dodd-Frank Wall Street Reform and Consumer Protection Act (the ``Dodd-Frank Act''). Specifically, the proposed rules contained herein impose new requirements on derivatives clearing organizations (``DCOs''), designated contract markets......

  10. Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents.

    PubMed

    Zhao, Xiao-Bo; Goto, Masuo; Song, Zi-Long; Morris-Natschke, Susan L; Zhao, Yu; Wu, Dan; Yang, Liu; Li, Shu-Gang; Liu, Ying-Qian; Zhu, Gao-Xiang; Wu, Xiao-Bing; Lee, Kuo-Hsiung

    2014-08-15

    A series of novel 7-(N-substituted-methyl)-camptothecin derivatives was designed, synthesized, and evaluated for in vitro cytotoxicity against four human tumor cell lines, A-549, MDA-MB-231, KB, and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, with IC50 values ranging from 0.0023 to 1.11 μM, and were as or more potent than topotecan. Compounds 9d, 9e, and 9r exhibited the highest antiproliferative activity among all prepared derivatives. Furthermore, all of the compounds were more potent than paclitaxel against the multidrug-resistant (MDR) KBvin subline. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, compounds 9d, 9e, and 9r merit further development as a new generation of camptothecin-derived anticancer clinical trial candidates.

  11. The scheme machine: A case study in progress in design derivation at system levels

    NASA Technical Reports Server (NTRS)

    Johnson, Steven D.

    1995-01-01

    The Scheme Machine is one of several design projects of the Digital Design Derivation group at Indiana University. It differs from the other projects in its focus on issues of system design and its connection to surrounding research in programming language semantics, compiler construction, and programming methodology underway at Indiana and elsewhere. The genesis of the project dates to the early 1980's, when digital design derivation research branched from the surrounding research effort in programming languages. Both branches have continued to develop in parallel, with this particular project serving as a bridge. However, by 1990 there remained little real interaction between the branches and recently we have undertaken to reintegrate them. On the software side, researchers have refined a mathematically rigorous (but not mechanized) treatment starting with the fully abstract semantic definition of Scheme and resulting in an efficient implementation consisting of a compiler and virtual machine model, the latter typically realized with a general purpose microprocessor. The derivation includes a number of sophisticated factorizations and representations and is also deep example of the underlying engineering methodology. The hardware research has created a mechanized algebra supporting the tedious and massive transformations often seen at lower levels of design. This work has progressed to the point that large scale devices, such as processors, can be derived from first-order finite state machine specifications. This is roughly where the language oriented research stops; thus, together, the two efforts establish a thread from the highest levels of abstract specification to detailed digital implementation. The Scheme Machine project challenges hardware derivation research in several ways, although the individual components of the system are of a similar scale to those we have worked with before. The machine has a custom dual-ported memory to support garbage collection

  12. Surface-enhanced Raman difference between bombesin and its modified analogues on the colloidal and electrochemically roughen silver surfaces.

    PubMed

    Podstawka, Edyta; Ozaki, Yukihiro

    2008-10-01

    In this article, surface-enhanced Raman scattering (SERS) spectra of bombesin (BN) and its six modified analogues ([D-Phe(12)]BN, [Tyr(4)]BN, [Tyr(4),D-Phe(12)]BN, [D-Phe(12),Leu(14)]BN, [Leu(13)-(R)-Leu(14)]BN, and [Lys(3)]BN) on a colloidal silver surface are reported and compared with SERS spectra of these species immobilized onto an ellectrochemically roughen silver electrode. Changes in enhancement and wavenumber of proper bands upon adsorption on different silver surfaces are consistent with BN and its analogues adsorption primarily through Trp(8). Slightly different adsorption states of these molecules are observed depending upon natural amino acids substitution. For example, the indole ring in all the peptides interacts with silver nanoparticles in a edge-on orientation. It is additionally coordinated to the silver through the N(1)--H bond for all the peptides, except [Phe(12)]BN. This is in contrary to the results obtained for the silver roughen electrode that show direct but not strong N(1)--H/Ag interaction for all peptides except [D-Phe(12),Leu(14)]BN and [Leu(13)-(R)-Leu(14)]BN. For BN only C==O is not involved in the chemical coordination with the colloidal surface. [Lys(3)]BN and BN also adsorb with the C--N bond of NH(2) group normal and horizontal, respectively, to the colloidal surface, whereas C--NH(2) in other peptides is tilted to this surface. Also, the Trp(8) --CH(2)-- moiety of only [Tyr(4)]BN, [Lys(3)]BN, and [Tyr(4),D-Phe(12)]BN coordinates to Ag, whereas the Phe(12) ring of [Phe(12)]BN, [Tyr(4),D-Phe(12)]BN, and [D-Phe(12),Leu(14)]BN assists in the peptides binding only on the colloidal silver.

  13. Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments.

    PubMed

    Metzger, Joseph M; Gagen, Karen; Raustad, Kate A; Yang, Liming; White, Amanda; Wang, Sheng-Ping; Craw, Stephanie; Liu, Ping; Lanza, Thomas; Lin, Linus S; Nargund, Ravi P; Guan, Xiao-Ming; Strack, Alison M; Reitman, Marc L

    2010-11-01

    Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (T(b)) is regulated in part by nutritional status, with a reduced T(b) during fasting. We report that fed Brs3 knockout mice have a lower T(b), which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) increase attenuated despite continued weight loss efficacy. The increase in T(b) was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a β-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting T(b) reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, β₃-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted T(b) and the fasted, resting metabolic rates. The T(b) assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery.

  14. Structures and bonding on a colloidal silver surface of the various length carboxyl terminal fragments of bombesin.

    PubMed

    Podstawka, Edyta; Ozaki, Yukihiro; Proniewicz, Leonard M

    2008-10-07

    Raman (RS) and surface-enhanced Raman scattering spectra (SERS) were measured for various length carboxyl terminal fragments (X-14 of amino acid sequence) of bombesin ( BN): BN13-14, BN12-14, BN11-14, BN10-14, BN9-14, and BN8-14 in silver colloidal solutions. Density functional theory (DFT) calculations of Raman wavenumbers and intensities with extended basis sets (B3LYP/6-31++G**) were performed with the aim of providing the definitive band allocations to the normal coordinates. The proposed band assignment is consistent with the assignment for similar compounds reported in the literature. The nonadsorbed and adsorbed molecular structures were deducted by detailed spectral analysis of the RS and SERS spectra, respectively. This analysis also allowed us to propose the particular surface geometry and orientation of these peptides on silver surface, and their specific interaction with the surface. For example, a SERS spectrum of BN8-14 indicates that the interaction of a thioether atom and Trp8 with the silver surface is favorable and may dictate the orientation and conformation of adsorbed peptide. One of the most prominent and common features in all of the fragments' SERS spectra is a approximately 692 cm (-1) band due to nu(C-S) accompanied by two or three bands of different C-S conformers for all, except BN8-14, which suggests that all of the above-mentioned compounds adsorb on the silver surface through the thioether atom and that the attachment of Trp8 produces limitation in a number of possible C-S conformers adopted on this surface. Our results also show clearly that His12 and CO do not interact with the colloid surface, which supports our earlier results.

  15. Gut regulatory peptides bombesin and neurotensin reduce hepatic oxidative stress and histological alterations in bile duct ligated rats.

    PubMed

    Assimakopoulos, Stelios F; Vagianos, Constantine E; Zervoudakis, George; Filos, Kriton S; Georgiou, Christos; Nikolopoulou, Vassiliki; Scopa, Chrisoula D

    2004-08-15

    Gut regulatory peptides bombesin (BBS) and neurotensin (NT) exert a wide spectrum of biological actions on gastrointestinal tissues and we have previously shown that they improve intestinal barrier function and oxidative stress in experimentally jaundiced rats. In the present study, we explored their potential action on liver histology and oxidative status in bile duct ligated rats. Seventy male Wistar rats were randomly divided into five groups: controls, sham operated, bile duct ligated (BDL), BDL + BBS (10 microg/kg, s.c. x3), BDL + NT (300 microg/kg, i.p.). At the end of the experiment, on day 10, serum total bilirubin and alanine aminotransferase (ALT) levels were determined and endotoxin was measured in portal and aortic blood. Liver tissue samples were examined histologically for evaluation of the ratio of portal tracts presenting changes of obstructive cholangiopathy and neutrophils' number in portal tracts. In addition, hepatic oxidative status was estimated on liver homogenates by measurements of lipid peroxidation (malondialdehyde), protein oxidation (protein carbonyl groups) and thiol redox state [reduced glutathione (GSH), oxidized glutathione (GSSG), total non-protein mixed disulfides (NPSSR) and protein thiols (PSH)]. Administration of BBS or NT significantly reduced portal and aortic endotoxaemia observed in obstructive jaundice. Both agents significantly ameliorated liver injury, as demonstrated by improvement of obstructive cholangiopathy and reduction of ALT. This effect was accompanied by prevention of lipid peroxidation, protein oxidation and decrease of the oxidized forms GSSG and NPSSR. Moreover, neutrophil accumulation in portal tracts was significantly decreased. In conclusion, this study shows that gut regulatory peptides BBS and NT reduce cholestatic liver injury, exerting protective effects on portal tract architecture, neutrophil infiltration and hepatic oxidative stress in bile duct ligated rats.

  16. Sigmoid function based integral-derivative observer and application to autopilot design

    NASA Astrophysics Data System (ADS)

    Shao, Xingling; Wang, Honglun; Liu, Jun; Tang, Jun; Li, Jie; Zhang, Xiaoming; Shen, Chong

    2017-02-01

    To handle problems of accurate signal reconstruction and controller implementation with integral and derivative components in the presence of noisy measurement, motivated by the design principle of sigmoid function based tracking differentiator and nonlinear continuous integral-derivative observer, a novel integral-derivative observer (SIDO) using sigmoid function is developed. The key merit of the proposed SIDO is that it can simultaneously provide continuous integral and differential estimates with almost no drift phenomena and chattering effect, as well as acceptable noise-tolerance performance from output measurement, and the stability is established based on exponential stability and singular perturbation theory. In addition, the effectiveness of SIDO in suppressing drift phenomena and high frequency noises is firstly revealed using describing function and confirmed through simulation comparisons. Finally, the theoretical results on SIDO are demonstrated with application to autopilot design: 1) the integral and tracking estimates are extracted from the sensed pitch angular rate contaminated by nonwhite noises in feedback loop, 2) the PID(proportional-integral-derivative) based attitude controller is realized by adopting the error estimates offered by SIDO instead of using the ideal integral and derivative operator to achieve satisfactory tracking performance under control constraint.

  17. Design and one-pot synthesis of new 7-acyl camptothecin derivatives as potent cytotoxic agents.

    PubMed

    Liu, Ying-Qian; Dai, Wei; Wang, Chih-Ya; Morris-Natschke, Susan L; Zhou, Xing-Wen; Yang, Liu; Yang, Xiao-Ming; Li, Wen-Qun; Lee, Kuo-Hsiung

    2012-12-15

    New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC(50) values ranging from 0.01538 to 13.342 μM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates.

  18. Application of derivative matrices of skew rays to design of compound dispersion prisms.

    PubMed

    Lin, Psang Dain

    2016-09-01

    Numerous optimization methods have been developed in recent decades for optical system design. However, these methods rely heavily on ray tracing and finite difference techniques to estimate the derivative matrices of the rays. Consequently, the accuracy of the results obtained from these methods is critically dependent on the incremental step size used in the tuning stage. To overcome this limitation, the present study proposes a comprehensive methodology for the design of compound dispersion prisms based on the first- and second-order derivative matrices of skew rays. The proposed method facilitates the analysis and design of prisms with respect to arbitrary system variables and provides an ideal basis for automatic prism design applications. Four illustrative examples are given. It is shown that the optical quantities required to evaluate the prism performance can be extracted directly from the proposed derivative matrices. In addition, it is shown in this study that the single-element 3D prism can have the same deviation angle and spectral dispersion as the 2D compound prism.

  19. Parallel Calculation of Sensitivity Derivatives for Aircraft Design using Automatic Differentiation

    NASA Technical Reports Server (NTRS)

    Bischof, c. H.; Green, L. L.; Haigler, K. J.; Knauff, T. L., Jr.

    1994-01-01

    Sensitivity derivative (SD) calculation via automatic differentiation (AD) typical of that required for the aerodynamic design of a transport-type aircraft is considered. Two ways of computing SD via code generated by the ADIFOR automatic differentiation tool are compared for efficiency and applicability to problems involving large numbers of design variables. A vector implementation on a Cray Y-MP computer is compared with a coarse-grained parallel implementation on an IBM SP1 computer, employing a Fortran M wrapper. The SD are computed for a swept transport wing in turbulent, transonic flow; the number of geometric design variables varies from 1 to 60 with coupling between a wing grid generation program and a state-of-the-art, 3-D computational fluid dynamics program, both augmented for derivative computation via AD. For a small number of design variables, the Cray Y-MP implementation is much faster. As the number of design variables grows, however, the IBM SP1 becomes an attractive alternative in terms of compute speed, job turnaround time, and total memory available for solutions with large numbers of design variables. The coarse-grained parallel implementation also can be moved easily to a network of workstations.

  20. Design, synthesis, and insecticidal activity of some novel diacylhydrazine and acylhydrazone derivatives.

    PubMed

    Sun, Jialong; Zhou, Yuanming

    2015-03-30

    In this study a series of diacylhydrazine and acylhydrazone derivatives were designed and synthesized according to the method of active group combination and the principles of aromatic group bioisosterism. The structures of the novel derivatives were determined on the basis on 1H-NMR, IR and ESI-MS spectral data. All of the compounds were evaluated for their in vivo insecticidal activity against the third instar larvae of Spodoptera exigua Hiibner, Helicoverpa armigera Hubner, Plutella xyllostella Linnaeus and Pieris rapae Linne, respectively, at a concentration of 10 mg/L. The results showed that all of the derivatives displayed high insecticidal activity. Most of the compounds presented higher insecticidal activity against S. exigua than the reference compounds tebufenozide, metaflumizone and tolfenpyrad, and approximately identical insecticidal activity against H. armigera, P. xyllostella and P. rapae as the references metaflumizone and tolfenpyrad.

  1. Design, synthesis and evaluation of 4-dimethylamine flavonoid derivatives as potential multifunctional anti-Alzheimer agents.

    PubMed

    Luo, Wen; Wang, Ting; Hong, Chen; Yang, Ya-Chen; Chen, Ying; Cen, Juan; Xie, Song-Qiang; Wang, Chao-Jie

    2016-10-21

    A new series of 4-dimethylamine flavonoid derivatives were designed and synthesized as potential multifunctional anti-Alzheimer agents. The inhibition of cholinesterase activity, self-induced β-amyloid (Aβ) aggregation, and antioxidant activity by these derivatives was investigated. Most of the compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The derivatives showed potent self-induced Aβ aggregation inhibition and peroxyl radical absorbance activity. Moreover, compound 6d significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Thus, these compounds could become multifunctional agents for further development for the treatment of AD.

  2. A coupling of homology modeling with multiple molecular dynamics simulation for identifying representative conformation of GPCR structures: a case study on human bombesin receptor subtype-3.

    PubMed

    Nowroozi, Amin; Shahlaei, Mohsen

    2017-02-01

    In this study, a computational pipeline was therefore devised to overcome homology modeling (HM) bottlenecks. The coupling of HM with molecular dynamics (MD) simulation is useful in that it tackles the sampling deficiency of dynamics simulations by providing good-quality initial guesses for the native structure. Indeed, HM also relaxes the severe requirement of force fields to explore the huge conformational space of protein structures. In this study, the interaction between the human bombesin receptor subtype-3 and MK-5046 was investigated integrating HM, molecular docking, and MD simulations. To improve conformational sampling in typical MD simulations of GPCRs, as in other biomolecules, multiple trajectories with different initial conditions can be employed rather than a single long trajectory. Multiple MD simulations of human bombesin receptor subtype-3 with different initial atomic velocities are applied to sample conformations in the vicinity of the structure generated by HM. The backbone atom conformational space distribution of replicates is analyzed employing principal components analysis. As a result, the averages of structural and dynamic properties over the twenty-one trajectories differ significantly from those obtained from individual trajectories.

  3. Regulation of glucose transport by insulin, bombesin, and bradykinin in Swiss 3T3 fibroblasts: Involvement of protein kinase C-dependent and -independent mechanisms

    SciTech Connect

    Dettori, C.; Meldolesi, J. )

    1989-05-01

    Glucose transport stimulation by insulin, bombesin, and bradykinin in Swiss 3T3 fibroblasts was compared with the phosphoinositide hydrolysis effects of the same stimulants in a variety of experimental paradigms known to affect generation and/or functioning of intracellular second messengers: short- and long-term treatments with phorbol dibutyrate, that cause activation and down-regulation of protein kinase C, respectively; cell loading with high (quin2), that causes clamping of (Ca{sup 2+}){sub i} near the resting level; poisoning with pertussis toxin, that affects the GTP binding proteins of the Go/Gi class; treatment with Ca{sup 2+} ionophores. ({sup 14}C) glucose transport stimulation by maximal (insulin) was affected by neither pertussis toxin nor protein kinase C down-regulation. This result correlates with the lack of effect of insulin on phosphoinositide hydrolysis. In contrast, part of the glucose transport responses induced by bombesin and bradykinin appeared to be mediated by protein kinase C in proportion with the stimulation induced by these peptides on the phosphoinositide hydrolysis. The protein kinase C-independent portion of the response to bradykinin was found to be inhibitable by pertussis toxin. This latter result might suggest an interaction between the bradykinin receptor and a glucose transporter, mediated by a protein of the Go/Gi class.

  4. Design, synthesis and 3D-QSAR study of cytotoxic flavonoid derivatives.

    PubMed

    Ou, Lili; Han, Shuang; Ding, Wenbo; Chen, Zhe; Ye, Ziqi; Yang, Hongyu; Zhang, Goulin; Lou, Yijia; Chen, Jian-Zhong; Yu, Yongping

    2011-08-01

    Three series of flavonoid derivatives were designed and synthesized. All synthesized compounds were evaluated for cytotoxic activities against five human cancer cell lines, including K562, PC-3, MCF-7, A549, and HO8910. Among the compounds tested, compound 9 d exhibited the most potent cytotoxic activity with IC(50) values of 2.76-6.98 μM. Further comparative molecular field analysis was performed to conduct a 3D quantitative structure-activity relationship study. The generated 3D-QSAR model could be used for further rational design of novel flavonoid analogs as highly potent cytotoxic agents.

  5. Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

    PubMed Central

    Datar, Prasanna A.; Jadhav, Sonali R.

    2015-01-01

    Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series. PMID:25734015

  6. Derivation of Design Loads and Random Vibration specifications for Spacecraft Instruments and Sub-Units

    NASA Astrophysics Data System (ADS)

    Fransen, S.; Yamawaki, T.; Akagi, H.; Eggens, M.; van Baren, C.

    2014-06-01

    After a first estimation based on statistics, the design loads for instruments are generally estimated by coupled spacecraft/instrument sine analysis once an FE-model of the spacecraft is available. When the design loads for the instrument have been derived, the next step in the process is to estimate the random vibration environment at the instrument base and to compute the RMS load at the centre of gravity of the instrument by means of vibro-acoustic analysis. Finally the design loads of the light-weight sub-units of the instrument can be estimated through random vibration analysis at instrument level, taking into account the notches required to protect the instrument interfaces in the hard- mounted random vibration test. This paper presents the aforementioned steps of instrument and sub-units loads derivation in the preliminary design phase of the spacecraft and identifies the problems that may be encountered in terms of design load consistency between low-frequency and high-frequency environments. The SpicA FAR-infrared Instrument (SAFARI) which is currently developed for the Space Infrared Telescope for Cosmology and Astrophysics (SPICA) will be used as a guiding example.

  7. Novel leucine ureido derivatives as aminopeptidase N inhibitors. Design, synthesis and activity evaluation.

    PubMed

    Ma, Chunhua; Cao, Jiangying; Liang, Xuewu; Huang, Yongxue; Wu, Ping; Li, Yingxia; Xu, Wenfang; Zhang, Yingjie

    2016-01-27

    Aminopeptidase N (APN/CD13) over-expressed on tumor cells and tumor microenvironment, plays critical roles in tumor invasion, metastasis and angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 7a had the most potent inhibitory activity against APN with the IC50 value of 20 nM, which could be used for further anticancer agent research.

  8. [Benzimidazole and its derivatives--from fungicides to designer drugs. A new occupational and environmental hazards].

    PubMed

    Lutz, Piotr

    2012-01-01

    Benzimidazole and benzimidazole derivatives play an important role in controlling various fungal pathogens. The benzimidazoles are also used to treat nematode and trematode infections in humans and animals. It acts by binding to the microtubules and stopping hyphal growth. It also binds to the spindle microtubules and blocks nuclear division. The most popular fungicide is carbendazim. The fungicide is used to control plant diseases in cereals and fruits. Laboratory studies have shown that carbendazim cause infertility and destroy the testicles of laboratory animals. Other benzimidazole derivatives are used as a preservative in paint, textile, papermaking, leather industry, and warehousing practices, as well as a preservative of fruits. Occupational exposure to benzimidazole may occur through inhalation and dermal contact with those compounds at workplaces where benzimidazole is used or produced. Some of the benzimidazoles are common environmental pollutants. They are often found in food and fruit products. Some of the benzimidazoles, like a astemizole or esomeprazole have found applications in diverse therapeutical areas. Despite of the clear advantages afforded by the use of benzimidazole derivatives, they share a danger potential. The most hazardous, however, are new illegally synthesed psychoactive drugs known as designer drugs. Some of them, like nitazene, etonitazene or clonitazene belong to benzimidazole derivatives. Laboratory animal studies revealed that etonitazene produced very similar effects in central nervous system as those observed after morphine administration. Considering etonitazene's properties, it seems reasonable to expected that long-term exposure to other benzimidazole derivatives may result in drug abuse and development of drug dependence.

  9. Derivation and application of the energy dissipation factor in the design of fishways

    USGS Publications Warehouse

    Towler, Brett; Mulligan, Kevin; Haro, Alexander J.

    2015-01-01

    Reducing turbulence and associated air entrainment is generally considered advantageous in the engineering design of fish passage facilities. The well-known energy dissipation factor, or EDF, correlates with observations of the phenomena. However, inconsistencies in EDF forms exist and the bases for volumetric energy dissipation rate criteria are often misunderstood. A comprehensive survey of EDF criteria is presented. Clarity in the application of the EDF and resolutions to these inconsistencies are provided through formal derivations; it is demonstrated that kinetic energy represents only 1/3 of the total energy input for the special case of a broad-crested weir. Specific errors in published design manuals are identified and resolved. New, fundamentally sound, design equations for culvert outlet pools and standard Denil Fishway resting pools are developed. The findings underscore the utility of EDF equations, demonstrate the transferability of volumetric energy dissipation rates, and provide a foundation for future refinement of component-, species-, and life-stage-specific EDF criteria.

  10. Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus.

    PubMed

    Jorge, Salomão Dória; Masunari, Andrea; Rangel-Yagui, Carlota Oliveira; Pasqualoto, Kerly Fernanda Mesquita; Tavares, Leoberto Costa

    2009-04-15

    Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N'-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF(3) substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 microg/mL, and a ClogP value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates.

  11. Novel hydrazone derivatives containing pyridine amide moiety: Design, synthesis, and insecticidal activity.

    PubMed

    Yang, Zai-Bo; Hu, De-Yu; Zeng, Song; Song, Bao-An

    2016-02-15

    A series of novel hydrazone derivatives containing pyridine amide moiety were designed, synthesized, and evaluated for their insecticidal activity. Bioassays indicated that some of the target compounds exhibited good insecticidal activities against Nilaparvata lugens (N. lugens), Plutella xylostella (P. xylostella), Mythimna separata (M. separata), Helicoverpa armigera (H. armigera), Pyrausta nubilalis (P. nubilalis), and Culex pipiens pallens (C. pipiens pallens). In particular, compound 5j revealed excellent insecticidal activity against C. pipiens pallens, with the 50% lethal concentration (LC50) and the 95% lethal concentration (LC95) values of 2.44 and 5.76 mg/L, respectively, which were similar to those of chlorpyrifos (3.26 and 6.98 mg/L, respectively), tebufenozide (1.22 and 2.49 mg/L, respectively), and RH-5849 (2.61 and 6.37 mg/L, respectively). These results indicated that hydrazone derivatives containing pyridine amide moiety could be developed as novel and promising insecticides.

  12. Design and synthesis of chroman derivatives with dual anti-breast cancer and antiepileptic activities

    PubMed Central

    Rawat, Pinki; Verma, Saurabh Manaswita

    2016-01-01

    A series of chroman derivatives was designed, prepared, and examined for their anti-breast cancer and antiepileptic activities. All synthesized compounds yielded results that were in good agreement with spectral data. The bioassay showed that some of the resultant compounds exerted remarkable inhibitory effects on growth of human breast cancer cell line MCF-7. In particular, compound 6i (the concentration required for 50% inhibition of cell growth [GI50] =34.7 µM) exerted promising anticancer activity toward MCF-7 cell line. Additionally, compounds 6b, 6c, 6d, 6e, 6g, 6i, and 6l showed advanced antiepileptic activity than reference drugs. None of the compounds showed neurotoxicity, as determined by the rotarod test. The obtained results proved that these distinctive compounds could be relevant as models for future discovery and research, as well as for the production of more number of active derivatives. PMID:27621598

  13. Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents.

    PubMed

    Suthar, Sharad Kumar; Bansal, Sumit; Alam, Md Maqusood; Jaiswal, Varun; Tiwari, Amit; Chaudhary, Anil; Alex, Angel Treasa; Joseph, Alex

    2015-11-15

    The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 μmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 μmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.

  14. Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger.

    PubMed

    Borges, Rosivaldo S; Pereira, Glaécia A N; Vale, Joyce K L; França, Luiz C S; Monteiro, Marta C; Alves, Cláudio N; da Silva, Albérico B F

    2013-03-01

    This theoretical and experimental study describes the design and evaluation of the free-radical scavenging effect for the molecular association of 4-aminophenol and salicylate derivatives. For this purpose, we employed theoretical methods for the selection of antioxidant drugs and the rapid methods of evaluation: the 1,1-diphenyl-2-picrylhydrazyl radical and the thiobarbituric acid reactive substances in the lipid peroxidation initiated by Fe(2+) and ascorbic acid in human erythrocytes. The associate derivatives exhibited a more potent inhibition than the salicylic acid, while the benzoyl compound exhibited a more potent inhibition than paracetamol. The molecular parameters related to the electron distribution and structure (ionization potential and energy of the highest occupied molecular orbital) correlated very well with the antioxidant action of the compounds studied here in different tests.

  15. Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

    PubMed Central

    GONZÁLEZ, NIEVES; MARTÍN-DUCE, ANTONIO; MARTÍNEZ-ARRIETA, FÉLIX; MORENO-VILLEGAS, ZAIDA; PORTAL-NÚÑEZ, SERGIO; SANZ, RAÚL; EGIDO, JESÚS

    2015-01-01

    Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein-coupled receptor (GPCR) member of the bombesin receptor family. Several studies have suggested an association between obesity, alterations in glucose metabolism, diabetes and the BRS-3 receptor. In this study, we focused on patients simultaneously diagnosed with obesity and type 2 diabetes (OB/T2D). The analysis of BRS-3 expression in the skeletal muscle of these patients revealed a marked decrease in the expression of BRS-3 at the mRNA (23.6±1.3-fold downregulation, p<0.0001) and protein level (49±7% decrease, p<0.05) compared to the normal patients (no obesity and diabetes). Moreover, in cultured primary myocytes from patients with OB/T2D, the synthetic BRS-3 agonist, [D-Try6,β-Ala11,Phe13,Nle14]bombesin6–14, significantly increased the phosphorylation levels of mitogen-activated protein kinase (MAPK), p90RSK1, protein kinase B (PKB) and p70s6K. Specifically, the ligand at 10−11 M induced the maximal phosphorylation of MAPKs (p42, 159±15% of the control; p44, 166±11% of the control; p<0.0001) and p90RSK1 (148±2% of the control, p<0.0001). The basal phosphorylation levels of all kinases were reduced (p<0.05) in the patients with OB/T2D compared to the normal patients. Furthermore, the BRS-3 agonist stimulated glucose transport, which was already detected at 10−12 M (133±9% of the control), reached maximal levels at 10−11 M (160±9%, p<0.0001) and was maintained at up to 10−8 M (overall mean, 153±7%; p<0.007). This effect was less promiment than that attained with 10−8 M insulin (202±9%, p=0.009). The effect of the agonist on glycogen synthase a activity achieved the maximum effect at 10−11 M (165±16% of the control; p<0.0001), which did not differ from that observed with higher concentrations of the agonist. These results suggest that muscle cells isolated from patients with OB/T2D have extremely high sensitivity to the synthetic ligand, and the effects are particularly observed on

  16. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents

    NASA Astrophysics Data System (ADS)

    Santoshi, Seneha; Manchukonda, Naresh Kumar; Suri, Charu; Sharma, Manya; Sridhar, Balasubramanian; Joseph, Silja; Lopus, Manu; Kantevari, Srinivas; Baitharu, Iswar; Naik, Pradeep Kumar

    2015-03-01

    We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔGbind, pred) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔGbind, expt (calculated from the Kd value) are consistent with the predicted value of ΔGbind, pred calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological

  17. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents.

    PubMed

    Santoshi, Seneha; Manchukonda, Naresh Kumar; Suri, Charu; Sharma, Manya; Sridhar, Balasubramanian; Joseph, Silja; Lopus, Manu; Kantevari, Srinivas; Baitharu, Iswar; Naik, Pradeep Kumar

    2015-03-01

    We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔG(bind, pred)) of these derivatives (ranging from -5.568 to -5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (-5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔG(bind, expt) (calculated from the Kd value) are consistent with the predicted value of ΔG(bind, pred) calculated based on LIE-SGB. Based on these results, one of the derivative 5e of this series was used for further

  18. Design and study of some novel ibuprofen derivatives with potential nootropic and neuroprotective properties.

    PubMed

    Siskou, Ioanna C; Rekka, Eleni A; Kourounakis, Angeliki P; Chrysselis, Michael C; Tsiakitzis, Kariofyllis; Kourounakis, Panos N

    2007-01-15

    Six novel ibuprofen derivatives and related structures, incorporating a proline moiety and designed for neurodegenerative disorders, are studied. They possess anti-inflammatory properties and three of them inhibited lipoxygenase. One compound was found to inhibit cyclooxygenase (COX)-2 production in spleenocytes from arthritic rats. The HS-containing compounds are potent antioxidants and one of them protected against glutathione loss after cerebral ischemia/reperfusion. They demonstrated lipid-lowering ability and seem to acquire low gastrointestinal toxicity. Acetylcholinesterase inhibitory activity, found in two of these compounds, may be an asset to their actions.

  19. Design and synthesis of 1,4-dihydropyridine derivatives as anti-cancer agent.

    PubMed

    Viradiya, Denish; Mirza, Sheefa; Shaikh, Faraz; Kakadiya, Rajesh; Rathod, Anand; Jain, Nayan; Rawal, Rakesh; Shah, Anamik

    2016-12-06

    A series of 1,4-dihydropyridine based compounds bearing benzylpyridinium moiety have been designed and evaluated for in vitro anticancer activity against glioblastoma U87MG, lung cancer A549 and colorectal adenocarcinoma Caco-2 cell lines using the MTT assay. Among these compounds, 7b, 7d, 7e, and 7f exhibited potent anticancer activity against the cell lines tested. The cytotoxicity of the synthesized derivatives was compared to standard drugs (carboplatin, gemcitabine, and daunorubicin). Thus, synthesized 1,4-dihydropyridines can be considered as the encouraging molecules for further drug development as anticancer agents.

  20. Design of two-channel filter bank using nature inspired optimization based fractional derivative constraints.

    PubMed

    Kuldeep, B; Singh, V K; Kumar, A; Singh, G K

    2015-01-01

    In this article, a novel approach for 2-channel linear phase quadrature mirror filter (QMF) bank design based on a hybrid of gradient based optimization and optimization of fractional derivative constraints is introduced. For the purpose of this work, recently proposed nature inspired optimization techniques such as cuckoo search (CS), modified cuckoo search (MCS) and wind driven optimization (WDO) are explored for the design of QMF bank. 2-Channel QMF is also designed with particle swarm optimization (PSO) and artificial bee colony (ABC) nature inspired optimization techniques. The design problem is formulated in frequency domain as sum of L2 norm of error in passband, stopband and transition band at quadrature frequency. The contribution of this work is the novel hybrid combination of gradient based optimization (Lagrange multiplier method) and nature inspired optimization (CS, MCS, WDO, PSO and ABC) and its usage for optimizing the design problem. Performance of the proposed method is evaluated by passband error (ϕp), stopband error (ϕs), transition band error (ϕt), peak reconstruction error (PRE), stopband attenuation (As) and computational time. The design examples illustrate the ingenuity of the proposed method. Results are also compared with the other existing algorithms, and it was found that the proposed method gives best result in terms of peak reconstruction error and transition band error while it is comparable in terms of passband and stopband error. Results show that the proposed method is successful for both lower and higher order 2-channel QMF bank design. A comparative study of various nature inspired optimization techniques is also presented, and the study singles out CS as a best QMF optimization technique.

  1. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives.

    PubMed

    Yang, Lei Xiang; Huang, Ke Xin; Li, Hai Bo; Gong, Jing Xu; Wang, Feng; Feng, Yu Bing; Tao, Qiao Feng; Wu, Yi Hang; Li, Xiao Kun; Wu, Xiu Mei; Zeng, Su; Spencer, Shawn; Zhao, Yu; Qu, Jia

    2009-12-10

    A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe(2+) chelation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether at C7-OH and C20-OH as well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe(2+) chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H(2)O(2)-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

  2. Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives.

    PubMed

    Liao, Sheng-Rong; Qin, Xiao-Chu; Wang, Zhen; Li, Ding; Xu, Liang; Li, Jin-Sheng; Tu, Zheng-Chao; Liu, Yonghong

    2016-10-04

    A series of novel N-1-monoallylated 2,5-diketopiperazine derivatives were designed, synthesized, and evaluated as cytotoxic agents against eight cancer cell lines by using CCK8 assay. These derivatives were substituted with methoxyphenyl groups at C-6 position, and various long alkyl side chains at C-3-position of the 2,5-diketopiperazine ring. The cytotoxic results showed that 4-methoxyphenyl group was better than 2-methoxyphenyl group as optimal substitutive group, while 3-methoxyphenyl group was not a suitable one. When the number (n value) of the methylene groups for the long alkyl side chain was 3 (compounds 1c and 3c), the derivatives had the strongest cytotoxicities. Compound 3c substituted with 4-methoxyphenyl group and pentylidene side chain exhibited strong activity (IC50 = 0.36-1.9 μM) against all cancer cell lines, and could obviously induce apoptosis of cancer cell line U937 at 1.0 μM after 48 h treatment.

  3. Synthesis and vasodilatory activity of new N-acylhydrazone derivatives, designed as LASSBio-294 analogues.

    PubMed

    Silva, Alexandre G; Zapata-Sudo, Gisele; Kummerle, Arthur E; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T

    2005-05-16

    Conventional therapy to treat hypertension often involves arterial vasodilation. Decrease of blood pressure by vasodilators is normally associated with adverse effects because of their low vascular selectivity. This is of interest to develop new molecules with potential for clinical use and fewer side effects. Recently, a new bioactive compound of the N-acylhydrazone class, LASSBio-294, was shown to produce a cardioinotropic effect and vasodilation. In this report, new derivatives of LASSBio-294 were designed and tested on the contractile response of vascular smooth muscle from Wistar rats. Phenylephrine-induced contracture in the aorta was inhibited by the derivatives LASSBio-785 and LASSBio-788. The concentrations necessary to cause 50% reduction of the maximal vascular response (IC50) were 10.2 +/- 0.5 and 67.9 +/- 6.5 microM. Vasodilation induced by both derivatives is likely to be mediated by a direct effect on smooth muscle because it was not dependent on the integrity of vascular endothelium. LASSBio-785 was seven times more potent than the reference compound LASSBio-294 (IC50 = 74 microM) in producing an endothelium-independent vasodilator effect.

  4. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.

    PubMed

    Song, Zi-Long; Wang, Mei-Juan; Li, Lanlan; Wu, Dan; Wang, Yu-Han; Yan, Li-Ting; Morris-Natschke, Susan L; Liu, Ying-Qian; Zhao, Yong-Long; Wang, Chih-Ya; Liu, Huanxiang; Goto, Masuo; Liu, Heng; Zhu, Gao-Xiang; Lee, Kuo-Hsiung

    2016-06-10

    In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

  5. Molecular design, synthesis and bioactivity of glycosyl hydrazine and hydrazone derivatives: notable effects of the sugar moiety.

    PubMed

    Cui, Zining; Yang, Xinling; Shi, Yanxia; Uzawa, Hirotaka; Cui, Jingrong; Dohi, Hirofumi; Nishida, Yoshihiro

    2011-12-01

    Assuming that the water solubility of our previous hydrazone derivatives would improve after modification with sugars while keeping or modulating their notable biological activities, we designed and synthesized some glycosyl hydrazine and hydrazone derivatives. Bioassay results indicated that the antitumor activity of our previously prepared hydrazones reduced or disappeared after modification with sugars. On the contrary, some glycosyl derivatives displayed much better antifungal activity against selected fungi. Obviously, a small sugar can change the biological activity of hydrazones significantly.

  6. ESAS-Derived Earth Departure Stage Design for Human Mars Exploration

    NASA Technical Reports Server (NTRS)

    Flaherty, Kevin; Grant, Michael; Korzun, Ashley; Malo-Molina, Faure; Steinfeldt, Bradley; Stahl, Benjamin; Wilhite, Alan

    2007-01-01

    The Vision for Space Exploration has set the nation on a course to have humans on Mars as early as 2030. To reduce the cost and risk associated with human Mars exploration, NASA is planning for the Mars architecture to leverage the lunar architecture as fully as possible. This study takes the defined launch vehicles and system capabilities from ESAS and extends their application to DRM 3.0 to design an Earth Departure Stage suitable for the cargo and crew missions to Mars. The impact of a propellant depot in LEO was assessed and sLzed for use with the EDS. To quantitatively assess and compare the effectiveness of alternative designs, an initial baseline architecture was defined using the ESAS launch vehicles and DRM 3.0. The baseline architecture uses three NTR engines, LH2 propellant, no propellant depot in LEO, and launches on the Ares I and Ares V. The Mars transfer and surface elements from DRM 3.0 were considered to be fixed payloads in the design of the EDS. Feasible architecture alternatives were identified from previous architecture studies and anticipated capabilities and compiled in a morphological matrix. ESAS FOMs were used to determine the most critical design attributes for the effectiveness of the EDS. The ESAS-derived FOMs used in this study to assess alternative designs are effectiveness and performance, affordability, reliability, and risk. The individual FOMs were prioritized using the AHP, a method for pairwise comparison. All trades performed were evaluated with respect to the weighted FOMs, creating a Pareto frontier of equivalently ideal solutions. Additionally, each design on the frontier was evaluated based on its fulfillment of the weighted FOMs using TOPSIS, a quantitative method for ordinal ranking of the alternatives. The designs were assessed in an integrated environment using physics-based models for subsystem analysis where possible. However, for certain attributes such as engine type, historical, performance-based mass estimating

  7. Design, synthesis and biological activity of aromatic diketone derivatives as HIV-1 integrase inhibitors.

    PubMed

    Hu, Liming; Li, Zhipeng; Wang, Zhanyang; Liu, Gengxin; He, Xianzhuo; Wang, Xiaoli; Zeng, Chengchu

    2015-01-01

    A series of aromatic diketone derivatives were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated to determine their ability to inhibit the strand transfer process of HIV-1 integrase. The results indicate that (Z)-1-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-3-hydroxy-3-(substituted)phenylprop-2-en-1-one (5a-5d) can moderately inhibit HIV-1 integrase. The cyclization and condensation products (6a-6c and 7e-7f) of compounds 5a-5d show poor inhibitory activity against HIV-1 integrase. The molecular docking results indicate that the different types of compounds act on HIV-1 integrase in different ways, and these results can explain the differences in the inhibitory activities.

  8. Design, synthesis and antibacterial activity of isatin derivatives as FtsZ inhibitors

    NASA Astrophysics Data System (ADS)

    Lian, Zhi-Min; Sun, Juan; Zhu, Hai-Liang

    2016-08-01

    Seven isatin derivatives have been designed, and their chemical structures were characterized by single crystal X-ray diffraction studies, 1H NMR, MS, and elemental analysis. Structural stabilization followed by intramolecular as well as intermolecular H-bonds makes these molecules as perfect examples in molecular recognition with self-complementary donor and acceptor units within a single molecule. These compounds were evaluated for antimicrobial activities. Docking simulations have been performed to position compounds into the FtsZ active site to determine their probable binding models. All of the compounds exhibited better antibacterial activities. Interestingly, compound 5c and 5d exhibited better antibacterial activities with IC50 values of 0.03 and 0.05 μmol/mL against Staphylococcus aureus, respectively. Compound 5g displays antibacterial activity with IC50 values of 0.672 and 0.830 μmol/mL against Escherichia coli and Pseudomonas aeruginosa, respectively.

  9. Design, synthesis and cytotoxic activity of novel sulfonylurea derivatives of podophyllotoxin.

    PubMed

    Zhang, Zhi-Jun; Tian, Jing; Wang, Li-Ting; Wang, Mei-Juan; Nan, Xiang; Yang, Liu; Liu, Ying-Qian; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2014-01-01

    Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC₅₀: 1.41-1.76 μM) and 14e (IC₅₀: 1.72-2.01 μM) showed superior cytotoxic activity compared with etoposide (IC₅₀: 2.03 to >20 μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4'-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin's 4β position can significantly improve cytotoxic activity.

  10. Design, Synthesis, and Structure-Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety.

    PubMed

    Guan, Aiying; Liu, Changling; Chen, Wei; Yang, Fan; Xie, Yong; Zhang, Jinbo; Li, Zhinian; Wang, Mingan

    2017-02-15

    The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by (1)H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC50 = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.

  11. Design, synthesis and 3D-QSAR of beta-carboline derivatives as potent antitumor agents.

    PubMed

    Cao, Rihui; Guan, Xiangdong; Shi, Buxi; Chen, Zhiyong; Ren, Zhenhua; Peng, Wenlie; Song, Huacan

    2010-06-01

    In a continuing effort to develop novel beta-carbolines endowed with better pharmacological profiles, a series of beta-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N2-benzylated beta-carbolinium bromides 56-60 represented the most potent compounds with IC50 values lower than 10 microM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA (q2=0.513, r2=0.862) and CoMSIA (q2=0.503, r2=0.831) models were developed for a set of 47 beta-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of beta-carboline ring.

  12. Design of Assembled Systems Based on Conjugated Polyphenylene Derivatives and Carbon Nanohorns.

    PubMed

    Iglesias, Daniel; Guerra, Javier; Gómez, M Victoria; Rodríguez, Antonio M; Prieto, Pilar; Vázquez, Ester; Herrero, M Antonia

    2016-08-08

    Promising materials have been designed and fully characterised by an effective interaction between versatile platforms such as carbon nanohorns (CNHs) and conjugated molecules based on thiophene derivatives. Easy and non-aggressive methods have been described for the synthesis and purification of the final systems. Oligothiophenephenylvinylene (OTP) systems with different geometries and electron density are coupled to the CNHs. A wide range of characterization techniques have been used to confirm the effective interaction between the donor (OTP) and the acceptor (CNH) systems. These hybrid materials show potential for integration into solar cell devices. Importantly, surface-enhanced Raman spectroscopy (SERS) effects are observed without the presence of any metal surface in the system. Theoretical calculations have been performed to study the optimised geometries of the noncovalent interaction between the surface and the organic molecule. The calculations allow information on the monoelectronic energies of HOMO-LUMO orbitals and band gap of different donor systems to be extracted.

  13. Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors.

    PubMed

    Choi, Soo-Jeong; Cho, Joong-Heui; Im, Isak; Lee, So-Deok; Jang, Ji-Yeon; Oh, Yu-Min; Jung, Yong-Keun; Jeon, Eun-Seok; Kim, Yong-Chul

    2010-06-01

    BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC50 values in the range 8-30 microM, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors.

  14. Amino Acid Derivatives as New Zinc Binding Groups for the Design of Selective Matrix Metalloproteinase Inhibitors

    PubMed Central

    Giustiniano, Mariateresa; Agamennone, Mariangela; Rossello, Armando; Gomez-Monterrey, Isabel; Novellino, Ettore; Campiglia, Pietro; Vernieri, Ermelinda; Bertamino, Alessia; Carotenuto, Alfonso

    2013-01-01

    A number of matrix metalloproteinases (MMPs) are important medicinal targets for conditions ranging from rheumatoid arthritis to cardiomyopathy, periodontal disease, liver cirrhosis, multiple sclerosis, and cancer invasion and metastasis, where they showed to have a dual role, inhibiting or promoting important processes involved in the pathology. MMPs contain a zinc (II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In an effort to devise new approaches to selective inhibitors, in this paper, we describe the synthesis and preliminary biological evaluation of amino acid derivatives as new zinc binding groups (ZBGs). The incorporation of selected metal-binding functions in more complex biphenyl sulfonamide moieties allowed the identification of one compound able to interact selectively with different MMP enzymatic isoforms. PMID:23555050

  15. Design, Synthesis, and Biological Evaluation of Novel CNS 7056 Derivatives as Sedatives in Rats and Rabbits.

    PubMed

    Liu, Yan; Xu, Xiangqing; Xie, Jianyong; Ma, Huan; Wang, Tao; Zhang, Guisen; Li, Qingeng

    2016-07-01

    A new water-soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL-001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL-001 was chosen as the optimal compound for studies of ED50 , LD50 , latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL-001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL-001 has a shorter period of induction despite a slightly longer sedative duration and recovery time.

  16. Design, synthesis and biological evaluation studies of novel quinazoline derivatives as cytotoxic agents.

    PubMed

    Zayed, M F; Hassan, M H

    2013-04-01

    Some novel quinazoline derivatives 6a-h were designed, synthesized and evaluated for their in vitro cytotoxic activity against lymphoma cell line compared to etoposide as a reference drug. Compounds (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-phenylpropanoic acid (6 f), (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-(1H-imidazol-4-yl)propanoic acid (6 g) and (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-(1H-indol-3-yl) propanoic acid (6 h) had comparable higher cytotoxic activity than the reference drug. Compound 6 f, the most active compound, had IC50=13.2 µM. In an attempt to interpret such anti-cancer activity of these derivatives, their anti-inflammatory action was examined using the carrageenan induced rat paw edema method. The most active compounds showed moderate anti-inflammatory activity compared to the reference drug. In order to identify the most relevant physicochemical features important for high antitumor activity of the target compounds, specific 2D descriptors were calculated and correlated with the antileukemic activity.

  17. Maximum likelihood identification and optimal input design for identifying aircraft stability and control derivatives

    NASA Technical Reports Server (NTRS)

    Stepner, D. E.; Mehra, R. K.

    1973-01-01

    A new method of extracting aircraft stability and control derivatives from flight test data is developed based on the maximum likelihood cirterion. It is shown that this new method is capable of processing data from both linear and nonlinear models, both with and without process noise and includes output error and equation error methods as special cases. The first application of this method to flight test data is reported for lateral maneuvers of the HL-10 and M2/F3 lifting bodies, including the extraction of stability and control derivatives in the presence of wind gusts. All the problems encountered in this identification study are discussed. Several different methods (including a priori weighting, parameter fixing and constrained parameter values) for dealing with identifiability and uniqueness problems are introduced and the results given. The method for the design of optimal inputs for identifying the parameters of linear dynamic systems is also given. The criterion used for the optimization is the sensitivity of the system output to the unknown parameters. Several simple examples are first given and then the results of an extensive stability and control dervative identification simulation for a C-8 aircraft are detailed.

  18. Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors.

    PubMed

    He, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-Wu

    2014-06-15

    By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.

  19. Designing molecular complexes using free-energy derivatives from liquid-state integral equation theory

    NASA Astrophysics Data System (ADS)

    Mrugalla, Florian; Kast, Stefan M.

    2016-09-01

    Complex formation between molecules in solution is the key process by which molecular interactions are translated into functional systems. These processes are governed by the binding or free energy of association which depends on both direct molecular interactions and the solvation contribution. A design goal frequently addressed in pharmaceutical sciences is the optimization of chemical properties of the complex partners in the sense of minimizing their binding free energy with respect to a change in chemical structure. Here, we demonstrate that liquid-state theory in the form of the solute-solute equation of the reference interaction site model provides all necessary information for such a task with high efficiency. In particular, computing derivatives of the potential of mean force (PMF), which defines the free-energy surface of complex formation, with respect to potential parameters can be viewed as a means to define a direction in chemical space toward better binders. We illustrate the methodology in the benchmark case of alkali ion binding to the crown ether 18-crown-6 in aqueous solution. In order to examine the validity of the underlying solute-solute theory, we first compare PMFs computed by different approaches, including explicit free-energy molecular dynamics simulations as a reference. Predictions of an optimally binding ion radius based on free-energy derivatives are then shown to yield consistent results for different ion parameter sets and to compare well with earlier, orders-of-magnitude more costly explicit simulation results. This proof-of-principle study, therefore, demonstrates the potential of liquid-state theory for molecular design problems.

  20. Designing molecular complexes using free-energy derivatives from liquid-state integral equation theory.

    PubMed

    Mrugalla, Florian; Kast, Stefan M

    2016-09-01

    Complex formation between molecules in solution is the key process by which molecular interactions are translated into functional systems. These processes are governed by the binding or free energy of association which depends on both direct molecular interactions and the solvation contribution. A design goal frequently addressed in pharmaceutical sciences is the optimization of chemical properties of the complex partners in the sense of minimizing their binding free energy with respect to a change in chemical structure. Here, we demonstrate that liquid-state theory in the form of the solute-solute equation of the reference interaction site model provides all necessary information for such a task with high efficiency. In particular, computing derivatives of the potential of mean force (PMF), which defines the free-energy surface of complex formation, with respect to potential parameters can be viewed as a means to define a direction in chemical space toward better binders. We illustrate the methodology in the benchmark case of alkali ion binding to the crown ether 18-crown-6 in aqueous solution. In order to examine the validity of the underlying solute-solute theory, we first compare PMFs computed by different approaches, including explicit free-energy molecular dynamics simulations as a reference. Predictions of an optimally binding ion radius based on free-energy derivatives are then shown to yield consistent results for different ion parameter sets and to compare well with earlier, orders-of-magnitude more costly explicit simulation results. This proof-of-principle study, therefore, demonstrates the potential of liquid-state theory for molecular design problems.

  1. Part IV: Design, synthesis and antitumor activity of fluoroquinolone C-3 heterocycles: bis-oxadiazole methylsulfide derivatives derived from ciprofloxacin.

    PubMed

    Hu, Guo-qiang; Hou, Li-li; Wang, Guo-qiang; Duan, Nan-nan; Wen, Xiao-yi; Cao, Tie-yao; Yin, Jun; Wang, Wei; Xie, Song-qiang; Huang, Wen-long

    2012-08-01

    To explore an efficient strategy for further development of anticancer fluoroquinolone candidates derived from ciprofloxacin, a heterocyclic ring as the bioisosteric replacement of C3 carboxyl group led to a key intermediate, oxadiazole thiol (5), which was further modified to the bis-oxadiazole methylsulfides (7a-7h) and the corresponding dimethylpiperazinium iodides (8a-8h), respectively. Structures were characterized by elemental analysis and spectra data, and their anticancer activities in vitro against CHO, HL60 and L1210 cancer cells were also evaluated by MTT assay. The preliminary results show that piperazinium compounds (8) possess more potent activity than that of corresponding free bases (7).

  2. Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors.

    PubMed

    af Gennäs, Gustav Boije; Mologni, Luca; Ahmed, Shaheen; Rajaratnam, Mohanathas; Marin, Oriano; Lindholm, Niko; Viltadi, Michela; Gambacorti-Passerini, Carlo; Scapozza, Leonardo; Yli-Kauhaluoma, Jari

    2011-09-05

    In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.

  3. Design considerations and operating experience in firing refuse derived fuel in a circulating fluidized bed combustor

    SciTech Connect

    Piekos, S.J.; Matuny, M.

    1997-12-31

    The worldwide demand for cleaner, more efficient methods to dispose of municipal solid waste has stimulated interest in processing solid waste to produce refuse derived fuel (RDF) for use in circulating fluidized bed (CFB) boilers. The combination of waste processing and materials recovery systems and CFB boiler technology provides the greatest recovery of useful resources from trash and uses the cleanest combustion technology available today to generate power. Foster Wheeler Power Systems along with Foster Wheeler Energy Corporation and several other Foster Wheeler sister companies designed, built, and now operates a 1600 tons per day (TPD) (1450 metric tons) municipal waste-to-energy project located in Robbins, Illinois, a suburb of Chicago. This project incorporates waste processing systems to recover recyclable materials and produce RDF. It is the first project in the United States to use CFB boiler technology to combust RDF. This paper will provide an overview of the Robbins, Illinois waste-to-energy project and will examine the technical and environmental reasons for selecting RDF waste processing and CFB combustion technology. Additionally, this paper will present experience with handling and combusting RDF and review the special design features incorporated into the CFB boiler and waste processing system that make it work.

  4. Design and construction of nanoscale material for ultrasonic assisted adsorption of dyes: Application of derivative spectrophotometry and experimental design methodology.

    PubMed

    Bagheri, Ahmad Reza; Ghaedi, Mehrorang; Asfaram, Arash; Jannesar, Ramin; Goudarzi, Alireza

    2017-03-01

    Response surface methodology (RSM) based on central rotatable experimental design was used to investigate the effect of ultrasound assisted simultaneous adsorption process variables on Cu: ZnS-NPs-AC from aqueous solution. Cu: ZnS-NPs-AC was characterized using field emission scanning electron microscopy (FE-SEM), Energy Dispersive X-ray Spectroscopy (EDX) and X-ray diffraction (XRD). To overcome the severe methylene blue (MB) and brilliant green (BG) dyes spectral overlapping, derivative spectrophotometric method were successfully applied for the simultaneous determination of dyes in their binary solutions. Simultaneous determination of the dyes can be carried out using the first-order and second order derivative signal at 664 and 663nm for BG and MB, respectively. The factors investigated were pH (2.5-8.5), adsorbent mass (0.006-0.030g), sonication time (1-5min) and initial MB and BG concentration (3-15mgL(-1)). Five levels, which were low level, center point, upper level and two axillar points, were considered for each of the factors. The desirability function (DF: 0.9853) on the STATISTICA version 10.0 software showed that the optimum removal (99.832 and 99.423% for MB and BG, respectively) was obtained at pH 8.0, adsorbent mass 0.024g, sonication time 4min and 9mgL(-1) initial concentration for each dye. Besides, the results show that obtained data were adequately fitted into the second-order polynomial model, since the calculated model F value (172.96 and 96.35 for MB and BG, respectively) is higher than the critical F value. The values of coefficient of determination (0.9968 and 0.9943 for MB and BG, respectively) and adjusted coefficient of determination (0.9911 and 0.9840 for MB and BG, respectively) are close to 1, indicating a high correlation between the observed and the predicted values. The ultrasonic amplitude and adsorbent mass were found to be the most effective variable influencing the adsorption process. The adsorption equilibrium was well

  5. Analysis and design of prisms using the derivatives of a ray. Part II: the derivatives of boundary variable vector with respect to system variable vector.

    PubMed

    Lin, Psang Dain

    2013-06-20

    To evaluate the merit function of an optical system, it is necessary to determine the first- and second-order derivative matrices of the boundary variable vector with respect to the system variable vector. Accordingly, the present study proposes a computationally efficient method for determining both matrices for optical systems containing only flat boundary surfaces. The validity of the proposed method is demonstrated by means of two illustrative prism design problems. In general, the results show that the proposed method can provide efficient search directions in many gradient-based optical design optimization methods.

  6. Synthesis and characterization of designed BMHP1-derived self-assembling peptides for tissue engineering applications

    NASA Astrophysics Data System (ADS)

    Silva, Diego; Natalello, Antonino; Sanii, Babak; Vasita, Rajesh; Saracino, Gloria; Zuckermann, Ronald N.; Doglia, Silvia Maria; Gelain, Fabrizio

    2012-12-01

    The importance of self-assembling peptides (SAPs) in regenerative medicine is becoming increasingly recognized. The propensity of SAPs to form nanostructured fibers is governed by multiple forces including hydrogen bonds, hydrophobic interactions and π-π aromatic interactions among side chains of the amino acids. Single residue modifications in SAP sequences can significantly affect these forces. BMHP1-derived SAPs is a class of biotinylated oligopeptides, which self-assemble in β-structured fibers to form a self-healing hydrogel. In the current study, selected modifications in previously described BMHP1-derived SAPs were designed in order to investigate the influence of modified residues on self-assembly kinetics and scaffold formation properties. The Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis demonstrated the secondary structure (β-sheet) formation in all modified SAP sequences, whereas atomic force microscopy (AFM) analysis further confirmed the presence of nanofibers. Furthermore, the fiber shape and dimension analysis by AFM showed flattened and twisted fiber morphology ranging from ~8 nm to ~70 nm. The mechanical properties of the pre-assembled and post assembled solution were investigated by rheometry. The shear-thinning behavior and rapid re-healing properties of the pre-assembled solutions make them a preferable choice for injectable scaffolds. The wide range of stiffnesses (G') -from ~1000 to ~27 000 Pa - exhibited by the post-assembled scaffolds demonstrated their potential for a variety of tissue engineering applications. The extra cellular matrix (ECM) mimicking (physically and chemically) properties of SAP scaffolds enhanced cell adhesion and proliferation. The capability of the scaffold to facilitate murine neural stem cell (mNSC) proliferation was evaluated in vitro: the increased mNSCs adhesion and proliferation demonstrated the potential of newly synthesized SAPs for regenerative medicine approaches

  7. Design, synthesis, and antiviral, fungicidal, and insecticidal activities of tetrahydro-β-carboline-3-carbohydrazide derivatives.

    PubMed

    Liu, Yongxian; Song, Hongjian; Huang, Yuanqiong; Li, Jiarui; Zhao, Sheng; Song, Yuchuan; Yang, Peiwen; Xiao, Zhixin; Liu, Yuxiu; Li, Yongqiang; Shang, Hui; Wang, Qingmin

    2014-10-15

    According to our previous research on the antiviral activity of β-carboline and tetrahydro-β-carboline derivatives, using (1S,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (1) as a lead compound, series of novel tetrahydro-β-carboline derivatives containing acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. Most of these compounds exhibited excellent antiviral activity both in vitro and in vivo. The in vivo inactivation, curative, and protection activities of compounds 8, 9, 12, 16, 28, 29, and 30 were much higher than that of ribavirin (37.6%, 39.4%, and 37.9% at 500 μg/mL) and the lead compound (40.0%, 42.3%, and 39.6% at 500 μg/mL). Especially, the in vitro and in vivo activities of compound 16 (36.9%, 33.6%, 30.2%, and 35.8%) at 100 μg/mL, which were very close to that of ribavirin (40.0% for in vitro activity) at 500 μg/mL. Compounds 9 and 29 were chosen for the field trials of antiviral efficacy against TMV (tobacco mosaic virus); the results exhibited that both compounds, especially compound 29, showed better activities than control plant virus inhibitors. At the same time, the fungicidal results showed that compounds 6, 9, and 11 exhibited good fungicidal activities against 14 kinds of phytopathogens. Additionally, compounds 3 and 23 exhibited moderate insecticidal activity against the four tested species of insects.

  8. Natural product-based design, synthesis and biological evaluation of Albiziabioside A derivatives that selectively induce HCT116 cell death.

    PubMed

    Wei, Gaofei; Cui, Shanshan; Luan, Weijing; Wang, Shuai; Hou, Zhuang; Liu, Yongxiang; Liu, Yang; Cheng, Maosheng

    2016-05-04

    A series of Albiziabioside A coupled substituents of cinnamoyl derivatives were designed and synthesized. The synthesized compounds were screened for anticancer activity against a panel of six human cancer cell lines using a MTT assay. Synthetic derivatives showed excellent selectivity, as they were toxic against only HCT116 cell line. Some compounds exhibited better anti-cancer activity against HCT116 compared to positive controls, such as 5-fluorouracil and Albiziabioside A. Compound 8n was the most active derivative. Importantly, it was also found that the anti-proliferative activity of 8n could be attributed to the induction of cell cycle arrest and apoptosis in HCT116 cells.

  9. Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues.

    PubMed

    Sahu, Pramod K

    2016-10-04

    New fourteen 3,4-dihydropyrimidine derivatives/analogues of curcumin (2a-2n) were designed, synthesized and biologically evaluated for their cytotoxicity and antioxidant activity. Cytotoxicity effect has been evaluated against three cell lines HeLa, HCT-116 and QG-56 by MTT assay method. From SAR study, it has been revealed that particularly, compound 2e and 2j (IC50 value 12.5 μM) have shown better cytotoxicity effect against three cell lines. According to results of SAR study, it was found that 3,4-dihydropyrimidines of curcumin, 2c, 2d, 2j and 2n exhibited better antioxidant activity than curcumin. A correlation of structure and activities relationship of these compounds with respect to drug score profiles and other physico-chemical properties of drugs are described and verified experimentally. Therefore, we conclude that physico-chemical analyses may prove structural features of curcumin analogues with their promising combined cytotoxicity/antioxidant activity and it is also concluded from virtual and practical screening that the compounds were varied to possess a broad range of lipophilic character, revealed by Log P values.

  10. Docking, synthesis and antiproliferative activity of N-acylhydrazone derivatives designed as combretastatin A4 analogues.

    PubMed

    do Amaral, Daniel Nascimento; Cavalcanti, Bruno C; Bezerra, Daniel P; Ferreira, Paulo Michel P; Castro, Rosane de Paula; Sabino, José Ricardo; Machado, Camila Maria Longo; Chammas, Roger; Pessoa, Claudia; Sant'Anna, Carlos M R; Barreiro, Eliezer J; Lima, Lídia Moreira

    2014-01-01

    Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.

  11. Design and Synthesis of Coumarin Derivatives as Novel PI3K Inhibitors.

    PubMed

    Chen-Chen, Ma; Liu, Zhao-Peng

    2016-02-23

    A variety of coumarin derivatives possessing the pyridinylurea units were designed to increase their potency and isoform selectivity against PI3Ks. These novel coumarins 4a-m were prepared from 5-methyl-pyridin-2-ylamine in a straightforward way via the protection of the amino by Boc groups, benzyl bromination, ethyl acetoacetate alkylation with the generated bromomethyl pyridine, Pechmann coumarin core construction, and ureas formation by the coupling of amine 3 with a variety of aryl isocyanates. When the alkylated acetoacetate 2 was reacted with resorcinol in concentrated sulfuric acid, a cascade reaction occurred that included the Pechmann cyclization to form the coumarin core, removal of the N-Boc protective groups to generate a tert-butyl carbocation, and the Friedel-Crafts tert-butylation of the phenol ring. In general, these coumarin analogs exhibited good in vitro growth inhibitory activities against tumor K562, Hela, A549 and MCF-7 cells. Some of them showed comparable or better potency than BENC-511. Compounds 4b and 4h were found to be much more potent PI3K (~10-fold) inhibitors than S14161 or BENC-511. In addition, coumarin 4b was more selective to PI3Kα/β over PI3Kδ/γ, while analog 4h was a selective PI3Kα/β/δ inhibitor. Moreover, compound 4h suppressed the phosphorylation of Akt, increased the cleaved caspase 3 and PARP, and induced K562 cell apoptosis.

  12. Design, synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives.

    PubMed

    Fang, Lei; Gou, Shaohua; Liu, Xuying; Cao, Feng; Cheng, Lin

    2014-01-01

    Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC50 1.5-29.9μM) and galvinoxyl radicals (IC50 4.9-41.1μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH=7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (logP=3.48), suggesting a potential ability to penetrate the blood-brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7mg/mL) has also been significantly improved as compared with curcumin (<0.1mg/mL).

  13. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.

    PubMed

    Chen, Jia-Nian; Wang, Xian-Fu; Li, Ting; Wu, De-Wen; Fu, Xiao-Bo; Zhang, Guang-Ji; Shen, Xing-Can; Wang, Heng-Shan

    2016-01-01

    Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7 g, 7 m, 7 o, 8 e, 8 g, and 8 m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8 g exhibited the strongest activity. In particular, compound 8 g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8 g may be a potent antitumor agent, representing a promising lead for further optimization.

  14. Structure-based approaches for the design of benzimidazole-2-carbamate derivatives as tubulin polymerization inhibitors.

    PubMed

    Aguayo-Ortiz, Rodrigo; Cano-González, Lucia; Castillo, Rafael; Hernández-Campos, Alicia; Dominguez, Laura

    2016-12-22

    Microtubules are highly dynamic assemblies of α/β-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (βI) and class III (βIII) β-tubulin isotypes in breast and lung cancers and the highly expressed class VI (βVI) β-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the β-tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between β-tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole-2-carbamete (BzC) derivatives in the βI-, βIII-, and βVI-tubulin isotypes. Our results demonstrate that Ala198 in the βVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between βI- and βIII-BzC complexes were observed; however, Ser239 in the βIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the β-tubulin-BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.

  15. Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

    PubMed Central

    Huang, Jun; Chen, An-Liang; Zhang, Hui; Yu, Zhen; Li, Mei-Hong; Li, Na; Lin, Jia-Tan; Bai, Hua

    2015-01-01

    Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs. PMID:26025902

  16. Molecular design, synthesis and physical properties of novel Cytisine-derivatives - Experimental and theoretical study

    NASA Astrophysics Data System (ADS)

    Ivanova, Bojidarka; Spiteller, Michael

    2013-02-01

    The paper presented a comprehensive theoretical and experimental study on the molecular drugs-design, synthesis, isolation, physical spectroscopic and mass spectrometric elucidation of novel functionalization derivatives of Cytisine (Cyt), using nucleosidic residues. Since these alkaloids have established biochemical profile, related the binding affinity of the nicotinic acetylcholine receptors (nAChRs), particularly α7 sub-type, the presented correlation between the molecular structure and properties allowed to evaluated the highlights of the biochemical hypothesises related the Schizophrenia. The anticancer activity of α7 subtype agonists and the crucial role of the nucleoside-based medications in the cancer therapy provided opportunity for further study on the biochemical relationship between Schizophrenia and few kinds of cancers, which has been hypothesized recently. The physical electronic absorptions (EAs), circular dichroic (CD) and Raman spectroscopic (RS) properties as well as mass spectrometric (MS) data, obtained using electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) methods under the positive single (MS) and tandem (MS/MS) modes of operation are discussed. Taking into account reports on a fatal intoxication of Cyt, the presented data would be of interest in the field of forensic chemistry, through development of highly selective and sensitive analytical protocols. Quantum chemical method is used to predict the physical properties of the isolated alkaloids, their affinity to the receptor loop and gas-phase stabilized species, observed mass spectrometrically.

  17. Toxicokinetics and analytical toxicology of amphetamine-derived designer drugs ('Ecstasy').

    PubMed

    Maurer, H H; Bickeboeller-Friedrich, J; Kraemer, T; Peters, F T

    2000-03-15

    The phase I and II metabolites of the designer drugs methylenedioxyamphetamine (MDA), R,S-methylenedioxymethamphetamine (MDMA), R,S-methylenedioxyethylamphetamine (MDE), R, S-benzodioxazolylbutanamine (BDB) and R, S-N-methyl-benzodioxazolylbutanamine (MBDB) were identified by gas chromatography-mass spectrometry (GC-MS) or liquid chromotography-mass spectrometry (LC-MS) in urine and liver microsomes of humans and rats. Two overlapping pathways could be postulated: (1) demethylenation followed by catechol-O-methyl-transferase (COMT) catalyzed methylation and/or glucuronidation/sulfatation; (2) N-dealkylation, deamination and only for MDA, MDMA, MDE oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Demethylenation was mainly catalyzed by CYP2D1/6 or CYP3A2/4, but also by CYP independent mechanisms. In humans, MDMA and MBDB could also be demethylenated by CYP1A2. N-demethylation was mainly catalyzed by CYP1A2, N-deethylation by CYP3A2/4. Based on these studies, GC-MS procedures were developed for the toxicological analysis in urine and plasma. Finally, toxicokinetic parameters are reviewed.

  18. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria

    PubMed Central

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-01-01

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs. PMID:26198225

  19. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

    PubMed

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-07-07

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

  20. Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study

    NASA Astrophysics Data System (ADS)

    Kulkarni, Ravindra G.; Srivani, Palukuri; Achaiah, Garlapati; Sastry, G. Narahari

    2007-04-01

    The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r 2 ( q 2) value of 0.516 and conventional r 2 of 0.950, while the best CoMSIA model yielded a q 2 of 0.455 and r 2 of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein-inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.

  1. Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities.

    PubMed

    Huang, Jun; Chen, An-Liang; Zhang, Hui; Yu, Zhen; Li, Mei-Hong; Li, Na; Lin, Jia-Tan; Bai, Hua; Wang, Ji-Dong; Zheng, Yu-Guo

    2015-08-15

    Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs.

  2. Docking, Synthesis and Antiproliferative Activity of N-Acylhydrazone Derivatives Designed as Combretastatin A4 Analogues

    PubMed Central

    do Amaral, Daniel Nascimento; Cavalcanti, Bruno C.; Bezerra, Daniel P.; Ferreira, Paulo Michel P.; Castro, Rosane de Paula; Sabino, José Ricardo; Machado, Camila Maria Longo; Chammas, Roger; Pessoa, Claudia; Sant'Anna, Carlos M. R.; Barreiro, Eliezer J.; Lima, Lídia Moreira

    2014-01-01

    Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a–r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells. PMID:24614859

  3. Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors.

    PubMed

    Honda, Eiji; Ishichi, Yuji; Kimura, Eiji; Yoshikawa, Masato; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Terauchi, Jun

    2014-08-15

    A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.

  4. Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives.

    PubMed

    Jagu, Elodie; Djilali, Rachid; Pomel, Sébastien; Ramiandrasoa, Florence; Pethe, Stéphanie; Labruère, Raphaël; Loiseau, Philippe M; Blonski, Casimir

    2015-01-15

    A structure-activity relationship study on polyamine derivatives led to the synthesis and the determination of antikinetoplastid activity of 17 compounds. Among them, a spermidine derivative (compound 13) was specifically active in vitro against Leishmania donovani axenic amastigotes (IC50 at 5.4μM; Selectivity Index >18.5) and a spermine derivative (compound 28) specifically active against Trypanosoma brucei gambiense (IC50 at 1.9μM; Selectivity Index >52).

  5. Synthesis and characterization of Bombesin-superparamagnetic iron oxide nanoparticles as a targeted contrast agent for imaging of breast cancer using MRI

    NASA Astrophysics Data System (ADS)

    Jafari, Atefeh; Salouti, Mojtaba; Farjami Shayesteh, Saber; Heidari, Zahra; Bitarafan Rajabi, Ahmad; Boustani, Komail; Nahardani, Ali

    2015-02-01

    The targeted delivery of superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent may facilitate their accumulation in cancer cells and enhance the sensitivity of MR imaging. In this study, SPIONs coated with dextran (DSPIONs) were conjugated with bombesin (BBN) to produce a targeting contrast agent for detection of breast cancer using MRI. X-ray diffraction, transmission electron microscopy, and vibrating sample magnetometer analyses indicated the formation of dextran-coated superparamagnetic iron oxide nanoparticles with an average size of 6.0 ± 0.5 nm. Fourier transform infrared spectroscopy confirmed the conjugation of the BBN with the DSPIONs. A stability study proved the high optical stability of DSPION-BBN in human blood serum. DSPION-BBN biocompatibility was confirmed by cytotoxicity evaluation. A binding study showed the targeting ability of DSPION-BBN to bind to T47D breast cancer cells overexpressing gastrin-releasing peptide (GRP) receptors. T2-weighted and T2*-weighted color map MR images were acquired. The MRI study indicated that the DSPION-BBN possessed good diagnostic ability as a GRP-specific contrast agent, with appropriate signal reduction in T2*-weighted color map MR images in mice with breast tumors.

  6. Intravenous infusion of gastrin-releasing peptide-27 and bombesin in rats reveals differential effects on meal size and intermeal interval length.

    PubMed

    Washington, Martha C; Salyer, Sarah; Aglan, Amnah H; Sayegh, Ayman I

    2014-01-01

    We have previously shown that the intraperitoneal (i.p.) administration of gastrin-releasing peptide-27 (GRP-27) or bombesin (BN) (at 0.21, 0.41 and 1.03nmol/kg) reduces meal size (MS) and prolongs the intermeal interval (IMI). Here, we hypothesized that the intravenous (i.v.) administration of the same doses of GRP-27 and BN will be as effective as the i.p. administration in evoking these feeding responses. To test this hypothesis, we administered GRP-27 and BN i.v. and measured first MS (10% sucrose), IMI, satiety ratio (SR, IMI/MS) and second MS in overnight food-deprived but not water-deprived male Sprague Dawley rats. We found that (1) only GRP-27 reduced the first MS, (2) BN prolonged the IMI, (3) GRP-27 and BN increased the SR and (4) only BN reduced the size of the second meal. Contrary to our hypothesis, the i.v. administration of GRP-27 and BN affected the MS and IMI differently than did the i.p. administration. In conclusion, this pharmacological study suggests that the MS and IMI are regulated at different sites.

  7. Intravenous infusion of gastrin-releasing peptide-27 and bombesin in rats reveals differential effects on meal size and intermeal interval length

    PubMed Central

    Washington, Martha C.; Salyer, Sarah; Aglan, Amnah H.; Sayegh, Ayman I.

    2016-01-01

    We have previously shown that the intraperitoneal (i.p) administration of gastrin-releasing peptide-27 (GRP-27) or bombesin (BN) (at 0.21, 0.41 and 1.03 nmol/kg) reduces meal size (MS) and prolongs the intermeal interval (IMI). Here, we hypothesized that the intravenous (i.v) administration of the same doses of GRP-27 and BN will be as effective as the i.p administration in evoking these feeding responses. To test this hypothesis, we administered GRP-27 and BN i.v and measured first MS (10% sucrose), IMI, satiety ratio (SR, IMI/MS) and second MS in overnight food-deprived but not water-deprived male Sprague Dawley rats. We found that (1) only GRP-27 reduced the first MS, (2) BN prolonged the IMI, (3) GRP-27 and BN increased the SR and (4) only BN reduced the size of the second meal. Contrary to our hypothesis, the i.v administration of GRP-27 and BN affected the MS and IMI differently than did the i.p administration. In conclusion, this pharmacological study suggests that the MS and IMI are regulated at different sites. PMID:24291388

  8. Novel theoretically designed HIV-1 non-nucleoside reverse transcriptase inhibitors derived from nevirapine.

    PubMed

    Liu, Jinfeng; He, Xiao; Zhang, John Z H

    2014-10-01

    A common problem with non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 is the emergence of mutations in the HIV-1 RT, in particular Lys103 → Asn (K103N) and Tyr181 → Cys (Y181C), which lead to resistance to this entire class of inhibitors. In this study, we theoretically designed two new non-nucleoside HIV-1 RT inhibitors, Mnev-1 and Mnev-2, derived from nevirapine, in order to reduce the resistance caused by those HIV-1 RT mutations. The binding modes of Mnev-1 and Mnev-2 with the wild-type HIV-1 RT and its mutants (K103N and Y181C) were suggested by molecular docking followed by 20-ns molecular dynamics (MD) simulations in explicit water of those binding complexes (HIV-1 RTs with the new inhibitors). A molecular mechanics/generalized Born surface area (MM/GBSA) calculation was carried out for multiple snapshots extracted from the MD trajectory to estimate the binding free energy. The results of the calculations show that each of the new inhibitors forms a stable hydrogen bond with His235 during the MD simulations, leading to tighter binding of the new inhibitors with their targets. In addition, the repulsive interaction with Cys181 in the Y181C-nevirapine complex is not present in the novel inhibitors. The binding affinities predicted using the MM/GBSA calculations indicate that the new inhibitors could be effective at bypassing the drug resistance of these HIV-1 RT mutants.

  9. Designing Learning Strategy to Improve Undergraduate Students' Problem Solving in Derivatives and Integrals: A Conceptual Framework

    ERIC Educational Resources Information Center

    Hashemi, Nourooz; Abu, Mohd Salleh; Kashefi, Hamidreza; Mokhtar, Mahani; Rahimi, Khadijeh

    2015-01-01

    Derivatives and integrals are two important concepts of calculus which are precondition topics for most of mathematics courses and other courses in different fields of studies. A majority of students at the undergraduate level have to master derivatives and integrals if they want to be successful in their studies However, students encounter…

  10. Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors

    PubMed Central

    2015-01-01

    Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo. PMID:26396688

  11. Design, synthesis and antibacterial evaluation of novel pleuromutilin derivatives possessing piperazine linker.

    PubMed

    Gao, Mei-Ling; Zeng, Jie; Fang, Xi; Luo, Jian; Jin, Zhen; Liu, Ya-Hong; Tang, You-Zhi

    2017-02-15

    A series of pleuromutilin derivatives bearing piperazine ring have been reported. The in vitro antibacterial activities of the synthetic derivatives against MRSA (ATCC 43300), Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212), Enterococcus faecium (ATCC35667) and Escherichia coli (ATCC25922) were evaluated by the broth dilution method. Most of the synthesized derivatives displayed potent activities. Compounds 11c, 12a and 12c were found to be the most active antibacterial derivatives against MRSA (minimum inhibitory concentration = 0.015 μg/mL). The binding of compounds 11c, 12a and 12c to the 50s ribosome were investigated by molecular modeling. Compound 11c possessed lower binding free energy compared with compounds 12a and 12c. Compound 11c was further evaluated in MRSA systemic infection model and displayed superior in vivo efficacy to that of tiamulin.

  12. Design, synthesis, biological evaluation and binding mode modeling of benzimidazole derivatives targeting the cannabinoid receptor type 1.

    PubMed

    Espinosa-Bustos, Christian; Lagos, Carlos F; Romero-Parra, Javier; Zárate, Ana M; Mella-Raipán, Jaime; Pessoa-Mahana, Hernán; Recabarren-Gajardo, Gonzalo; Iturriaga-Vásquez, Patricio; Tapia, Ricardo A; Pessoa-Mahana, C David

    2015-02-01

    A series of N-acyl-2,5-dimethoxyphenyl-1H-benzimidazoles were designed based on a CoMFA model for cannabinoid receptor type 1 (CB1) ligands. Compounds were synthesized and radioligand binding affinity assays were performed. Eight novel benzimidazoles exhibited affinity for the CB1 receptor in the nanomolar range, and the most promising derivative compound 5 displayed a K(i) value of 1.2 nM when compared to CP55,940. These results confirm our previously reported QSAR model on benzimidazole derivatives, providing new information for the development of small molecules with high CB1 affinity.

  13. Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease.

    PubMed

    Konno, Hiroyuki; Wakabayashi, Masaki; Takanuma, Daiki; Saito, Yota; Akaji, Kenichi

    2016-03-15

    Synthesis of serine derivatives having the essential functional groups for the inhibitor of SARS 3CL protease and evaluation of their inhibitory activities using SARS 3CL R188I mutant protease are described. The lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and Bai's cinnamoly inhibitor, and additionally performed with simulation on GOLD softwear. Structure activity relationship studies of the candidate compounds were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant protease. These inhibitors showed protease selectivity and no cytotoxicity.

  14. Design of Fuzzy Functional Observer-Controller via Higher Order Derivatives of Lyapunov Function for Nonlinear Systems.

    PubMed

    Liu, Chuang; Lam, Hak-Keung; Fernando, Tyrone; Iu, Herbert Ho-Ching

    2016-05-02

    In this paper, we investigate the stability of Takagi-Sugeno fuzzy-model-based (FMB) functional observer-control system. When system states are not measurable for state-feedback control, a fuzzy functional observer is designed to directly estimate the control input instead of the system states. Although the fuzzy functional observer can reduce the order of the observer, it leads to a number of observer gains to be determined. Therefore, a new form of fuzzy functional observer is proposed to facilitate the stability analysis such that the observer gains can be numerically obtained and the stability can be guaranteed simultaneously. The proposed form is also in favor of applying separation principle to separately design the fuzzy controller and the fuzzy functional observer. To design the fuzzy controller with the consideration of system stability, higher order derivatives of Lyapunov function (HODLF) are employed to reduce the conservativeness of stability conditions. The HODLF generalizes the commonly used first-order derivative. By exploiting the properties of membership functions and the dynamics of the FMB control system, convex and relaxed stability conditions can be derived. Simulation examples are provided to show the relaxation of the proposed stability conditions and the feasibility of designed fuzzy functional observer-controller.

  15. Parallel calculation of sensitivity derivatives for aircraft design using automatic differentiation

    SciTech Connect

    Bischof, C.H.; Knauff, T.L. Jr.; Green, L.L.; Haigler, K.J.

    1994-01-01

    Realistic multidisciplinary design optimization (MDO) of advanced aircraft using state-of-the-art computers is an extremely challenging problem from both the physical modelling and computer science points of view. In order to produce an efficient aircraft design, many trade-offs must be made among the various physical design variables. Similarly, in order to produce an efficient design scheme, many trade-offs must be made among the various MDO implementation options. In this paper, we examine the effects of vectorization and coarse-grained parallelization on the SD calculation using a representative example taken from a transonic transport design problem.

  16. Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species.

    PubMed

    Vistoli, Giulio; Orioli, Marica; Pedretti, Alessandro; Regazzoni, Luca; Canevotti, Renato; Negrisoli, Gianpaolo; Carini, Marina; Aldini, Giancarlo

    2009-06-01

    Carnosine aryl derivatives as sequestering agents of RCS: Reactive carbonyl species (RCS) are cytotoxic mediators representing a novel drug target, as they are presumed to play a pathogenic role in several diseases. Carnosine is a selective RCS-sequestering agent, but is rapidly hydrolyzed by serum carnosinase. Herein we describe the in silico design, synthesis, and evaluation of a set of carnosine aryl derivatives.Reactive carbonyl species (RCS) are important cytotoxic mediators generated by lipid oxidation of polyunsaturated fatty acids (PUFAs) and represent a novel drug target, as they are presumed to play a pathogenic role in several diseases. L-Carnosine (L-CAR, beta-alanyl-L-histidine) is a specific detoxifying agent of RCS, but is rapidly hydrolyzed in human serum by carnosinase, a specific dipeptidase. Herein we describe the in silico design, synthesis, and biological evaluation of carnosine derivatives that are resistant to carnosinase and that have increased quenching efficacy. Stability against carnosinase-mediated turnover was achieved by isomerization of the histidine residue, leading to D-carnosine (D-CAR, beta-alanyl-D-histidine), which maintains the same quenching activity of L-carnosine. A molecular modeling approach was then used to design derivatives characterized by an increased quenching efficacy. The most promising candidates were synthesized, and their stability and quenching activity were evaluated. This study describes a set of aryl derivatives that are characterized by high stability in human plasma and a quenching activity toward 4-hydroxy-trans-2-nonenal (HNE), chosen as a model of RCS, up to threefold greater than D-carnosine.

  17. Design and synthesis of coumarin-3-acylamino derivatives to scavenge radicals and to protect DNA.

    PubMed

    Yang, Yang; Liu, Qing-Wen; Shi, Ye; Song, Zhi-Guang; Jin, Ying-Hua; Liu, Zai-Qun

    2014-09-12

    In this study, a series of coumarin-3-acylamino derivatives containing phenethylamine moiety or tyramine moiety were synthesized and their antioxidant activities were evaluated by Cu(2+)/glutathione(GSH)-, ˙OH- and 2,2'-azobis(2-amidinopropane hydrochloride)(AAPH)-induced oxidation of DNA. It was found that both hydroxyl and ortho-methoxy groups at A ring, hydroxyl group at B ring and peptide bond can enhance the abilities of coumarin-3-acylamino derivatives to protect DNA against ˙OH- and AAPH-induced oxidation. Moreover, these coumarin-3-acylamino derivatives were employed to scavenge 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+˙)). We found that tyramine moiety, hydroxyl and ortho-methoxy are the key groups to enhance the activities of antioxidants to quench ABTS(+˙). Therefore, tyramine linked with coumarin-3-carboxyl acid which containing hydroxyl and ortho-methoxy exhibited powerful antioxidant abilities.

  18. Approach for Input Uncertainty Propagation and Robust Design in CFD Using Sensitivity Derivatives

    NASA Technical Reports Server (NTRS)

    Putko, Michele M.; Taylor, Arthur C., III; Newman, Perry A.; Green, Lawrence L.

    2002-01-01

    An implementation of the approximate statistical moment method for uncertainty propagation and robust optimization for quasi 3-D Euler CFD code is presented. Given uncertainties in statistically independent, random, normally distributed input variables, first- and second-order statistical moment procedures are performed to approximate the uncertainty in the CFD output. Efficient calculation of both first- and second-order sensitivity derivatives is required. In order to assess the validity of the approximations, these moments are compared with statistical moments generated through Monte Carlo simulations. The uncertainties in the CFD input variables are also incorporated into a robust optimization procedure. For this optimization, statistical moments involving first-order sensitivity derivatives appear in the objective function and system constraints. Second-order sensitivity derivatives are used in a gradient-based search to successfully execute a robust optimization. The approximate methods used throughout the analyses are found to be valid when considering robustness about input parameter mean values.

  19. Derivative matrices of a skew ray for spherical boundary surfaces and their applications in system analysis and design.

    PubMed

    Lin, Psang Dain

    2014-05-10

    In a previous paper [Appl. Opt.52, 4151 (2013)], we presented the first- and second-order derivatives of a ray for a flat boundary surface to design prisms. In this paper, that scheme is extended to determine the Jacobian and Hessian matrices of a skew ray as it is reflected/refracted at a spherical boundary surface. The validity of the proposed approach as an analysis and design tool is demonstrated using an axis-symmetrical system for illustration purpose. It is found that these two matrices can provide the search direction used by existing gradient-based schemes to minimize the merit function during the optimization stage of the optical system design process. It is also possible to make the optical system designs more automatic, if the image defects can be extracted from the Jacobian and Hessian matrices of a skew ray.

  20. A satellite digital controller or 'play that PID tune again, Sam'. [Position, Integral, Derivative feedback control algorithm for design strategy

    NASA Technical Reports Server (NTRS)

    Seltzer, S. M.

    1976-01-01

    The problem discussed is to design a digital controller for a typical satellite. The controlled plant is considered to be a rigid body acting in a plane. The controller is assumed to be a digital computer which, when combined with the proposed control algorithm, can be represented as a sampled-data system. The objective is to present a design strategy and technique for selecting numerical values for the control gains (assuming position, integral, and derivative feedback) and the sample rate. The technique is based on the parameter plane method and requires that the system be amenable to z-transform analysis.

  1. Design, Synthesis and Biological Evaluation of Biphenylamide Derivatives as Hsp90 C-terminal Inhibitors

    PubMed Central

    Zhao, Huiping; Garg, Gaurav; Zhao, Jinbo; Moroni, Elisabetta; Girgis, Antwan; Franco, Lucas S.; Singh, Swapnil; Colombo, Giorgio; Blagg, Brian S. J.

    2015-01-01

    Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure-activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition. PMID:25462258

  2. Blockade of Rostral Ventrolateral Medulla (RVLM) Bombesin Receptor Type 1 Decreases Blood Pressure and Sympathetic Activity in Anesthetized Spontaneously Hypertensive Rats

    PubMed Central

    Pinto, Izabella S.; Mourão, Aline A.; da Silva, Elaine F.; Camargo, Amanda S.; Marques, Stefanne M.; Gomes, Karina P.; Fajemiroye, James O.; da Silva Reis, Angela A.; Rebelo, Ana C. S.; Ferreira-Neto, Marcos L.; Rosa, Daniel A.; Freiria-Oliveira, André H.; Castro, Carlos H.; Colombari, Eduardo; Colugnati, Diego B.; Pedrino, Gustavo R.

    2016-01-01

    Intrathecal injection of bombesin (BBS) promoted hypertensive and sympathoexcitatory effects in normotensive (NT) rats. However, the involvement of rostral ventrolateral medulla (RVLM) in these responses is still unclear. In the present study, we investigated: (1) the effects of BBS injected bilaterally into RVLM on cardiorespiratory and sympathetic activity in NT and spontaneously hypertensive rats (SHR); (2) the contribution of RVLM BBS type 1 receptors (BB1) to the maintenance of hypertension in SHR. Urethane-anesthetized rats (1.2 g · kg−1, i.v.) were instrumented to record mean arterial pressure (MAP), diaphragm (DIA) motor, and renal sympathetic nerve activity (RSNA). In NT rats and SHR, BBS (0.3 mM) nanoinjected into RVLM increased MAP (33.9 ± 6.6 and 37.1 ± 4.5 mmHg, respectively; p < 0.05) and RSNA (97.8 ± 12.9 and 84.5 ± 18.1%, respectively; p < 0.05). In SHR, BBS also increased DIA burst amplitude (115.3 ± 22.7%; p < 0.05). BB1 receptors antagonist (BIM-23127; 3 mM) reduced MAP (–19.9 ± 4.4 mmHg; p < 0.05) and RSNA (−17.7 ± 3.8%; p < 0.05) in SHR, but not in NT rats (−2.5 ± 2.8 mmHg; −2.7 ± 5.6%, respectively). These results show that BBS can evoke sympathoexcitatory and pressor responses by activating RVLM BB1 receptors. This pathway might be involved in the maintenance of high levels of arterial blood pressure in SHR. PMID:27313544

  3. Bombesin receptors and transplanted stem cells in rat brain: High-resolution scan with 99mTc BN1.1

    NASA Astrophysics Data System (ADS)

    Scopinaro, F.; Paschali, E.; Di Santo, G.; Antonellis, T.; Massari, R.; Trotta, C.; Gourni, H.; Bouziotis, P.; David, V.; Soluri, A.; Varvarigou, A. D.

    2006-12-01

    The aim of this work is to detect the presence of transplanted stem cells (TSC) in rat brain with high-resolution (HR) scintigraphy and labelled bombesin (BN). BN is a morphogen for Central Nervous System (CNS) as well as for other organs: CNS-oriented TSC over-express BN Receptors (BNR). BN is also a neurotransmitter and modulates several functions of CNS. 99mTc labelled BN-like peptide scan of CNS is the ideal method to detect growing TSC once knowing normal distribution of BNRs in CNS. HR Planar and single photon emission computerized tomography (SPECT) images of rat brain were performed with new HR detectors (Li-tech, Italy). Pertechnetate, 99mTc HMPAO and the new 99mTc BN1.1 (patented) were i.v. administered in five rats. HR SPECT of 99mTc BN1.1 detected olfactory tract, fronto-lateral cortex, cerebellum, basal ganglia and amygdale. Results of SPECT were confirmed by bio-distribution study performed after autopsy of three of the five rats. The remaining two rats underwent cerebral lesions followed by transplant of TSC. Three months later, HR scintigraphy was repeated and showed images completely different from previous basal study, with hot spot of 99mTc BN1.1 corresponding to the site of TSC transplant. Immuno-histochemistry confirmed the presence of viable TSC. Not only 99mTc BN1.1 HR scan showed viability of transplanted TSC but also the "background brain" was the still now unknown map of BNR in mammalian brain.

  4. Design and Synthesis of New Benzimidazole and Pyrimidine Derivatives as α-glucosidase Inhibitor.

    PubMed

    Mobinikhaledi, Akbar; Asghari, Behvar; Jabbarpour, Mahsa

    2015-01-01

    In an endeavor to find a novel series of antihyperglycemic agents, new benzimidazole and pyrimidine derivatives were successfully synthesized efficiently in high yield with high purity, starting from amino acids in the presence of phosphorus oxychloride (POCl3). The synthesized compounds were identified by (1)H-NMR, (13)C-NMR, FT-IR spectroscopic techniques and elemental analysis. All products were assayed for their inhibitory effects on yeast and rat intestinal α-glucosidases. The results revealed that compounds with aromatic amino acids moiety showed significant inhibition activity on the tested enzymes. Among the benzimidazole derivatives 4c and 4d exhibited the best activity against both of the tested enzymes. Also, among the pyrimidine derivatives 5c and 5d possessed significant inhibition action on the enzymes. The IC50 values for the most potent benzimidazole yeast and intestinal α-glucosidases inhibitor (4d) were found to be 9.1 and 36.7 µM, respectively. The IC50 values for the inhibition of yeast and intestinal α-glucosidases by the most active pyrimidine compound (5d) were calculated to be 8.3 and 21.8 µM, respectively. Overall, this study proved that benzimidazole and pyrimidine derivatives with aromatic amino acids moieties can represent novel promising α-glucosidase inhibitors.

  5. Design and Synthesis of New Benzimidazole and Pyrimidine Derivatives as α-glucosidase Inhibitor

    PubMed Central

    Mobinikhaledi, Akbar; Asghari, Behvar; Jabbarpour, Mahsa

    2015-01-01

    In an endeavor to find a novel series of antihyperglycemic agents, new benzimidazole and pyrimidine derivatives were successfully synthesized efficiently in high yield with high purity, starting from amino acids in the presence of phosphorus oxychloride (POCl3). The synthesized compounds were identified by 1H-NMR, 13C-NMR, FT-IR spectroscopic techniques and elemental analysis. All products were assayed for their inhibitory effects on yeast and rat intestinal α-glucosidases. The results revealed that compounds with aromatic amino acids moiety showed significant inhibition activity on the tested enzymes. Among the benzimidazole derivatives 4c and 4d exhibited the best activity against both of the tested enzymes. Also, among the pyrimidine derivatives 5c and 5d possessed significant inhibition action on the enzymes. The IC50 values for the most potent benzimidazole yeast and intestinal α-glucosidases inhibitor (4d) were found to be 9.1 and 36.7 µM, respectively. The IC50 values for the inhibition of yeast and intestinal α-glucosidases by the most active pyrimidine compound (5d) were calculated to be 8.3 and 21.8 µM, respectively. Overall, this study proved that benzimidazole and pyrimidine derivatives with aromatic amino acids moieties can represent novel promising α-glucosidase inhibitors. PMID:26330860

  6. Design and synthesis of new dihydrotestosterone derivative with positive inotropic activity.

    PubMed

    Lauro, Figueroa-Valverde; Francisco, Díaz-Cedillo; Elodia, García-Cervera; Eduardo, Pool-Gómez; Marcela, Rosas-Nexticapa; Lenin, Hau-Heredia; Betty, Sarabia Alcocer

    2015-03-01

    There are several reports which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action of steroid derivatives at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, two dihydrotestosterone derivatives (compounds 5 and 10) were synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. In the first stage, the Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the steroid derivatives. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the compound 5 was evaluated by measuring left ventricular pressure in absence or presence of following compounds; nifedipine, flutamide, indomethacin, prazosin, isoproterenol, propranolol and metoprolol. The results showed that the compound 5 significantly increased the perfusion pressure and coronary resistance in comparison with dihydrotestosterone, compound 10 and the control conditions. Other data indicate that 5 increase left ventricular pressure in a dose-dependent manner (0.001-100 nM); nevertheless, this phenomenon was significantly inhibited only by propranolol or metoprolol at a dose of 1 nM. These data suggest that positive inotropic activity induced by the compound 5 is through β1-adrenergic receptor however, this effect was independent of cAMP levels. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.

  7. Design, fabrication and test of the RL10 derivative II chamber/primary nozzle

    NASA Technical Reports Server (NTRS)

    Marable, R. W.

    1989-01-01

    The design, fabrication and test of the RL10-II chamber/primary nozzle was accomplished as part of the RL10 Product Improvement Program (PIP). The overall goal of the RL10 PIP was to gain the knowledge and experience necessary to develop new cryogenic upper stage engines to fulfill future NASA requirements. The goal would be reached by producing an RL10 engine designed to be reusable, operate at several thrust levels, and have increased performance. The goals for the chamber/primary nozzle task were: (1) to design a reusable assembly capable of operation at increased mixture ratio and low thrust; (2) to fabricate three assemblies using new or updated techniques where possible; and (3) to test one assembly to verify the design and construction. The design and fabrication phases produced an assembly having improved features such as single piece reinforcing band segments (i.e., Mae West segments) and relocated tube exit braze joints (i.e., hooked tube exit). In addition, a computer program was developed to design the chamber tubes to meet both performance and heat transfer requirements. The test phase showed the specific impulse of the test bed engine system to be as predicted. These results, along with the heat transfer data obtained, sufficiently proved the overall design of the RL10-II recontoured and shortened chamber/primary nozzle assembly.

  8. Design, synthesis and molecular modeling of aloe-emodin derivatives as potent xanthine oxidase inhibitors.

    PubMed

    Shi, Da-Hua; Huang, Wei; Li, Chao; Liu, Yu-Wei; Wang, Shi-Fan

    2014-03-21

    A series of aloe-emodin derivatives were synthesized and evaluated as xanthine oxidase inhibitors. Among them, four aloe-emodin derivatives showed significant inhibitory activities against xanthine oxidase. The compound 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carbaldehyde (A1) possessed the best xanthine oxidase inhibitory activity with IC50 of 2.79 μM. Lineweaver-Burk plot analysis revealed that A1 acted as a mixed-type inhibitor for xanthine oxidase. The docking study revealed that the molecule A1 had strong interactions with the active site of xanthine oxidase and this result was in agreement with kinetic study. Consequently, compound A1 is a new-type candidate for further development for the treatment of gout.

  9. Design, synthesis and cytotoxic activity of novel spin-labeled rotenone derivatives.

    PubMed

    Liu, Ying-Qian; Ohkoshi, Emika; Li, Lin-Hai; Yang, Liu; Lee, Kuo-Hsiung

    2012-01-15

    Three series of novel spin-labeled rotenone derivatives were synthesized and evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tumor cell lines tested, with IC(50) values ranging from 0.075 to 0.738μg/mL. Remarkably, all of the compounds were more potent than paclitaxel against KBvin in vitro, and compounds 3a and 3d displayed the highest cytotoxicity against this cell line (IC(50) 0.075 and 0.092μg/mL, respectively). Based on the observed cytotoxicity, structure-activity relationships have been described.

  10. Structure-Based Design of Molecules to Reactivate Tumor-Derived p53 Mutations

    DTIC Science & Technology

    2007-06-01

    peptide called FL-CDB3, (2)Use the Multiple Solvent Crystal Structures (MSCS) technique, to identify novel p53 stabilization sites, (3) Use the... peptides for the reactivation of tumor derived p53 mutants, and (4) Functionally characterize the p53-stabilizing and p53- reactivation properties of the...prepared by mixing the p53 core domain with the Fl-CDB3 peptide . Unfortunately, the structure did not reveal ordered electron density for the peptide

  11. D-ring modified novel isosteviol derivatives: design, synthesis and cytotoxic activity evaluation.

    PubMed

    Zhang, Tao; Lu, Li-Hui; Liu, Hao; Wang, Jun-Wei; Wang, Rui-Xue; Zhang, Yun-Xiao; Tao, Jing-Chao

    2012-09-15

    A series of polyhydric, amino alcohol and tricyclic derivatives were facilely synthesized by D-ring modification of isosteviol. These compounds were screened for their cytotoxic activities against four human tumor cell lines in vitro. Among them, the 15-α-aminomethyl-16-β-hydroxyl isosteviol 23 exhibits significant cytotoxicity superior to the positive control (cisplatin) against EC9706, PC-3 and HCT-116 cell lines.

  12. Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives.

    PubMed

    Wang, Rui; Shi, Hong-Fan; Zhao, Jing-Feng; He, Yan-Ping; Zhang, Hong-Bin; Liu, Jian-Ping

    2013-03-15

    A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aromatase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should be avoided in order to keep a relative small volume for this kind of molecules.

  13. Approach for Uncertainty Propagation and Robust Design in CFD Using Sensitivity Derivatives

    NASA Technical Reports Server (NTRS)

    Putko, Michele M.; Newman, Perry A.; Taylor, Arthur C., III; Green, Lawrence L.

    2001-01-01

    This paper presents an implementation of the approximate statistical moment method for uncertainty propagation and robust optimization for a quasi 1-D Euler CFD (computational fluid dynamics) code. Given uncertainties in statistically independent, random, normally distributed input variables, a first- and second-order statistical moment matching procedure is performed to approximate the uncertainty in the CFD output. Efficient calculation of both first- and second-order sensitivity derivatives is required. In order to assess the validity of the approximations, the moments are compared with statistical moments generated through Monte Carlo simulations. The uncertainties in the CFD input variables are also incorporated into a robust optimization procedure. For this optimization, statistical moments involving first-order sensitivity derivatives appear in the objective function and system constraints. Second-order sensitivity derivatives are used in a gradient-based search to successfully execute a robust optimization. The approximate methods used throughout the analyses are found to be valid when considering robustness about input parameter mean values.

  14. Design, synthesis, crystal structure, insecticidal activity, molecular docking, and QSAR studies of novel N3-substituted imidacloprid derivatives.

    PubMed

    Wang, Mei-Juan; Zhao, Xiao-Bo; Wu, Dan; Liu, Ying-Qian; Zhang, Yan; Nan, Xiang; Liu, Huanxiang; Yu, Hai-Tao; Hu, Guan-Fang; Yan, Li-Ting

    2014-06-18

    Three novel series of N3-substituted imidacloprid derivatives were designed and synthesized, and their structures were identified on the basis of satisfactory analytical and spectral ((1)H NMR, (13)C NMR, MS, elemental analysis, and X-ray) data. Preliminary bioassays indicated that all of the derivatives exhibited significant insecticidal activities against Aphis craccivora, with LC50 values ranging from 0.00895 to 0.49947 mmol/L, and the insecticidal activities of some of them were comparable to those of the control imidacloprid. Some key structural features related to their insecticidal activities were identified, and the binding modes between target compounds and nAChR model were also further explored by molecular docking. By comparing the interaction features of imidacloprid and compound 26 with highest insecticidal activity, the origin of the high insecticidal activity of compound 26 was identified. On the basis of the conformations generated by molecular docking, a satisfactory 2D-QSAR model with six selected descriptors was built using genetic algorithm-multiple linear regression (GA-MLR) method. The analysis of the built model showed the molecular size, shape, and the ability to form hydrogen bond were important for insecticidal potency. The information obtained in the study will be very helpful for the design of new derivatives with high insecticidal activities.

  15. Designing green derivatives of β-blocker Metoprolol: a tiered approach for green and sustainable pharmacy and chemistry.

    PubMed

    Rastogi, Tushar; Leder, Christoph; Kümmerer, Klaus

    2014-09-01

    The presences of micro-pollutants (active pharmaceutical ingredients, APIs) are increasingly seen as a challenge of the sustainable management of water resources worldwide due to ineffective effluent treatment and other measures for their input prevention. Therefore, novel approaches are needed like designing greener pharmaceuticals, i.e. better biodegradability in the environment. This study addresses a tiered approach of implementing green and sustainable chemistry principles for theoretically designing better biodegradable and pharmacologically improved pharmaceuticals. Photodegradation process coupled with LC-MS(n) analysis and in silico tools such as quantitative structure-activity relationships (QSAR) analysis and molecular docking proved to be a very significant approach for the preliminary stages of designing chemical structures that would fit into the "benign by design" concept in the direction of green and sustainable pharmacy. Metoprolol (MTL) was used as an example, which itself is not readily biodegradable under conditions found in sewage treatment and the aquatic environment. The study provides the theoretical design of new derivatives of MTL which might have the same or improved pharmacological activity and are more degradable in the environment than MTL. However, the in silico toxicity prediction by QSAR of those photo-TPs indicated few of them might be possibly mutagenic and require further testing. This novel approach of theoretically designing 'green' pharmaceuticals can be considered as a step forward towards the green and sustainable pharmacy field. However, more knowledge and further experience have to be collected on the full scope, opportunities and limitations of this approach.

  16. Design, synthesis, and characterization of a protein sequencing reagent yielding amino acid derivatives with enhanced detectability by mass spectrometry.

    PubMed Central

    Aebersold, R.; Bures, E. J.; Namchuk, M.; Goghari, M. H.; Shushan, B.; Covey, T. C.

    1992-01-01

    We report the design, chemical synthesis, and structural and functional characterization of a novel reagent for protein sequence analysis by the Edman degradation, yielding amino acid derivatives rapidly detectable at high sensitivity by ion-evaporation mass spectrometry. We demonstrate that the reagent 3-[4'(ethylene-N,N,N-trimethylamino)phenyl]-2-isothiocyanate is chemically stable and shows coupling and cyclization/cleavage yields comparable to phenylisothiocyanate, the standard reagent in chemical sequence analysis, under conditions typically encountered in manual or automated sequence analysis. Amino acid derivatives generated with this reagent were detectable by ion-evaporation mass spectrometry at the subfemtomole sensitivity level at a pace of one sample per minute. Furthermore, derivatives were identified by their mass, thus permitting the rapid and highly sensitive determination of the molecular nature of modified amino acids. Derivatives of amino acids with acidic, basic, polar, or hydrophobic side chains were reproducibly detectable at comparable sensitivities. The polar nature of the reagent required covalent immobilization of polypeptides prior to automated sequence analysis. This reagent, used in automated sequence analysis, has the potential for overcoming the limitations in sensitivity, speed, and the ability to characterize modified amino acid residues inherent in the chemical sequencing methods that are currently used. PMID:1304351

  17. Designing anthradithiophene derivatives suitable for applications in organic electronics and optoelectronics

    NASA Astrophysics Data System (ADS)

    Hallani, Rawad

    Anthradithiophene (ADT) derivatives have proven to be a front-runner in the world of small molecule semiconductors for organic electronics and optoelectronics. This is mainly due to the improved stability, easy tuning of chemical and physical properties, and impressive device performance that these molecules possess, especially in organic field effect transistors (OFET) and organic photovoltaics (OPV). The second chapter of this dissertation shows that reducing the amount of alkylsilylethynyl groups, used for functionalizing and solubilizing the ADT backbone, does alter the chemical, physical and crystallographic properties of ADTs. These changes offer the opportunity to study and observe different intermolecular interactions as well as monitoring their influence on sulfur scrambling in solid state. Additionally, from the early days ADTs and functionalized ADTs have been synthesized as isomeric mixtures. In chapter three, I demonstrate a new and simple method that can separate the syn and anti isomers of the F-TES-ADT and F-TEG-ADT chromatographically. The effects of isomeric purity on crystal packing and field effect transistor performance were studied extensively. Chapter four of this dissertation reveals a new generation of acceptor (electron poor) ADT derivatives obtained by attaching cyanide as electron withdrawing group (EWG) to the ADT chromophore. An extensive study was conducted on CN-ADT (acceptor) molecules in small molecule (F-TES-ADT) donor/ small molecule (CN-ADT) acceptor binary BHJ blends as well as P3HT/CN-ADT/PCBM ternary BHJ blends. Photophysical studies of the Donor/ acceptor blends (interface, domains, and crystal orientation) were conducted to obtain a better understanding of the film morphology and its effect on solar cell performance. Finally, the last part of the dissertation, Chapter five, focus on studying singlet fission in ADT derivatives, as well as the effect of varying the size of the alkylsilylethynyl functional group (used for

  18. Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators.

    PubMed

    Mao, Weiwei; Ning, Mengmeng; Liu, Zhiqing; Zhu, Qingzhang; Leng, Ying; Zhang, Ao

    2012-05-01

    A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC(50) values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.

  19. Design, Synthesis, and Biological Evaluation of 1,4-dihydropyridine Derivatives as Potent Antitubercular Agents.

    PubMed

    Desai, Nisheeth C; Trivedi, Amit R; Somani, Hardik C; Bhatt, Kandarp A

    2015-09-01

    A series of novel 1,4-dihydropyridine-3,5-dicarbamoyl derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, (1) H NMR, (13) C NMR, and mass spectroscopy. The synthesized compounds 3a-p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 μg/mL and SI > 500, making it more potent than first-line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity.

  20. Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors.

    PubMed

    Belluti, Federica; Piazzi, Lorna; Bisi, Alessandra; Gobbi, Silvia; Bartolini, Manuela; Cavalli, Andrea; Valenti, Piero; Rampa, Angela

    2009-03-01

    Starting from a structure-based drug design, new acetylcholinesterase inhibitors were designed and synthesized as analogues of donepezil. The compounds were composed by an aromatic function and a tertiary amino moiety connected by a suitable spacer. In particular, the benzophenone nucleus and the N,N-benzylmethylamine function were selected. The easily accessible three-step synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compounds 1 and 10 were the most potent inhibitors of the series.

  1. Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists.

    PubMed

    Koura, Minoru; Matsuda, Takayuki; Okuda, Ayumu; Watanabe, Yuichiro; Yamaguchi, Yuki; Kurobuchi, Sayaka; Matsumoto, Yuuki; Shibuya, Kimiyuki

    2015-07-01

    A novel series of 1,3-bistrifluoromethylcarbinol derivatives that act as liver X receptor (LXR) β-selective agonists was discovered. Structure-activity relationship studies led to the identification of molecule 62, which was more effective (Emax) and selective toward LXRβ than T0901317 and GW3965. Furthermore, 62 decreased LDL-C without elevating the plasma TG level and significantly suppressed the lipid-accumulation area in the aortic arch in a Bio F1B hamster fed a diet high in fat and cholesterol. We demonstrated that our LXRβ agonist would be potentially useful as a hypolipidemic and anti-atherosclerotic agent. In this manuscript, we report the design, synthesis and pharmacology of 1,3-bistrifluoromethylcarbinol derivatives.

  2. Design, synthesis, and evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors.

    PubMed

    Jeong, Yunkyung; Lee, Jooyeon; Ryu, Jae-Sang

    2016-05-01

    A series of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives were designed, synthesized, and evaluated for the Aurora kinase inhibitory activities. The novel hinge-binder tethered 1,2,3-triazolylsalicylamide scaffold was effectively assembled by Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). A variety of alkynes with hinge binders were used to search proper structures-binding relationship to the hinge region. The synthesized 1,2,3-triazolylsalicylamide derivatives showed significant Aurora kinase inhibitory activity. In particular, 8a inhibited Aurora A kinase with an IC50 value of 0.284 μM, whereas 8m inhibited Aurora B kinase with an IC50 value of 0.364 μM.

  3. FUNCTIONAL ANALYSIS OF A NOVEL POSITIVE ALLOSTERIC MODULATOR OF AMPA RECEPTORS DERIVED FROM A STRUCTURE-BASED DRUG DESIGN STRATEGY

    PubMed Central

    Harms, Jonathan E.; Benveniste, Morris; Maclean, John K. F.; Partin, Kathryn M.; Jamieson, Craig

    2012-01-01

    Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket. Here, we describe the electrophysiological properties of a new chemotype derived from a structure-based drug design strategy (SBDD), which makes similar receptor interactions compared to previously reported classes of modulator. This pyrazole amide derivative, JAMI1001A, with a promising developability profile, efficaciously modulates AMPA receptor deactivation and desensitization of both flip and flop receptor isoforms. PMID:22735771

  4. Design, synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors.

    PubMed

    Wang, Guangcheng; He, Dianxiong; Li, Xin; Li, Juan; Peng, Zhiyun

    2016-04-01

    A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by (1)H NMR, (13)C NMR and element analysis, evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC50 values in the range of 6.24±0.07-81.69±0.39μM, when compared to the standard acarbose (IC50=43.26±0.19μM). Structure-activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC50=6.24±0.07μM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a Ki of 6.86μM. Furthermore, the binding interactions of compound 7e with the active site of α-glucosidase were confirmed through molecular docking. This study has identified a new class of potent α-glucosidase inhibitors for further investigation.

  5. Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents.

    PubMed

    Mhiri, Chourouk; Boudriga, Sarra; Askri, Moheddine; Knorr, Michael; Sriram, Dharmarajan; Yogeeswari, Perumal; Nana, Frédéric; Golz, Christopher; Strohmann, Carsten

    2015-10-01

    With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.

  6. Enhanced textile dye decolorization by marine-derived basidiomycete Peniophora sp. CBMAI 1063 using integrated statistical design.

    PubMed

    Bonugli-Santos, Rafaella C; Vieira, Gabriela A L; Collins, Catherine; Fernandes, Thaís Cristina C; Marin-Morales, Maria Aparecida; Murray, Patrick; Sette, Lara D

    2016-05-01

    In the present study, the biotechnological potential of the marine-derived fungus Peniophora sp. CBMAI 1063 was investigated in relation to Reactive Black 5 (RB5) dye decolorization and degradation using an integrated statistical design composed of Plackett-Burman design (P&B), central composite design (CCD), and response surface methodology (RSM). RB5 dye was effectively decolorized (94 %) in saline conditions, without any detection of mutagenic compounds, and simultaneously, 57 % of total organic carbon (TOC) was removed in 7 days. The activity of lignin peroxidase (LiP) was not detected during the process. The gene expression of laccase (Lac) and manganese peroxidase (MnP) enzymes produced during the process was evaluated, and results from this experiment coupled with LC-MS analyses revealed that in the early stage of dye decolorization, a higher MnP gene expression and significant enzymatic activity was detected in Peniophora sp. CBMAI 1063 with the formation of p-Base and TAHNDS compounds. This paper reports innovative data related to the textile dye decolorization by the marine-derived basidiomycete Peniophora sp. CBMAI 1063, showing the metabolites formed and enzymatic action throughout the process in saline condition. The strategy used showed to be an efficient statistical approach that provides an attractive solution for the screening and simultaneous optimization of the degradation process.

  7. Deriving Function-failure Similarity Information for Failure-free Rotorcraft Component Design

    NASA Technical Reports Server (NTRS)

    Roberts, Rory A.; Stone, Robert B.; Tumer, Irem Y.; Clancy, Daniel (Technical Monitor)

    2002-01-01

    Performance and safety are the top concerns of high-risk aerospace applications at NASA. Eliminating or reducing performance and safety problems can be achieved with a thorough understanding of potential failure modes in the design that lead to these problems. The majority of techniques use prior knowledge and experience as well as Failure Modes and Effects as methods to determine potential failure modes of aircraft. The aircraft design needs to be passed through a general technique to ensure that every potential failure mode is considered, while avoiding spending time on improbable failure modes. In this work, this is accomplished by mapping failure modes to certain components, which are described by their functionality. In turn, the failure modes are then linked to the basic functions that are carried within the components of the aircraft. Using the technique proposed in this paper, designers can examine the basic functions, and select appropriate analyses to eliminate or design out the potential failure modes. This method was previously applied to a simple rotating machine test rig with basic functions that are common to a rotorcraft. In this paper, this technique is applied to the engine and power train of a rotorcraft, using failures and functions obtained from accident reports and engineering drawings.

  8. Deriving Empirically-Based Design Guidelines for Advanced Learning Technologies that Foster Disciplinary Comprehension

    ERIC Educational Resources Information Center

    Poitras, Eric; Trevors, Gregory

    2012-01-01

    Planning, conducting, and reporting leading-edge research requires professionals who are capable of highly skilled reading. This study reports the development of an empirically informed computer-based learning environment designed to foster the acquisition of reading comprehension strategies that mediate expertise in the social sciences. Empirical…

  9. Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors

    PubMed Central

    Kumbar, Mahadev N.; Kamble, Ravindra R.; Kamble, Atulkumar A.; Salian, Sujith Raj; Kumari, Sandhya; Nair, Ramya; Kalthur, Guruprasad; Adiga, Satish Kumar; Prasad, D. Jagadeesh

    2016-01-01

    Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE. PMID:26998358

  10. Discovery of oxazole and triazole derivatives as potent and selective S1P(1) agonists through pharmacophore-guided design.

    PubMed

    Tian, Yulin; Jin, Jing; Wang, Xiaojian; Hu, Jinping; Xiao, Qiong; Zhou, Wanqi; Chen, Xiaoguang; Yin, Dali

    2014-10-06

    We have discovered a series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives as potent and selective S1P1 agonists (prodrugs) based on pharmacophore-guided rational design. Most compounds showed high affinity and selectivity for S1P1 receptor. Compounds 19b, 19d and 19p displayed clear dose responsiveness in the lymphocyte reduction model when administered orally at doses of 0.3, 1.0, 3.0 mg/kg with reduced effect on heart rate. These three compounds were also identified to have favorable pharmacokinetic properties.

  11. Design, synthesis and biological evaluation of N-sulfonyl homoserine lactone derivatives as inhibitors of quorum sensing in Chromobacterium violaceum.

    PubMed

    Zhao, Mingming; Yu, Yingying; Hua, Yuhui; Feng, Fan; Tong, Yigang; Yang, Xiaohong; Xiao, Junhai; Song, Hongrui

    2013-03-13

    A novel series of N-sulfonyl homoserine lactone derivatives 5a-l has been designed, synthesized and evaluated for quorum sensing inhibitory activities towards violacein production. Of the compounds synthesized, compound 5h was found to possess an excellent level of enantiopurity (99.2% e.e.). The results indicated that compounds bearing an ortho substituent on their phenyl ring exhibited excellent levels of inhibitory activity against violacein production. Compounds 5h and 5k in particular, with IC₅₀ values of 1.64 and 1.66 µM, respectively, were identified as promising lead compounds for further structural modification.

  12. Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents

    PubMed Central

    Kar, Sidhartha S; Bhat G, Varadaraj; Rao, Praveen PN; Shenoy, Vishnu P; Bairy, Indira; Shenoy, G Gautham

    2016-01-01

    A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs. PMID:27486307

  13. Design, Synthesis and Evaluation of Naphthalimide Derivatives as Potential Anticancer Agents for Hepatocellular Carcinoma.

    PubMed

    Ge, Chaochao; Chang, Liping; Zhao, Ying; Chang, Congcong; Xu, Xiaojuan; He, Haoying; Wang, Yuxia; Dai, Fujun; Xie, Songqiang; Wang, Chaojie

    2017-02-22

    Two kinds of naphthalimide derivatives were synthesized and evaluated for in vitro their anti-hepatocellular carcinoma properties. Compound 3a with a fused thiazole fragment to naphthalimide skeleton inhibited cell migration of SMMC-7721 and HepG2, and further in vivo trials with two animal models confirmed that compound 3a moderately inhibited primary H22 tumor growth (52.6%) and potently interrupted lung metastasis (75.7%) without obvious systemic toxicity at the therapeutic dose. Mechanistic research revealed that compound 3a inhibited cancerous liver cell growth mostly by inducing G2/M phase arrest. Western blotting experiments corroborated that 3a could up-regulate the cell cycle related protein expression of cyclin B1, CDK1 and p21, and inhibit cell migration by elevating the E-cadherin and attenuating integrin α6 expression. Our study showed that compound 3a is a valuable lead compound worthy of further investigation.

  14. Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors.

    PubMed

    Garella, Davide; Atlante, Sandra; Borretto, Emily; Cocco, Mattia; Giorgis, Marta; Costale, Annalisa; Stevanato, Livio; Miglio, Gianluca; Cencioni, Chiara; Fernández-de Gortari, Eli; Medina-Franco, José L; Spallotta, Francesco; Gaetano, Carlo; Bertinaria, Massimo

    2016-11-01

    The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure-activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.

  15. Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: design, synthesis and biological evaluation.

    PubMed

    Wang, Chen; Gao, Hongping; Dong, Jinyun; Zhang, Yanmin; Su, Ping; Shi, Yaling; Zhang, Jie

    2014-01-01

    A series of novel biphenyl urea derivates were synthesized and investigated for their potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2). In particular, A7, B3 and B4 displayed significant enzymatic inhibitory activities, with IC₅₀ values of 4.06, 4.55 and 5.26 nM. Compound A7 exhibited potent antiproliferative activity on several cell lines. SAR study suggested that the introduction of methyl at ortho-position of the biphenyl urea and tertiary amine moiety could improve VEGFR-2 inhibitory activity and antitumor effects. Molecular docking indicated that the urea moiety formed four hydrogen bonds with DFG residue. These biphenyl ureas could serve as promising lead compounds for further optimization.

  16. Design and synthesis of novel spin-labeled camptothecin derivatives as potent cytotoxic agents.

    PubMed

    Zhao, Xiao-Bo; Wu, Dan; Wang, Mei-Juan; Goto, Masuo; Morris-Natschke, Susan L; Liu, Ying-Qian; Wu, Xiao-Bing; Song, Zi-Long; Zhu, Gao-Xiang; Lee, Kuo-Hsiung

    2014-11-15

    In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d-9k, 9m-9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC50 0.057 and 0.072μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.

  17. TECHNICAL DESIGN NOTE: Digital proportional-integral-derivative velocity controller of a Mössbauer spectrometer

    NASA Astrophysics Data System (ADS)

    Pechousek, J.; Prochazka, R.; Mashlan, M.; Jancik, D.; Frydrych, J.

    2009-01-01

    The digital proportional-integral-derivative (PID) velocity controller used in the Mössbauer spectrometer implemented in field programmable gate array (FPGA) is based on the National Instruments CompactRIO embedded system and LabVIEW graphical programming tools. The system works as a remote system accessible via the Ethernet. The digital controller operates in real-time conditions, and the maximum sampling frequency is approximately 227 kS s-1. The system was tested with standard sample measurements of α-Fe and α-57Fe2O3 on two different electromechanical velocity transducers. The nonlinearities of the velocity scales in the relative form are better than 0.2%. The replacement of the standard analog PID controller by the new system brings the possibility of optimizing the control process more precisely.

  18. Convoluted nozzle design for the RL10 derivative 2B engine

    NASA Technical Reports Server (NTRS)

    1985-01-01

    The convoluted nozzle is a conventional refractory metal nozzle extension that is formed with a portion of the nozzle convoluted to show the extendible nozzle within the length of the rocket engine. The convoluted nozzle (CN) was deployed by a system of four gas driven actuators. For spacecraft applications the optimum CN may be self-deployed by internal pressure retained, during deployment, by a jettisonable exit closure. The convoluted nozzle is included in a study of extendible nozzles for the RL10 Engine Derivative 2B for use in an early orbit transfer vehicle (OTV). Four extendible nozzle configurations for the RL10-2B engine were evaluated. Three configurations of the two position nozzle were studied including a hydrogen dump cooled metal nozzle and radiation cooled nozzles of refractory metal and carbon/carbon composite construction respectively.

  19. Design, Synthesis, and Evaluation of Biotinylated Opioid Derivatives as Novel Probes to Study Opioid Pharmacology

    PubMed Central

    Li, Ya; Chase, Anna R.; Slivka, Peter F.; Baggett, Clyde T.; Zhao, Tina X.; Yin, Hang

    2009-01-01

    A generally applicable strategy of chemically labeling (−)-morphine (1) is described. The synthesis starts from commercially available starting materials and can be completed in two steps with an overall yield of 23 %. In silico simulation and NMR results show that the binding of (−)-morphine to one of its molecular targets, toll-like receptor 4 (TLR4), was not affected by the modification. Secreted Embryonic Alkaline Phosphatase (SEAP) reporter assay results demonstrate that C3 biotinylated and unmodified (−)-morphine show similar biological activities in live cells. To our knowledge, these studies provide the first practical and concise method to label various opioid derivatives, a group of important therapeutics in pain management, for biochemical/pharmacological studies. PMID:19090701

  20. Design, Synthesis, and Potential Antidepressant-like Activity of 7-prenyloxy-2,3-dihydroflavanone Derivatives.

    PubMed

    Zhen, Xing-Hua; Quan, Ying-Chun; Peng, Zhou; Han, Yan; Zheng, Zhou-Jun; Guan, Li-Ping

    2016-06-01

    A series of 7-prenyloxy-2, 3-dihydroflavanone derivatives were synthesized and screened for their antidepressant-like activity. Among them, it was observed that compounds 5j and 5k were found to be the most antidepressant-like activity. In addition, it was found that compounds 5j and 5k significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus, and cortex. Compounds 5j and 5k also significantly increased the contents of 5-HIAA in the hippocampus and cortex, shut down 5-HT metabolism compared with mice treated with stress vehicle. These results suggested that compounds 5j and 5k displayed potent antidepressant-like properties that were mediated via neurochemical systems.

  1. Design, synthesis, and biological properties of triazole derived compounds and their transition metal complexes.

    PubMed

    Chohan, Zahid H; Hanif, Muhammad

    2010-10-01

    Triazole derived Schiff bases and their metal complexes (cobalt(II), copper(II), nickel(II), and zinc(II)) have been prepared and characterized using IR, (1)H and (13)C NMR, mass spectrometry, magnetic susceptibility and conductivity measurements, and CHN analysis data. The structure of L(2), N-[(5-methylthiophen-2-yl)methylidene]-1H-1,2,4-triazol-3-amine, has also been determined by the X-ray diffraction method. All the metal(II) complexes showed octahedral geometry except the copper(II) complexes, which showed distorted octahedral geometry. The triazole ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic activity. All the synthesized compounds showed moderate to significant antibacterial activity against one or more bacterial strains. It is revealed that all the synthesized complexes showed better activity than the ligands, due to coordination.

  2. Design, synthesis and in vitro trypanocidal and leishmanicidal activities of novel semicarbazone derivatives.

    PubMed

    Alves, Marina A; de Queiroz, Aline C; Alexandre-Moreira, Magna Suzana; Varela, Javier; Cerecetto, Hugo; González, Mercedes; Doriguetto, Antonio C; Landre, Iara M; Barreiro, Eliezer J; Lima, Lídia M

    2015-07-15

    Trypanosomatids are protozoan parasites that cause various diseases in human, such as leishmaniasis, Chagas disease and sleeping sickness. The highly syntenic genomes of the trypanosomatid species lead the assumption that they can encode similar proteins, indicating the possibility to design new antitrypanosomatid drugs with dual trypanosomicidal and leishmanicidal activities. In this work a series of compounds (6a-h and 7a-h), containing a semicarbazone scaffold as a peptide mimetic framework, was designed and synthesized. From this series compound 7g (LASSBio-1483) highlighted, showing dual in vitro trypanosomicidal and leishmanicidal activities, with potency similar to the standard drugs nifurtimox and pentamidine. This data, taken together with its good in silico druglikeness profile and its great chemical and plasma stability, make LASSBio-1483 (7g) a new antitrypanosomatid lead-candidate.

  3. Design, Synthesis and Bioactivities of Novel Dichloro-Allyloxy-Phenol-Containing Pyrazole Oxime Derivatives.

    PubMed

    Dai, Hong; Ye, Linyu; Zhuang, Huiyang; Dai, Baojiang; Fang, Yuan; Shi, Yujun

    2015-12-08

    In this study, in order to find novel biologically active pyrazole oxime compounds, a number of dichloro-allyloxy-phenol-containing pyrazole oximes were designed and synthesized according to the method of active group combination. All of the target compounds were confirmed by ¹H-NMR, (13)C-NMR and elemental analysis. In addition, bioassays showed that all of the newly synthesized compounds had no acaricidal activity against Tetranychus cinnabarinus and low insecticidal activity against Aphis craccivora at tested concentrations. However, most of them displayed excellent insecticidal activity against Oriental armyworm at a concentration of 500 μg/mL, and some designed compounds still exhibited potent insecticidal activity against Oriental armyworm even at the dose of 20 μg/mL, especially compounds 7f, 7n and 7p had 100%, 90% and 90% inhibition rates, respectively, which were comparable to that of the control pyridalyl.

  4. New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers.

    PubMed

    Mrózek, Lech; Coufalová, Lenka; Rárová, Lucie; Plaček, Lukáš; Opatřilová, Radka; Dohnal, Jiří; Kráľová, Katarína; Paleta, Oldřich; Král, Vladimír; Drašar, Pavel; Jampílek, Josef

    2013-09-01

    A series of final six propanoyloxy derivatives of 5β-cholan-24-oic acid (tridecafluoroctylsulfanyl- and tridecafluoroctylsulfinylethoxycarbonylpropanoyloxy derivatives) as potential drug absorption promoters (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (logS), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukaemia cell line and breast adenocarcinoma cell line. One compound showed high selective cytotoxicity against human skin fibroblast cells and another compound possessed high cytotoxicity against breast adenocarcinoma cell line and skin fibroblast cells. Only one compound expressed anti-proliferative effect on leukaemia and breast adenocarcinoma cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and penetration enhancement effect are discussed in this article.

  5. Molecular modeling and statistical analysis in the design of derivatives of human dipeptidyl peptidase IV.

    PubMed

    Pereira, Alison L E; Dos Santos, Gabriela B; Franco, Márcia S F; Federico, Leonardo B; da Silva, Carlos H T P; Santos, Cleydson B R

    2017-01-24

    Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.

  6. High-resolution scintigraphy and 99mTc Bombesin are able to guide Mammotome biopsy and to detect lymph node invasion

    NASA Astrophysics Data System (ADS)

    Di Santo, G.; Archimandritis, S.; Soluri, A.; Trotta, C.; Massari, R.; Parisella, M. G.; Anastasia, A.; Mattei, M.; Monteleone, F.; Chiacchiararelli, L.; Varvarigou, A.; Scopinaro, F.

    2006-12-01

    High-resolution (HR) γ-ray detector 99mTc Bombesin ( 99mTcBN) and 99mTc sestamibi ( 99mTcSM), have been used to drive Mammotome biopsy after fusion of scintigraphic with digital X-ray images. We studied eight patients with class V microcalcifications. An HR detector with spatial resolution of 3 mm was matched with Mammotome biopsy system provided with Fisher digital X-ray device: images were fused to use the pointer indifferently on X-ray, scintigraphic and fused images. Fusion between X-ray and HR image has previously been reported. The 12 Mammotome samples/patient were weighted and counted in a well counter. Tumour/bkg (T/B) ratio was measured on HR images as well as on biopsy samples. Axilla was also explored with the portable HR device in order to diagnose node invasion. Conventional histology assessment and immunohystochemical study with anti BN receptor antibody was blindly performed on samples. All the patients studied with 99mTcSM showed T1b cancer, 99mTcBN detected one T1a and two T1b cancers. HR scan of axilla detected node metastases in two patients, both studied with 99mTcBN. All the biopsies showed cancer on at least one of the 12 samples. Histology found node metastases in three patients: the two 99mTcBN positive and one studied with 99mTcSM whose axilla was negative at HR scan. Samples showed T/B ratio of 6.6±0.4 for 99mTcSM and 11.3±0.9 for 99mTcBN ( p<0.01). Note that also the patient with T1a cancer, showing 10.4 T/B ratio was included in the 99mTcBN series. Not only 99mTcBN HR is able to show breast cancer and to guide biopsy, but also detects node metastases. Our is the first ex vivo measurement of T/B ratio of 99mTcBN on humans.

  7. Design, synthesis, and antifungal activities of novel triazole derivatives containing the benzyl group

    PubMed Central

    Xu, Kehan; Huang, Lei; Xu, Zheng; Wang, Yanwei; Bai, Guojing; Wu, Qiuye; Wang, Xiaoyan; Yu, Shichong; Jiang, Yuanying

    2015-01-01

    In previous studies undertaken by our group, a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a–r), which were analogs of fluconazole, was designed and synthesized by click chemistry. In the study reported here, the in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compounds 1a, 1q, and 1r showed the more antifungal activity than the others. PMID:25792806

  8. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity.

    PubMed

    Koufaki, Maria; Kiziridi, Christina; Nikoloudaki, Faidra; Alexis, Michael N

    2007-08-01

    We designed and synthesized new analogues containing 1,2-dithiolane-3-alkyl and protected or free catechol moieties connected through heteroaromatic rings such as triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, tetrazole or thiazole in order to explore the influence of the bioisosteric replacement of the amide group on the neuroprotective activity of the lipoic acid/dopamine conjugate. Evaluation of the activity of the new compounds, using glutamate-challenged hippocampal HT22 cells, showed that incorporation of heteroaromatic rings in the alkyl-1,2-dithiolane moieties in conjunction with another antioxidant, in this case catechol, may result in strong neuroprotective activity.

  9. Application of "hydrogen bonding interaction" in new drug development: design, synthesis, antiviral activity, and SARs of thiourea derivatives.

    PubMed

    Lu, Aidang; Wang, Ziwen; Zhou, Zhenghong; Chen, Jianxin; Wang, Qingmin

    2015-02-11

    A series of simple thiourea derivatives were designed based on the structure of natural product harmine and lead compound and synthesized from amines in one step. The antiviral activity of these thiourea derivatives was evaluated. Most of them exhibited significantly higher anti-TMV activity than commercial plant virucides ribavirin, harmine, and lead compound. The hydrogen bond was found to be important but not the more the better. The optimal compound (R,R)-20 showed the best anti-TMV activity in vitro and in vivo (in vitro activity, 75%/500 μg/mL and 39%/100 μg/mL; inactivation activity, 71%/500 μg/mL and 35%/100 μg/mL; curative activity, 73%/500 μg/mL and 37%/100 μg/mL; protection activity, 69%/500 μg/mL and 33%/100 μg/mL), which is significantly higher than that of Ningnanmycin. The systematic study provides strong evidence that these simple thiourea derivatives could become potential TMV inhibitors.

  10. Design, synthesis, α-glucosidase inhibitory activity, molecular docking and QSAR studies of benzimidazole derivatives

    NASA Astrophysics Data System (ADS)

    Dinparast, Leila; Valizadeh, Hassan; Bahadori, Mir Babak; Soltani, Somaieh; Asghari, Behvar; Rashidi, Mohammad-Reza

    2016-06-01

    In this study the green, one-pot, solvent-free and selective synthesis of benzimidazole derivatives is reported. The reactions were catalyzed by ZnO/MgO containing ZnO nanoparticles as a highly effective, non-toxic and environmentally friendly catalyst. The structure of synthesized benzimidazoles was characterized using spectroscopic technics (FT-IR, 1HNMR, 13CNMR). Synthesized compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 3c, 3e, 3l and 4n were potent inhibitors with IC50 values ranging from 60.7 to 168.4 μM. In silico studies were performed to explore the binding modes and interactions between enzyme and synthesized benzimidazoles. Developed linear QSAR model based on density and molecular weight could predict bioactivity of newly synthesized compounds well. Molecular docking studies revealed the availability of some hydrophobic interactions. In addition, the bioactivity of most potent compounds had good correlation with estimated free energy of binding (ΔGbinding) which was calculated according to docked best conformations.

  11. Controlled manipulation of the Co-Alq3 interface by rational design of Alq3 derivatives.

    PubMed

    Großmann, Nicolas; Magri, Andrea; Laux, Martin; Stadtmüller, Benjamin; Thielen, Philip; Schäfer, Bernhard; Fuhr, Olaf; Ruben, Mario; Cinchetti, Mirko; Aeschlimann, Martin

    2016-11-15

    Recently, research has revealed that molecules can be used to steer the local spin properties of ferromagnetic surfaces. One possibility to manipulate ferromagnetic-metal-molecule interfaces in a controlled way is to synthesize specific, non-magnetic molecules to obtain a desired interaction with the ferromagnetic substrate. Here, we have synthesized derivatives of the well-known semiconductor Alq3 (with q = 8-hydroxyquinolinate), in which the 8-hydroxyquinolinate ligands are partially or completely replaced by similar ligands bearing O- or N-donor sets. The goal of this study was to investigate how the presence of (i) different donor atom sets and (ii) aromaticity in different conjugated π-systems influences the spin properties of the metal-molecule interface formed with a Co(100) surface. The spin-dependent metal-molecule-interface properties have been measured by spin-resolved photoemission spectroscopy, backed up by DFT calculations. Overall, our results show that, in the case of the Co-molecule interface, chemical synthesis of organic ligands leads to specific electronic properties of the interface, such as exciton formation or highly spin-polarized interface states. We find that these properties are even additive, i.e. they can be engineered into one single molecular system that incorporates all the relevant ligands.

  12. Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist.

    PubMed

    Hwang, Tsong-Long; Hung, Chih-Hao; Hsu, Ching-Yun; Huang, Yin-Ting; Tsai, Yu-Chi; Hsieh, Pei-Wen

    2013-06-14

    Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2˙(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 μM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp-Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein.

  13. Design, Synthesis, Molecular Docking, and Antibacterial Evaluation of Some Novel Flouroquinolone Derivatives as Potent Antibacterial Agent

    PubMed Central

    Patel, Mehul M.; Patel, Laxman J.

    2014-01-01

    Objective. Quinolone moiety is an important class of nitrogen containing heterocycles widely used as key building blocks for medicinal agents. It exhibits a wide spectrum of pharmacophores and has bactericidal, antiviral, antimalarial, and anticancer activities. In view of the reported antimicrobial activity of various fluoroquinolones, the importance of the C-7 substituents is that they exhibit potent antimicrobial activities. Our objective was to synthesize newer quinolone analogues with increasing bulk at C-7 position of the main 6-fluoroquinolone scaffold to produce the target compounds which have potent antimicrobial activity. Methods. A novel series of 1-ethyl-6-fluoro-4-oxo-7-{4-[2-(4-substituted phenyl)-2-(substituted)-ethyl]-1-piperazinyl}-1,4-dihydroquinoline-3-carboxylic acid derivatives were synthesized. To understand the interaction of binding sites with bacterial protein receptor, the docking study was performed using topoisomerase II DNA gyrase enzymes (PDB ID: 2XCT) by Schrodinger's Maestro program. In vitro antibacterial activity of the synthesized compounds was studied and the MIC value was calculated by the broth dilution method. Results. Among all the synthesized compounds, some compounds showed potent antimicrobial activity. The compound 8g exhibited good antibacterial activity. Conclusion. This investigation identified the potent antibacterial agents against certain infections. PMID:25574496

  14. A simple and versatile design concept for fluorophore derivatives with intramolecular photostabilization

    NASA Astrophysics Data System (ADS)

    van der Velde, Jasper H. M.; Oelerich, Jens; Huang, Jingyi; Smit, Jochem H.; Aminian Jazi, Atieh; Galiani, Silvia; Kolmakov, Kirill; Guoridis, Giorgos; Eggeling, Christian; Herrmann, Andreas; Roelfes, Gerard; Cordes, Thorben

    2016-01-01

    Intramolecular photostabilization via triple-state quenching was recently revived as a tool to impart synthetic organic fluorophores with `self-healing' properties. To date, utilization of such fluorophore derivatives is rare due to their elaborate multi-step synthesis. Here we present a general strategy to covalently link a synthetic organic fluorophore simultaneously to a photostabilizer and biomolecular target via unnatural amino acids. The modular approach uses commercially available starting materials and simple chemical transformations. The resulting photostabilizer-dye conjugates are based on rhodamines, carbopyronines and cyanines with excellent photophysical properties, that is, high photostability and minimal signal fluctuations. Their versatile use is demonstrated by single-step labelling of DNA, antibodies and proteins, as well as applications in single-molecule and super-resolution fluorescence microscopy. We are convinced that the presented scaffolding strategy and the improved characteristics of the conjugates in applications will trigger the broader use of intramolecular photostabilization and help to emerge this approach as a new gold standard.

  15. A simple and versatile design concept for fluorophore derivatives with intramolecular photostabilization

    PubMed Central

    van der Velde, Jasper H. M.; Oelerich, Jens; Huang, Jingyi; Smit, Jochem H.; Aminian Jazi, Atieh; Galiani, Silvia; Kolmakov, Kirill; Guoridis, Giorgos; Eggeling, Christian; Herrmann, Andreas; Roelfes, Gerard; Cordes, Thorben

    2016-01-01

    Intramolecular photostabilization via triple-state quenching was recently revived as a tool to impart synthetic organic fluorophores with ‘self-healing' properties. To date, utilization of such fluorophore derivatives is rare due to their elaborate multi-step synthesis. Here we present a general strategy to covalently link a synthetic organic fluorophore simultaneously to a photostabilizer and biomolecular target via unnatural amino acids. The modular approach uses commercially available starting materials and simple chemical transformations. The resulting photostabilizer–dye conjugates are based on rhodamines, carbopyronines and cyanines with excellent photophysical properties, that is, high photostability and minimal signal fluctuations. Their versatile use is demonstrated by single-step labelling of DNA, antibodies and proteins, as well as applications in single-molecule and super-resolution fluorescence microscopy. We are convinced that the presented scaffolding strategy and the improved characteristics of the conjugates in applications will trigger the broader use of intramolecular photostabilization and help to emerge this approach as a new gold standard. PMID:26751640

  16. A simple and versatile design concept for fluorophore derivatives with intramolecular photostabilization.

    PubMed

    van der Velde, Jasper H M; Oelerich, Jens; Huang, Jingyi; Smit, Jochem H; Aminian Jazi, Atieh; Galiani, Silvia; Kolmakov, Kirill; Guoridis, Giorgos; Eggeling, Christian; Herrmann, Andreas; Roelfes, Gerard; Cordes, Thorben

    2016-01-11

    Intramolecular photostabilization via triple-state quenching was recently revived as a tool to impart synthetic organic fluorophores with 'self-healing' properties. To date, utilization of such fluorophore derivatives is rare due to their elaborate multi-step synthesis. Here we present a general strategy to covalently link a synthetic organic fluorophore simultaneously to a photostabilizer and biomolecular target via unnatural amino acids. The modular approach uses commercially available starting materials and simple chemical transformations. The resulting photostabilizer-dye conjugates are based on rhodamines, carbopyronines and cyanines with excellent photophysical properties, that is, high photostability and minimal signal fluctuations. Their versatile use is demonstrated by single-step labelling of DNA, antibodies and proteins, as well as applications in single-molecule and super-resolution fluorescence microscopy. We are convinced that the presented scaffolding strategy and the improved characteristics of the conjugates in applications will trigger the broader use of intramolecular photostabilization and help to emerge this approach as a new gold standard.

  17. Design, synthesis, structural elucidation, pharmacological evaluation of metal complexes with pyrazoline derivatives.

    PubMed

    Muneera, M Sirajul; Joseph, J

    2016-10-01

    A bioactive pyrazoline derivatives have been synthesized by the base-catalyzed Claisen-Schmidt condensation of imidazole-2-carboxaldehyde with 1-acetyl-2-hydroxynaphthalene followed by cyclization with phenylhydrazine (L(1))/2,3-dimethylphenylhydrazine (L(2)) and 3-nitrophenylhydrazine (L(3)). The metal(II) complexes [Ni(II), Co(II), Cu(II) and Zn(II)] were formed by reacting the corresponding metal acetates with the ligands. All complexes were characterized by elemental analyses, electronic, IR, NMR, mass and ESR spectroscopic techniques. The synthesized metal complexes of pyrazoline compounds showed significant antibacterial activity against the organisms Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Proteus mirabilis and Salmonella typhii when compared with the standard antibiotic (Streptomycin). The ligands and their metal complexes were screened for antioxidant activity using DPPH radical scavenging and superoxide radical scavenging assay methods. All the complexes showed good free radical scavenging activity which is comparable to that of the standards. Among the metal complexes, the copper complex has showed higher activity. The results were indicated that 2-pyrazoline (structural core) and copper ion could be responsible for the potential candidate eliciting antioxidant activity. All compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. The ligands and metal complexes were subjected to fluorescence properties and exhibited that the variable fluorescence emission behavior of complexes. It can be attributed to the combined effect of the substituents and naphthyl structural core present in the ligands.

  18. Design, Synthesis, and Acaricidal/Insecticidal Activities of Oxazoline Derivatives Containing a Sulfur Ether Moiety.

    PubMed

    Yu, Xiuling; Liu, Yuxiu; Li, Yongqiang; Wang, Qingmin

    2015-11-11

    On the basis of etoxazole, a series of novel 2-(2,6-difluorophenyl)-4-(4-substituted phenyl)-1,3-oxazolines containing a sulfur ether moiety were designed and synthesized via the key intermediate N-(1-(4-(bromomethyl)phenyl)-2-chloroethyl)-2,6-difluorobenzamide. The bioassay results showed that most of these designed target compounds exhibited excellent acaricidal activity against both the eggs and larvae of Tetranychus cinnabarinus, especially the eggs. Among compounds with high activity against the eggs of mites, the LC50 values of 2, 11, 17, and 19 were 0.0003, 0.0002, 0.0005, and 0.0008 mg L(-1), respectively, much lower than that of etoxazole (0.0089 mg L(-1)). Compound 2 was chosen to evaluate the acaricidal activity in the field, and the results displayed that at a concentration of 22 mg kg(-1), 2 had a much better control effect than etoxazole against both T. cinnabarinus and P. latus on eggplant. Some compounds also showed good insecticidal activities against oriental armyworm and mosquito. On the basis of our research, the newly found structure-activity relationship may guide the development of new acaricides/pesticides that are required in the agriculture market.

  19. A Generalized Framework for Constrained Design Optimization of General Supersonic Configurations Using Adjoint Based Sensitivity Derivatives

    NASA Technical Reports Server (NTRS)

    Karman, Steve L., Jr.

    2011-01-01

    The Aeronautics Research Mission Directorate (ARMD) sent out an NASA Research Announcement (NRA) for proposals soliciting research and technical development. The proposed research program was aimed at addressing the desired milestones and outcomes of ROA (ROA-2006) Subtopic A.4.1.1 Advanced Computational Methods. The second milestone, SUP.1.06.02 Robust, validated mesh adaptation and error quantification for near field Computational Fluid Dynamics (CFD), was addressed by the proposed research. Additional research utilizing the direct links to geometry through a CAD interface enabled by this work will allow for geometric constraints to be applied and address the final milestone, SUP2.07.06 Constrained low-drag supersonic aerodynamic design capability. The original product of the proposed research program was an integrated system of tools that can be used for the mesh mechanics required for rapid high fidelity analysis and for design of supersonic cruise vehicles. These Euler and Navier-Stokes volume grid manipulation tools were proposed to efficiently use parallel processing. The mesh adaptation provides a systematic approach for achieving demonstrated levels of accuracy in the solutions. NASA chose to fund only the mesh generation/adaptation portion of the proposal. So this report describes the completion of the proposed tasks for mesh creation, manipulation and adaptation as it pertains to sonic boom prediction of supersonic configurations.

  20. Computer aided chemical design: using quantum chemical calculations to predict properties of a series of halochromic guaiazulene derivatives

    PubMed Central

    Woodward, Adam W.; Ghazvini Zadeh, Ebrahim H.; Bondar, Mykhailo V.

    2016-01-01

    With the scientific community becoming increasingly aware of the need for greener products and methodologies, the optimization of synthetic design is of greater importance. Building on experimental data collected from a synthesized guaiazulene derivative, a series of analogous structures were investigated with time-dependent density functional theory (TD-DFT) methods in an effort to identify a compound with desirable photophysical properties. This in silico analysis may eliminate the need to synthesize numerous materials that, when investigated, do not possess viable characteristics. The synthesis of several computationally investigated structures revealed discrepancies in the calculation results. Further refined computational study of the molecules yielded results closer to those observed experimentally and helps set the stage for computationally guided design of organic photonic materials. Three novel derivatives were synthesized from guaiazulene, a naturally occurring chromophore, exhibiting distinct halochromic behaviour, which may have potential in a switchable optoelectronic system or combined with a photoacid generator for data storage. The protonated forms were readily excitable via two-photon absorption. PMID:28018614

  1. Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives.

    PubMed

    Manetti, Fabrizio; Petricci, Elena; Gabrielli, Annalisa; Mann, Andrè; Faure, Hélène; Gorojankina, Tatiana; Brasseur, Laurent; Hoch, Lucile; Ruat, Martial; Taddei, Maurizio

    2016-10-04

    Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts. The submicromolar activity of several of these new quinolones (0.4-0.9 μM) is comparable to or better than that of SAG and purmorphamine, two reference Smo agonists. Structure-activity relationships allow identification of several molecular determinants important for the activity of these compounds.

  2. Design, synthesis and evaluation of novel diaryl urea derivatives as potential antitumor agents.

    PubMed

    Lu, Chenshu; Tang, Ke; Li, Yan; Li, Peng; Lin, Ziyun; Yin, Dali; Chen, Xiaoguang; Huang, Haihong

    2014-04-22

    A novel series of diaryl ureas containing different linker groups were designed and synthesized. Their in vitro antitumor activity against MX-1, A375, HepG2, Ketr3 and HT-29 was evaluated using the standard MTT assay. Compounds having a rigid linker group such as vinyl, ethynyl and phenyl showed significant inhibitory activity against a variety of cancer cell lines. Specifically, compound 23 with a phenyl linker group demonstrated broad-spectrum antitumor activity with IC50 values of 5.17-6.46 μM against five tested tumor cell lines. Compound 23 is more potent than reference drug sorafenib (8.27-15.2 μM), representing a promising lead for further optimization.

  3. Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors.

    PubMed

    Ge, Ying; Li, Aibo; Wu, Jianwei; Feng, Haiwei; Wang, Letian; Liu, Hongwu; Xu, Yungen; Xu, Qingxiang; Zhao, Li; Li, Yuyan

    2017-03-10

    A novel series of non-peptide proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S proteasome, five compounds showed IC50 values in the nanomolar range. Docking experiments into the yeast 20S proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins. Furthermore, in the microsomal stability assay compound 3e demonstrated much improved metabolic stability compared to bortezomib, emerging as a promising lead compound for further design of non-peptide proteasome inhibitors.

  4. Design and synthesis of novel diphenyl oxalamide and diphenyl acetamide derivatives as anticonvulsants.

    PubMed

    Nikalje, Anna Pratima G; Ghodke, Mangesh; Girbane, Amol

    2012-01-01

    A series of novel N(1) -substituted-N(2) ,N(2) -diphenyl oxalamides 3a-l were synthesized in good yield by stirring diphenylcarbamoyl formyl chloride (2) and various substituted aliphatic, alicyclic, aromatic, heterocyclic amines in DMF and K(2) CO(3) . Also 2-substituted amino-N,N-diphenylacetamides 5a-m were designed by pharmacophore generation and synthesized by stirring 2-chloro-N,N-diphenylacetamide (4) and various substituted amines in acetone using triethyl amine as a catalyst. All the synthesized compounds were screened for anticonvulsant activity in Swiss albino mice by MES and ScPTZ induced seizure tests. Neurotoxicity screening and behavioral testing was also carried out. Some of the synthesized test compounds were found to be more potent than the standard drug.

  5. Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents.

    PubMed

    Wu, Lin-tao; Jiang, Zhi; Shen, Jia-jia; Yi, Hong; Zhan, Yue-chen; Sha, Ming-quan; Wang, Zhen; Xue, Si-tu; Li, Zhuo-rong

    2016-05-23

    A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06-3.64 μM and 0.04-9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96-174.50 μM) and were close to that of Paclitaxel (IC50: 0.026-1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.

  6. Design of novel bioadhesive materials based on mussel-derived glues

    NASA Astrophysics Data System (ADS)

    Lee, Bruce Po-Shu

    2005-11-01

    3,4-dihydroxyphenylalanine (DOPA), a unique amino acid found in mussel adhesive proteins (MAPS), was incorporated into polyethylene glycol) (PEG)-based hydrogels using several methods in an attempt to create a novel adhesive biomaterial that can potentially function as a wound closure material, a tissue engineering scaffold, or a mucoadhesive drug carrier. MAP sequences contain as much as 25 mol% DOPA, which is responsible for both strong water-resistant adhesion and rapid curing of these proteins. In the first strategy, DOPA was chemically attached to PEG and both enzymatic and chemical oxidizing reagents were used to induce oxidative cross-linking of DOPA, which resulted in rapid gel formation. Although DOPA was incorporated into a biocompatible PEG-based gel, the oxidized-forms of DOPA are believed to be less adhesive than the catecholic form. Thus, the second focus of the thesis was to incorporate the reduced form of DOPA into a gel network through photopolymerization. This was accomplished by copolymerizing N-methacrylated DOPA with PEG-diacrylate (PEG-DA). While catechol integration was demonstrated, the presence of DOPA lengthened gelation time and reduced the extent of gelation and the mechanical integrity of photocured hydrogels. In the third part of this thesis, the inhibitive effect of DOPA on photopolymerization was eliminated through the design of methacrylated amphiphilic block copolymers consisting of PEG and poly(lactide) (PLA). The self-assembling ability of these polymers was exploited to separate DOPA residues from methacrylate groups. Rapid gelation was achieved (<30 sec) to form DOPA-functionalized hydrogels that degraded in vitro within 2 weeks. The final objective was aimed at increasing DOPA content in the gel network by custom-designing a new methacrylated PEG-b-PLA copolymer with a free --NH2 group on the PEG backbone and to incorporate short poly(DOPA) and poly(DOPA-Lys) peptides through N-carboxyanhydride (NCA) polymerization. Contact

  7. Design, Synthesis, Acaricidal Activity, and Mechanism of Oxazoline Derivatives Containing an Oxime Ether Moiety.

    PubMed

    Li, Yongqiang; Li, Chaojie; Zheng, Yanlong; Wei, Xingcun; Ma, Qiaoqiao; Wei, Peng; Liu, Yuxiu; Qin, Yaoguo; Yang, Na; Sun, Yufeng; Ling, Yun; Yang, Xinling; Wang, Qingmin

    2014-03-27

    Two series of novel 2,4-diphenyl-1,3-oxazolines containing an oxime ether moiety were designed and synthesized via the key intermediate N-(2-chloro-1-(p-tolyl)ethyl)-2,6-difluorobenzamide. The bioassay results showed that the target compounds with an oxime ether substituent at the para position of 4-phenyl exhibited excellent acaricidal activity against Tetranychus cinnabarinus in the laboratory. Moreover, all of the target compounds had much higher activities than etoxazole, as the ovicidal and larvicidal activities of the target compounds I-a-I-l and II-a-II-n against T. cinnabarinus were all over 90% at 0.001 mg L(-1), but etoxazole gave only 30% and 40% respectively at the same concentration. The activity order of compounds with regard to acaricidal activity in vivo was almost consistent with their affinity activity with sulfonylurea receptor (SUR) of Blattella germanica in vitro, hence, it was supposed that the acaricidal mechanism of action of the target compounds was that they can bind with the site of SUR and therefore inhibit chitin synthesis. Moreover, the eminent effect of the compound II-l, [2-(trifluoromethyl)benzaldehyde O-(4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl) oxime], against Panonychus citri and T. cinnabarinus in the field indicated that II-l exhibited a promising application prospect as a new candicate for controlling spider mites in the field.

  8. Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents

    PubMed Central

    Mahto, Manoj kumar; Yellapu, Nanda Kumar; Kilaru, Ravendra Babu; Chamarthi, Naga Raju; Bhaskar, Matcha

    2014-01-01

    Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell lines. PMID:24966524

  9. Design, synthesis, and evaluation of curcumin derivatives as Nrf2 activators and cytoprotectors against oxidative death.

    PubMed

    Tu, Zhi-Shan; Wang, Qi; Sun, Dan-Dan; Dai, Fang; Zhou, Bo

    2017-04-05

    Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent Nrf2 activator and cancer chemopreventive agent. In this study, we synthesized a series of curcumin analogs by introducing the geminal dimethyl substituents on the active methylene group to find more potent Nrf2 activators and cytoprotectors against oxidative death. The geminally dimethylated and catechol-type curcumin analog (compound 3) was identified as a promising lead molecule in terms of its increased stability and cytoprotective activity against the tert-butyl hydroperoxide (t-BHP)-induced death of HepG2 cells. Mechanism studies indicate that its cytoprotective effects are mediated by activating the Nrf2 signaling pathway in the Michael acceptor- and catechol-dependent manners. Additionally, we verified by using copper and iron ion chelators that the two metal ion-mediated oxidations of compound 3 to its corresponding electrophilic o-quinone, contribute significantly to its Nrf2-dependent cytoprotection. This work provides an example of successfully designing natural curcumin-directed Nrf2 activators by a stability-increasing and proelectrophilic strategy.

  10. Charge density distributions derived from smoothed electrostatic potential functions: design of protein reduced point charge models.

    PubMed

    Leherte, Laurence; Vercauteren, Daniel P

    2011-10-01

    To generate reduced point charge models of proteins, we developed an original approach to hierarchically locate extrema in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions. A charge fitting program was used to assign charge values to the so-obtained reduced representations. In continuation to a previous work, the Amber99 force field was selected. To easily generate reduced point charge models for protein structures, a library of amino acid templates was designed. Applications to four small peptides, a set of 53 protein structures, and four KcsA ion channel models, are presented. Electrostatic potential and solvation free energy values generated by the reduced models are compared with the corresponding values obtained using the original set of atomic charges. Results are in closer agreement with the original all-atom electrostatic properties than those obtained with a previous reduced model that was directly built from the smoothed MEP functions [Leherte and Vercauteren in J Chem Theory Comput 5:3279-3298, 2009].

  11. Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase.

    PubMed

    Arias, D G; Herrera, F E; Garay, A S; Rodrigues, D; Forastieri, P S; Luna, L E; Bürgi, M D L M; Prieto, C; Iglesias, A A; Cravero, R M; Guerrero, S A

    2017-01-05

    The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC50 of 1.0 ± 0.1 μM and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 μM, 61 μM and 68 μM for 8, 12 and 13, respectively, compared with 245 μM for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction.

  12. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship

    NASA Astrophysics Data System (ADS)

    Akhtar, Muhammad Nadeem; Sakeh, Nurshafika M.; Zareen, Seema; Gul, Sana; Lo, Kong Mun; Ul-Haq, Zaheer; Shah, Syed Adnan Ali; Ahmad, Syahida

    2015-04-01

    Browning of fruits and vegetables is a serious issue in the food industry, as it damages the organoleptic properties of the final products. Overproduction of melanin causes aesthetic problems such as melisma, freckles and lentigo. In this study, a series of chalcones (1-10) have been synthesized and examined for their tryrosinase inhibitory activity. The results showed that flavokawain B (1), flavokawain A (2) and compound 3 were found to be potential tyrosinase inhibitors, indicating IC50 14.20-14.38 μM values. This demonstrates that 4-substituted phenolic compound especially at ring A exhibited significant tyrosinase inhibition. Additionally, molecular docking results showed a strong binding affinity for compounds 1-3 through chelation between copper metal and ligands. The detailed molecular docking and SARs studies correlate well with the tyrosinase inhibition studies in vitro. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and single X-ray crystallographic techniques. These findings could lead to design and discover of new tyrosinase inhibitors to control the melanine overproduction and overcome the economic loss of food industry.

  13. Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives

    NASA Astrophysics Data System (ADS)

    War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

    2017-02-01

    The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues.

  14. Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents

    PubMed Central

    Ravula, Parameshwar; Vamaraju, Harinadha Babu; Paturi, Manichandrika; Chandra JN, Narendra Sharath; Kolli, Swetha

    2016-01-01

    A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity. PMID:27103897

  15. Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents.

    PubMed

    Ravula, Parameshwar; Vamaraju, Harinadha Babu; Paturi, Manichandrika; Chandra Jn, Narendra Sharath; Kolli, Swetha

    2016-01-01

    A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

  16. Synthesis and evaluation of Lys¹(α,γ-Folate)Lys³(¹⁷⁷Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer.

    PubMed

    Aranda-Lara, Liliana; Ferro-Flores, Guillermina; Azorín-Vega, Erika; Ramírez, Flor de María; Jiménez-Mancilla, Nallely; Ocampo-García, Blanca; Santos-Cuevas, Clara; Isaac-Olivé, Keila

    2016-01-01

    The aim of this work was to synthesize Lys(1)(α,γ-Folate)-Lys(3)((177)Lu-DOTA)-Bombesin (1-14) ((177)Lu-Folate-BN), as well as to assess its potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (FR) and gastrin-releasing peptide receptors (GRPR). Radiation absorbed doses of (177)Lu-Folate-BN (74 MBq, i.v.) estimated in athymic mice with T47D-induced breast tumors (positive to FR and GRPR), showed tumor doses of 23.9±2.1 Gy. T47D-tumors were clearly visible (Micro-SPECT/CT images). (177)Lu-Folate-BN demonstrated properties suitable as a theranostic radiopharmaceutical.

  17. 1,5-Benzodiazepine derivatives as potential antimicrobial agents: design, synthesis, biological evaluation, and structure-activity relationships.

    PubMed

    Wang, Lan-Zhi; Li, Xiao-Qing; An, Ying-Shuang

    2015-05-21

    36 Novel 1,5-benzodiazepine derivatives were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,5-benzodiazepines, thiophene or thiazole and ester group. The structures of the target compounds have been characterized by IR, (1)H NMR, (13)C NMR, MS and elemental analysis. The structure of 1v was further determined using X-ray single crystal diffraction. All synthesized 1,5-benzodiazepine derivatives were evaluated for their in vitro antimicrobial activity against C. neoformans, C. neoformans clinical isolates, C. albicans, E. coli and S. aureus. The bioactive assay results revealed that most of the 1,5-benzodiazepine derivatives exhibited considerable potency against all of the tested strains. In particular, compounds 1v and 1w (MIC: 2-6 μg mL(-1), MFC: 10-14 μg mL(-1)) exhibited excellent antifungal activity and were found to be 32-64 and 9-12.8 times more potent than the reference drugs against C. neoformans, respectively. Moreover, compound (MIC: 40 μg mL(-1)) displayed equipotent antibacterial activity against E. coli and S. aureus compared to the reference drugs. The most potent of the synthesized compounds 1v and 1w were further studied by evaluating their cytotoxicities, and the results showed that they had relatively low level cytotoxicity for BV2 cell. A preliminary study of the structure-activity relationship revealed that substituents in the phenyl ring and the thiophene ring had a great effect on the antimicrobial activity of these compounds. In addition, the thiazole ring at C2 may be a pharmacophore of these compounds and COOC2H5 group at C3 is the best substituent for the maintenance of antimicrobial activities at low concentrations (1.5625 μg per disc).

  18. Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids.

    PubMed

    Steffan, Tobias; Renukappa-Gutke, Thejavathi; Höfner, Georg; Wanner, Klaus T

    2015-03-15

    In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114.

  19. Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

    PubMed

    Nakajima, Yutaka; Aoyama, Naohiro; Takahashi, Fumie; Sasaki, Hiroshi; Hatanaka, Keiko; Moritomo, Ayako; Inami, Masamichi; Ito, Misato; Nakamura, Koji; Nakamori, Fumihiro; Inoue, Takayuki; Shirakami, Shohei

    2016-10-01

    In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.

  20. Design and synthesis of aloe-emodin derivatives as potent anti-tyrosinase, antibacterial and anti-inflammatory agents.

    PubMed

    Liu, Jinbing; Wu, Fengyan; Chen, Changhong

    2015-11-15

    Twenty aloe-emodin derivatives were designed, synthesized, and their biological activities were evaluated. Some compounds displayed potent tyrosinase inhibitory activities, especially, compounds with thiosemicarbazide moiety showed more potent inhibitory effects than the other compounds. The structure-activity relationships (SARs) were preliminarily discussed. The inhibition mechanism of selected compounds 1 and 13 were investigated. The results showed compound 1 was reversible inhibitor, however, compound 13 was irreversible. Kinetic analysis indicated that compound 1 was competitive tyrosinase inhibitor. Furthermore, the antibacterial activities and anti-inflammatory activities of some selected compounds were also screened. The results showed that compound 3 exhibited more potent antibacterial activity than the aloe-emodin, compounds 5 and 6 possessed more potent anti-inflammatory activities than the diacerein.

  1. Discovery of hybrid dual N-acylhydrazone and diaryl urea derivatives as potent antitumor agents: design, synthesis and cytotoxicity evaluation.

    PubMed

    Zhai, Xin; Huang, Qiang; Jiang, Nan; Wu, Di; Zhou, Hongyu; Gong, Ping

    2013-03-04

    Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications.

  2. Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ.

    PubMed

    Li, Xin; Sheng, Juzheng; Huang, Guihua; Ma, Ruixin; Yin, Fengxin; Song, Di; Zhao, Can; Ma, Shutao

    2015-06-05

    In an attempt to discover potential antibacterial agents against the increasing bacterial resistance, novel cinnamaldehyde derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method, and their cell division inhibitory activity against four representative strains. In the in vitro antibacterial activity, the newly synthesized compounds generally displayed better efficacy against Staphylococcus aureus ATCC25923 than the others. In particular, compounds 3, 8 and 10 exerted superior or comparable activity to all the reference drugs. In the cell division inhibitory activity, all the compounds showed the same trend as their in vitro antibacterial activity, exhibiting better activity against S. aureus ATCC25923 than the other strains. Additionally, compounds 3, 6, 7 and 8 displayed potent cell division inhibitory activity with an MIC value of below 1 μg/mL, over 256-fold better than all the reference drugs.

  3. Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment.

    PubMed

    Xia, Chun-Li; Wang, Ning; Guo, Qian-Liang; Liu, Zhen-Quan; Wu, Jia-Qiang; Huang, Shi-Liang; Ou, Tian-Miao; Tan, Jia-Heng; Wang, Hong-Gen; Li, Ding; Huang, Zhi-Shu

    2017-04-21

    A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349-361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.

  4. Design, synthesis, and evaluation of resveratrol derivatives as Aß(₁-₄₂) aggregation inhibitors, antioxidants, and neuroprotective agents.

    PubMed

    Lu, Chuanjun; Guo, Yueyan; Li, Jianheng; Yao, Meicun; Liao, Qiongfeng; Xie, Zhiyong; Li, Xingshu

    2012-12-15

    A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

  5. Follow-up: Prospective compound design using the 'SAR Matrix' method and matrix-derived conditional probabilities of activity.

    PubMed

    Gupta-Ostermann, Disha; Hirose, Yoichiro; Odagami, Takenao; Kouji, Hiroyuki; Bajorath, Jürgen

    2015-01-01

    In a previous Method Article, we have presented the 'Structure-Activity Relationship (SAR) Matrix' (SARM) approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a "chemical space envelope" around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach.

  6. Design and synthesis of natural product derivatives with selective and improved cytotoxicity based on a sesquiterpene scaffold.

    PubMed

    Zhang, Yang; Zhang, Zhuowei; Wang, Bo; Liu, Ling; Che, Yongsheng

    2016-04-15

    Brasilamide E (1) is a bisabolane sesquiterpenoid isolated from the solid-substrate fermentation cultures of a plant endophytic fungus Paraconiothyrium brasiliense. The compound specifically inhibited proliferation of the MCF-7 cells, but did not show cytotoxicity towards the negative controls HaCaT and NIH3T3 cells (IC50>50 μM). To improve its potency while maintain selectivity, a total of 27 derivatives of 1 were designed, synthesized, and evaluated for in vitro cytotoxicity against six tumor cell lines and the negative control NIH3T3 cells. Among these compounds, compound 12b showed significantly improved potency against the MCF-7, HeLa, and HO8910 cells with IC50 values of 0.13-0.25 μM compared to 1 (IC50 8.47-18.00 μM), and remained nontoxic to the NIH3T3 cells.

  7. Design, Synthesis and Biological Evaluation of Stilbene Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B.

    PubMed

    He, Haibing; Ge, Yinghua; Dai, Hong; Cui, Song; Ye, Fei; Jin, Jia; Shi, Yujun

    2016-12-16

    By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by ¹H-NMR, (13)C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B. Among them, compound 29 (IC50 = 0.91 ± 0.33 μM), characterized by a 5-(2,3-dichlorophenyl) isoxazole moiety, exhibited an activity about 14-fold higher than the lead compound LCA and a 4.2-fold selectivity over TCPTP. Compound 29 was identified as a competitive inhibitor of PTP1B with a Ki value of 0.78 μM in enzyme kinetic studies.

  8. Conceptual Engine System Design for NERVA derived 66.7KN and 111.2KN Thrust Nuclear Thermal Rockets

    NASA Astrophysics Data System (ADS)

    Fittje, James E.; Buehrle, Robert J.

    2006-01-01

    The Nuclear Thermal Rocket concept is being evaluated as an advanced propulsion concept for missions to the moon and Mars. A tremendous effort was undertaken during the 1960's and 1970's to develop and test NERVA derived Nuclear Thermal Rockets in the 111.2 KN to 1112 KN pound thrust class. NASA GRC is leveraging this past NTR investment in their vehicle concepts and mission analysis studies, and has been evaluating NERVA derived engines in the 66.7 KN to the 111.2 KN thrust range. The liquid hydrogen propellant feed system, including the turbopumps, is an essential component of the overall operation of this system. The NASA GRC team is evaluating numerous propellant feed system designs with both single and twin turbopumps. The Nuclear Engine System Simulation code is being exercised to analyze thermodynamic cycle points for these selected concepts. This paper will present propellant feed system concepts and the corresponding thermodynamic cycle points for 66.7 KN and 111.2 KN thrust NTR engine systems. A pump out condition for a twin turbopump concept will also be evaluated, and the NESS code will be assessed against the Small Nuclear Rocket Engine preliminary thermodynamic data.

  9. Design, synthesis, and biological evaluation of new arylamide derivatives possessing sulfonate or sulfamate moieties as steroid sulfatase enzyme inhibitors.

    PubMed

    El-Gamal, Mohammed I; Semreen, Mohammad H; Foster, Paul A; Potter, Barry V L

    2016-06-15

    A series of new arylamide derivatives possessing terminal sulfonate or sulfamate moieties was designed and synthesized. The target compounds were tested for in vitro inhibitory effects against the steroid sulfatase (STS) enzyme in a cell-free assay system. The free sulfamate derivative 1j was the most active. It inhibited the enzymatic activity by 72.0% and 55.7% at 20μM and 10μM, respectively. Compound 1j was further tested for STS inhibition in JEG-3 placental carcinoma cells with high STS enzyme activity. It inhibited 93.9% of the enzyme activity in JEG-3 placental carcinoma cells at 20μM with an efficacy near to that of the well-established drug STX64 as reference. At 10μM, 1j inhibited 86.1% of the STS activity of JEG-3. Its IC50 value against the STS enzyme in JEG-3 cells was 0.421μM. Thus, 1j represents an attractive new non-steroidal lead for further optimization.

  10. Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC "click" chemistry as potential anticancer agents.

    PubMed

    Jin, Xin; Yan, Tian-Hua; Yan, Lan; Li, Qian; Wang, Rui-Lian; Hu, Zhen-Lin; Jiang, Yuan-Ying; Sun, Qing-Yan; Cao, Yong-Bing

    2014-01-01

    A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC.

  11. [Designation, solid-phase synthesis and antimicrobial activity of Mytilin derived peptides based on Mytilin-1 from Mytilus coruscus].

    PubMed

    Liu, Mei; Wu, Mei; Zhou, Shiquan; Gao, Peng; Lu, Tao; Wang, Rixin; Shi, Ge; Liao, Zhi

    2010-04-01

    As a key role in mussel defense system, Mytilin is an important antibacterial peptide isolated from the mussel serum. The structural and functional researches on Mytilin showed that the fragment connecting two beta-sheets in a stable beta-hairpin structure was probably required for antimicrobial activity. To elucidate the structural features and the antimicrobial activity of this fragment, we re-designed and synthesized two peptides corresponding to the main mimic structures of Mytilin-1 from Mytilus coruscus, we named these two peptides Mytilin Derived Peptide-1 and Mytilin Derived Peptide-2, respectively. Using a liquid growth inhibition assay, we evaluated their activity towards Gram-positive, Gram-negative bacteria and fungus. The results showed that both peptides can inhibit the growth of Gram-positive, Gram-negative bacteria and fungus. Besides, these two peptides showed high stability in heat water and human serum. These works laid the foundation for further research on the molecular mechanism of Mytilin and for further exploitation of antibacterial peptides with lower molecular mass and more stable structure.

  12. A Series of New Ligustrazine-Triterpenes Derivatives as Anti-Tumor Agents: Design, Synthesis, and Biological Evaluation

    PubMed Central

    Xu, Bing; Chu, Fuhao; Zhang, Yuzhong; Wang, Xiaobo; Li, Qiang; Liu, Wei; Xu, Xin; Xing, Yanyi; Chen, Jing; Wang, Penglong; Lei, Haimin

    2015-01-01

    A series of novel ligustrazine-triterpenes derivatives was designed, synthesized and screened for their cytotoxicity against five cancer cell lines (Bel-7402, HepG2, HT-29, Hela, and MCF-7) and Madin-Darby canine kidney (MDCK). Current study suggested that most of the ligustrazine-triterpenes conjunctions showed better cytotoxicity than the starting materials. In particular, compound 4a exhibited better cytotoxic activity (IC50 < 5.23 μM) against Bel-7402, HT-29, MCF-7, Hela, and HepG2 than the standard anticancer drug cisplatin (DDP). The cytotoxicity selectivity detection revealed that 4a exhibited low cytotoxicity (IC50 > 20 μM) towards MDCK cells. A combination of fluorescence staining observation and flow cytometric analysis indicated that 4a could induce HepG2 cell apoptosis. Further studies suggested that 4a-induced apoptosis is mediated through depolarization of the mitochondrial membrane potential and increase of intracellular free Ca2+ concentration. In addition, the structure-activity relationships of these derivatives were briefly discussed. PMID:26404253

  13. Conceptual Engine System Design for NERVA derived 66.7KN and 111.2KN Thrust Nuclear Thermal Rockets

    SciTech Connect

    Fittje, James E.; Buehrle, Robert J.

    2006-01-20

    The Nuclear Thermal Rocket concept is being evaluated as an advanced propulsion concept for missions to the moon and Mars. A tremendous effort was undertaken during the 1960's and 1970's to develop and test NERVA derived Nuclear Thermal Rockets in the 111.2 KN to 1112 KN pound thrust class. NASA GRC is leveraging this past NTR investment in their vehicle concepts and mission analysis studies, and has been evaluating NERVA derived engines in the 66.7 KN to the 111.2 KN thrust range. The liquid hydrogen propellant feed system, including the turbopumps, is an essential component of the overall operation of this system. The NASA GRC team is evaluating numerous propellant feed system designs with both single and twin turbopumps. The Nuclear Engine System Simulation code is being exercised to analyze thermodynamic cycle points for these selected concepts. This paper will present propellant feed system concepts and the corresponding thermodynamic cycle points for 66.7 KN and 111.2 KN thrust NTR engine systems. A pump out condition for a twin turbopump concept will also be evaluated, and the NESS code will be assessed against the Small Nuclear Rocket Engine preliminary thermodynamic data.

  14. Design, synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents.

    PubMed

    Luo, Wen; Su, Ya-Bin; Hong, Chen; Tian, Run-Guo; Su, Lei-Peng; Wang, Yue-Qiao; Li, Yang; Yue, Jun-Jie; Wang, Chao-Jie

    2013-12-01

    A series of 4-dimethylamine flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC50, 1.83-33.20 μM for AChE and 0.82-11.45 μM for BChE). A Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aβ aggregation inhibitory activity at 20 μM with percentage from 25% to 48%. In addition, some compounds (5j-5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer's disease.

  15. Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities.

    PubMed

    Luo, Wen; Chen, Ying; Wang, Ting; Hong, Chen; Chang, Li-Ping; Chang, Cong-Cong; Yang, Ya-Cheng; Xie, Song-Qiang; Wang, Chao-Jie

    2016-02-15

    A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64μM for AChE and 0.42μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.

  16. Design, synthesis, physicochemical studies, solvation, and DNA damage of quinoline-appended chalcone derivative: comprehensive spectroscopic approach toward drug discovery.

    PubMed

    Kumar, Himank; Chattopadhyay, Anjan; Prasath, R; Devaraji, Vinod; Joshi, Ritika; Bhavana, P; Saini, Praveen; Ghosh, Sujit Kumar

    2014-07-03

    The present study epitomizes the design, synthesis, photophysics, solvation, and interaction with calf-thymus DNA of a potential antitumor, anticancer quinoline-appended chalcone derivative, (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) using steady state absorption and fluorescence spectroscopy, molecular modeling, molecular docking, Fourier-transform infrared spectroscopy (FTIR), molecular dynamics (MD) simulation, and gel electrophoresis studies. ADMQ shows an unusual photophysical behavior in a variety of solvents of different polarity. The dual emission has been observed along with the formation of twisted intramolecular charge transfer (TICT) excited state. The radiationless deactivation of the TICT state is found to be promoted strongly by hydrogen bonding. Quantum mechanical (DFT, TDDFT, and ZINDO-CI) calculations show that the ADMQ is sort of molecular rotor which undergoes intramolecular twist followed by a complete charge transfer in the optimized excited state. FTIR studies reveals that ADMQ undergoes important structural change from its native structure to a β-hydroxy keto form in water at physiological pH. The concentration-dependent DNA cleavage has been identified in agarose gel DNA electrophoresis experiment and has been further supported by MD simulation. ADMQ forms hydrogen bond with the deoxyribose sugar attached with the nucleobase adenine DA-17 (chain A) and result in significant structural changes which potentially cleave DNA double helix. The compound does not exhibit any deleterious effect or toxicity to the E. coli strain in cytotoxicity studies. The consolidated spectroscopic research described herein can provide enormous information to open up new avenues for designing and synthesizing chalcone derivatives with low systematic toxicity for medicinal chemistry research.

  17. Design, synthesis and biological evaluation of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors.

    PubMed

    Ha, Young Mi; Park, Yun Jung; Lee, Ji Yeon; Park, Daeui; Choi, Yeon Ja; Lee, Eun Kyeong; Kim, Ji Min; Kim, Jin-Ah; Park, Ji Young; Lee, Hye Jin; Moon, Hyung Ryong; Chung, Hae Young

    2012-02-01

    Herein we describe the design, synthesis and biological activities of 2-(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors. The target compounds 2a-2j were designed and synthesized from the structural characteristics of N-phenylthiourea, tyrosinase inhibitor and tyrosine, and l-DOPA, the natural substrates of tyrosinase. Among them, (2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid (2g) caused the greatest inhibition 66.47% at 20 μM of l-DOPA oxidase activity of mushroom tyrosinase. Kinetic analysis of tyrosinase inhibition revealed that 2g is a competitive inhibitor. We predicted the tertiary structure of tyrosinase, and simulated the docking of mushroom tyrosinase with 2g. These results suggest that the binding affinity of 2g with tyrosinase is high. Also, 2g effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-MSH. These data strongly suggest that 2g can suppress the production of melanin via the inhibition of tyrosinase activity.

  18. Nonlinear fractional order proportion-integral-derivative active disturbance rejection control method design for hypersonic vehicle attitude control

    NASA Astrophysics Data System (ADS)

    Song, Jia; Wang, Lun; Cai, Guobiao; Qi, Xiaoqiang

    2015-06-01

    Near space hypersonic vehicle model is nonlinear, multivariable and couples in the reentry process, which are challenging for the controller design. In this paper, a nonlinear fractional order proportion integral derivative (NFOPIλDμ) active disturbance rejection control (ADRC) strategy based on a natural selection particle swarm (NSPSO) algorithm is proposed for the hypersonic vehicle flight control. The NFOPIλDμ ADRC method consists of a tracking-differentiator (TD), an NFOPIλDμ controller and an extended state observer (ESO). The NFOPIλDμ controller designed by combining an FOPIλDμ method and a nonlinear states error feedback control law (NLSEF) is to overcome concussion caused by the NLSEF and conversely compensate the insufficiency for relatively simple and rough signal processing caused by the FOPIλDμ method. The TD is applied to coordinate the contradiction between rapidity and overshoot. By attributing all uncertain factors to unknown disturbances, the ESO can achieve dynamic feedback compensation for these disturbances and thus reduce their effects. Simulation results show that the NFOPIλDμ ADRC method can make the hypersonic vehicle six-degree-of-freedom nonlinear model track desired nominal signals accurately and fast, has good stability, dynamic properties and strong robustness against external environmental disturbances.

  19. Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl)methanol derivatives

    PubMed Central

    Kim, Do Hyun; Kim, Su Jeong; Ullah, Sultan; Yun, Hwi Young; Chun, Pusoon; Moon, Hyung Ryong

    2017-01-01

    The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 μM, and five of the PDTM derivatives (PDTM3, PDTM7–PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 μM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 μM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7–PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition. PMID:28352157

  20. Design, synthesis, in vitro MAO-B inhibitory evaluation, and computational studies of some 6-nitrobenzothiazole-derived semicarbazones.

    PubMed

    Tripathi, Rati K P; Goshain, Omprakash; Ayyannan, Senthil Raja

    2013-03-01

    Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDock 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50): 0.004±0.001 μM) and in computational docking studies (K(i): 1.08 μM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors.

  1. Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor*S⃞

    PubMed Central

    Fletcher, Jordan M.; Morton, Craig J.; Zwar, Richard A.; Murray, Simon S.; O'Leary, Paul D.; Hughes, Richard A.

    2008-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of neurotrophic factors. BDNF has long been recognized to have potential for the treatment of a variety of human neurodegenerative diseases. However, clinical trials with recombinant BDNF have yet to yield success, leading to the suggestion that alternative means of harnessing BDNF actions for therapeutic use may be required. Here we describe an approach to create low molecular weight peptides that, like BDNF, promote neuronal survival. The peptides were designed to mimic a cationic tripeptide sequence in loop 4 of BDNF shown in previous studies to contribute to the binding of BDNF to the common neurotrophin receptor p75NTR. The best of these peptides, the cyclic pentapeptide 2 (cyclo(-d-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (Mr 580), was found to be an effective promoter of the survival of embryonic chick dorsal root ganglion sensory neurons in vitro (maximal survival, 68 ± 3% of neurons supported by BDNF). Pentapeptide 2 did not affect the phosphorylation of either TrkB (the receptor tyrosine kinase for BDNF) or the downstream signaling molecule MAPK, indicating that its mechanism of neuronal survival action is independent of TrkB. NMR studies reveal that pentapeptide 2 adopts a well defined backbone conformation in solution. Furthermore, pentapeptide 2 was found to be effectively resistant to proteolysis when incubated in a solution of rat plasma in vitro. These properties of pentapeptide 2 (low molecular weight, appropriate pharmacological actions, a well defined solution conformation, and proteolytic stability) render it worthy of further investigation, either as a template for the further design of neuronal survival promoting agents or as a lead compound with therapeutic potential in its own right. PMID:18809686

  2. Biological evaluation of structurally diverse amaryllidaceae alkaloids and their synthetic derivatives: discovery of novel leads for anticancer drug design.

    PubMed

    Evidente, Antonio; Kireev, Artem S; Jenkins, Aaron R; Romero, Anntherese E; Steelant, Wim F A; Van Slambrouck, Severine; Kornienko, Alexander

    2009-04-01

    Twenty-nine Amaryllidaceae alkaloids and their derivatives belonging to the five most common groups, including lycorine, lycorenine, tazettine, crinine, and narciclasine types, were evaluated for antiproliferative, apoptosis-inducing, and anti-invasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine, and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis mediated. Thus, apoptosis in Jurkat cells was triggered by narciclasine, narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydronarciclasine, trans-dihydronarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of narciclasine, lycorine, and haemanthamine, the apoptosis-inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent anti-invasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The anti-invasive activity of buphanamine is particularly promising because this alkaloid is not toxic to cells even at much higher doses. This work has resulted in the identification of several novel leads for anticancer drug design.

  3. Biological Evaluation of Structurally Diverse Amaryllidaceae Alkaloids and their Synthetic Derivatives: Discovery of Novel Leads for Anticancer Drug Design

    PubMed Central

    Evidente, Antonio; Kireev, Artem S.; Jenkins, Aaron R.; Romero, Anntherese E.; Steelant, Wim F. A.; Van slambrouck, Severine; Kornienko, Alexander

    2011-01-01

    Twenty nine Amaryllidaceae alkaloids and their derivatives belonging to five most common groups, including lycorine-, lycorenine-, tazettine-, crinine-, and narciclasine-types, were evaluated for antiproliferative, apoptosis inducing and antiinvasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis-mediated. Thus, apoptosis in Jurkat cells was triggered by narciclasine, narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydronarciclasine, trans-dihydronarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of narciclasine, lycorine and haemanthamine, the apoptosis inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent antiinvasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The antiinvasive activity of buphanamine is particularly promising since this alkaloid is not toxic to cells even at much higher doses. This work has resulted in identification of several novel leads for anticancer drug design. PMID:19235683

  4. Additive effects on the improvement of insecticidal activity: Design, synthesis, and insecticidal activity of novel pymetrozine derivatives.

    PubMed

    Yang, Yan; Liu, Yuxiu; Song, Hongjian; Li, Yongqiang; Wang, Qingmin

    2016-02-01

    A series of new pymetrozine analogues containing both methyl on the imine carbon and phenoxy group at the pyridine ring were designed and synthesized. Their insecticidal activities against bean aphid (Aphis craccivora), mosquito larvae (Culex pipiens pallens), cotton bollworm (Helicoverpa armigera), corn borer (Ostrinia nubilalis) and oriental armyworm (Mythimna separata) were evaluated. The results of bioassays indicated that most of the target compounds showed good insecticidal activity against bean aphid; especially, IIIf (80%) and IIIl (80%) exhibited higher aphicidal activity than pymetrozine (30%) at 5mg/kg, and the two compounds still showed 20% and 30% mortality at 2.5mg/kg, respectively, whereas pymetrozine displayed no activity at the same concentration. These compounds exhibited a completely different structure-activity relationship to that of known pymetrozine derivatives, in which it is thought introducing alkyl group on the imine carbon could be detrimental to the activities. Our new result suggested that the methyl on the imine carbon and phenoxy group at the pyridine ring of phenoxy group may play additive effects on the improvement of aphicidal activity. Besides this, compound IIIs, containing an allyl at the para position of phenoxy group, exhibited excellent insecticidal activity against mosquito larvae, lepidoptera pests cotton bollworm, corn borer and oriental armyworm.

  5. Development of a new class of aromatase inhibitors: Design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives

    PubMed Central

    Bonfield, Kevin; Amato, Erica; Bankemper, Tony; Agard, Hannah; Steller, Jeffrey; Keeler, James M.; Roy, David; McCallum, Adam; Paula, Stefan; Ma, Lili

    2014-01-01

    Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC50 values of 2.4 μM, 0.26 μM and 5.8 μM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors. PMID:22444875

  6. Design, synthesis and antibacterial study of new potent and selective coumarin-chalcone derivatives for the treatment of tenacibaculosis.

    PubMed

    Vazquez-Rodriguez, Saleta; Lama López, Raquel; Matos, Maria João; Armesto-Quintas, Gabriel; Serra, Silvia; Uriarte, Eugenio; Santana, Lourdes; Borges, Fernanda; Muñoz Crego, Angeles; Santos, Ysabel

    2015-11-01

    With the aim of finding new chemical entities selective for fish pathogens to avoid drug resistance in humans, a series of coumarin-chalcone hybrid compounds with different patterns of substitution were designed and synthesized. Their antibacterial activity was evaluated against important types of human bacteria strains (Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa) and against a fourteen strains of the marine pathogen Tenacibaculum maritimum, responsible for tenacibaculosis in fish, which is an important disease that causes great economical loss in the aquaculture industry. All the amino derivatives 5-12 presented high activity against different strains of T. maritimum, no activity against any of the three human pathogenic bacteria strains and no toxicity. Compounds 6, 7 and 11 were the most promising molecules. The most sensitive strains to these compounds were LL01 8.3.8 and LL01 8.3.1, being compound 11 up to 20 times more active than enrofloxacin. Therefore these scaffolds are good candidates for aquaculture treatments, avoiding possible drug resistance problems in humans.

  7. Design, synthesis and in vitro evaluation of novel dehydroabietic acid derivatives containing a dipeptide moiety as potential anticancer agents.

    PubMed

    Huang, Xiao-Chao; Jin, Le; Wang, Meng; Liang, Dong; Chen, Zhen-Feng; Zhang, Ye; Pan, Ying-Ming; Wang, Heng-Shan

    2015-01-07

    A series of novel dehydroabietic acid (DHA) chiral dipeptide derivatives were designed and synthesized as potent antitumor agents. The inhibitory activities of these compounds against NCI-H460 (lung), HeLa (epithelial cervical) and MGC-803 (gastric) human cancer cell lines were estimated by MTT assay in vitro. The antitumor activities screening indicated that many compounds showed moderate to high levels of antitumor activities against these three cancer cell lines and most of these compounds displayed more potent inhibitory activities compared with commercial anticancer drug 5-fluorouracil (5-FU). The induction of apoptosis and affects on the cell cycle distribution with compound 8k were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining, TUNEL assay, flow cytometry and the activities of caspase-3 and -9 assay in Hela cells, which exhibited that the compound could induce cell apoptosis in Hela cells. In addition, further investigation showed that apoptosis were associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of Bax expression, down-regulation of Bcl-2, and the activation of caspase-9 and -3.

  8. Antimicrobial Peptides Derived from Fusion Peptides of Influenza A Viruses, a Promising Approach to Designing Potent Antimicrobial Agents.

    PubMed

    Wang, Jingyu; Zhong, Wenjing; Lin, Dongguo; Xia, Fan; Wu, Wenjiao; Zhang, Heyuan; Lv, Lin; Liu, Shuwen; He, Jian

    2015-10-01

    The emergence and dissemination of antibiotic-resistant bacterial pathogens have spurred the urgent need to develop novel antimicrobial agents with different mode of action. In this respect, we turned several fusogenic peptides (FPs) derived from the hemagglutinin glycoproteins (HAs) of IAV into potent antibacterials by replacing the negatively or neutrally charged residues of FPs with positively charged lysines. Their antibacterial activities were evaluated by testing the MICs against a panel of bacterial strains including S. aureus, S. mutans, P. aeruginosa, and E. coli. The results showed that peptides HA-FP-1, HA-FP-2-1, and HA-FP-3-1 were effective against both Gram-positive and Gram-negative bacteria with MICs ranging from 1.9 to 16.0 μm, while the toxicities toward mammalian cells were low. In addition, the mode of action and the secondary structure of these peptides were also discussed. These data not only provide several potent peptides displaying promising potential in development as broad antimicrobial agents, but also present a useful strategy in designing new antimicrobial agents.

  9. Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms. part II: furoxan derivatives.

    PubMed

    Dos Santos, Jean Leandro; Lanaro, Carolina; Chelucci, Rafael Consolin; Gambero, Sheley; Bosquesi, Priscila Longhin; Reis, Juliana Santana; Lima, Lídia Moreira; Cerecetto, Hugo; González, Mercedes; Costa, Fernando Ferreira; Chung, Man Chin

    2012-09-13

    Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a-g) were designed, synthesized, and evaluated in vitro and in vivo for their potential uses in the oral treatment of sickle cell disease symptoms. All compounds (3a-g) demonstrated NO-donor properties at different levels. Moreover, compounds 3b and 3c demonstrated analgesic activity. Compound 3b was determined to be a promising drug candidate for the aforementioned uses, and it was further evaluated in K562 culture cells to determine its ability to increase levels of γ-globin expression. After 96 h at 5 μM, compound 3b was able to induce γ-globin expression by nearly three times. Mutagenic studies using micronucleus tests in peripheral blood cells of mice demonstrated that compound 3b reduces the mutagenic profile as compared with hydroxyurea. Compound 3b has emerged as a new leading drug candidate with multiple beneficial effects for the treatment of sickle cell disease symptoms and provides an alternative to hydroxyurea treatment.

  10. Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in Pseudomonas aeruginosa

    PubMed Central

    Wang, Chao; Liu, Xiaoling; Wang, Jing; Zhou, Jianuan; Cui, Zining; Zhang, Lian-Hui

    2016-01-01

    The type III secretion system (TTSS) of Pseudomonas aeruginosa is a key virulence determinant for infection of eukaryotic hosts. Based on the findings that spermidine-mediated host-pathogen signalling is important for activation of type III secretion systems (TTSS), in this study, we designed, synthesized and evaluated a series of polyamine derivatives for their potentials in inhibiting the expression TTSS in P. aeruginosa. In vitro assay of 15 compounds synthesized in this study unveiled stringent structural requirements for TTSS-inhibitory activity. Among them, R101SPM, a conjugate between rhodamine 101 and spermine, showed a potent activity in inhibition of the TTSS gene expression and in attenuation of the TTSS-mediated cytotoxicity on human cells. In vivo analysis demonstrated that R101SPM could rescue mice from the lethal infection by P. aeruginosa. Moreover, genetic analysis showed that the full TTSS-inhibitory activity of R101SPM required a functional spermidine transporter. Taken together, our results present a new class of lead molecules for developing anti-virulence drugs and demonstrate that the spermidine transporter SpuDEGHF of P. aeruginosa is a promising drug target. PMID:27484745

  11. Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors.

    PubMed

    Li, Ya-Sheng; Hu, De-Kun; Zhao, Dong-Sheng; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning; Zhang, Lian-Hui

    2017-03-15

    In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4μM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

  12. Design, synthesis and biological evaluation of thienopyrimidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors.

    PubMed

    Wang, Jiang; Su, Mingbo; Li, Tingting; Gao, Anhui; Yang, Wei; Sheng, Li; Zang, Yi; Li, Jia; Liu, Hong

    2017-03-10

    New thienopyrimidine hydroxamic acid derivatives as HDACs inhibitors were designed, synthesized and evaluated. All compounds were evaluated for their ability to inhibit recombinant human HDAC1, HDAC3, and HDAC6 isoforms and in vitro anti-proliferative activity on tumor cell lines RMPI 8226 and HCT 116. Most of these compounds displayed good to excellent inhibitory activities against HDACs. The IC50 values of compound 9m against HDAC1, HDAC3, and HDAC6 was 29.81 ± 0.52 nM, 24.71 ± 1.16 nM, and 21.29 ± 0.32 nM. Most of these compounds showed strong anti-proliferative activity against human cancer cell lines including RMPI 8226 and HCT 116. The IC50 values of compound 9m against RPMI 8226 and HCT 116 proliferation were 0.97 ± 0.072 μM and 1.01 ± 0.033 μM, respectively. In addition, compound 9m noticeably up-regulated the level of histone H3 acetylation at the low concentration of 0.3 μM.

  13. Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives.

    PubMed

    Montanari, Serena; Bartolini, Manuela; Neviani, Paolo; Belluti, Federica; Gobbi, Silvia; Pruccoli, Letizia; Tarozzi, Andrea; Falchi, Federico; Andrisano, Vincenza; Miszta, Przemysław; Cavalli, Andrea; Filipek, Sławomir; Bisi, Alessandra; Rampa, Angela

    2016-06-20

    Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease-modifying therapies. Following the multitarget-directed ligand approach, a small library of coumarin-based derivatives was designed and synthesized as a follow-up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6- or 7-position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3-(4-{[Benzyl(ethyl)amino]methyl}phenyl)-6-({5-[(7-methoxy-6H-indeno[2,1-b]quinolin-11-yl)amino]pentyl}oxy)-2H-chromen-2-one, bearing the bulkiest amine, emerged as a non-neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-6-{[5-(diethylamino)pentyl]oxy}-2H-chromen-2-one and 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self-aggregation, whereas the reference compound was completely ineffective. Furthermore, 3-(4-{[benzyl(ethyl)amino]methyl}phenyl)-7-[4-(diethylamino)butoxy]-2H-chromen-2-one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease-modifying agent.

  14. Design and Generation of Humanized Single-chain Fv Derived from Mouse Hybridoma for Potential Targeting Application.

    PubMed

    Khantasup, Kannika; Chantima, Warangkana; Sangma, Chak; Poomputsa, Kanokwan; Dharakul, Tararaj

    2015-12-01

    Single-chain variable antibody fragments (scFvs) are attractive candidates for targeted immunotherapy in several human diseases. In this study, a concise humanization strategy combined with an optimized production method for humanizing scFvs was successfully employed. Two antibody clones, one directed against the hemagglutinin of H5N1 influenza virus, the other against EpCAM, a cancer biomarker, were used to demonstrate the validity of the method. Heavy chain (VH) and light chain (VL) variable regions of immunoglobulin genes from mouse hybridoma cells were sequenced and subjected to the construction of mouse scFv 3-D structure. Based on in silico modeling, the humanized version of the scFv was designed via complementarity-determining region (CDR) grafting with the retention of mouse framework region (FR) residues identified by primary sequence analysis. Root-mean-square deviation (RMSD) value between mouse and humanized scFv structures was calculated to evaluate the preservation of CDR conformation. Mouse and humanized scFv genes were then constructed and expressed in Escherichia coli. Using this method, we successfully generated humanized scFvs that retained the targeting activity of their respective mouse scFv counterparts. In addition, the humanized scFvs were engineered with a C-terminal cysteine residue (hscFv-C) for site-directed conjugation for use in future targeting applications. The hscFv-C expression was extensively optimized to improve protein production yield. The protocol yielded a 20-fold increase in production of hscFv-Cs in E. coli periplasm. The strategy described in this study may be applicable in the humanization of other antibodies derived from mouse hybridoma.

  15. In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach.

    PubMed

    Dinger, Julia; Meyer, Markus R; Maurer, Hans H

    2016-02-01

    In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50 % inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.

  16. Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase – a template for drug design

    PubMed Central

    Saravanamuthu, Ahilan; Vickers, Tim J.; Bond, Charles S.; Peterson, Mark R.; Hunter, William N.; Fairlamb, Alan H.

    2012-01-01

    SUMMARY Trypanothione reductase is a key enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes. Since this system is absent in humans, being replaced with glutathione and glutathione reductase, it offers a target for selective inhibition. The rational design of potent inhibitors requires accurate structures of enzyme-inhibitor complexes, but this is lacking for trypanothione reductase. We therefore used quinacrine mustard, an alkylating derivative of the competitive inhibitor quinacrine, to probe the active site of this dimeric flavoprotein. Quinacrine mustard irreversibly inactivates Trypanosoma cruzi trypanothione reductase, but not human glutathione reductase, in a time-dependent manner with a stoichiometry of two inhibitors bound per monomer. The rate of inactivation is dependent upon the oxidation state of trypanothione reductase, with the NADPH-reduced form being inactivated significantly faster than the oxidised form. Inactivation is slowed by clomipramine and a melarsen oxide-trypanothione adduct (both are competitive inhibitors) but accelerated by quinacrine. The structure of the trypanothione reductase-quinacrine mustard adduct was determined to 2.7 Å, revealing two molecules of inhibitor bound in the trypanothione-binding site. The acridine moieties interact with each other through π-stacking effects, and one acridine interacts in a similar fashion with a tryptophan residue. These interactions provide a molecular explanation for the differing effects of clomipramine and quinacrine on inactivation by quinacrine mustard. Synergism with quinacrine occurs as a result of these planar acridines being able to stack together in the active site cleft, thereby gaining an increased number of binding interactions, whereas antagonism occurs with non-planar molecules, such as clomipramine, where stacking is not possible. PMID:15102853

  17. Multifunctional targeted therapy system based on (99m) Tc/(177) Lu-labeled gold nanoparticles-Tat(49-57)-Lys(3) -bombesin internalized in nuclei of prostate cancer cells.

    PubMed

    Jiménez-Mancilla, Nallely; Ferro-Flores, Guillermina; Santos-Cuevas, Clara; Ocampo-García, Blanca; Luna-Gutiérrez, Myrna; Azorín-Vega, Erika; Isaac-Olivé, Keila; Camacho-López, Miguel; Torres-García, Eugenio

    2013-11-01

    Radiolabeled gold nanoparticles may function simultaneously as radiotherapy and thermal ablation systems. The gastrin-releasing peptide receptor (GRP-r) is overexpressed in prostate cancer, and Lys(3) -bombesin is a peptide that binds with high affinity to the GRP-r. HIV Tat(49-57) is a cell-penetrating peptide that reaches the DNA. In cancer cells, (177) Lu shows efficient crossfire effect, whereas (99m) Tc that is internalized in the cancer cell nuclei acts as an effective system of targeted radiotherapy because of the biological Auger effect. The aim of this research was to evaluate the in vitro potential of (99m) Tc-labeled and (177) Lu-labeled gold nanoparticles conjugated to Tat(49-57)-Lys(3) -bombesin peptides ((99m) Tc/(177) Lu-AuNP-Tat-BN) as a plasmonic photothermal therapy and targeted radiotherapy system in PC3 prostate cancer cells. Peptides were conjugated to AuNPs (5 nm) by spontaneous reaction with the thiol group of cysteine (Cys). The effect on PC3 cell viability after laser heating of the AuNP-Tat-BN incubated with the cancer cells was conducted using an Nd:YAG laser pulsed for 5 ns at 532 nm (0.65 W/cm(2) ). For the (99m) Tc/(177) Lu-AuNP-Tat-BN to be obtained, the (177) Lu-DOTA-Gly-Gly-Cys and (99m) Tc-HYNIC-octreotide radiopeptides were first prepared and added simultaneously to a solution of AuNP-Tat-BN. (99m) Tc/(177) Lu-AuNP-Tat-BN (20 Bq/cell) was incubated with PC3 cells, and the effect on the cell proliferation was evaluated after 3 days. Fluorescence images of (99m) Tc/(177) Lu-AuNP-Tat-BN internalized in nuclei of PC3 were also obtained. After laser irradiation, the presence of AuNP-Tat-BN caused a significant increase in the temperature of the medium (46.4 vs 39.5 °C of that without AuNP) resulting in a significant decrease in PC3 cell viability down to 1.3%. After treatment with (99m) Tc/(177) Lu-AuNP-Tat-BN, the PC3 cell proliferation was inhibited. The nanosystem exhibited properties suitable for plasmonic

  18. Design, synthesis of novel starch derivative bearing 1,2,3-triazolium and pyridinium and evaluation of its antifungal activity.

    PubMed

    Tan, Wenqiang; Li, Qing; Gao, Zhenpeng; Qiu, Shuai; Dong, Fang; Guo, Zhanyong

    2017-02-10

    Based on cuprous-catalyzed azide-alkyne cycloaddition (CuAAC), starch derivative bearing 1,2,3-triazole and pyridine (II) was prepared and subsequently followed by alkylation with iodomethane to synthesize starch derivative bearing 1,2,3-triazolium and pyridinium (III). The antifungal activities of starch derivatives against Colletotrichum lagenarium, Watermelon fusarium, and Phomopsis asparagi, were then assayed by hypha measurement in vitro. Apparently, starch derivatives showed enhanced antifungal activity against three fungi at the tested concentrations compared with starch. Especially, the best inhibitory index of starch derivative (III) against Colletotrichum lagenarium attained 97% above at 1.0mg/mL. Meanwhile, starch derivative (III) had stronger antifungal activity than starch derivative (II), which was reasonable to propose that the alkylation of 1,2,3-triazole and pyridine was significant for enhanced antifungal activity. As this novel starch derivative bearing 1,2,3-triazolium and pyridinium could be prepared efficiently and exhibited superduper antifungal activity, this material might provide an effective way and notion to prepare novel antifungal agents.

  19. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth.

    PubMed

    Chollet, Aurélien; Mori, Giorgia; Menendez, Christophe; Rodriguez, Frédéric; Fabing, Isabelle; Pasca, Maria Rosalia; Madacki, Jan; Korduláková, Jana; Constant, Patricia; Quémard, Annaïk; Bernardes-Génisson, Vania; Lherbet, Christian; Baltas, Michel

    2015-08-28

    A series of fluorene-based derivatives was synthesized and evaluated for inhibiting both InhA and Mycobacterium tuberculosis growth. These compounds were inspired by the previously reported Genz-10850 molecule, a good InhA inhibitor, but with a poor activity against M. tuberculosis growth. Structure-activity relationships were performed by introducing the following chemical modifications: 1) the piperazine ring; 2) the amide group; 3) the aryl moiety; and 4) the fluorene moiety. Among these new derivatives, one of them was more effective against both the InhA activity and mycobacterial growth, compared to the hit compound. Docking studies were also performed to rationalize activities of these derivatives. Furthermore, we showed for the first time that efflux pump inhibitors potentiated the efficacy of Genz-10850 (GEQ) derivatives against M. tuberculosis growth, demonstrating that these compounds could be substrates of some efflux pumps.

  20. Pm-149 DOTA bombesin analogs for potential radiotherapy. in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-betaAla-BBN(7-14)NH(2).

    PubMed

    Hu, Fang; Cutler, Cathy S; Hoffman, Timothy; Sieckman, Gary; Volkert, Wynn A; Jurisson, Silvia S

    2002-05-01

    Promethium-149 (149Pm) is one of only three radiolanthanides that can be prepared in no carrier added concentrations. This high specific activity radiolanthanide is thus suitable for targeting limited numbers of specific receptors found on many tumor cells. Promethium-149 is a moderate energy beta(-) emitter (1.07 MeV (95.9%)) with a half-life of 2.21 days. Pm-149 also emits a low abundance of an imageable gamma ray (286 keV (3%)) that may allow in vivo tracking of the therapeutic dose. The 149Pm and Sm complexes with the DO3A-amide chelator with zero and three carbon spacers to the bombesin peptide analog BBN(7-14)NH(2) were synthesized and characterized. The Sm complexes were synthesized for macroscopic characterization purposes (ESI-MS, in vitro cell binding) since no stable isotopes of Pm are known. The biological properties of the 149Pm, 153Sm and 177Lu-DO3A-amide-betaAla-BBN complexes were compared in normal mouse biodistribution studies.

  1. A User-Centered Framework for Deriving A Conceptual Design From User Experiences: Leveraging Personas and Patterns to Create Usable Designs

    NASA Astrophysics Data System (ADS)

    Javahery, Homa; Deichman, Alexander; Seffah, Ahmed; Taleb, Mohamed

    Patterns are a design tool to capture best practices, tackling problems that occur in different contexts. A user interface (UI) design pattern spans several levels of design abstraction ranging from high-level navigation to low-level idioms detailing a screen layout. One challenge is to combine a set of patterns to create a conceptual design that reflects user experiences. In this chapter, we detail a user-centered design (UCD) framework that exploits the novel idea of using personas and patterns together. Personas are used initially to collect and model user experiences. UI patterns are selected based on personas pecifications; these patterns are then used as building blocks for constructing conceptual designs. Through the use of a case study, we illustrate how personas and patterns can act as complementary techniques in narrowing the gap between two major steps in UCD: capturing users and their experiences, and building an early design based on that information. As a result of lessons learned from the study and by refining our framework, we define a more systematic process called UX-P (User Experiences to Pattern), with a supporting tool. The process introduces intermediate analytical steps and supports designers in creating usable designs.

  2. Molecular design of Cy3 derivative for highly sensitive in-stem molecular beacon and its application to the wash-free FISH.

    PubMed

    Kashida, Hiromu; Osawa, Takuya; Morimoto, Kazuhiro; Kamiya, Yukiko; Asanuma, Hiroyuki

    2015-04-15

    We herein describe a novel in-stem molecular beacon (ISMB) containing multiple Cy3-quencher pairs on d-threoninol scaffolds in the stem region. The designed Cy3 derivative was not significantly quenched by the adjacent nucleobases, self-quenching of the fluorophore was minimal, and the fluorophore did not severely destabilize the duplex. Using newly designed Cy3, we synthesized ISMBs containing two Cy3 moieties. The signal to background ratio of the ISMB containing two Cy3 moieties was above 100, whereas that with one Cy3 was 30. A Cy3-derivative containing ISMB used in a fluorescence in situ hybridization (FISH) detected endogenous β-actin mRNA in fixed cells without need for washing procedures.

  3. Design, synthesis and evaluation of PEGylated lipoic acid derivatives with functionality as potent anti-melanogenic agents.

    PubMed

    Lu, Chichong; Kim, Bo-Mi; Chai, Kyu Yun

    2011-10-01

    The novel PEGylated lipoic acid (LA) derivatives with functionality were synthesized in satisfactory yield by simple procedures and evaluated about its anti-melanogenic activity on the B16F10 melanoma cells. Grafting a PEG moiety onto the carboxyl group of LA has reduced the cell cytotoxicity and provided the water solubility and functionality to incorporate the other bioactive moieties. We have found that derivatives showed inhibition of melanin formation by up to 36.5% at 0.1 mM, whereas LA decreased the melanin formation by 8.6%. In addition, it also inhibits at least 86.4% UV-induced MMP-1 expression at 0.1 mM which is higher than LA. These data suggest that the novel PEGylated LA derivatives with functionality may thus serve as a potentially effective anti-melanogenic and anti-aging agent.

  4. Design, synthesis, characterization, quantum-chemical calculations and anti-inflammatory activity of novel series of thiophene derivatives

    NASA Astrophysics Data System (ADS)

    Helal, M. H.; Salem, M. A.; Gouda, M. A.; Ahmed, N. S.; El-Sherif, A. A.

    2015-08-01

    Interaction of 1-(4-morpholinophenyl)ethanone 1 with either malononitrile or ethyl cyanoacetate 2 afforded Knoevenagel-Cope product 3. In subsequent treatment of 3 with sulfur, the 2-aminothiophene derivatives (4a, 4b) are formed under basic conditions. The solvent-free reaction of thiophene derivative 4a with ethyl cyanoacetate afforded thieno[2,3-d][1,3]oxazine derivative 6. The base catalyzed condensation of 2-aminothiophene derivative (4a) with ethyl cyanoacetate afforded N-(thieno-2-yl) cyanoacetamide derivative 7. The latter was used to synthesize different heterocyclic derivatives comprising, pyridine and coumarin rings. Also, several substituted thieno[2,3-d]pyrimidines have been prepared from reaction of 2-aminothiophene-3-carbonitrile 4b with some electrophilic reagents. The structure of the newly compounds were confirmed on the basis of elemental analysis and spectral data. The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Evaluation of anti-inflammatory activity of the tested compounds was performed in albino rats by producing carrageenan induced paw oedema and measuring the zone of inflammation at different time intervals i.e. 1, 2, 3 and 4 h after carrageenan injection. Results indicated that most of the tested compounds showed moderate to good activity comparable to indomethacin. Also, compound 16 with additional morpholine ring beside the thiophene ring inhibits carrageenan induced paw oedema more than the standard indomethacin drug at all the time scales studied. Thus, compound 16 is considered as a promising compound for further modification to obtain clinically useful anti-inflammatory agent.

  5. Conformational analysis of thioglycoside derivatives of histo-blood group ABH antigens using an ab initio-derived reparameterization of MM4: implications for design of non-hydrolysable mimetics

    NASA Astrophysics Data System (ADS)

    Strino, Francesco; Lii, Jenn-Huei; Gabius, Hans-Joachim; Nyholm, Per-Georg

    2009-12-01

    Histo-blood group ABH antigens serve as recognition sites for infectious microorganisms and tissue lectins in intercellular communication, e.g. in tumor progression. Thus, they are of interest as a starting point for drug design. In this respect, potent non-hydrolysable derivatives such as thioglycosides are of special interest. As prerequisite to enable estimations of ligand properties relative to their natural counterparts, conformational properties of the thioglycosidic derivatives of ABH trisaccharides and their disaccharide units were calculated using systematic and filtered systematic searches with the MM4 force field. Parameters for the glycosidic torsions of thioglycosides were independently derived from ab initio calculations. The resulting energy deviations required a reparameterization of MM4 to a new parameter set called MM4R. The data sets obtained using MM4R reveal that the thioglycosides have somewhat increased levels of flexibility about the major low-energy conformations shared with the corresponding O-glycosides. In the trisaccharides, the thiosubstitution of the Gal[NAc]α1-3Gal linkage leads to a preference for a conformation which is the secondary minimum of the natural counterparts. This conformation also generates contacts between the N-acetyl group and the fucose moiety in the blood group A derivative. Calculations further indicate that thiosubstitution of only the Fucα1-2Gal linkage does not affect the conformational preferences compared to the natural trisaccharide. Thiosubstitution of both linkages in the trisaccharide results in increased flexibility but the favored conformation of the natural trisaccharides is preferred. The study suggests that thioglycoside derivatives of ABH antigens could have pharmaceutical interest as ligands of lectins and other carbohydrate-binding proteins.

  6. Conceptual/preliminary design study of subsonic v/stol and stovl aircraft derivatives of the S-3A

    NASA Technical Reports Server (NTRS)

    Kidwell, G. H., Jr.

    1981-01-01

    A computerized aircraft synthesis program was used to examine the feasibility and capability of a V/STOL aircraft based on the Navy S-3A aircraft. Two major airframe modifications are considered: replacement of the wing, and substitution of deflected thrust turbofan engines similar to the Pegasus engine. Three planform configurations for the all composite wing were investigated: an unconstrained span design, a design with the span constrained to 64 feet, and an unconstrained span oblique wing design. Each design was optimized using the same design variables, and performance and control analyses were performed. The oblique wing configuration was found to have the greatest potential in this application. The mission performance of these V/STOL aircraft compares favorably with that of the CTOL S-3A.

  7. A novel approach to evaluate the pharmacokinetic biocomparability of a monoclonal antibody derived from two different cell lines using simultaneous crossover design.

    PubMed

    Han, Chao; McIntosh, Thomas S; Geist, Brian J; Jiao, Trina; Puchalski, Thomas A; Goldberg, Kenneth M; Yang, Tong-Yuan; Pendley, Charles E; Zhou, Honghui; Davis, Hugh M

    2014-01-01

    A parallel study design with a large number of subjects has been a typical path for pharmacokinetic (PK) biocomparability assessment of biotherapeutics with long half-lives and immunogenic propensity, for example, monoclonal antibodies (mAb). A recently published innovative bioanalytical method that can quantify mAb produced from two different cell lines in the same sample opened an avenue to exploring a simultaneous crossover study design for PK biocomparability assessment of biotherapeutics. Siltuximab, a chimeric IgG1 mAb-targeting interleukin-6, was studied as an example. The pharmacokinetic biocomparability of siltuximab derived from mouse myeloma (Sp2/0) cells and Chinese hamster ovary cells was previously assessed and demonstrated in a clinical PK biocomparability study that enrolled more than 140 healthy subjects using a parallel trial design. The biocomparability was successfully shown in six cynomolgus monkeys in a preclinical proof-of-concept study using the new crossover study design supported by the analytical method. The impact of antidrug antibodies on the assessment of biocomparability was minimal. This novel approach opened up a new arena for the evaluation of PK biocomparability of biotherapeutics with unique molecular signatures such as a mAb derived from different cell lines.

  8. Design, synthesis, and antiproliferative activity of 3,4-diarylpyrazole-1-carboxamide derivatives against melanoma cell line.

    PubMed

    El-Gamal, Mohammed I; Choi, Hong Seok; Cho, Hae-Guk; Hong, Jun Hee; Yoo, Kyung Ho; Oh, Chang-Hyun

    2011-11-01

    Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied.

  9. Design, synthesis, pharmacological evaluation and molecular dynamics of β-amino acids morphan-derivatives as novel ligands for opioid receptors.

    PubMed

    Nieto, Carlos T; Gonzalez-Nunez, Veronica; Rodríguez, Raquel E; Diez, David; Garrido, Narciso M

    2015-08-28

    Structure-Activity Relationship (SAR) is a current approach in the design of new pharmacological agents. We previously reported the synthesis of a novel analogue of morphine, a 2-azabicyclo[3.3.1]nonane, which contains a β-amino acid. This bicyclic core exhibits two distinctive chemical handles for further elaboration, which allowed us to create a library of morphan-containing compounds by in silico molecular docking on the μ opioid receptor. Lead candidates were synthesized and biological tests were performed to evaluate their ability to bind to opioid receptors. The four top compounds, three phenyl esters and an N-phenylethyl morphan derivative, were selected for Molecular Dynamics simulations to get topological and thermodynamic information. Aromatic morphan derivatives displayed an interacting domain which fits into a hydrophobic cleft and the effect of the substituents in their affinity was explained by the differences in the calculated binding free energies. Our results indicate that the 3D arrangement of the aromatic ring in the morphine derivatives is not a key issue for a specific ligand - μ receptor interaction. Thus, these morphan derivatives represent a new class of opioid receptor ligands which may be of great use in the clinical practice.

  10. In vitro and in vivo evaluation of Alexa Fluor 680-bombesin[7-14]NH2 peptide conjugate, a high-affinity fluorescent probe with high selectivity for the gastrin-releasing peptide receptor.

    PubMed

    Ma, Lixin; Yu, Ping; Veerendra, Bhadrasetty; Rold, Tammy L; Retzloff, Lauren; Prasanphanich, Adam; Sieckman, Gary; Hoffman, Timothy J; Volkert, Wynn A; Smith, Charles J

    2007-01-01

    Gastrin-releasing peptide (GRP) receptors are overexpressed on several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. Bombesin (BBN), a 14-amino acid peptide that is an analogue of human GRP, binds to GRP receptors with very high affinity and specificity. The aim of this study was to develop a new fluorescent probe based on BBN having high tumor uptake and optimal pharmacokinetics for specific targeting and optical imaging of human breast cancer tissue. In this study, solid-phase peptide synthesis was used to produce H(2)N-glycylglycylglycine-BBN[7-14]NH(2) peptide with the following general sequence: H(2)N-G-G-G-Q-W-A-V-G-H-L-M-(NH(2)). This conjugate was purified by reversed-phase high-performance liquid chromatography and characterized by electrospray-ionization mass spectra. The fluorescent probe Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) conjugate was prepared by reaction of Alexa Fluor 680 succinimidyl ester to H(2)N-G-G-G-BBN[7-14]NH(2) in dimethylformamide (DMF). In vitro competitive binding assays, using (125)I-Tyr(4)-BBN as the radiolabeling gold standard, demonstrated an inhibitory concentration 50% value of 7.7 +/- 1.4 nM in human T-47D breast cancer cells. Confocal fluorescence microscopy images of Alexa Fluor 680-G-G-G-BBN[7-14]NH(2) in human T-47D breast cancer cells indicated specific uptake, internalization, and receptor blocking of the fluorescent bioprobe in vitro. In vivo investigations in SCID mice bearing xenografted T-47D breast cancer lesions demonstrated the ability of this new conjugate to specifically target tumor tissue with high selectivity and affinity.

  11. Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles.

    PubMed

    Challa, Krishna; Bhargavi, M Vijaya; Krupadanam, G L David

    2016-12-01

    Taking into consideration of the biological activity of betulinic acid derivatives containing a oxadiazole ring, the semisynthetic betulinic acid-1,2,4-oxadiazole esters (14-25) were synthesized starting from betulinic acid (1) and 5-(bromomethyl)-3-aryl-1,2,4-oxadiazoles (2-13) and final compounds were tested for cytotoxic activity on three human cancer cell lines in vitro. All tested compounds showed good cytotoxic activity. The structures of synthesized compounds are established based on infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry.

  12. System analysis approach to deriving design criteria (Loads) for Space Shuttle and its payloads. Volume 2: Typical examples

    NASA Technical Reports Server (NTRS)

    Ryan, R. S.; Bullock, T.; Holland, W. B.; Kross, D. A.; Kiefling, L. A.

    1981-01-01

    The achievement of an optimized design from the system standpoint under the low cost, high risk constraints of the present day environment was analyzed. Space Shuttle illustrates the requirement for an analysis approach that considers all major disciplines (coupling between structures control, propulsion, thermal, aeroelastic, and performance), simultaneously. The Space Shuttle and certain payloads, Space Telescope and Spacelab, are examined. The requirements for system analysis approaches and criteria, including dynamic modeling requirements, test requirements, control requirements, and the resulting design verification approaches are illustrated. A survey of the problem, potential approaches available as solutions, implications for future systems, and projected technology development areas are addressed.

  13. System analysis approach to deriving design criteria (loads) for Space Shuttle and its payloads. Volume 1: General statement of approach

    NASA Technical Reports Server (NTRS)

    Ryan, R. S.; Bullock, T.; Holland, W. B.; Kross, D. A.; Kiefling, L. A.

    1981-01-01

    Space shuttle, the most complex transportation system designed to date, illustrates the requirement for an analysis approach that considers all major disciplines simultaneously. Its unique cross coupling and high sensitivity to aerodynamic uncertainties and high performance requirements dictated a less conservative approach than those taken in programs. Analyses performed for the space shuttle and certain payloads, Space Telescope and Spacelab, are used a examples. These illustrate the requirements for system analysis approaches and criteria, including dynamic modeling requirements, test requirements control requirements and the resulting design verification approaches. A survey of the problem, potential approaches available as solutions, implications for future systems, and projected technology development areas are addressed.

  14. Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.

    PubMed

    Tang, Li; Zhao, Liying; Hong, Lingjuan; Yang, Fenyan; Sheng, Rong; Chen, Jianzhong; Shi, Ying; Zhou, Naimin; Hu, Yongzhou

    2013-10-01

    A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.

  15. Design, synthesis, and pharmacological evaluation of 5-oxo-1,2,4-oxadiazole derivatives as AT1 antagonists with antihypertension activities.

    PubMed

    Zhu, Weibo; Bao, Xiaolu; Ren, He; Liao, Pingyong; Zhu, Wei; Yan, Yijia; Wang, Li; Chen, Zhilong

    A series of new 5-oxo-1,2,4-oxadiazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole group was designed, synthesized, and pharmacologically evaluated. These derivatives displayed high affinities to the AT1 receptor at the same order of magnitude to losartan. The methyl ester with 1, 4-disubsituted indole group, 1 (5.01 ± 1.67 nM) showed high antihypertension activity on spontaneously hypertensive rats (SHRs). Its maximal response lowered 30 mmHg of mean blood pressure (MBP) at 10 mg/kg after oral administration, which was better than irbesartan, and the antihypertensive effect lasted beyond 24 h. These results made 1 deserve further investigation.

  16. Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: new lead-agents with analgesic and antipyretic properties.

    PubMed

    Bezerra-Netto, Heleno J C; Lacerda, Daniel I; Miranda, Ana Luisa P; Alves, Hélio M; Barreiro, Eliezer J; Fraga, Carlos A M

    2006-12-01

    In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.

  17. Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co-crystal structure.

    PubMed

    Esvan, Yannick J; Zeinyeh, Wael; Boibessot, Thibaut; Nauton, Lionel; Théry, Vincent; Knapp, Stefan; Chaikuad, Apirat; Loaëc, Nadège; Meijer, Laurent; Anizon, Fabrice; Giraud, Francis; Moreau, Pascale

    2016-08-08

    The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.

  18. Design and synthesis of (S)- and (R)-α-(phenyl)ethylamine-derived NH-type ligands and their application for the chemical resolution of α-amino acids.

    PubMed

    Takeda, Ryosuke; Kawamura, Akie; Kawashima, Aki; Moriwaki, Hiroki; Sato, Tatsunori; Aceña, José Luis; Soloshonok, Vadim A

    2014-08-28

    This work presents the first chemical approach for the resolution of α-amino acids offering the following advantages: (1) The specially designed resolving reagent is derived from α-(phenyl)ethylamine, the most inexpensive chiral auxiliary, which can be recycled and reused, rendering the cost structure of the complete process very attractive; (2) the time-efficient two-step process can be conducted under operationally convenient conditions with virtually quantitative yields; and (3) the process can readily be adapted to large-scale use.

  19. Design of proportional-derivative-type state feedback controllers for congestion control of transmission control protocol networks

    NASA Astrophysics Data System (ADS)

    Azadegan, Masoumeh; Beheshti, Mohammad T. H.; Tavassoli, Babak

    2015-07-01

    A new proportional-derivative-type state feedback controller is proposed for congestion control of transmission control protocol (TCP) networks. An analytical TCP model is adopted. In the proposed control scheme, it is possible to efficiently control the TCP traffic using only the queue length at the router without the need to know the TCP window size which is not available locally. The results are presented in terms of delay-dependent linear matrix inequality. The proposed method is verified by simulation examples using NS software, and the effectiveness and superiority of our method over other control schemes, such as the proportional-integral, random early detection and generalised minimum variancemethods, are also shown.

  20. Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase.

    PubMed

    Crocetti, Letizia; Giovannoni, Maria Paola; Schepetkin, Igor A; Quinn, Mark T; Khlebnikov, Andrei I; Cilibrizzi, Agostino; Piaz, Vittorio Dal; Graziano, Alessia; Vergelli, Claudia

    2011-08-01

    Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC₅₀ values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.

  1. Rational Design and Synthesis of [5]Helicene-Derived Phosphine Ligands and Their Application in Pd-Catalyzed Asymmetric Reactions

    NASA Astrophysics Data System (ADS)

    Yamamoto, Kosuke; Shimizu, Takashi; Igawa, Kazunobu; Tomooka, Katsuhiko; Hirai, Go; Suemune, Hiroshi; Usui, Kazuteru

    2016-11-01

    A series of novel optically active [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure- and L2, with a fully aromatic [5]helicene core structure) were synthesized. Despite their structural similarities, L1 and L2 exhibit particularly different characteristics in their use as chiral ligands. L1 was highly effective in the asymmetric allylation of indoles with 1,3-diphenylallyl acetate (up to 99% ee), and in the etherification of alcohols (up to 96% ee). In contrast, L2 was highly effective in the stereocontrol of helical chirality in Suzuki–Miyaura coupling (SMC) reaction (up to 99% ee). Density functional theory analysis was employed to propose a model that accounts for the origin of the enantioselectivity in these reactions.

  2. Design, synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents.

    PubMed

    Guo, Zhi-Hua; Yin, Yong; Wang, Cong; Wang, Peng-Fei; Zhang, Xing-Tao; Wang, Zhong-Chang; Zhu, Hai-Liang

    2015-09-15

    A series of novel salicylic acid derivatives containing metronidazole as Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) inhibitors have been synthesized and evaluated their biology activities as potential antibacterial agents. Among these compounds, compound 5r exhibited the most potent antibacterial activity against Gram-positive (S. aureus ATCC 6538 and Bacillus subtilis ATCC 6633) and Gram-negative (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) with MICs of 0.39-1.57 μg/mL and showed the most potent S. aureus Tyrosyl-tRNA synthetase inhibitory with 2.3 μM. Docking simulation was performed to insert compound 5r into the crystal structure of S. aureus Tyrosyl-tRNA synthetase active site to determine the probable binding model. These results suggested that compound 5r may be a promising antibacterial agent.

  3. Reflection and refraction of narrow Gaussian beams with general astigmatism at tilted optical surfaces: a derivation oriented toward lens design.

    PubMed

    Greco, Vincenzo; Giusfredi, Giovanni

    2007-02-01

    The formulas for the reflection and refraction of a narrow Gaussian beam with general astigmatism at a tilted optical surface are derived by ray-tracing techniques. The propagation direction of the reflected and refracted beams is computed by tracing the central ray of the incident beam, and the characteristic parameters of the respective wavefronts are worked out by applying the formulas developed for the generalized ray tracing. Moreover, the Gaussian form of the reflected and refracted amplitude distributions along the transverse coordinates is determined by requiring the matching of the incident, reflected, and refracted light spots on the optical surface. No limiting assumptions are made regarding the form of the optical interface or the orientation of the incident astigmatic wavefront. In the end, to illustrate a simple application of these formulas, the reflection of a Gaussian beam at a conicoid is considered, and a simple property of the conicoidal mirrors is reported.

  4. Novel molecular combination deriving from natural aminoacids and polyphenols: Design, synthesis and free-radical scavenging activities.

    PubMed

    Silvia, Vertuani; Baldisserotto, Anna; Scalambra, Emanuela; Malisardi, Gemma; Durini, Elisa; Manfredini, Stefano

    2012-04-01

    Following the recent output of scientific publications in the matter of synergic activity between different antioxidants, we have undertaken the present study with the aim to synthesize new molecules with radical-scavengers activity based on the conjugation of bioactive portions (i.e. phenols, cysteine, methionine or tyrosine), characterized by different structures and mechanisms of action, to promote the simultaneous quenching of different radical species in the site of the oxidative damage. In this context, derivatives of phenolic acid, aminoacids and dopamine have been also prepared. The newly synthesized compounds were evaluated in vitro applying specific and complementary antioxidant test such as DPPH assay and ORAC test. As emerged from the evaluation, prerequisites for the activity of the synthesized molecules were: i) the maintenance of at least two hydroxylic groups on the aromatic moiety of phenolic portion, ii) the presence of a spacer between the aromatic moiety and the carbonilic group.

  5. Rational Design and Synthesis of [5]Helicene-Derived Phosphine Ligands and Their Application in Pd-Catalyzed Asymmetric Reactions

    PubMed Central

    Yamamoto, Kosuke; Shimizu, Takashi; Igawa, Kazunobu; Tomooka, Katsuhiko; Hirai, Go; Suemune, Hiroshi; Usui, Kazuteru

    2016-01-01

    A series of novel optically active [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure- and L2, with a fully aromatic [5]helicene core structure) were synthesized. Despite their structural similarities, L1 and L2 exhibit particularly different characteristics in their use as chiral ligands. L1 was highly effective in the asymmetric allylation of indoles with 1,3-diphenylallyl acetate (up to 99% ee), and in the etherification of alcohols (up to 96% ee). In contrast, L2 was highly effective in the stereocontrol of helical chirality in Suzuki–Miyaura coupling (SMC) reaction (up to 99% ee). Density functional theory analysis was employed to propose a model that accounts for the origin of the enantioselectivity in these reactions. PMID:27824074

  6. Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions.

    PubMed

    Burster, Timo; Marin-Esteban, Viviana; Boehm, Bernhard O; Dunn, Shannon; Rotzschke, Olaf; Falk, Kirsten; Weber, Ekkehard; Verhelst, Steven H L; Kalbacher, Hubert; Driessen, Christoph

    2007-11-15

    Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics.

  7. Determination of 32 cathinone derivatives and other designer drugs in serum by comprehensive LC-QQQ-MS/MS analysis.

    PubMed

    Swortwood, Madeleine J; Boland, Diane M; DeCaprio, Anthony P

    2013-02-01

    Recently, clandestine drug lab operators have attempted to bypass controlled substances laws and regulations with "designer" compounds chemically and pharmacologically similar to controlled substances. For example, "bath salts" have erupted onto the scene as "legal highs" containing cathinone analogs that have produced severe side effects in users worldwide. These products have sparked concern among law enforcement agencies, and emergency bans have been placed on the sale of such items. Despite the increasing number of designer drugs available, there are few comprehensive screening techniques for their detection and quantification in biological specimens. The liquid chromatography triple quadrupole tandem mass spectrometry (LC-QQQ-MS/MS) method presented here encompasses over thirty important compounds within the phenethylamine, tryptamine, and piperazine designer drug classes. Analytes were determined by LC-QQQ-MS/MS in the multiple-reaction monitoring mode after mixed-mode solid-phase extraction. The bioanalytical method was fully validated according to recommended international guidelines. The assay was selective for all analytes with acceptable accuracy and precision. Limits of quantification were in the range of 1-10 ng/mL for each compound with limits of detection near 10 pg/mL. In order to evaluate its applicability in a forensic toxicological setting, the validated method was used to analyze post-mortem specimens from two cases that were suspected of containing designer drugs. The method was able to identify and quantify seven of these compounds at concentrations as low as 11 ng/mL. The method should have wide applicability for rapid screening of important new drugs of abuse at high sensitivity in both post- and ante-mortem forensic analysis.

  8. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2001-04-01

    During the period January 1, 2001-March 31, 2001, Allegheny Energy Supply Co., LLC (Allegheny) finalized the engineering of the Willow Island cofiring project, completed the fuel characterizations for both the Willow Island and Albright Generating Station projects, and initiated construction of both projects. Allegheny and its contractor, Foster Wheeler, selected appropriate fuel blends and issued purchase orders for all processing and mechanical equipment to be installed at both sites. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations. The third quarter of the project involved completing the detailed designs for the Willow Island Designer Fuel project. It also included complete characterization of the coal and biomass fuels being burned, focusing upon the following characteristics: proximate and ultimate analysis; higher heating value; carbon 13 nuclear magnetic resonance testing for aromaticity, number of aromatic carbons per cluster, and the structural characteristics of oxygen in the fuel; drop tube reactor testing for high temperature devolatilization kinetics and generation of fuel chars; thermogravimetric analyses (TGA) for char oxidation kinetics; and related testing. The construction at both sites commenced during this quarter, and was largely completed at the Albright Generating Station site.

  9. ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents.

    PubMed

    Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled A M; Abou El Ella, Dalal A; Ismail, Nasser S M

    2009-05-15

    A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.

  10. Design, synthesis, molecular modeling and biological evaluation of novel 2,3-dihydrophthalazine-1,4-dione derivatives as potential anticonvulsant agents

    NASA Astrophysics Data System (ADS)

    El-Helby, Abdel Ghany A.; Ayyad, Rezk R.; Sakr, Helmy M.; Abdelrahim, Adel S.; El-Adl, K.; Sherbiny, Farag S.; Eissa, Ibrahim H.; Khalifa, Mohamed M.

    2017-02-01

    In view of their expected anticonvulsant activity, some novel derivatives of 2,3-dihydrophthalazine-1,4-dione 4-22 were designed, synthesized and evaluated using pentylenetetrazole (PTZ) and picrotoxin as convulsion-inducing models. Moreover, the most active compounds were tested against electrical induced convulsion using maximal electroshock (MES) models of seizures. Most of the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 13 and 14g were proved to be the most potent compounds of this series with relatively low toxicity in the median lethal dose test when compared with the reference drug. Molecular modeling studies were done to verify the biological activity. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogues.

  11. Observations on the design and operation of pulsejet engines as derived from an experimental and theoretical investigation

    SciTech Connect

    Richardson, J.S.; Artt, D.W.; Blair, G.P.

    1984-01-01

    This paper describes some of the experimental and theoretical work carried out at the Queen's University, Belfast in connection with a pulsejet project. It starts from the earliest stages of trying to achieve a working reed valved engine and continues to the present where valveless pulsejets have been designed with the aid of a simulation program. Suggestions are made regarding the manner in which various parameters such as duct and intake geometry, orientation and flight speed can affect performance. It suggest four main criteria which must be fulfilled for any valveless pulsejet to operate successfully and discusses methods by which these can be achieved.

  12. Structure-Based Design of Novel Tetrahydro-Beta-Carboline Derivatives with a Hydrophilic Side Chain as Potential Phosphodiesterase Inhibitors

    PubMed Central

    Elhady, Ahmed K.; Sigler, Sara C.; Noureldin, Nazih; Canzoneri, Joshua C.; Ahmed, Nermin S.; Piazza, Gary A.; Abadi, Ashraf H.

    2015-01-01

    Tadalafil is a clinically approved phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction and pulmonary arterial hypertension. It contains two chiral carbons, and the marketed isomer is the 6R, 12aR isomer with a methyl substituent on the terminal nitrogen of the piperazinedione ring. In this report, tadalafil analogues with an extended hydrophilic side chain on the piperazine nitrogen were designed to interact with particular hydrophilic residues in the binding pocket. This leads to analogues with moderate inhibitory activity on phosphodiesterase-5, even for isomers in which chiral carbons are of the S configuration. PMID:28117310

  13. Design, synthesis and biological evaluation of sugar-derived esters, [alpha]-ketoesters and [alpha]-ketoamides as inhibitors for Mycobacterium tuberculosis antigen 85C

    SciTech Connect

    Sanki, Aditya K.; Boucau, Julie; Umesiri, Francis E.; Ronning, Donald R.; Sucheck, Steven J.

    2010-08-16

    Peptide-based 1,2-dicarbonyl compounds have emerged as potent inhibitors for serine proteases. Herein, we have designed and synthesized D-arabinose and D-trehalose-based esters, {alpha}-ketoesters and {alpha}-ketoamides, and evaluated their inhibitory activity against Mycobacterium tuberculosis (Mtb) antigen 85C (ag85C), an acyltransferase in the serine hydrolase superfamily. In addition the compounds were evaluated for the ability to inhibit the growth of Mycobacterium smegmatis ATCC 14468, a non-pathogenic surrogate for Mtb. Among the synthetic analogs evaluated only the methyl ester1 derived from D-arabinose was found to inhibit the acyltransferase activity of ag85C (IC{sub 50} = 25 mM). Based on this weak inhibitory activity it was not surprising that none of the compounds inhibits the growth of M. smegmatis. In spite of the weak inhibitory activity of 1, X-ray crystallography on crystals of ag85C soaked with 1 suggested the formation of a covalent ester adduct between 1 and the Ser124 side chain hydroxyl moiety found within the catalytic site of ag85C; however, some of the active site electron density appears to result from bound glycerol. The lack of activity associated with the {alpha}-ketoester and {alpha}-ketoamide derivatives of D-trehalose may be the result of intramolecular cyclization of the {alpha}-keto moiety with the nearby C-4/4' hydroxyls leading to the formation of stable bicyclo-ester and amide derivatives.

  14. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives.

    PubMed

    Ruddarraju, Radhakrishnam Raju; Murugulla, Adharvana Chari; Kotla, Ravindar; Chandra Babu Tirumalasetty, Muni; Wudayagiri, Rajendra; Donthabakthuni, Shobha; Maroju, Ravichandar; Baburao, K; Parasa, Lakshmana Swamy

    2016-11-10

    A new series of theophylline containing acetylene derivatives (6a-6b and 7-13) and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives (20-32) have been designed and synthesized. These compounds were screened for anticancer and antimicrobial activity. Further the computational docking and 2D QSAR were performed using MOE software to identify novel scaffolds. The results showed that compound 29 and 30 exhibit significant cytotoxic effect on all four cancer cells such as lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375) with IC50 values of 2.56, 2.19, 1.89, 4.89 μM and 3.57, 2.90, 2.10, 5.81 μM respectively. Whereas quite different results were observed for these compounds in antimicrobial studies. Compounds 11, 21 and 26 have exhibited significant minimum inhibitory concentrations (MIC) against Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa. The docking studies demonstrate that compound 27, 28, 29 and 30 have good dock score and binding affinities with various therapeutic targets in cancer cell proliferation. In addition these compounds have shown acceptable correlation with bioassay results in the regression plots generated in 2D QSAR models. This is the first report to demonstrate the theophylline containing acetylene derivatives and theophylline containing 1,2,3-triazole nucleoside hybrids as potential anticancer and antimicrobial agents with comprehensive in silico analysis.

  15. Design and application of anthracene derivative with aggregation-induced emission charateristics for visualization and monitoring of erythropoietin unfolding.

    PubMed

    Sun, Binjie; Yang, Xiaojun; Ma, Lin; Niu, Caixia; Wang, Fangfang; Na, Na; Wen, Jiying; Ouyang, Jin

    2013-02-12

    Erythropoietin (EPO) is an attractive protein-unfolding/folding model because of its high degree of unfolding and folding reversibility and intermediate size. Due to its function for regulating red blood cell production by stimulating late erythroid precursor cells, EPO presents obvious values to biological research. A nonemissive anthracene derivative, that is 9,10-bis[4-(3-sulfonatopropoxyl)-styryl]anthracene sodium salt (BSPSA), with aggregation-induced emission (AIE) charateristics shows a novel phenomenon of AIE when EPO is added. The AIE biosensor for EPO shows the limit of detection is 1 × 10(-9) M. Utilizing the AIE feature of BSPSA, the unfolding process of EPO using guanidine hydrochloride is monitored, which indicates three steps for the folding structures of EPO to transform to random coil. Computational modeling suggests that the BSPSA luminogens prefer docking in the hydrophobic cavity in the EPO folding structures, and the assembly of BSPSA in this cavity makes the AIE available, making the monitoring of unfolding of EPO possible.

  16. Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents.

    PubMed

    Revathi, Rajappan; Venkatesha Perumal, Ramachandran; Pai, Karkala Sreedhara Ranganath; Arunkumar, Govindakarnavar; Sriram, Dharmarajan; Kini, Suvarna Ganesh

    2015-01-01

    Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl) piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski's rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski's rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene] hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N-hydroxy-hydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 µg/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy.

  17. Design, synthesis, antibacterial evaluation and docking study of novel 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone.

    PubMed

    Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin

    2015-01-01

    A novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolones 6a-o were synthesized and evaluated for their in vitro antibacterial activity. Most of the target compounds exhibited potent activity against Gram-positive strains. Among them, moxifloxacin analog 6n displayed the most potent activity against Gram-positive strains including S. epidermidis (MIC = 0.06 μg/mL), MSSE (MIC = 0.125 μg/mL), MRSE (MIC = 0.03 μg/mL), S. aureus (MIC = 0.125 μg/mL), MSSA (MIC = 0.125 μg/mL), (MIC = 2 μg/mL). Its activity against MRSA was eightfold more potent than reference drug gatifloxacin. Finally, docking study of the target compound 6n revealed that the binding model of quinolone nucleus was similar to that of gatifloxacin and the 2-hydroxy-3-(nitroimidazolyl)-propyl group formed two additional hydrogen bonds.

  18. Design and Synthesis of Acetylenyl Benzamide Derivatives as Novel Glucokinase Activators for the Treatment of T2DM

    PubMed Central

    2015-01-01

    Novel acetylenyl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mM glucose concentration and glucose uptake in rat hepatocytes. Lead optimization of an acetylenyl benzamide series led to the discovery of several active compounds via in vitro enzyme assays (EC50 < 40 nM) and in vivo OGTT assays (AUC reduction > 40% at 50 mg/kg). Of the active compounds tested, 3-(3-amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-benzamide (19) was identified as a potent glucokinase activator exhibiting an EC50 of 27 nM and eliciting a 2.16-fold increase in glucose uptake. Compound 19 caused a glucose AUC reduction of 47.4% (30 mg/kg) in an OGTT study in C57BL/6J mice compared to 22.6% for sitagliptin (30 mg/kg). Single treatment of the compound 19 in C57BL/6J mice elicited basal glucose lowering activity without any significant evidence for hypoglycemia risk. Compound 19 was therefore selected as a candidate for further preclinical development for the treatment of type 2 diabetes. PMID:25815149

  19. Design, Synthesis and Biological Evaluation of New 1, 4-Dihydropyridine (DHP) Derivatives as Selective Cyclooxygenase-2 Inhibitors.

    PubMed

    Sabakhi, Iman; Topuzyan, Vigen; Hajimahdi, Zahra; Daraei, Bahram; Arefi, Hadi; Zarghi, Afshin

    2015-01-01

    As a continuous research for discovery of new COX-2 inhibitors, chemical synthesis, in vitro biological activity and molecular docking study of a new group of 1, 4-dihydropyridine (DHP) derivatives were presented. Novel synthesized compounds possessing a COX-2 SO2Me pharmacophore at the para position of C-4 phenyl ring, different hydrophobic groups (R1) at C-2 position and alkoxycarbonyl groups (COOR2) at C-3 position of 1, 4-dihydropyridine, displayed selective inhibitory activity against COX-2 isozyme. Among them, compound 5e was identified as the most potent and selective COX-2 inhibitor with IC50 value of 0.30 μM and COX-2 selectivity index of 92. Molecular docking study was performed to determine probable binding models of compound 5e. The study showed that the p-SO2Me-phenyl fragment of 5e inserted inside secondary COX-2 binding site (Arg(513), Phe(518), Gly(519), and His(90)). The structure-activity relationships acquired reveal that compound 5e with methyl and ethoxycarbonyl as R1 and COOR2 substitutions has the necessary geometry to provide selective inhibition of the COX-2 isozyme and it can be a good basis for the development of new hits.

  20. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2001-01-01

    During the period October 1, 2000 - December 31, 2000, Allegheny Energy Supply Co., LLC (Allegheny) executed a Cooperative Agreement with the National Energy Technology Laboratory to implement a major cofiring demonstration at the Willow Island Generating Station Boiler No.2. Willow Island Boiler No.2 is a cyclone boiler. Allegheny also will demonstrate separate injection cofiring at the Albright Generating Station Boiler No.3, a tangentially fired boiler. The Allegheny team includes Foster Wheeler as its primary subcontractor. Additional subcontractors are Cofiring Alternatives and N.S. Harding and Associates. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations. The second quarter of the project involved completing the designs for each location. Further, geotechnical investigations proceeded at each site. Preparations were made to perform demolition on two small buildings at the Willow Island site. Fuels strategies were initiated for each site. Test planning commenced for each site. A groundbreaking ceremony was held at the Willow Island site on October 18, with Governor C. Underwood being the featured speaker.

  1. N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells.

    PubMed

    Prestegui-Martel, Berenice; Bermúdez-Lugo, Jorge Antonio; Chávez-Blanco, Alma; Dueñas-González, Alfonso; García-Sánchez, José Rubén; Pérez-González, Oscar Alberto; Padilla-Martínez, Itzia Irene; Fragoso-Vázquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Correa-Basurto, Ana María; Méndez-Luna, David; Trujillo-Ferrara, José; Correa-Basurto, José

    2016-01-01

    Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

  2. Derivation and implementation of a nonlinear experimental design criterion and its application to seismic network expansion at Kawerau geothermal field, New Zealand

    NASA Astrophysics Data System (ADS)

    Rawlinson, Z. J.; Townend, J.; Arnold, R.; Bannister, S.

    2012-09-01

    The accuracy with which geophysical observations are made is inherently determined by the geometry of the observation network, and typically depends on a highly non-linear relationship between data and earth parameters. Statistical experimental design provides a means of optimizing the network geometry to provide maximum information about parameters of interest. Here, we re-derive the nonlinear experimental design DN optimization method, without the need for the usual assumption of a multivariate normal model of data uncertainties. We demonstrate the criterion's utility by applying it to the problem of seismic network expansion in the active Kawerau geothermal field, Taupo Volcanic Zone, New Zealand. The design calculations maximize the ratio of the hypocentre data generalized variance (attributable to resolvable spatial separation of earthquakes) to the measurement error generalized variance (attributable to observational uncertainties), and incorporate realistic 3-D velocity and attenuation models, surface noise sources, and both P- and S-wave data. In geologically complex areas, statistical experimental design provides a means of objectively deploying finite observational resources to target areas of particular interest while taking into account environmental and logistical factors.

  3. Design, in silico studies, synthesis and in vitro evaluation of oseltamivir derivatives as inhibitors of neuraminidase from influenza A virus H1N1.

    PubMed

    Neri-Bazán, Rocío M; García-Machorro, Jazmín; Méndez-Luna, David; Tolentino-López, Luis E; Martínez-Ramos, Federico; Padilla-Martínez, Itzia I; Aguilar-Faisal, Leopoldo; Soriano-Ursúa, Marvin A; Trujillo-Ferrara, José G; Fragoso-Vázquez, M Jonathan; Barrón, Blanca L; Correa-Basurto, José

    2017-03-10

    Since the neuraminidase (NA) enzyme of the influenza A virus plays a key role in the process of release of new viral particles from a host cell, it is often a target for new drug design. The emergence of NA mutations, such as H275Y, has led to great resistance against neuraminidase inhibitors, including oseltamivir and zanamivir. Hence, we herein designed a set of derivatives by modifying the amine and/or carboxylic groups of oseltamivir. After being screened for their physicochemical (Lipinski's rule) and toxicological properties, the remaining compounds were submitted to molecular and theoretical studies. The docking simulations provided insights into NA recognition patterns, demonstrating that oseltamivir modified at the carboxylic moiety and coupled with anilines had higher affinity and a better binding pose for NA than the derivatives modified at the amine group. Based on these theoretical studies, the new oseltamivir derivatives may have higher affinity to mutant variants and possibly to other viral subtypes. Accordingly, two compounds were selected for synthesis, which together with their respective intermediates were evaluated for their cytotoxicity and antiviral activities. Their biological activity was then tested in cells infected with the A/Puerto Rico/916/34 (H1N1) influenza virus, and virus yield reduction assays were performed. Additionally, by measuring neuraminidase activity with the neuraminidase assay kit it was found that the compounds produced inhibitory activity on this enzyme. Finally, the infected cells were analysed with atomic force microscopy (AFM), observing morphological changes strongly suggesting that these compounds interfered with cellular release of viral particles.

  4. Structure-based design and synthesis of Harmine derivatives with different selectivity profiles in kinase vs monoamine oxidase inhibition.

    PubMed

    Balint, Balazs; Weber, Csaba; Cruzalegui, Francisco; Burbridge, Mike; Kotschy, Andras

    2017-03-06

    DYRK1A is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design we have synthesized a collection of harmine analogs with tunable selectivity towards these two enzymes. Modifications in position 7 typically decreased affinity for DYRK1A while substitution in position 9 had a similar effect on MAO-A inhibition while maintaining DYRK1A inhibition. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.

  5. Deriving the concentration of airborne ash with a CAS-DPOL instrument: assessing uncertainties introduced by the instrument design

    NASA Astrophysics Data System (ADS)

    Spanu, Antonio; Weinzierl, Bernadett; Freudenthaler, Volker; Sauer, Daniel; Gasteiger, Josef

    2016-04-01

    Explosive volcanic eruptions inject large amounts of gas and particles into the atmosphere resulting in strong impacts on anthropic systems and climate. Fine ash particles in suspension, even if at low concentrations, are a serious aviation safety hazard. A key point to predict the dispersion and deposition of volcanic ash is the knowledge of emitted mass and its particle size distribution. Usually the deposit is used to characterize the source but a large uncertainty is present for fine and very fine ash particles which are usually not well preserved. Conversely, satellite observations provide only column-integrated information and are strongly sensitive to cloud conditions above the ash plumes. Consequently, in situ measurements are fundamental to extend our knowledge on ash clouds, their properties, and interactions over the vertical extent of the atmosphere. Different in-situ instruments are available covering different particle size ranges using a variety of measurement techniques. Depending on the measurement technique, artefacts due to instrument setup and ambient conditions can strongly modify the measured number concentration and size distribution of the airborne particles. It is fundamental to correct for those effects to quantify the uncertainty associated with the measurement. Here we evaluate the potential of our optical light-scattering spectrometer CAS-DPOL to detect airborne mineral dust and volcanic ash (in the size range between 0.7μm and 50μm) and to provide a reliable estimation of the mass concentration, investigating the associate uncertainty. The CAS-DPOL instrument sizes particles by detecting the light scattered off the particle into a defined angle. The associated uncertainty depends on the optical instrument design and on unknown particles characteristics such as shape and material. Indirect measurements of mass concentrations are statistically reconstructed using the air flow velocity. Therefore, the detected concentration is strongly

  6. Multivariable Control Law Design for Enhanced Air Combat Maneuvering. F-15/STOL (Short Take-Off and Landing) Derivative Fighter.

    DTIC Science & Technology

    1985-12-01

    controller matrix K(1 (alpha)K0.- 4. Irregular design: M = 0.3, 0 , OIT. 354 (LI -JJC H . -r G -~ -- J 5 -2. 8 c355 77F r - .- hzI...Integral Gain, 0 1(1=6.67*1( 0 (O.3M, FL200).............81 4.3b Direct Climb: High Integral Gain, 1(1=6.67*1( 0 (0.3M, FL200) ............ 81 4.4a Direct...Plant+Actuators (0.9M/FL200)..................115 0 5.27 Vertical Trans: Plant+Actuators+Delay - (0.9M/FL200)..................116.. 5.28 Vertical Trans

  7. Imidazole incorporated semicarbazone derivatives as a new class of anticonvulsants: design, synthesis and in-vivo screening.

    PubMed

    Amir, Mohammad; Ali, Israr; Hassan, Mohd Zaheen

    2013-06-01

    A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, 1H NMR, 13C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of γ-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug.

  8. Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach

    PubMed Central

    Zhao, Li-Ming; Ma, Feng-Yan; Jin, Hai-Shan; Zheng, Shilong; Zhong, Qiu; Wang, Guangdi

    2016-01-01

    A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1′-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer. PMID:26291039

  9. Design of a Retrovirus-Derived Vector for Expression and Transduction of Exogenous Genes in Mammalian Cells

    PubMed Central

    Perkins, Archibald S.; Kirschmeier, Paul T.; Gattoni-Celli, Sebastiano; Weinstein, I. Bernard

    1983-01-01

    We have developed a transfection vector for animal cells that contains long terminal repeat (LTR) sequences to promote expression. Plasmid p101/101, a derivative of plasmid pBR322 containing the complete Moloney murine sarcoma virus genome, was cut with restriction enzymes and religated so that both the 5′ and 3′ LTRs were retained and all but about 700 base pairs of the intervening viral sequences were removed. To test this vector, the Escherichia coli gene gpt was cloned into a unique PstI site, between the two LTRs, with guanine and cytosine tailing, a method that can be generalized for insertion of any DNA segment into this vector. When DNA from recombinant plasmids in which the gpt gene was inserted in the same transcriptional polarity as the LTR sequences was transfected onto murine or rat fibroblast cultures, we obtained a high yield of Gpt+ colonies. However, plasmid constructs with the gpt gene in the opposite polarity were virtually devoid of activity. With gpt in the proper orientation, restriction enzyme cuts within the LTRs or between the 5′ LTR and the gpt gene reduced transfection by more than 98%, whereas a cut between the gpt gene and the 3′ LTR gave an 80% reduction in activity. Thus, both 5′ and 3′ LTR sequences are essential for optimal gpt expression, although the 5′ LTR appears to play a more important role. When the LTR-gpt plasmid was transfected onto murine leukemia virus-infected mouse fibroblasts, we obtained evidence that RNA copies became pseudotyped into viral particles which could transfer the Gpt+ phenotype into rodent cells with extremely high efficiency. This vector should prove useful for high-efficiency transduction of a variety of genes in mammalian cells. Images PMID:6308426

  10. Digital mapping of the Mars Pathfinder landing site: Design, acquisition, and derivation of cartographic products for science applications

    USGS Publications Warehouse

    Gaddis, L.R.; Kirk, R.L.; Johnson, J. R.; Soderblom, L.A.; Ward, A.W.; Barrett, J.; Becker, K.; Decker, T.; Blue, J.; Cook, D.; Eliason, E.; Hare, T.; Howington-Kraus, E.; Isbell, C.; Lee, E.M.; Redding, B.; Sucharski, R.; Sucharski, T.; Smith, P.H.; Britt, D.T.

    1999-01-01

    The Imager for Mars Pathfinder (IMP) acquired more than 16,000 images and provided panoramic views of the surface of Mars at the Mars Pathfinder landing site in Ares Vallis. This paper describes the stereoscopic, multispectral IMP imaging sequences and focuses on their use for digital mapping of the landing site and for deriving cartographic products to support science applications of these data. Two-dimensional cartographic processing of IMP data, as performed via techniques and specialized software developed for ISIS (the U.S.Geological Survey image processing software package), is emphasized. Cartographic processing of IMP data includes ingestion, radiometric correction, establishment of geometric control, coregistration of multiple bands, reprojection, and mosaicking. Photogrammetric processing, an integral part of this cartographic work which utilizes the three-dimensional character of the IMP data, supplements standard processing with geometric control and topographic information [Kirk et al., this issue]. Both cartographic and photogrammetric processing are required for producing seamless image mosaics and for coregistering the multispectral IMP data. Final, controlled IMP cartographic products include spectral cubes, panoramic (360?? azimuthal coverage) and planimetric (top view) maps, and topographic data, to be archived on four CD-ROM volumes. Uncontrolled and semicontrolled versions of these products were used to support geologic characterization of the landing site during the nominal and extended missions. Controlled products have allowed determination of the topography of the landing site and environs out to ???60 m, and these data have been used to unravel the history of large- and small-scale geologic processes which shaped the observed landing site. We conclude by summarizing several lessons learned from cartographic processing of IMP data. Copyright 1999 by the American Geophysical Union.

  11. Design and synthesis of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as novel tyrosinase inhibitors.

    PubMed

    Ha, Young Mi; Park, Yun Jung; Kim, Jin-Ah; Park, Daeui; Park, Ji Young; Lee, Hye Jin; Lee, Ji Yeon; Moon, Hyung Ryong; Chung, Hae Young

    2012-03-01

    In continuing our search for novel tyrosinase inhibitors, a series of 5-(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a-2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and L-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC(50) values of 13.36 and 9.87 μM, respectively, than kojic acid (IC(50) = 24.72 μM). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-melanocyte-stimulating hormone (α-MSH). These data strongly suggest that compounds 2a and 2f suppress the production of melanin via the inhibition of tyrosinase activity.

  12. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

    PubMed

    Mazella, Jean; Pétrault, Olivier; Lucas, Guillaume; Deval, Emmanuel; Béraud-Dufour, Sophie; Gandin, Carine; El-Yacoubi, Malika; Widmann, Catherine; Guyon, Alice; Chevet, Eric; Taouji, Said; Conductier, Grégory; Corinus, Alain; Coppola, Thierry; Gobbi, Gabriella; Nahon, Jean-Louis; Heurteaux, Catherine; Borsotto, Marc

    2010-04-13

    Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative

  13. Design, Synthesis and Biological Evaluation of Novel Phosphorylated Abacavir Derivatives as Antiviral Agents Against Newcastle Disease Virus Infection in Chicken.

    PubMed

    K A, Suresh; Venkata Subbaiah, Kadiam C; Lavanya, Rayapu; Chandrasekhar, Kuruva; Chamarti, Naga Raju; Kumar, M Suresh; Wudayagiri, Rajendra; Valluru, Lokanatha

    2016-09-01

    Newcastle disease virus is the most devastating virus in poultry industry. It can eradicate the entire poultry flocks once infected. This study is aimed to investigate the antiviral efficacy of novel phosphorylated analogues of the drug abacavir (ABC) against Newcastle disease virus (NDV). About 16 analogues of ABC were designed and docking was performed against fusion protein of NDV. Three compounds were identified and selected for synthesis and biological evaluation based on binding affinity and docking scores. The compounds were synthesized and characterized by IR, (1)H, (13)C, (31)P and CHN analysis and mass spectra. These compounds were tested for antiviral efficacy against NDV-infected DF-1 cells. Compound ABC-1 had shown potent antiviral activity as evidenced by significant reduction in plaque units and cytopathic effect. Therefore, ABC-1 was selected to test for NDV-infected chicken survival rate. Effective dose50 concentrations were determined for ABC-1. Antioxidant enzyme levels in brain, liver and lung tissues were estimated. Superoxide dismutase and catalase were significantly raised and lipid peroxidation and HA titer levels were decreased upon treatment with 2 mg/kg body weight ABC-1. Histopathological modifications were also restored in the ABC-1-treated group. These findings demonstrated ABC-1 as a potential antiviral agent against NDV in chicken.

  14. Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer.

    PubMed

    Bassetto, Marcella; Ferla, Salvatore; Pertusati, Fabrizio; Kandil, Sahar; Westwell, Andrew D; Brancale, Andrea; McGuigan, Christopher

    2016-08-08

    Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

  15. Molecular Design, Graft Polymerization and Performance Evaluation of Radiation Curable Flame Retardant Monomers Derived from Phosphorus-Nitrogen Systems

    NASA Astrophysics Data System (ADS)

    Edwards, Brian Tyndall

    The textile industry is constantly seeking new technologies to make its production more efficient, economical and environmentally friendly. An exciting new strategy to impart value-added functional finishes to textiles is the use of radiation, such as ultraviolet (UV) light, to drive the polymerization of monomers onto the surface of the substrates. These grafted polymeric layers provide the fiber or fabric with interesting new properties, such as antimicrobial behavior, water and oil repellency or flame retardancy. With the aid of a photoinitiator, UV curing can take place very rapidly and the process is waterless and uses less energy than traditional textile wet processing. With these thoughts in mind, this research explores the molecular design, synthesis, UV induced graft polymerization and performance evaluation of nine phosphorus-based flame retardant monomers for cellulosic cotton substrates. All monomers in this work were easily prepared using one-pot reactions procedures. With the assistance of Irgacure 819 photoinitiator, seven of the nine monomers were shown to simultaneously graft and polymerize onto the surface of cotton fabrics under UV radiation. JMPRTM Pro 10 software was used to explore the effect of variables, such as monomer concentration, photoinitiator concentration and UV exposure time, on the yield of the grafted polymeric layer. Burn testing of the treated fabrics in the vertical, 45° and horizontal orientations showed that all nine monomers were effective flame retardants that function via the condensed phase mechanism by encouraging the formation of nonflammable char. These burn test results were validated by thermogravimetric analysis, which demonstrated quantitatively that all nine monomers strongly promote the generation of a protective char. Finally, scanning electron microscopy was used to examine the surface morphology of the treated fabrics and visualize the grafted polymeric layer.

  16. The economical production of alcohol fuels from coal-derived synthesis gas: Case studies, design, and economics

    SciTech Connect

    1995-10-01

    This project is a combination of process simulation and catalyst development aimed at identifying the most economical method for converting coal to syngas to linear higher alcohols to be used as oxygenated fuel additives. There are two tasks. The goal of Task 1 is to discover, study, and evaluate novel heterogeneous catalytic systems for the production of oxygenated fuel enhancers from synthesis gas, and to explore, analytically and on the bench scale, novel reactor and process concepts for use in converting syngas to liquid fuel products. The goal of Task 2 is to simulate, by computer, energy efficient and economically efficient processes for converting coal to energy (fuel alcohols and/or power). The primary focus is to convert syngas to fuel alcohols. This report contains results from Task 2. The first step for Task 2 was to develop computer simulations of alternative coal to syngas to linear higher alcohol processes, to evaluate and compare the economics and energy efficiency of these alternative processes, and to make a preliminary determination as to the most attractive process configuration. A benefit of this approach is that simulations will be debugged and available for use when Task 1 results are available. Seven cases were developed using different gasifier technologies, different methods for altering the H{sub 2}/CO ratio of the syngas to the desired 1.1/1, and with the higher alcohol fuel additives as primary products and as by-products of a power generation facility. Texaco, Shell, and Lurgi gasifier designs were used to test gasifying coal. Steam reforming of natural gas, sour gas shift conversion, or pressure swing adsorption were used to alter the H{sub 2}/CO ratio of the syngas. In addition, a case using only natural gas was prepared to compare coal and natural gas as a source of syngas.

  17. Design, synthesis, insecticidal activity, and structure-activity relationship (SAR): studies of novel triazone derivatives containing a urea bridge group based on transient receptor potential (TRP) channels.

    PubMed

    Yang, Yan; Liu, Yuxiu; Song, Hongjian; Li, Yongqiang; Wang, Qingmin

    2016-11-01

    Numerous compounds containing urea bridge and biurea moieties are used in a variety of fields, especially as drugs and pesticides. To search for novel, environmentally benign and ecologically safe pesticides with unique modes of action, four series of novel triazone analogues containing urea, thiourea, biurea, and thiobiurea bridge, respectively, were designed and synthesized, according to various calcium ion channel inhibitors which act on transient receptor potential protein. Their structures were characterized by [Formula: see text] NMR, [Formula: see text] NMR, and HRMS. The insecticidal activities of the new compounds were obtained. The bioassay results indicated that compounds containing a thiourea bridge and a thiobiurea bridge exhibited excellent insecticidal activities against bean aphid. Specifically, compounds [Formula: see text], [Formula: see text], and [Formula: see text] exhibited 85, 90, and 95 % activities, respectively, at 10 mg/kg. Compounds [Formula: see text] (30 %), [Formula: see text] (35 %), [Formula: see text] (30 %), and [Formula: see text] (40 %) exhibited the approximate aphicidal activity of pymetrozine (30 %) at 5 mg/kg. In addition, some target compounds exhibited insecticidal activities against lepidopteran pests. From a molecular design standpoint, the information obtained in this study could help in the further design of new derivatives with improved insecticidal activities.

  18. Quinic acid derivatives as sialyl Lewis(x)-mimicking selectin inhibitors: design, synthesis, and crystal structure in complex with E-selectin.

    PubMed

    Kaila, Neelu; Somers, William S; Thomas, Bert E; Thakker, Paresh; Janz, Kristin; DeBernardo, Silvano; Tam, Steve; Moore, William J; Yang, Ruiyang; Wrona, Wojciech; Bedard, Patricia W; Crommie, Deidre; Keith, James C; Tsao, Desiree H H; Alvarez, Juan C; Ni, Heyu; Marchese, Erik; Patton, John T; Magnani, John L; Camphausen, Raymond T

    2005-06-30

    A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.

  19. Design and synthesis of novel benzo[d]oxazol-2(3H)-one derivatives bearing 7-substituted-4-enthoxyquinoline moieties as c-Met kinase inhibitors.

    PubMed

    Lu, Dong; Shen, Aijun; Liu, Yang; Peng, Xia; Xing, Weiqiang; Ai, Jing; Geng, Meiyu; Hu, Youhong

    2016-06-10

    Analysis of the results of studies of docking 1 and 7a with c-Met kinase led to the identification of benzo[d]oxazol-2(3H)-one-quinolone derivatives as potential inhibitors of this enzyme. A molecular hybrid strategy, using a 4-ethoxy-7-substituted-quinoline core and a benzo[d]oxazol-2(3H)-one scaffold, was employed to design members of this family for study as inhibitors of the kinase and proliferation of EBC-1 cells. Most of the substances were found to display good to excellent c-Met kinase inhibitory activities. The results of a structure-activity relationship (SAR) study led to the discovery of benzo[d]oxazol-2(3H)-one-quinolone 13, which has IC50 values of 1 nM against c-Met kinase and 5 nM against proliferation of the EBC-1 cell line.

  20. Structure-Based Design, Synthesis, and Evaluation of 2'-(2-Hydroxyethyl)-2'-deoxyadenosine and the 5'-Diphosphate Derivative as Ribonucleotide Reductase Inhibitors

    SciTech Connect

    Sun, D.; Xu, H.; Wijerathna, S.R.; Dealwis, C.; Lee, R.E.

    2010-08-27

    Analysis of the recently solved X-ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2'-hydroxy group of the nucleoside ribose. In this study 2'-(2-hydroxyethyl)-2'-deoxyadenosine 1 and the 5'-diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2, and the co-crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized.

  1. Inhibitory effect of isothiocyanate derivant targeting AGPS by computer-aid drug design on proliferation of glioma and hepatic carcinoma cells.

    PubMed

    Zhu, Yu; Li, Wen-Ming; Zhang, Ling; Xue, Jing; Zhao, Meng; Yang, Ping

    2015-01-01

    Lipids metabolism was involved in the process of many types of tumor and alkylglycerone phosphate synthase (AGPS) was considered implicated in tumor process. Benzyl isothiocyanate (BITC) showed the inhibitory effect of tumor and AGPS activity, therefore, we screened a group of small molecular compound based on BITC by computer-aid design targeting AGPS and the results showed that the derivants could suppress the proliferation, the expression of tumor related genes such as survivin and Bcl-2, and the level of ether lipids such as lysophosphatidic acid ether (LPAe) and platelet activating factor ether (PAFe); however, the activity of caspase-3/8 was improved in glioma U87MG and hepatic carcinoma HepG2 cells in vitro.

  2. Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.

    PubMed

    Li, Guo; Aschenbach, Lindsey C; Chen, Jianyang; Cassidy, Michael P; Stevens, David L; Gabra, Bichoy H; Selley, Dana E; Dewey, William L; Westkaemper, Richard B; Zhang, Yan

    2009-03-12

    Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible mu opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K(i) = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the delta receptor (DOR) and more than 150-fold selectivity over the kappa receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.

  3. Design, synthesis and antiepileptic properties of novel 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl)urea derivatives.

    PubMed

    Prakash, Chinnasamy Rajaram; Raja, Sundararajan

    2011-12-01

    Twenty new 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) urea derivatives were designed and synthesized. Antiepileptic screening was performed using MES and scPTZ seizures tests. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 5c, 5g, 5j and 5n were found active in MES model, while 5o showed significant antiepileptic activity in scPTZ model. Further all these five compounds were administered orally to rats, 5c, 5g and 5n showed better activity than Phenytoin in oral route. Among these compounds 5c revealed protection in MES at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration respectively. This molecule provided also protection in the scPTZ at a dose of 300 mg/kg in both time intervals.

  4. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2003-01-01

    During the period October 1, 2002--December 31, 2002, Allegheny Energy Supply Co., LLC (Allegheny) completed the first year of testing at the Willow Island cofiring project. This included data acquisition and analysis associated with certain operating parameters and environmental results. Over 2000 hours of cofiring operation were logged at Willow Island, and about 4,000 tons of sawdust were burned along with slightly more tire-derived fuel (TDF). The results were generally favorable. During this period, also, a new grinder was ordered for the Albright Generating Station to handle oversized material rejected by the disc screen. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations. It details the test results at Willow Island and summarizes the grinder program at Albright.

  5. Design, Synthesis, and Antitumor Activity of Novel 5-Pyridyl-1,3,4-oxadiazole Derivatives against the Breast Cancer Cell Line MCF-7.

    PubMed

    Khalil, Nadia Abdalla; Kamal, Aliaa Moh; Emam, Soha Hussein

    2015-01-01

    Various 1,3,4-oxadiazole-2-thiol derivatives have considerable potential in the field of antitumor activity. On the basis of the structure of the highly active reported oxadiazole analogues, 36 novel compounds were designed. Their molecular transport properties were predicted using a computer-aided program, and they were then synthesized and tested for anticancer activity against the breast cancer cell line MCF-7. Most of the tested compounds showed excellent to potent cytotoxic activity. Docking studies were carried out to examine the possibilities of the target compounds to become lead compounds in the future after more biological investigations. Compounds 18 and 22 were more active than the reference drug with IC₅₀ values of 0.010 µM and 0.012 µM, respectively, and binding energy scores of -10.32 and -10.25, respectively.

  6. Design and synthesis of new imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrazine derivatives with antiproliferative activity against melanoma cells.

    PubMed

    Garamvölgyi, Rita; Dobos, Judit; Sipos, Anna; Boros, Sándor; Illyés, Eszter; Baska, Ferenc; Kékesi, László; Szabadkai, István; Szántai-Kis, Csaba; Kéri, György; Őrfi, László

    2016-01-27

    Melanoma is an aggressive form of skin cancer and it is generally associated with poor prognosis in patients with late-stage disease. Due to the increasing occurrence of melanoma, there is a need for the development of novel therapies. A new series of diarylamide and diarylurea derivatives containing imidazo[1,2-a]pyridine or imidazo[1,2-a]pyrazine scaffold was designed and synthesized to investigate their in vitro efficacy against the A375P human melanoma cell line. We found several compounds expressing submicromolar IC50 values against the A375P cells, from which 15d, 17e, 18c, 18h, 18i demonstrated the highest potencies with IC50 below 0.06 μM.

  7. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives.

    PubMed

    Okaniwa, Masanori; Hirose, Masaaki; Arita, Takeo; Yabuki, Masato; Nakamura, Akito; Takagi, Terufumi; Kawamoto, Tomohiro; Uchiyama, Noriko; Sumita, Akihiko; Tsutsumi, Shunichirou; Tottori, Tsuneaki; Inui, Yoshitaka; Sang, Bi-Ching; Yano, Jason; Aertgeerts, Kathleen; Yoshida, Sei; Ishikawa, Tomoyasu

    2013-08-22

    With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.

  8. Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC “click” chemistry as potential anticancer agents

    PubMed Central

    Jin, Xin; Yan, Tian-Hua; Yan, Lan; Li, Qian; Wang, Rui-Lian; Hu, Zhen-Lin; Jiang, Yuan-Ying; Sun, Qing-Yan; Cao, Yong-Bing

    2014-01-01

    A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC. PMID:25120353

  9. Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists

    PubMed Central

    2016-01-01

    UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models. PMID:27331270

  10. Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists.

    PubMed

    Lingam, V S Prasadarao; Dahale, Dnyaneshwar H; Rathi, Vijay E; Shingote, Yogesh B; Thakur, Rajni R; Mindhe, Ajit S; Kummari, Srinivas; Khairatkar-Joshi, Neelima; Bajpai, Malini; Shah, Daisy M; Sapalya, Ratika S; Gullapalli, Srinivas; Gupta, Praveen K; Gudi, Girish S; Jadhav, Satyawan B; Pattem, Rambabu; Thomas, Abraham

    2015-10-22

    We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.

  11. Hexadentate bispidine derivatives as versatile bifunctional chelate agents for copper(II) radioisotopes.

    PubMed

    Juran, Stefanie; Walther, Martin; Stephan, Holger; Bergmann, Ralf; Steinbach, Jörg; Kraus, Werner; Emmerling, Franziska; Comba, Peter

    2009-02-01

    The preparation and use of bispidine derivatives (3,7-diazabicyclo[3.3.1]nonane) as chelate ligands for radioactive copper isotopes for diagnosis (64Cu) or therapy (67Cu) are reported. Starting from the hexadentate bispidine-based bis(amine)tetrakis(pyridine) ligand 1 with a keto and two ester substituents, the corresponding mono-ol 2 and two dicarboxylic acid derivatives 3 and 5 have been synthesized. A range of techniques, including single-crystal X-ray structure analysis, UV/vis spectroscopy, cyclic voltammetry, thin-layer- (TLC), and high-performance liquid chromatography (HPLC), have been used to characterize the structure and stability of the copper(II)-bispidine complexes. A rapid formation (within 1 min) of stable copper(II)-bispidine complexes under mild conditions (ambient temperature, aqueous solution) has been observed. Challenge experiments of these complexes in the presence of a high excess of competing ligands, such as glutathione, cyclam, or superoxide dismutase (SOD), as well as in rat plasma, gave no evidence of demetalation or transchelation. The bifunctional bispidine derivative 5 can be readily functionalized with biologically active molecules at the pendant carboxylate groups. The coupling of a bombesin analogue betahomo-Glu-betaAla-betaAla-[Cha(13),Nle(14)]BBN(7-14), by condensation of a carboxylate of the bispidine backbone with the N-terminus of the peptide produced the bifunctional ligand 6. The radiocopper(II) complex of this bombesin-bispidine conjugate has a considerable hydrophilicity (log D(o/w) < -2.4), and this leads to a very fast blood clearance (blood: 0.28 +/- 0.02 SUV, 1 h p.i.), low liver tissue accumulation (liver: 1.20 +/- 0.27 SUV, 1 h p.i.), and rapid renal-urinary excretion (kidneys: 6.06 +/- 2.96 SUV, 1 h p.i.) as shown by biodistribution studies of 64Cu-6 in Wistar rats. Preliminary in vivo studies of 64Cu-6 in NMRI nu/nu mice, bearing the human prostate tumor PC-3 showed an accumulation of the conjugate in the tumor (2

  12. De novo design, synthesis and spectroscopic characterization of chiral benzimidazole-derived amino acid Zn(II) complexes: Development of tryptophan-derived specific hydrolytic DNA artificial nuclease agent

    NASA Astrophysics Data System (ADS)

    Parveen, Shazia; Arjmand, Farukh

    2012-01-01

    Novel ternary dizinc(II) complexes 1- 3, derived from 1,2-bis(1H-benzimidazol-2-yl)ethane-1,2-diol and L-form of amino acids (viz., tryptophan, leucine and valine) were synthesized and characterized by spectroscopic (IR, 1H NMR, UV-vis, ESI-MS) and other analytical methods. To evaluate the biological preference of chiral drugs for inherently chiral target DNA, interaction of 1- 3 with calf thymus DNA in Tris-HCl buffer was studied by various biophysical techniques which reveal that all these complexes bind to CT DNA non-covalently via electrostatic interaction. The higher Kb value of L-tryptophan complex 1 suggested greater DNA binding propensity. Further, to evaluate the mode of action at the molecular level, interaction studies of complexes 1 and 2 with nucleotides (5'-GMP and 5'-TMP) were carried out by UV-vis titrations, 1H and 31P NMR which implicates the preferential selectivity of these complexes to N3 of thymine rather than N7 of guanine. Furthermore, complex 1 exhibits efficient DNA cleavage with supercoiled pBR322. The complex 1 cleaves DNA efficiently involving hydrolytic cleavage pathway. Such chiral synthetic hydrolytic nucleases with asymmetric centers are gaining considerable attention owing to their importance in biotechnology and drug design, in particular to cleave DNA with sequence selectivity different from that of the natural enzymes.

  13. Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study.

    PubMed

    Shahraki, Omolbanin; Edraki, Najmeh; Khoshneviszadeh, Mehdi; Zargari, Farshid; Ranjbar, Sara; Saso, Luciano; Firuzi, Omidreza; Miri, Ramin

    2017-01-01

    Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.

  14. Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

    PubMed Central

    Shahraki, Omolbanin; Edraki, Najmeh; Khoshneviszadeh, Mehdi; Zargari, Farshid; Ranjbar, Sara; Saso, Luciano; Firuzi, Omidreza; Miri, Ramin

    2017-01-01

    Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells’ sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal. PMID:28243063

  15. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors.

    PubMed

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-06-08

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.

  16. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors

    NASA Astrophysics Data System (ADS)

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-06-01

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.

  17. In silico design, chemical synthesis and toxicological evaluation of 1,3-thiazolidine-2,4-dione derivatives as PPARγ agonists.

    PubMed

    Alemán-González-Duhart, Diana; Tamay-Cach, Feliciano; Correa-Basurto, José; Padilla-Martínez, Itzia Irene; Álvarez-Almazán, Samuel; Mendieta-Wejebe, Jessica Elena

    2017-02-12

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the metabolism of lipids and carbohydrates. The exogenous ligands of these receptors are thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus (DM2). However, drugs from this group produce adverse effects such as hepatic steatosis. Hence, the aim of this work was to design a set of small molecules that can activate the γ isoform of PPARs while minimizing the adverse effects. The derivatives were designed containing the polar head of TZD and an aromatic body, serving simultaneously as the body and tail. Two ligands were selected out of 130 tested. These compounds were synthesized in a solvent-free reaction and their physicochemical properties and toxicity were examined. Acute oral toxicity was determined by administering these compounds to female Wistar rats in increasing doses (as per the OECD protocol 425). The median lethal dose (LD50) of the compound substituted with a hydroxyl heteroatom was above 2000 mg/kg, and that of the compound substituted with halogens was 700-1400 mg/kg. The results suggest that the compounds can interact with PPARγ and elicit biological responses similar to other TZDs, but without showing adverse effects. The compounds will be subsequently evaluated in a DM2 animal model.

  18. Design synthesis and structure–activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl) propionamide derivatives as opioid ligands

    PubMed Central

    Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd. W.; Porecca, Frank; Hruby, Victor J.

    2016-01-01

    Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850–4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75 ± 21 nM, and 190 ± 42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170 ± 42 nM, in contrast to its binding affinity results. PMID:26712115

  19. Structure-based design and evaluation of novel N-phenyl-1H-indol-2-amine derivatives for fat mass and obesity-associated (FTO) protein inhibition.

    PubMed

    Padariya, Monikaben; Kalathiya, Umesh

    2016-10-01

    Fat mass and obesity-associated (FTO) protein contributes to non-syndromic human obesity which refers to excessive fat accumulation in human body and results in health risk. FTO protein has become a promising target for anti-obesity medicines as there is an immense need for the rational design of potent inhibitors to treat obesity. In our study, a new scaffold N-phenyl-1H-indol-2-amine was selected as a base for FTO protein inhibitors by applying scaffold hopping approach. Using this novel scaffold, different derivatives were designed by extending scaffold structure with potential functional groups. Molecular docking simulations were carried out by using two different docking algorithm implemented in CDOCKER (flexible docking) and AutoDock programs (rigid docking). Analyzing results of rigid and flexible docking, compound MU06 was selected based on different properties and predicted binding affinities for further analysis. Molecular dynamics simulation of FTO/MU06 complex was performed to characterize structure rationale and binding stability. Certainly, Arg96 and His231 residue of FTO protein showed stable interaction with inhibitor MU06 throughout the production dynamics phase. Three residues of FTO protein (Arg96, Asp233, and His231) were found common in making H-bond interactions with MU06 during molecular dynamics simulation and CDOCKER docking.

  20. Design.

    ERIC Educational Resources Information Center

    Online-Offline, 1998

    1998-01-01

    Provides an annotated bibliography of resources on this month's theme "Design" for K-8 language arts, art and architecture, music and dance, science, math, social studies, health, and physical education. Includes Web sites, CD-ROMs and software, videos, books, audiotapes, magazines, professional resources and classroom activities.…

  1. Design

    ERIC Educational Resources Information Center

    Buchanan, Richard; Cross, Nigel; Durling, David; Nelson, Harold; Owen, Charles; Valtonen, Anna; Boling, Elizabeth; Gibbons, Andrew; Visscher-Voerman, Irene

    2013-01-01

    Scholars representing the field of design were asked to identify what they considered to be the most exciting and imaginative work currently being done in their field, as well as how that work might change our understanding. The scholars included Richard Buchanan, Nigel Cross, David Durling, Harold Nelson, Charles Owen, and Anna Valtonen. Scholars…

  2. Comparative techno-economic analysis and process design for indirect liquefaction pathways to distillate-range fuels via biomass-derived oxygenated intermediates upgrading: Liquid Transportation Fuel Production via Biomass-derived Oxygenated Intermediates Upgrading

    SciTech Connect

    Tan, Eric C. D.; Snowden-Swan, Lesley J.; Talmadge, Michael; Dutta, Abhijit; Jones, Susanne; Ramasamy, Karthikeyan K.; Gray, Michel; Dagle, Robert; Padmaperuma, Asanga; Gerber, Mark; Sahir, Asad H.; Tao, Ling; Zhang, Yanan

    2016-09-27

    This paper presents a comparative techno-economic analysis (TEA) of five conversion pathways from biomass to gasoline-, jet-, and diesel-range hydrocarbons via indirect liquefaction with specific focus on pathways utilizing oxygenated intermediates. The four emerging pathways of interest are compared with one conventional pathway (Fischer-Tropsch) for the production of the hydrocarbon blendstocks. The processing steps of the four emerging pathways include: biomass to syngas via indirect gasification, gas cleanup, conversion of syngas to alcohols/oxygenates followed by conversion of alcohols/oxygenates to hydrocarbon blendstocks via dehydration, oligomerization, and hydrogenation. Conversion of biomass-derived syngas to oxygenated intermediates occurs via three different pathways, producing: 1) mixed alcohols over a MoS2 catalyst, 2) mixed oxygenates (a mixture of C2+ oxygenated compounds, predominantly ethanol, acetic acid, acetaldehyde, ethyl acetate) using an Rh-based catalyst, and 3) ethanol from syngas fermentation. This is followed by the conversion of oxygenates/alcohols to fuel-range olefins in two approaches: 1) mixed alcohols/ethanol to 1-butanol rich mixture via Guerbet reaction, followed by alcohol dehydration, oligomerization, and hydrogenation, and 2) mixed oxygenates/ethanol to isobutene rich mixture and followed by oligomerization and hydrogenation. The design features a processing capacity of 2,000 tonnes/day (2,205 short tons) of dry biomass. The minimum fuel selling prices (MFSPs) for the four developing pathways range from $3.40 to $5.04 per gasoline-gallon equivalent (GGE), in 2011 US dollars. Sensitivity studies show that MFSPs can be improved with co-product credits and are comparable to the commercial Fischer-Tropsch benchmark ($3.58/GGE). Overall, this comparative TEA study documents potential economics for the developmental biofuel pathways via mixed oxygenates.

  3. Rational design, synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors.

    PubMed

    He, Haifeng; Wang, Wei; Zhou, Yuan; Xia, Qin; Ren, Yanliang; Feng, Jiangtao; Peng, Hao; He, Hongwu; Feng, Lingling

    2016-04-15

    On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC50 0.97-19.21 μM) and obvious inhibitory activity against cyanobacteria (EC50 0.83-9.86 μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC50<6.62 μM) and cyanobacteria (EC50<1.63 μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC50=0.97 μM) and cyanobacteria (EC50=0.83 μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1.

  4. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors

    PubMed Central

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-01-01

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future. PMID:27273260

  5. Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives.

    PubMed

    Abreu, Paula A; Castro, Helena C; Paes-de-Carvalho, Roberto; Rodrigues, Carlos R; Giongo, Viveca; Paixão, Izabel C N P; Santana, Marcos V; Ferreira, Jainne M; Caversan, Octavia M; Leão, Raquel A C; Marins, Luana M S; Henriques, André M; Farias, Florence M C; Albuquerque, Magaly G; Pinheiro, Sergio

    2013-02-01

    Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.

  6. Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Bao, Guanglong; Wang, Limei; Li, Wanting; Xu, Boxuan; Du, Baoquan; Lv, Jie; Zhai, Xin; Gong, Ping

    2015-01-01

    Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization.

  7. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

  8. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

    PubMed

    Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

    2016-06-06

    A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics.

  9. Design, Synthesis, and Evaluation of 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic Acid-Derived, Redox-Sensitive Contrast Agents for Magnetic Resonance Imaging

    PubMed Central

    Raghunand, Natarajan; Guntle, Gerald P.; Gokhale, Vijay; Nichol, Gary S.; Mash, Eugene A.; Jagadish, Bhumasamudram

    2010-01-01

    The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive Magnetic Resonance Imaging (MRI) contrast agents are reported. The linkers were selected based on computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r1) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 Tesla. The DO3A complexes exhibited smaller r1 values, in both bound and free states, than the DOTA complexes. PMID:20722424

  10. Design, synthesis and biological evaluation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives possessing a hydrazone moiety as antiproliferative agents.

    PubMed

    Li, Zhong-Hua; Yang, Dong-Xiao; Geng, Peng-Fei; Zhang, Ji; Wei, Hao-Ming; Hu, Biao; Guo, Qian; Zhang, Xin-Hui; Guo, Wen-Ge; Zhao, Bing; Yu, Bin; Ma, Li-Ying; Liu, Hong-Min

    2016-11-29

    A series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC50 values of 0.85 μM against MGC-803 and 56.17 μM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 μM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1.

  11. DESIGNING AND OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2004-06-01

    During the period July 1, 2000-March 31, 2004, Allegheny Energy Supply Co., LLC (Allegheny) conducted an extensive demonstration of woody biomass cofiring at its Willow Island and Albright Generating Stations. This demonstration, cofunded by USDOE and Allegheny, and supported by the Biomass Interest Group (BIG) of EPRI, evaluated the impacts of sawdust cofiring in both cyclone boilers and tangentially-fired pulverized coal boilers. The cofiring in the cyclone boiler--Willow Island Generating Station Unit No.2--evaluated the impacts of sawdust alone, and sawdust blended with tire-derived fuel. The biomass was blended with the coal on its way to the combustion system. The cofiring in the pulverized coal boiler--Albright Generating Station--evaluated the impact of cofiring on emissions of oxides of nitrogen (NO{sub x}) when the sawdust was injected separately into the furnace. The demonstration of woody biomass cofiring involved design, construction, and testing at each site. The results addressed impacts associated with operational issues--capacity, efficiency, and operability--as well as formation and control of airborne emissions such as NO{sub x}, sulfur dioxide (SO{sub 2}2), opacity, and mercury. The results of this extensive program are detailed in this report.

  12. Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents.

    PubMed

    Liu, Zijian; Wang, Yu; Lin, Huafang; Zuo, Dazhuang; Wang, Lihui; Zhao, Yanfang; Gong, Ping

    2014-10-06

    Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines.

  13. 5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis.

    PubMed

    Palace-Berl, Fanny; Jorge, Salomão Dória; Pasqualoto, Kerly Fernanda Mesquita; Ferreira, Adilson Kleber; Maria, Durvanei Augusto; Zorzi, Rodrigo Rocha; de Sá Bortolozzo, Leandro; Lindoso, José Ângelo Lauletta; Tavares, Leoberto Costa

    2013-09-01

    The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N'-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50=1.05μM±0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC50=8.27μM±0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50=22.69μM±1.96) and nifurtimox (IC50=3.78μM±0.10). Regarding the cytotoxicity assay, the 3g compound presented IC50 value of 28.05μM (SI=26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98μM (SI=93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400μM (SI >48), and for the FN1 cells its IC50 value was 186μM (SI=22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were ClogP and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.

  14. Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents.

    PubMed

    Tang, Jian-Feng; Lv, Xian-Hai; Wang, Xiao-Liang; Sun, Jian; Zhang, Yan-Bin; Yang, Yu-Shun; Gong, Hai-Bin; Zhu, Hai-Liang

    2012-07-15

    In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25μM to 7.60 μM against the T cells, and the IC(50) of positive control (csa) is 2.12 μM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 μM and 4.75 μM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.

  15. Comparative techno-economic analysis and process design for indirect liquefaction pathways to distillate-range fuels via biomass-derived oxygenated intermediates upgrading

    SciTech Connect

    Tan, Eric C. D.; Snowden-Swan, Lesley J.; Talmadge, Michael; Dutta, Abhijit; Jones, Susanne; Ramasamy, Karthikeyan K.; Gray, Michel; Dagle, Robert; Padmaperuma, Asanga; Gerber, Mark; Sahir, Asad H.; Tao, Ling; Zhang, Yanan

    2016-09-27

    This paper presents a comparative techno-economic analysis (TEA) of five conversion pathways from biomass to gasoline-, jet-, and diesel-range hydrocarbons via indirect liquefaction with a specific focus on pathways utilizing oxygenated intermediates. The four emerging pathways of interest are compared with one conventional pathway (Fischer-Tropsch) for the production of the hydrocarbon blendstocks. The processing steps of the four emerging pathways include biomass-to-syngas via indirect gasification, syngas clean-up, conversion of syngas to alcohols/oxygenates followed by conversion of alcohols/oxygenates to hydrocarbon blendstocks via dehydration, oligomerization, and hydrogenation. Conversion of biomass-derived syngas to oxygenated intermediates occurs via three different pathways, producing: (i) mixed alcohols over a MoS2 catalyst, (ii) mixed oxygenates (a mixture of C2+ oxygenated compounds, predominantly ethanol, acetic acid, acetaldehyde, ethyl acetate) using an Rh-based catalyst, and (iii) ethanol from syngas fermentation. This is followed by the conversion of oxygenates/alcohols to fuel-range olefins in two approaches: (i) mixed alcohols/ethanol to 1-butanol rich mixture via Guerbet reaction, followed by alcohol dehydration, oligomerization, and hydrogenation, and (ii) mixed oxygenates/ethanol to isobutene rich mixture and followed by oligomerization and hydrogenation. The design features a processing capacity of 2000 tonnes/day (2205 short tons) of dry biomass. The minimum fuel selling prices (MFSPs) for the four developing pathways range from 3.40 dollars to 5.04 dollars per gasoline-gallon equivalent (GGE), in 2011 US dollars. Sensitivity studies show that MFSPs can be improved with co-product credits and are comparable to the commercial Fischer-Tropsch benchmark ($3.58/GGE). Altogether, this comparative TEA study documents potential economics for the developmental biofuel pathways via mixed oxygenates.

  16. Comparative techno-economic analysis and process design for indirect liquefaction pathways to distillate-range fuels via biomass-derived oxygenated intermediates upgrading

    DOE PAGES

    Tan, Eric C. D.; Snowden-Swan, Lesley J.; Talmadge, Michael; ...

    2016-09-27

    This paper presents a comparative techno-economic analysis (TEA) of five conversion pathways from biomass to gasoline-, jet-, and diesel-range hydrocarbons via indirect liquefaction with a specific focus on pathways utilizing oxygenated intermediates. The four emerging pathways of interest are compared with one conventional pathway (Fischer-Tropsch) for the production of the hydrocarbon blendstocks. The processing steps of the four emerging pathways include biomass-to-syngas via indirect gasification, syngas clean-up, conversion of syngas to alcohols/oxygenates followed by conversion of alcohols/oxygenates to hydrocarbon blendstocks via dehydration, oligomerization, and hydrogenation. Conversion of biomass-derived syngas to oxygenated intermediates occurs via three different pathways, producing: (i) mixedmore » alcohols over a MoS2 catalyst, (ii) mixed oxygenates (a mixture of C2+ oxygenated compounds, predominantly ethanol, acetic acid, acetaldehyde, ethyl acetate) using an Rh-based catalyst, and (iii) ethanol from syngas fermentation. This is followed by the conversion of oxygenates/alcohols to fuel-range olefins in two approaches: (i) mixed alcohols/ethanol to 1-butanol rich mixture via Guerbet reaction, followed by alcohol dehydration, oligomerization, and hydrogenation, and (ii) mixed oxygenates/ethanol to isobutene rich mixture and followed by oligomerization and hydrogenation. The design features a processing capacity of 2000 tonnes/day (2205 short tons) of dry biomass. The minimum fuel selling prices (MFSPs) for the four developing pathways range from 3.40 dollars to 5.04 dollars per gasoline-gallon equivalent (GGE), in 2011 US dollars. Sensitivity studies show that MFSPs can be improved with co-product credits and are comparable to the commercial Fischer-Tropsch benchmark ($3.58/GGE). Altogether, this comparative TEA study documents potential economics for the developmental biofuel pathways via mixed oxygenates.« less

  17. Design, synthesis and pharmaco-toxicological assessment of 5-mercapto-1,2,4-triazole derivatives with antibacterial and antiproliferative activity

    PubMed Central

    Mioc, Marius; Soica, Codruta; Bercean, Vasile; Avram, Sorin; Balan-Porcarasu, Mihaela; Coricovac, Dorina; Ghiulai, Roxana; Muntean, Delia; Andrica, Florina; Dehelean, Cristina; Spandidos, Demetrios A.; Tsatsakis, Aristides M.; Kurunczi, Ludovic

    2017-01-01

    The extensive biochemical research of multiple types of cancer has revealed important enzymatic signaling pathways responsible for tumor occurrence and progression, thus compelling the need for the discovery of new means with which to block these signaling cascades. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which plays an important role in maintaining relevant cellular functions, exhibits various alterations in common human cancers, thus representing a suitable target in cancer treatment. Molecules bearing the 1,2,4-triazole moiety are known to possess multiple biological activities, including anticancer activity. The current study used molecular docking in the design of 5-mercapto-1,2,4-triazole derivatives with antiproliferative activity targeting the PI3K/AKT pathway. Three structures emerged as the result of this method, which indicated for these a highly favorable accommodation within the active binding site of PI3K protein, thus acting as potential PI3K inhibitors, and hence interfering with the above-mentioned pathway. The molecules were synthesized and their chemical structure was confirmed. The antiproliferative activity of these compounds was tested on 4 cancer cell lines (A375, B164A5, MDA-MB-231 and A549) and on normal human keratinocytes (HaCaT) by in vitro alamarBlue assay. The 3 compounds revealed antitumor activity against the breast cancer cell line (MDA-MB-231) and reduced toxicity on the normal cell line. The antibacterial activity of the compounds was also tested in vitro on Gram-positive and Gram-negative bacterial strains, revealing moderate activity. PMID:28350123

  18. Degradation kinetics and mechanism of an oxadiazole derivative, design of a stable drug product for BMS-708163, a γ-secretase inhibitor drug candidate.

    PubMed

    Hartley, Ruiling F; Huang, Yande; Cassidy, Michael; Razler, Thomas M; Qian, Feng; Hussain, Munir A

    2012-09-01

    The stability of a 1,2,4-oxadiazole derivative, BMS-708163, A, was studied in the cosolvent mixture of acetonitrile-water at various pH values, in the solid state and in the presence of various excipients. The objective of this study was to develop a deep understanding of the stability of compound A based on its degradation kinetics and mechanism to enable design of a robust drug product. A series of isotopically (13) C- and (15) N-labeled compounds were synthesized and their degradation was studied by liquid chromatography-mass spectrometry and nuclear magnetic resonance to prove the degradation mechanism. Compound A exhibited maximum stability at a pH range of 3-5. In forced degradation studies, higher or lower pH resulted in an increase in degradation rate. At low pH, the N-4 atom on the 1,2,4-oxadiazole ring is protonated, followed by nucleophilic attack on the activated methine carbon to cause ring opening to form aryl nitrile degradation product, compound B. At high pH, the nucleophilic attack occurs on the methine carbon to generate an anion on N-4. Subsequent proton capture from a proton donor, such as ambient water, facilitates ring opening to generate compound B. In the absence of a proton donor, such as in dry acetonitrile, anion on N-4 will go back to compound A. Therefore, compound A is stable in absence of proton donor. This study defines the package condition and microenvironmental pH under which compound A can be formulated into a stable product.

  19. Metal based biologically active compounds: design, synthesis, and antibacterial/antifungal/cytotoxic properties of triazole-derived Schiff bases and their oxovanadium(IV) complexes.

    PubMed

    Chohan, Zahid H; Sumrra, Sajjad H; Youssoufi, Moulay H; Hadda, Taibi B

    2010-07-01

    A new series of oxovanadium(IV) complexes have been designed and synthesized with a new class of triazole Schiff bases derived from the reaction of 3,5-diamino-1,2,4-triazole with 2-hydroxy-1-naphthaldehyde, pyrrole-2-carboxaldehyde, pyridine-2-carboxaldehyde and acetyl pyridine-2-carboxaldehyde, respectively. Physical (magnetic susceptibility, molar conductance), spectral (IR, (1)H NMR, (13)C NMR, mass and electronic) and analytical data have established the structures of these synthesized Schiff bases and their oxovanadium(IV) complexes. The Schiff bases, predominantly act as bidentate and coordinate with the vanadium(IV) metal to give a stoichiometric ratio of 1:2 [M:L], forming a general formulae, [M(L-H)(2)] and [M(L)(2)]SO(4) where L = (L(1))-(L(4)) and M = VO(IV) of these complexes in a square-pyramidal geometry. In order to evaluate the biological activity of Schiff bases and to assess the role of vanadium(IV) metal on biological activity, the triazole Schiff bases and their oxovanadium(IV) complexes have been studied for in vitro antibacterial activity against four Gram-negative (Escherichia coli, Shigella flexenari, Pseudomonas aeruginosa, Salmonella typhi) and two Gram-positive (Staphylococcus aureus, Bacillus subtilis) bacterial strains, in vitro antifungal activity against Trichophyton longifucus, Candida albican, Aspergillus flavus, Microscopum canis, Fusarium solani and Candida glaberata. The simple Schiff bases showed weaker to significant activity against one or more bacterial and fungal strains. In most of the cases higher activity was exhibited upon coordination with vanadium(IV) metal. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.

  20. Minimum Hamiltonian Ascent Trajectory Evaluation (MASTRE) program (update to automatic flight trajectory design, performance prediction, and vehicle sizing for support of Shuttle and Shuttle derived vehicles) engineering manual

    NASA Technical Reports Server (NTRS)

    Lyons, J. T.

    1993-01-01

    The Minimum Hamiltonian Ascent Trajectory Evaluation (MASTRE) program and its predecessors, the ROBOT and the RAGMOP programs, have had a long history of supporting MSFC in the simulation of space boosters for the purpose of performance evaluation. The ROBOT program was used in the simulation of the Saturn 1B and Saturn 5 vehicles in the 1960's and provided the first utilization of the minimum Hamiltonian (or min-H) methodology and the steepest ascent technique to solve the optimum trajectory problem. The advent of the Space Shuttle in the 1970's and its complex airplane design required a redesign of the trajectory simulation code since aerodynamic flight and controllability were required for proper simulation. The RAGMOP program was the first attempt to incorporate the complex equations of the Space Shuttle into an optimization tool by using an optimization method based on steepest ascent techniques (but without the min-H methodology). Development of the complex partial derivatives associated with the Space Shuttle configuration and using techniques from the RAGMOP program, the ROBOT program was redesigned to incorporate these additional complexities. This redesign created the MASTRE program, which was referred to as the Minimum Hamiltonian Ascent Shuttle TRajectory Evaluation program at that time. Unique to this program were first-stage (or booster) nonlinear aerodynamics, upper-stage linear aerodynamics, engine control via moment balance, liquid and solid thrust forces, variable liquid throttling to maintain constant acceleration limits, and a total upgrade of the equations used in the forward and backward integration segments of the program. This modification of the MASTRE code has been used to simulate the new space vehicles associated with the National Launch Systems (NLS). Although not as complicated as the Space Shuttle, the simulation and analysis of the NLS vehicles required additional modifications to the MASTRE program in the areas of providing

  1. Hemoglobin derivatives

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003371.htm Hemoglobin derivatives To use the sharing features on this page, please enable JavaScript. Hemoglobin derivatives are altered forms of hemoglobin . Hemoglobin is ...

  2. Design and synthesis of collagen mimetic peptide derivatives for studying triple helix assembly and collagen mimetic peptide-collagen binding interaction

    NASA Astrophysics Data System (ADS)

    Mo, Xiao

    2008-10-01

    Collagen is the principal tensile clement of the extra-cellular matrix in mammals and is the basic scaffold for cells and tissues. Collagen molecules are comprised of homo-trimeric helices (e.g. collagen type II and type III), ABB type hetero-trimeric helices (e.g. collagen type I, type IV, and type V), or ABC type hetero-trimeric helices (e.g. type V). Mimicry of collagen structures can help elucidate collagen triple helical conformation and provide insights into making novel collagen-like biomaterials. Our group previously reported a new physical collagen modification method, which was based on non-covalent interaction between collagen mimetic peptide (CMP: -(Pro-Hyp-Gly) x-) and natural collagen. We hypothesized that CMP binds to collagen through a process involving both strand invasion and triple helix assembly. The aim of this dissertation is to study structural formation and stability of collagen triple helix, and to investigate CMP-collagen binding interactions using two types of CMP derivatives: covalently templated CMP trimer and CMP-nanoparticle conjugates. We demonstrated that covalently templated ABB type CMP hetero-trimers could be prepared by a versatile synthetic strategy involving both solid phase and solution peptide coupling. Our thermal melting studies showed that the templated CMP hetero-trimers formed collagen-like triple helices and their folding kinetics correlated with the amino acid compositions of the individual CMP strands. We also studied the thermal melting behavior and folding kinetics of a templated hetero-trimer complex comprised of CMP and a peptide derived from collagen. This synthetic strategy can be readily extended to synthesize other ABB type hetero-trimers to investigate their local melting behavior and biological activity. We also prepared colloidally stable CMP functionalized gold nanoparticles (Au-CMPs) as a TEM marker for investigating the CMP-collagen interaction. Au-CMP showed preferential binding to collagen fiber's gap

  3. Molecular design, synthesis and biological evaluation of BP-O-DAPY and O-DAPY derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors.

    PubMed

    Yang, Shiqiong; Pannecouque, Christophe; Daelemans, Dirk; Ma, Xiao-Dong; Liu, Yang; Chen, Fen-Er; De Clercq, Erik

    2013-07-01

    This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.

  4. Identification and characterisation in vitro of cells with a non-SCLC cell-like phenotype derived from a continuous SCLC cell line.

    PubMed

    Khan, M Z; Freshney, R I; Murray, A M; Merry, S; Plumb, J A; McNicol, A M

    1991-01-01

    Two adherent sublines, H69V and H69VZ, have been isolated from the classic SCLC cell line NCI-H69. Significant morphological differences were observed between the parental and the derivative cell lines. While NCI-H69 grew as densely packed free floating cellular aggregates the derivative lines grew as a monolayer of epithelioid cells. The growth rates of both the derivative lines were faster than the parental line with doubling times closer to non-SCLC cell lines in the derivative lines. Both H69V and H69VZ either express very low levels or do not express neuroendocrine cell markers including L-dopa-decarboxylase (DDC), creatine kinase-BB isoenzyme (CK-BB), bombesin-like immunoreactivity (BLI), neuron specific enolase (NSE), and neurosecretory type dense core granules (DGCs), compared to the parental cell line. All the lines stained positive for epithelial markers such as CAM5.2. LDH isoenzyme and chromosome analyses confirmed the human origin of all the cell lines. Therefore, it appears that cell line NCI-H69 contains stem cell subpopulation capable of generating cells of both small and non-small cell like phenotypes.

  5. Design and selection of nitrogen-rich bridged di-1,3,5-triazine derivatives with high energy and reduced sensitivity.

    PubMed

    Pan, Yong; Zhu, Weihua; Xiao, Heming

    2012-07-01

    The heats of formation (HOFs), electronic structures, energetic properties, and thermal stabilities of a series of energetic bridged di-1,3,5-triazine derivatives with different substituents and linkages were studied using density functional theory. It was found that the groups -N(3) and -N=N- are effective structural units for improving the HOF values of the di-1,3,5-triazine derivatives. The effects of the substituents on the HOMO-LUMO gap combine with those of the bridge groups. The calculated detonation velocities and detonation pressures indicate that substituting the -ONO(2), -NF(2), or -N=N- group is very useful for enhancing the detonation performance of these derivatives. Analysis of the bond dissociation energies for several relatively weak bonds suggests that most of the derivatives have good thermal stability. On the whole, the -NH(2), -N(3), -NH-, and -CH=CH- groups are effective structural units for increasing the thermal stabilities of the derivatives. Based on detonation performance and thermal stability, nine of the compounds can be considered potential candidates for high energy density materials with reduced sensitivity.

  6. Design and biological evaluation of novel quinolone-based metronidazole derivatives as potent Cu(2+) mediated DNA-targeting antibacterial agents.

    PubMed

    Zhang, Ling; Kumar, Kannekanti Vijaya; Geng, Rong-Xia; Zhou, Cheng-He

    2015-09-01

    A series of novel quinolone-based metronidazole derivatives as new type of antimicrobial agents were developed and characterized. Most of them gave good antibacterial activity towards the Gram-positive and negative bacteria. Noticeably, quinolone derivative 3i exhibited low MIC value of 0.25 μg/mL against Pseudomonas aeruginosa, which was even superior to reference drugs Norfloxacin, Ciprofloxacin and Clinafloxacin. The further research revealed that compound 3i could intercalate into P. aeruginosa DNA through copper ion bridge to form a steady 3i-Cu(2+)-DNA ternary complex which might further block DNA replication to exert the powerful bioactivities.

  7. Design study of RL10 derivatives. Volume 3, part 1: Preliminary interface control document. [development of baseline engines for space tug vehicles

    NASA Technical Reports Server (NTRS)

    Adams, A.

    1973-01-01

    The Interface Control Document contains engine information necessary for installation of the baseline RL10 Derivative engines in the Space Tug vehicle. The ICD presents a description of the baseline engines and their operating characteristics, mass and load characteristics, and environmental criteria. The document defines the engine/vehicle mechanical, electrical, fluid and pneumatic interface requirements.

  8. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2004-01-01

    During the period October 1, 2003-December 31, 2003, Allegheny Energy Supply Co., LLC (Allegheny) continued with demonstration operations at the Willow Island Generating Station and improvements to the Albright Generating Station cofiring systems. The demonstration operations at Willow Island were designed to document integration of biomass cofiring into commercial operations, including evaluating new sources of biomass supply. The Albright improvements were designed to increase the resource base for the projects, and to address issues that came up during the first year of operations. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations.

  9. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2003-07-01

    During the period April 1, 2003--June 30, 2003, Allegheny Energy Supply Co., LLC (Allegheny) proceeded with demonstration operations at the Willow Island Generating Station and improvements to the Albright Generating Station cofiring systems. The demonstration operations at Willow Island were designed to document integration of biomass cofiring into commercial operations. The Albright improvements were designed to increase the resource base for the projects, and to address issues that came up during the first year of operations. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations.

  10. Natural products-based insecticidal agents 9. Design, semisynthesis and insecticidal activity of 28-acyloxy derivatives of toosendanin against Mythimna separata Walker in vivo.

    PubMed

    Xu, Hui; Zhang, Jun-Liang

    2011-04-01

    In continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, twelve 28-acyloxy derivatives of toosendanin (2a-l) were semisynthesized and preliminarily evaluated their activity against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1mg/mL. Some compounds exhibited the potent insecticidal activity. Especially compounds 2c and 2j displayed the more promising insecticidal activity than their natural precursor, toosendanin, a commercial insecticide derived from Melia azedarach at 1mg/mL. In general, it indicated that the butanoyloxy or phenylacryloyloxy moiety at the 28-position of toosendanin was essential for the insecticidal activity.

  11. Design and Synthesis of Novel N-Arylsulfonyl-3-(2-yl-ethanone)-6-methylindole Derivatives as Inhibitors of HIV-1 Replication

    PubMed Central

    Che, Zhiping; Liu, Shengming; Tian, Yuee; Hu, Zhenjie; Chen, Yingwu; Chen, Genqiang

    2015-01-01

    Seven novel N-arylsulfonyl-3-(2-yl-ethanone)-6-methylindole derivatives 4a–f and 6 were readily synthesized and have been identified as inhibitors of human immunodeficiency virus type-1 (HIV-1) replication. Initial biological studies indicated that among these derivatives, N-(p-ethyl)phenylsulfonyl-3-[2-morpholinoethanone]-6-methylindole (4f) and N-(p-ethyl)phenylsulfonyl-3-[2-(5-phenyl-1,3,4-oxadiazole-2-yl-thio)ethanone]-6-methylindole (6) showed the most promising activity against HIV-1 replication. The effective concentration (EC50) and therapeutic index (TI) values of 4f and 6 were 9.42/4.62 μM, and >49.77/66.95, respectively. The cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for any of these compounds. PMID:26110320

  12. Donor-acceptor-structured 1,4-diazatriphenylene derivatives exhibiting thermally activated delayed fluorescence: design and synthesis, photophysical properties and OLED characteristics

    NASA Astrophysics Data System (ADS)

    Takahashi, Takehiro; Shizu, Katsuyuki; Yasuda, Takuma; Togashi, Kazunori; Adachi, Chihaya

    2014-06-01

    A new series of luminescent 1,4-diazatriphenylene (ATP) derivatives with various peripheral donor units, including phenoxazine, 9,9-dimethylacridane and 3-(diphenylamino)carbazole, is synthesized and characterized as thermally activated delayed fluorescence (TADF) emitters. The influence of the donor substituents on the electronic and photophysical properties of the materials is investigated by theoretical calculations and experimental spectroscopic measurements. These ATP-based molecules with donor-acceptor-donor (D-A-D) structures can reduce the singlet-triplet energy gap (0.04-0.26 eV) upon chemical modification of the ATP core, and thus exhibit obvious TADF characteristics in solution and doped thin films. As a demonstration of the potential of these materials, organic light-emitting diodes containing the D-A-D-structured ATP derivatives as emitters are fabricated and tested. External electroluminescence quantum efficiencies above 12% and 8% for green- and sky-blue-emitting devices, respectively, are achieved.

  13. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2003-04-30

    During the period January 1, 2003--March 31, 2003, Allegheny Energy Supply Co., LLC (Allegheny) proceeded with improvements to both the Willow Island and Albright Generating Station cofiring systems. These improvements were designed to increase the resource base for the projects, and to address issues that came up during the first year of operations. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations.

  14. Derivative chameleons

    SciTech Connect

    Noller, Johannes

    2012-07-01

    We consider generalized chameleon models where the conformal coupling between matter and gravitational geometries is not only a function of the chameleon field φ, but also of its derivatives via higher order co-ordinate invariants (such as ∂{sub μ}φ∂{sup μ}φ,□φ,...). Specifically we consider the first such non-trivial conformal factor A(φ,∂{sub μ}φ∂{sup μ}φ). The associated phenomenology is investigated and we show that such theories have a new generic mass-altering mechanism, potentially assisting the generation of a sufficiently large chameleon mass in dense environments. The most general effective potential is derived for such derivative chameleon setups and explicit examples are given. Interestingly this points us to the existence of a purely derivative chameleon protected by a shift symmetry for φ → φ+c. We also discuss potential ghost-like instabilities associated with mass-lifting mechanisms and find another, mass-lowering and instability-free, branch of solutions. This suggests that, barring fine-tuning, stable derivative models are in fact typically anti-chameleons that suppress the field's mass in dense environments. Furthermore we investigate modifications to the thin-shell regime and prove a no-go theorem for chameleon effects in non-conformal geometries of the disformal type.

  15. Derivative chameleons

    NASA Astrophysics Data System (ADS)

    Noller, Johannes

    2012-07-01

    We consider generalized chameleon models where the conformal coupling between matter and gravitational geometries is not only a function of the chameleon field phi, but also of its derivatives via higher order co-ordinate invariants (such as ∂μphi∂μphi,squphi,...). Specifically we consider the first such non-trivial conformal factor A(phi,∂μphi∂μphi). The associated phenomenology is investigated and we show that such theories have a new generic mass-altering mechanism, potentially assisting the generation of a sufficiently large chameleon mass in dense environments. The most general effective potential is derived for such derivative chameleon setups and explicit examples are given. Interestingly this points us to the existence of a purely derivative chameleon protected by a shift symmetry for phi → phi+c. We also discuss potential ghost-like instabilities associated with mass-lifting mechanisms and find another, mass-lowering and instability-free, branch of solutions. This suggests that, barring fine-tuning, stable derivative models are in fact typically anti-chameleons that suppress the field's mass in dense environments. Furthermore we investigate modifications to the thin-shell regime and prove a no-go theorem for chameleon effects in non-conformal geometries of the disformal type.

  16. Design study of RL10 derivatives. Volume 3, part 2: Operational and flight support plan. [analysis of transportation requirements for rocket engine in support of space tug program

    NASA Technical Reports Server (NTRS)

    Shubert, W. C.

    1973-01-01

    Transportation requirements are considered during the engine design layout reviews and maintenance engineering analyses. Where designs cannot be influenced to avoid transportation problems, the transportation representative is advised of the problems permitting remedies early in the program. The transportation representative will monitor and be involved in the shipment of development engine and GSE hardware between FRDC and vehicle manufacturing plant and thereby will be provided an early evaluation of the transportation plans, methods and procedures to be used in the space tug support program. Unanticipated problems discovered in the shipment of development hardware will be known early enough to permit changes in packaging designs and transportation plans before the start of production hardware and engine shipments. All conventional transport media can be used for the movement of space tug engines. However, truck transport is recommended for ready availability, variety of routes, short transit time, and low cost.

  17. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2003-10-01

    During the period July 1, 2003-September 30, 2003, Allegheny Energy Supply Co., LLC (Allegheny) proceeded with demonstration operations at the Willow Island Generating Station and improvements to the Albright Generating Station cofiring systems. The demonstration operations at Willow Island were designed to document integration of bio mass cofiring into commercial operations, including evaluating new sources of biomass supply. The Albright improvements were designed to increase the resource base for the projects, and to address issues that came up during the first year of operations. During this period, a major presentation summarizing the program was presented at the Pittsburgh Coal Conference. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations.

  18. The computational design of test compounds with potentially specific biological activity: Histamine-H2 agonists derived from 5-HT/H2 antagonists

    NASA Astrophysics Data System (ADS)

    Topiol, Sid; Sabio, Michael

    1991-06-01

    The previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to test the H2-receptor model. The design strategy attempts to construct a compound with potentially selective H2 agonism. The design scheme maintains features which were previously used to explain selective recognition of SKF-10856 and 9,10-dihydro-LSD as well as reintroduces the chemical features proposed to be responsible for H2 activation. The existence of the H2 recognition and activation features in the proposed compound is verified, in a previously proposed model, by computational studies of the molecular electrostatic potentials and shifts in the tautomeric preference.

  19. Design, synthesis and biological evaluation of novel L-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors.

    PubMed

    Wang, Han; Xu, Renyang; Shi, Yongying; Si, Longlong; Jiao, Pingxuan; Fan, Zibo; Han, Xu; Wu, Xingyu; Zhou, Xiaoshu; Yu, Fei; Zhang, Yongmin; Zhang, Liangren; Zhang, Lihe; Zhou, Demin; Xiao, Sulong

    2016-03-03

    Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target.

  20. Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives.

    PubMed

    Guillon, Jean; Cohen, Anita; Gueddouda, Nassima Meriem; Das, Rabindra Nath; Moreau, Stéphane; Ronga, Luisa; Savrimoutou, Solène; Basmaciyan, Louise; Monnier, Alix; Monget, Myriam; Rubio, Sandra; Garnerin, Timothée; Azas, Nadine; Mergny, Jean-Louis; Mullié, Catherine; Sonnet, Pascal

    2017-12-01

    Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.

  1. Donor–acceptor-structured 1,4-diazatriphenylene derivatives exhibiting thermally activated delayed fluorescence: design and synthesis, photophysical properties and OLED characteristics

    PubMed Central

    Takahashi, Takehiro; Shizu, Katsuyuki; Yasuda, Takuma; Togashi, Kazunori; Adachi, Chihaya

    2014-01-01

    A new series of luminescent 1,4-diazatriphenylene (ATP) derivatives with various peripheral donor units, including phenoxazine, 9,9-dimethylacridane and 3-(diphenylamino)carbazole, is synthesized and characterized as thermally activated delayed fluorescence (TADF) emitters. The influence of the donor substituents on the electronic and photophysical properties of the materials is investigated by theoretical calculations and experimental spectroscopic measurements. These ATP-based molecules with donor–acceptor–donor (D–A–D) structures can reduce the singlet–triplet energy gap (0.04–0.26 eV) upon chemical modification of the ATP core, and thus exhibit obvious TADF characteristics in solution and doped thin films. As a demonstration of the potential of these materials, organic light-emitting diodes containing the D–A–D-structured ATP derivatives as emitters are fabricated and tested. External electroluminescence quantum efficiencies above 12% and 8% for green- and sky-blue-emitting devices, respectively, are achieved. PMID:27877670

  2. Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors

    SciTech Connect

    Ghosh, Arun K.; Martyr, Cuthbert D.; Steffey, Melinda; Wang, Yuan-Fang; Agniswamy, Johnson; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

    2012-06-18

    We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K{sub i} = 2.9 pM; IC{sub 50} = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.

  3. Complex derivatives

    NASA Astrophysics Data System (ADS)

    Battiston, Stefano; Caldarelli, Guido; Georg, Co-Pierre; May, Robert; Stiglitz, Joseph

    2013-03-01

    The intrinsic complexity of the financial derivatives market has emerged as both an incentive to engage in it, and a key source of its inherent instability. Regulators now faced with the challenge of taming this beast may find inspiration in the budding science of complex systems.

  4. Natural and synthetic poly(malic acid)-based derivates: a family of versatile biopolymers for the design of drug nanocarriers.

    PubMed

    Loyer, Pascal; Cammas-Marion, Sandrine

    2014-08-01

    The field of specific drug delivery is an expanding research domain. Besides the use of liposomes formed from various lipids, natural and synthetic polymers have been developed to prepare more efficient drug delivery systems either under macromolecular prodrugs or under particulate nanovectors. To ameliorate the biocompatibility of such nanocarriers, degradable natural or synthetic polymers have attracted the interest of many researchers. In this context, poly(malic acid) (PMLA) extracted from microorganisms or synthesized from malic or aspartic acid was used to prepare water-soluble drug carriers or nanoparticles. Within this review, both the preparation and the applications of PMLA derivatives are described emphasizing the in vitro and in vivo assays. The results obtained by several groups highlight the interest of such polyesters in the field of drug delivery.

  5. Design, synthesis, in silico and in vitro studies of novel 4-methylthiazole-5-carboxylic acid derivatives as potent anti-cancer agents.

    PubMed

    Kilaru, Ravendra Babu; Valasani, Koteswara Rao; Yellapu, Nanda Kumar; Osuru, Hari Prasad; Kuruva, Chandra Sekhar; Matcha, Bhaskar; Chamarthi, Naga Raju

    2014-09-15

    Since inhibitors of mucin onco proteins are potential targets for breast cancer therapy, a series of novel 4-methylthiazole-5-carboxylic acid (1) derivatives 3a-k were synthesized by the reaction of 1 with SOCl2 followed by different bases/alcohols in the presence of triethylamine. Once synthesized and characterized, their binding modes with MUC1 were studied by molecular docking analysis using Aruglab 4.0.1 and QSAR properties were determined using HyperChem. All synthesized compounds were screened for in vitro anti-breast cancer activity against MDA-MB-231 breast adenocarcinoma cell lines by Trypan-blue cell viability assay and MTT methods. Compounds 1, 3b, 3d, 3e, 3i and 3f showed good anti-breast cancer activity. Since 1 and 3d exhibited high potent activity against MDA-MB-231 cell lines, they show could be effective mucin onco protein inhibitors.

  6. Design and synthesis of a tetrahydroisoquinoline-based hydroxamate derivative (ZYJ-34v), an oral active histone deacetylase inhibitor with potent antitumor activity.

    PubMed

    Zhang, Yingjie; Liu, Chunxi; Chou, C James; Wang, Xuejian; Jia, Yuping; Xu, Wenfang

    2013-08-01

    In our previous study, we developed a novel series of tetrahydroisoquinoline-based hydroxamic acid derivatives as histone deacetylase inhibitors (Bioorg Med Chem, 2010, 18, 1761-1772; J Med Chem, 2011, 54, 2823-2838), among which, compound ZYJ-34c (1) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency (J Med Chem, 2011, 54, 5532-5539.). Herein, further modification in 1 afforded another oral active analog ZYJ-34v (2) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against histone deacetylase 1, 2, 3, and 6, which was confirmed by Western blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved histone deacetylase inhibitor SAHA.

  7. Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives Containing Benzo[d]thiazole-2-yl Urea as c-Met Kinase Inhibitors.

    PubMed

    Lei, Hongrui; Hu, Gang; Wang, Yu; Han, Pei; Liu, Zijian; Zhao, Yanfang; Gong, Ping

    2016-08-01

    A series of novel 4-phenoxyquinoline derivatives containing the benzo[d]thiazole-2-yl urea moiety were synthesized and evaluated for their cytotoxicity against the HT-29, MKN-45, and H460 cell lines. The structures of the target compounds were confirmed by (1) H NMR and MS spectra. Most of them showed moderate to excellent potency against the three tested cell lines. Especially, compound 23 was identified a promising agent (c-Met IC50  = 17.6 nM), showing the most potent anticancer activities with IC50 values of 0.18, 0.06, and 0.01 µM against the HT-29, MKN-45, and H460 cell lines, respectively. The docking results of 23 with the c-Met kinase model 3LQ8 showed a specific binding mode between the ligand and the target protein.

  8. Rationally designed benzopyran fused isoxazolidines and derived β(2,3,3)-amino alcohols as potent analgesics: Synthesis, biological evaluation and molecular docking analysis.

    PubMed

    Singh, Gagandeep; Singh, Gurjit; Bhatti, Rajbir; Gupta, Vivek; Mahajan, Ajay; Singh, Palwinder; Singh Ishar, Mohan Paul

    2017-02-15

    Based on structure activity analysis of morphine related opiates, we have synthesized some novel benzopyran fused isoxazolidines (2a-e) and derived conformationally constrained β(2,3,3)-amino alcohols (3a-e), which were evaluated in vivo for their anti-nociceptive activity through acetic acid induced writhing test (peripheral) and formalin induced algesia (central). Results showed that, compound 2a possesses significant opioid agonist activity. Further, molecular docking analysis reveals that compound 2a binds to δ-opioid receptor (DOR) with comparatively better D-score than to μ (MOR) and κ (KOR) receptors. Compound 2a did not show any toxicity up to a 2000 mg kg(-1) dose.

  9. Design and Development of Peptides from the Anti-Angiogenic Pigment Epithelial-Derived Factor for the Therapy of Prostate Cancer

    DTIC Science & Technology

    2007-12-01

    ABSTRACT To create PEDF based therapy for hormone-refractory CaP we have proposed to design short synthetic peptides corresponding to the 34- mer...anti-angiogenic epitope of PEDF . The 3D structure of PEDF 34-mer peptide was analyzed using Protean software in terms of relative hydrophobicity, charge...distribution, and antigenic index. Three synthetic peptides covering the 34-mer PEDF fragment were generated and tested for the ability to reproduce

  10. Stepwise design, synthesis, and in vitro antifungal screening of (Z)-substituted-propenoic acid derivatives with potent broad-spectrum antifungal activity

    PubMed Central

    Khedr, Mohammed A

    2015-01-01

    Fungal infections are a main reason for the high mortality rate worldwide. It is a challenge to design selective antifungal agents with broad-spectrum activity. Lanosterol 14α-demethylase is an attractive target in the design of antifungal agents. Seven compounds were selected from a number of designed compounds using a rational docking study. These compounds were synthesized and evaluated for their antifungal activity. In silico study results showed the high binding affinity to lanosterol 14α-demethylase (−24.49 and −25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (−18.19 kcal/mol) and fluconazole (−16.08 kcal/mol). Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively. The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole. PMID:26309398

  11. Theoretical design of triphenylamine-based derivatives with asymmetric D-D-π-A configuration for dye-sensitized solar cells

    NASA Astrophysics Data System (ADS)

    Balanay, Mannix P.; Enopia, Camille Marie G.; Lee, Sang Hee; Kim, Dong Hee

    2015-04-01

    The use of theoretical techniques in the structural development of dye-sensitized solar cells helps in the efficient screening of the dyes. To properly rationalize the dye's design process, benchmark calculations were conducted using long-range corrected exchange-correlation (xc) functionals with varying separation parameters to be able to predict the excited-state energies of triphenylamine-based dyes, namely: PPS, PSP, and PSS, wherein they differ at the π-conjugated bridge using thiophene and/or phenyl moieties. The results show that LC-ωPBE xc functional with an optimized parameter provided better correlation with the experimental results compared to the other functionals. The relative shifts of the absorption spectra, light harvesting efficiency, normal dipole moments, as well as the ionization potentials and electron affinities of the dyes were well-correlated with the experimental data. A new set of dyes was designed in an effort to increase its solar cell efficiency that was patterned after PSS with an additional donor moiety such as fluorene, cyclopentaindole, and pyrene attached asymmetrically at the triphenylamine ring. Among the newly designed dyes, analogs that contain 4-phenyl-1,2,3,4-tetrahydrocyclopenta[b]indole (I) and pyrido[2,3,4-5-imn]phenanthridine-5,10(4H,9H)-dione (P2) as the additional donor moiety produced the best photophysical properties and charge-transfer characteristics for a promising dye for solar cell applications.

  12. Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives

    PubMed Central

    Antypenko, Lyudmyla M.; Kovalenko, Sergey I.; Antypenko, Olexii M.; Katsev, Andrey M.; Achkasova, Olena M.

    2013-01-01

    The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N-dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, 1H, 13C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2–5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2-(tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5-c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 μM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could

  13. Biomimetic hybrid scaffolds for osteo-chondral tissue repair: Design and osteogenic differentiation of human placenta-derived cells (hPDC).

    PubMed

    Farè, Silvia; Bertoldi, Serena; Meskinfam, Masoumeh; Spoldi, Valentina; Tanzi, M Cristina; Parolini, Ornella

    2015-08-01

    A novel functionally-graded hybrid (FGHY) scaffold was designed and developed with a load-bearing structure represented by a PU foam loaded with a graded composition of CaPs (biomimetic component) and pectin gel as cell carrier. hPDC populations encapsulated in pectin gels and injected into the FGHY scaffolds demonstrated the ability to differentiate toward the osteogenic lineage. The ability of these biomimetic hybrid scaffolds to stimulate cell adhesion and proliferation and to support differentiation of hPDCs make these scaffolds excellent candidates for an use in bone regeneration.

  14. Combinatorial-Designed Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles for Encapsulation and Delivery of Lipid-Modified Platinum Derivatives in Wild-Type and Resistant Non-Small-Cell Lung Cancer Cells.

    PubMed

    Nascimento, Ana Vanessa; Singh, Amit; Bousbaa, Hassan; Ferreira, Domingos; Sarmento, Bruno; Amiji, Mansoor M

    2015-12-07

    Development of efficient and versatile drug delivery platforms to overcome the physical and biological challenges in cancer therapeutics is an area of great interest, and novel materials are actively sought for such applications. Recent strides in polymer science have led to a combinatorial approach for generating a library of materials with different functional identities that can be "mixed and matched" to attain desired characteristics of a delivery vector. We have applied the combinatorial design to chitosan (CS), where the polymer backbone has been modified with polyethylene glycol, epidermal growth factor receptor-binding peptide, and lipid derivatives of varying chain length to encapsulate hydrophobic drugs. Cisplatin, cis-([PtCl2(NH3)2]), is one of the most potent chemotherapy drugs broadly administered for cancer treatment. Cisplatin is a hydrophilic drug, and in order for it to be encapsulated in the developed nanosystems, it was modified with lipids of varying chain length. The library of four CS derivatives and six platinum derivatives was self-assembled in aqueous medium and evaluated for physicochemical characteristics and cytotoxic effects in platinum-sensitive and -resistant lung cancer cells. The results show that the lipid-modified platinate encapsulation into CS nanoparticles significantly improved cellular cytotoxicity of the drug. In this work, we have also reinforced the idea that CS is a multifaceted system that can be as successful in delivering small molecules as it has been as a nucleic acids carrier.

  15. Design and analysis of tilt integral derivative controller with filter for load frequency control of multi-area interconnected power systems.

    PubMed

    Kumar Sahu, Rabindra; Panda, Sidhartha; Biswal, Ashutosh; Chandra Sekhar, G T

    2016-03-01

    In this paper, a novel Tilt Integral Derivative controller with Filter (TIDF) is proposed for Load Frequency Control (LFC) of multi-area power systems. Initially, a two-area power system is considered and the parameters of the TIDF controller are optimized using Differential Evolution (DE) algorithm employing an Integral of Time multiplied Absolute Error (ITAE) criterion. The superiority of the proposed approach is demonstrated by comparing the results with some recently published heuristic approaches such as Firefly Algorithm (FA), Genetic Algorithm (GA) and Particle Swarm Optimization (PSO) optimized PID controllers for the same interconnected power system. Investigations reveal that proposed TIDF controllers provide better dynamic response compared to PID controller in terms of minimum undershoots and settling times of frequency as well as tie-line power deviations following a disturbance. The proposed approach is also extended to two widely used three area test systems considering nonlinearities such as Generation Rate Constraint (GRC) and Governor Dead Band (GDB). To improve the performance of the system, a Thyristor Controlled Series Compensator (TCSC) is also considered and the performance of TIDF controller in presence of TCSC is investigated. It is observed that system performance improves with the inclusion of TCSC. Finally, sensitivity analysis is carried out to test the robustness of the proposed controller by varying the system parameters, operating condition and load pattern. It is observed that the proposed controllers are robust and perform satisfactorily with variations in operating condition, system parameters and load pattern.

  16. (E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety as potential immunosuppressive agents: Design, synthesis, molecular docking and biological evaluation.

    PubMed

    Lv, Xian-Hai; Li, Qing-Shan; Ren, Zi-Li; Chu, Ming-Jie; Sun, Jian; Zhang, Xin; Xing, Man; Zhu, Hai-Liang; Cao, Hai-Qun

    2016-01-27

    A series of novel (E)-1,3-diphenyl-1H-pyrazole derivatives containing O-benzyl oxime moiety were firstly synthesized and their immunosuppressive activities were evaluated. Among all the compounds, 4n exhibited the most potent inhibitory activity (IC50 = 1.18 μM for lymph node cells and IC50 = 0.28 μM for PI3Kγ), which was comparable to that of positive control. Moreover, selected compounds were tested for their inhibitory activities against IL-6 released in ConA-simulated mouse lymph node cells, 4n exhibited the most potent inhibitory ability. Furthermore, in order to study the preliminary mechanism of the compounds with potent inhibitory activity, the RT-PCR experiment was performed to assay the effect of selected compounds on mRNA expression of IL-6. Among them, compound 4n strongly inhibited the expression of IL-6 mRNA.

  17. Polymer-Derived Silicoboron Carbonitride Foams for CO2 Capture: From Design to Application as Scaffolds for the in Situ Growth of Metal-Organic Frameworks.

    PubMed

    Sandra, Fabien; Depardieu, Martin; Mouline, Zineb; Vignoles, Gérard L; Iwamoto, Yuji; Miele, Philippe; Backov, Rénal; Bernard, Samuel

    2016-06-06

    A template-assisted polymer-derived ceramic route is investigated for preparing a series of silicoboron carbonitride (Si/B/C/N) foams with a hierarchical pore size distribution and tailorable interconnected porosity. A boron-modified polycarbosilazane was selected to impregnate monolithic silica and carbonaceous templates and form after pyrolysis and template removal Si/B/C/N foams. By changing the hard template nature and controlling the quantity of polymer to be impregnated, controlled micropore/macropore distributions with mesoscopic cell windows are generated. Specific surface areas from 29 to 239 m(2)  g(-1) and porosities from 51 to 77 % are achieved. These foams combine a low density with a thermal insulation and a relatively good thermostructural stability. Their particular structure allowed the in situ growth of metal-organic frameworks (MOFs) directly within the open-cell structure. MOFs offered a microporosity feature to the resulting Si/B/C/N@MOF composite foams that allowed increasing the specific surface area to provide CO2 uptake of 2.2 %.

  18. Design, Synthesis, in Vitro, and in Vivo Anticancer and Antiangiogenic Activity of Novel 3-Arylaminobenzofuran Derivatives Targeting the Colchicine Site on Tubulin

    PubMed Central

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Prencipe, Filippo; Lopez-Cara, Carlota; Ortega, Santiago Schiaffino; Brancale, Andrea; Hamel, Ernest; Castagliuolo, Ignazio; Mitola, Stefania; Ronca, Roberto; Bortolozzi, Roberta; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

    2015-01-01

    A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3′,4′,5′-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-6-methoxybenzo-[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3–27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate. PMID:25785605

  19. Design, synthesis, and antibacterial activity against rice bacterial leaf blight and leaf streak of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivative.

    PubMed

    Li, Pei; Shi, Li; Yang, Xia; Yang, Lei; Chen, Xue-Wen; Wu, Fang; Shi, Qing-Cai; Xu, Wei-Ming; He, Ming; Hu, De-Yu; Song, Bao-An

    2014-04-01

    A series of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivatives were synthesized and evaluated for their antibacterial activities against rice bacterial leaf blight and leaf streak caused by Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicolaby via the turbidimeter test in vitro. Antibacterial bioassay results indicated that most compounds demonstrated good inhibitory effect antibacterial bioactivities against rice bacterial leaf blight and leaf streak. Among the title compounds, compound 6c demonstrated the best inhibitory effect against rice bacterial leaf blight and leaf streak with half-maximal effective concentration (EC50) values of 1.07 and 7.14 μg/mL, respectively, which were even better than those of commercial agents such as Bismerthiazol and Thiediazole Copper. In vivo antibacterial activities tests at greenhouse conditions demonstrated that the controlling effect of compounds 6c (43.5%) and 6g (42.4%) against rice bacterial leaf blight were better than those of Bismerthiazol (25.5%) and Thiediazole Copper (37.5%).

  20. Design, synthesis and bioevaluation of novel N-substituted-3,5-bis(arylidene)-4-piperidone derivatives as cytotoxic and antitumor agents with fluorescent properties.

    PubMed

    Sun, Jufeng; Zhang, Shuping; Yu, Chen; Hou, Guige; Zhang, Xiaofan; Li, Keke; Zhao, Feng

    2014-04-01

    Ten new N-substituted-3,5-bis(arylidene)-4-piperidone derivatives (series 1 and 2) were synthesized and subsequently evaluated against human carcinoma cell lines SW1990, MIA PaCa-2, PG-BE1, NCI-H460, and SK-BR-3 for cytotoxic activity by the CCK-8 method, and their fluorescent properties were investigated as well. The compounds were confirmed to display greater cytotoxic activity to the neoplastic cells, and approximately 50% of the IC50 values were lower than 5 μm. In particular, compounds 1a, 1c, 1d, and 1e bearing 3-bromophenyl groups were revealed as the most active antitumor drug candidates and had the average IC50 values of 1.94, 1.11, 1.16, and 0.817 μm, respectively. Furthermore, their fluorescent properties were interesting and might contribute to the visualization of their distribution in tumor cells. Some possible reasons for the disparity between cytotoxic activity and fluorescent properties in the two series of compounds were explored. This study revealed high potential of these molecules for further development as fluorescent cytotoxic and antitumor agents.

  1. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors.

    PubMed

    Yang, Yu-Shun; Yang, Bing; Zou, Yan; Li, Guigen; Zhu, Hai-Liang

    2016-07-01

    A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-Raf(V600E) and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04μM and GI50 value of 0.87μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf(V600E) from B-Raf(WT), C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches.

  2. Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition.

    PubMed

    Sato, Ippei; Morihira, Koichiro; Inami, Hiroshi; Kubota, Hirokazu; Morokata, Tatsuaki; Suzuki, Keiko; Iura, Yosuke; Nitta, Aiko; Imaoka, Takayuki; Takahashi, Toshiya; Takeuchi, Makoto; Ohta, Mitsuaki; Tsukamoto, Shin-Ichi

    2008-09-15

    In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.

  3. Fibrin Scaffolds Designing in order to Human Adipose-derived Mesenchymal Stem Cells Differentiation to Chondrocytes in the Presence of TGF-β3

    PubMed Central

    Sheykhhasan, Mohsen; Qomi, Reza Tabatabaei; Ghiasi, Mahdieh

    2015-01-01

    Background and Objectives One of the most cellular source used for cartilage tissue engineering are mesenchymal stem cells (MSCs). In present study, human MSCs were used as cellular source. Since scaffold plays an important role in tissue engineering the aim of this study is to assess fibrin scaffold ability in chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs). Methods ADMSCs were isolated and cultured in DMEM medium supplemented with 10% FBS. Also ADMSCs expanded and characterised by flow cytometry. ADMSCs expressed CD44, CD90, CD105 but not CD34. After trypsinization, cells were entered within the fibrin scaffold. Then, chondrogenic medium was added to the scaffold. Seven days after cell culture, cell viability and proliferation were assessed by MTT test. Finally, 14 days after the ending of chondrogenic differentiation, analysis of chondrogenic genes expression was evaluated by RT-PCR and Real time PCR. Also, formation and development of chondrocyte cells was analysed by histological and immunohistochemistry evaluations. Results Viability and proliferation as well as chondrogenic genes expression within fibrin scaffold increased significantly compared with control group (cells free scaffold). Also, histological and immunohistochemistry evaluation showed that chondrocyte cells and collagen type II are formed on fibrin scaffold. Conclusions Fibrin is a suitable scaffold for chondrogenic differentiation of ADMSCs. PMID:26634070

  4. Evaluation of an asymmetric stent patch design for a patient specific intracranial aneurysm using computational fluid dynamic (CFD) calculations in the computed tomography (CT) derived lumen

    NASA Astrophysics Data System (ADS)

    Kim, Minsuok; Ionita, Ciprian; Tranquebar, Rekha; Hoffmann, Kenneth R.; Taulbee, Dale B.; Meng, Hui; Rudin, Stephen

    2006-03-01

    Stenting may provide a new, less invasive therapeutic option for cerebral aneurysms. However, a conventional porous stent may be insufficient in modifying the blood flow for clinical aneurysms. We designed an asymmetric stent consisting of a low porosity patch welded onto a porous stent for an anterior cerebral artery aneurysm of a specific patient geometry to block the strong inflow jet. To evaluate the effect of the patch on aneurysmal flow dynamics, we "virtually" implanted it into the patient's aneurysm geometry and performed Computational Fluid Dynamics (CFD) analysis. The patch was computationally deformed to fit into the vessel lumen segmented from the patient CT reconstructions. After the flow calculations, a patch with the same design was fabricated using laser cutting techniques and welded onto a commercial porous stent, creating a patient-specific asymmetric stent. This stent was implanted into a phantom, which was imaged with X-ray angiography. The hemodynamics of untreated and stented aneurysms were compared both computationally and experimentally. It was found from CFD of the patient aneurysm that the asymmetric stent effectively blocked the strong inflow jet into the aneurysm and eliminated the flow impingement on the aneurysm wall at the dome. The impact zone with elevated wall shear stress was eliminated, the aneurysmal flow activity was substantially reduced, and the flow was considerably reduced. Experimental observations corresponded well qualitatively with the CFD results. The demonstrated asymmetric stent could lead to a new minimally invasive image guided intervention to reduce aneurysm growth and rupture.

  5. Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

    SciTech Connect

    Zhao, Ying; Hammoudeh, Dalia; Yun, Mi-Kyung; Qi, Jianjun; White, Stephen W.; Lee, Richard E.

    2012-05-29

    Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent.

  6. Designing Complexity

    ERIC Educational Resources Information Center

    Glanville, Ranulph

    2007-01-01

    This article considers the nature of complexity and design, as well as relationships between the two, and suggests that design may have much potential as an approach to improving human performance in situations seen as complex. It is developed against two backgrounds. The first is a world view that derives from second order cybernetics and radical…

  7. Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket.

    PubMed

    Lerner, Christian; Jakob-Roetne, Roland; Buettelmann, Bernd; Ehler, Andreas; Rudolph, Markus; Rodríguez Sarmiento, Rosa María

    2016-11-23

    A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.

  8. Process Design and Economics for the Conversion of Algal Biomass to Biofuels: Algal Biomass Fractionation to Lipid- and Carbohydrate-Derived Fuel Products

    SciTech Connect

    Davis, R.; Kinchin, C.; Markham, J.; Tan, E.; Laurens, L.; Sexton, D.; Knorr, D.; Schoen, P.; Lukas, J.

    2014-09-01

    Beginning in 2013, NREL began transitioning from the singular focus on ethanol to a broad slate of products and conversion pathways, ultimately to establish similar benchmarking and targeting efforts. One of these pathways is the conversion of algal biomass to fuels via extraction of lipids (and potentially other components), termed the 'algal lipid upgrading' or ALU pathway. This report describes in detail one potential ALU approach based on a biochemical processing strategy to selectively recover and convert select algal biomass components to fuels, namely carbohydrates to ethanol and lipids to a renewable diesel blendstock (RDB) product. The overarching process design converts algal biomass delivered from upstream cultivation and dewatering (outside the present scope) to ethanol, RDB, and minor coproducts, using dilute-acid pretreatment, fermentation, lipid extraction, and hydrotreating.

  9. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2001-10-01

    During the period July 1, 2001--September 30, 2001, Allegheny Energy Supply Co., LLC (Allegheny) continued construction of the Willow Island cofiring project, completed the installation of the fuel storage facility, the fuel receiving facility, and the processing building. All mechanical equipment has been installed and electrical construction has proceeded. During this time period significant short term testing of the Albright Generating Station cofiring facility was completed, and the 100-hour test was planned for early October. The testing demonstrated that cofiring at the Albright Generating Station could contribute to a ''4P Strategy''--reduction of SO{sub 2}, NO{sub x}, mercury, and greenhouse gas emissions. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations. It details the construction activities at both sites along with the combustion modeling at the Willow Island site.

  10. Minimum Hamiltonian ascent trajectory evaluation (MASTRE) program (update to automatic flight trajectory design, performance prediction, and vehicle sizing for support of shuttle and shuttle derived vehicles) users manual

    NASA Technical Reports Server (NTRS)

    Lyons, J. T.; Borchers, William R.

    1993-01-01

    Documentation for the User Interface Program for the Minimum Hamiltonian Ascent Trajectory Evaluation (MASTRE) is provided. The User Interface Program is a separate software package designed to ease the user input requirements when using the MASTRE Trajectory Program. This document supplements documentation on the MASTRE Program that consists of the MASTRE Engineering Manual and the MASTRE Programmers Guide. The User Interface Program provides a series of menus and tables using the VAX Screen Management Guideline (SMG) software. These menus and tables allow the user to modify the MASTRE Program input without the need for learning the various program dependent mnemonics. In addition, the User Interface Program allows the user to modify and/or review additional input Namelist and data files, to build and review command files, to formulate and calculate mass properties related data, and to have a plotting capability.

  11. Design, synthesis and biological evaluation of 1,3,6-trisubstituted β-carboline derivatives for cytotoxic and anti-leishmanial potential.

    PubMed

    Lunagariya, Nitin A; Gohil, Vikrantsinh M; Kushwah, Varun; Neelagiri, Soumya; Jain, Sanyog; Singh, Sushma; Bhutani, Kamlesh K

    2016-02-01

    In the present study, 23 derivatives of 1,3,6-trisubstituted β-carboline were synthesized and evaluated for cytotoxic potential against four human cancer cells, namely A-549, HeLa, Hep G2 and MCF-7 as well as anti-leishmanial activity against Leishmania donovani (MHOM/80/IN/Dd8) promastigotes. Among the studied compounds, compounds 13c and 13q showed potent cytotoxic activity better than the parent compound 10. For instance, compound 13c was found to be the most cytotoxic with IC50 of 4.72, 3.59, 3.65 and 4.17 μM against A-549, HeLa, Hep G2 and MCF-7 respectively, while for compound 13q, IC50 were 15.47, 5.30, 6.15 and 13.39 μM against the same cancer cells respectively. Further, these two compounds were found to be apoptotic in A-549 and MCF-7 cells when observed using Annexin V/propidium iodide staining under confocal microscope. All the compounds were also tested for anti-leishmanial potential. In which, compounds 13u and 13c were found to show moderate inhibition with IC50 of 23.5±9.0 and 68.0±0.0 μM respectively, while compound 10 was the most active with IC50 of 9.0±2.8 μM, suggesting the modification at C-6 detrimental for anti-leishmanial activity. Interestingly, amongst all, compound 13c was found to be the most active for cytotoxic and moderately active for anti-leishmanial activity which can be further developed as a lead for these disease areas.

  12. Cytotoxic activity of secondary metabolites derived from Artemisia annua L. towards cancer cells in comparison to its designated active constituent artemisinin.

    PubMed

    Efferth, Thomas; Herrmann, Florian; Tahrani, Ahmed; Wink, Michael

    2011-08-15

    Artemisia annua L. (sweet wormwood, qinhao) has traditionally been used in Chinese medicine. The isolation of artemisinin from Artemisia annua and its worldwide accepted application in malaria therapy is one of the showcase success stories of phytomedicine during the past decades. Artemisinin-type compounds are also active towards other protozoal or viral diseases as well as cancer cells in vitro and in vivo. Nowadays, Artemisia annua tea is used as a self-reliant treatment in developing countries. The unsupervised use of Artemisia annua tea has been criticized to foster the development of artemisinin resistance in malaria and cancer due to insufficient artemisinin amounts in the plant as compared to standardized tablets with isolated artemisinin or semisynthetic artemisinin derivatives. However, artemisinin is not the only bioactive compound in Artemisia annua. In the present investigation, we analyzed different Artemisia annua extracts. Dichloromethane extracts were more cytotoxic (range of IC₅₀: 1.8-14.4 μg/ml) than methanol extracts towards Trypanosoma b. brucei (TC221 cells). The range of IC₅₀ values for HeLa cancer cells was 54.1-275.5 μg/ml for dichloromethane extracts and 276.3-1540.8 μg/ml for methanol extracts. Cancer and trypanosomal cells did not reveal cross-resistance among other compounds of Artemisia annua, namely the artemisinin-related artemisitene and arteanuine B as well as the unrelated compounds, scopoletin and 1,8-cineole. This indicates that cells resistant to one compound retained sensitivity to another one. These results were also supported by microarray-based mRNA expression profiling showing that molecular determinants of sensitivity and resistance were different between artemisinin and the other phytochemicals investigated.

  13. Design, Synthesis, and Cytotoxic Evaluation of Certain 7-Chloro-4-(piperazin-1-yl)quinoline Derivatives as VEGFR-II Inhibitors.

    PubMed

    Aboul-Enein, Mohamed Nabil; El-Azzouny, Aida M Abd El-Sattar; Ragab, Fatma Abdel-Fattah; Hamissa, Mohamed Farouk

    2017-03-17

    Signaling pathway inhibition of VEGFR-II is visualized as valuable tool in cancer management. In the current study, the synthesis of novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)-ethanone derivatives (4a-t) was achieved through the amination of 2-chloro-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (3) with different secondary amines. The structures of the target compounds were confirmed by IR, (1) H-NMR, (13) C-NMR, HRMS, and microanalysis. Compounds 4a-t were subjected to in vitro anticancer screening against human breast cancer (MCF-7) and prostate cancer (PC3) cell lines. The highest cytotoxicty against both cell lines was displayed by 2-(4-(4-bromobenzyl)piperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q), with IC50 values of 6.502 and 11.751 μM against MCF-7 and PC3 cells, respectively, compared with the standard drug doxorubicin (MCF-7: 6.774 μM, PC3: 7.7316 μM). Due to its notable activity toward MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC50 of 1.38 μM compared to sorafenib (0.33 μM). The docking study proved that 4q has a binding mode akin to that of VEGFR-II inhibitors.

  14. 5-(4-Chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivatives as lipophilic cyclic analogues of baclofen: design, synthesis, and neuropharmacological evaluation.

    PubMed

    Abdel-Hafez, Atef A; Abdel-Wahab, Basel A

    2008-09-01

    In trials to preserve the pharmacological profile and improve the bioavailability via lipophilicity increment of baclofen 1 and searching for more potent and less toxic muscle relaxants and analgesics, nine substituted cyclic analogues of 1 were designed and synthesized. The target derivatives 5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one (11-19) were obtained through amide formation to the corresponding intermediates (2-10) followed by cyclization using acetic anhydride. The structures of the target compounds (11-19) were confirmed by IR, (1)H NMR, MS, and elemental analyses. The neuropharmacological activities of these lipophilic cyclic analogues (11-19) were assessed for their effects on motor activity, muscle relaxation, pain relief and impaired cognition, by intraperitoneal administration at a dose of 3mg/kg with reference to those of baclofen 1. Our results showed that compounds 11-14 are devoid of all of the tested pharmacological effects associated with 1. In all paradigms tested, undecyl, tridecyl, heptdec-8-enyl and benzyl substituted analogue derivatives (15, 16, 18, and 19) revealed a significant neurological activity being vividly favorable comparable with baclofen 1. 2-Benzyl-5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 19 is the most active candidate with high significant neurological potencies, while 5-(4-chlorophenyl)-2-(dec-8-enyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 17 displayed activity at relatively higher time interval. These results probe a new structurally distinct class incorporating 1,3-oxazepine nucleus as promising candidates as GABA(B) agonists for further investigations.

  15. Designed single-step synthesis, structure, and derivative textural properties of well-ordered layered penta-coordinate silicon alcoholate complexes.

    PubMed

    Li, Xiansen; Michaelis, Vladimir K; Ong, Ta-Chung; Smith, Stacey J; Griffin, Robert G; Wang, Evelyn N

    2014-05-19

    The controllable synthesis of well-ordered layered materials with specific nanoarchitecture poses a grand challenge in materials chemistry. Here the solvothermal synthesis of two structurally analogous 5-coordinate organosilicate complexes through a novel transesterification mechanism is reported. Since the polycrystalline nature of the intrinsic hypervalent Si complex thwarts the endeavor in determining its structure, a novel strategy concerning the elegant addition of a small fraction of B species as an effective crystal growth mediator and a sacrificial agent is proposed to directly prepare diffraction-quality single crystals without disrupting the intrinsic elemental type. In the determined crystal structure, two monomeric primary building units (PBUs) self-assemble into a dimeric asymmetric secondary BU via strong Na(+)-O(2-) ionic bonds. The designed one-pot synthesis is straightforward, robust, and efficient, leading to a well-ordered (10ī)-parallel layered Si complex with its principal interlayers intercalated with extensive van der Waals gaps in spite of the presence of substantial Na(+) counter-ions as a result of unique atomic arrangement in its structure. However, upon fast pyrolysis, followed by acid leaching, both complexes are converted into two SiO2 composites bearing BET surface areas of 163.3 and 254.7 m(2)  g(-1) for the pyrolyzed intrinsic and B-assisted Si complexes, respectively. The transesterification methodology merely involving alcoholysis but without any hydrolysis side reaction is designed to have generalized applicability for use in synthesizing new layered metal-organic compounds with tailored PBUs and corresponding metal oxide particles with hierarchical porosity.

  16. Designed Single-Step Synthesis, Structure, and Derivative Textural Properties of Well-Ordered Layered Penta-Coordinate Silicon Alcoholate Complexes

    PubMed Central

    Li, Xiansen; Michaelis, Vladimir K.; Ong, Ta-Chung; Smith, Stacey J.; Griffin, Robert G.; Wang, Evelyn N.

    2014-01-01

    The controllable synthesis of well-ordered layered materials with specific nanoarchitecture poses a grand challenge in materials chemistry. We report the solvothermal synthesis of two structurally analogous 5-coordinate organosilicate complexes via a novel transesterification mechanism. Since the polycrystalline nature of the intrinsic hypervalent Si complex thwarts the endeavor in determining its structure, a novel strategy concerning the elegant addition of a small fraction of B species as an effective crystal growth mediator and a sacrificial agent is proposed to directly prepare diffraction-quality single crystals without disrupting the intrinsic elemental type. In the determined crystal structure, two monomeric primary building units (PBUs) self-assemble into a dimeric asymmetric secondary BU via strong Na+-O2− ionic bonds. The designed one-pot synthesis is straightforward, robust, and efficient, leading to a well-ordered (10ī)-parallel layered Si complex with its principal interlayers intercalated with extensive van der Waals gaps in spite of the presence of substantial Na+ counterions as a result of unique atomic arrangement in its structure. On the other hand, upon fast pyrolysis, followed by acid leaching, both complexes are converted into two SiO2 composites bearing BET surface areas of 163.3 and 254.7 m2 g−1 for the pyrolyzed intrinsic and B-assisted Si complexes, respectively. The transesterification methodology merely involving alcoholysis but without any hydrolysis side reaction is designed to have generalized applicability for use in synthesizing new layered metal-organic compounds with tailored PBUs and corresponding metal oxide particles with hierarchical porosity. PMID:24737615

  17. Designed Single-Step Synthesis, Structure, and Derivative Textural Properties of Well-Ordered Layered Penta-coordinate Silicon Alcoholate Complexes

    SciTech Connect

    Li, XS; Michaelis, VK; Ong, TC; Smith, SJ; Griffin, RG; Wang, EN

    2014-04-15

    The controllable synthesis of well-ordered layered materials with specific nanoarchitecture poses a grand challenge in materials chemistry. Here the solvothermal synthesis of two structurally analogous 5-coordinate organosilicate complexes through a novel transesterification mechanism is reported. Since the polycrystalline nature of the intrinsic hypervalent Si complex thwarts the endeavor in determining its structure, a novel strategy concerning the elegant addition of a small fraction of B species as an effective crystal growth mediator and a sacrificial agent is proposed to directly prepare diffraction-quality single crystals without disrupting the intrinsic elemental type. In the determined crystal structure, two monomeric primary building units (PBUs) self-assemble into a dimeric asymmetric secondary BU via strong Na+O2- ionic bonds. The designed one-pot synthesis is straightforward, robust, and efficient, leading to a well-ordered (10)-parallel layered Si complex with its principal interlayers intercalated with extensive van der Waals gaps in spite of the presence of substantial Na+ counter-ions as a result of unique atomic arrangement in its structure. However, upon fast pyrolysis, followed by acid leaching, both complexes are converted into two SiO2 composites bearing BET surface areas of 163.3 and 254.7m(2)g(-1) for the pyrolyzed intrinsic and B-assisted Si complexes, respectively. The transesterification methodology merely involving alcoholysis but without any hydrolysis side reaction is designed to have generalized applicability for use in synthesizing new layered metal-organic compounds with tailored PBUs and corresponding metal oxide particles with hierarchical porosity.

  18. Optimization of the enantioseparation of a diaryl-pyrazole sulfonamide derivative by capillary electrophoresis in a dual CD mode using experimental design.

    PubMed

    Rogez-Florent, Tiphaine; Foulon, Catherine; Six, Perrine; Goossens, Laurence; Danel, Cécile; Goossens, Jean-François

    2014-10-01

    A CE method using dual cationic and neutral cyclodextrins (CD) was optimized for the enantiomeric separation of a compound presenting a diaryl sulfonamide group. Preliminary studies were made to select the optimal CDs and pH of the BGE. Two CDs (amino-β-CD and β-CD) were selected to separate the enantiomers in a 67 mM phosphate buffer at pH 7.4. However, the repeatability of the analyses obtained on bare-fused silica capillary was not acceptable owing to the adsorption of the amino-β-CD to the capillary. To prevent this, a dynamic coating of the capillary was used employing five layers of ionic-polymer (poly(diallyldimethylammonium) chloride (PDADMAC) and poly(sodium 4-styrenesulfonate). The efficiency of the coating was assessed by measuring the EOF stability. Repeatability of the injections was obtained when intermediate coating with PDADMAC was performed between each run. Secondly, this enantioseparation method was optimized using a central composite circumscribed design including three factors: amino-β-CD and β-CD concentrations and the percentage of methanol. Under the optimal conditions (i.e. 16.6 mM of amino-β-CD, 2.6 mM of β-CD, 0% MeOH in 67 mM phosphate buffer (pH 7.4) as BGE, cathodic injection 0.5 psi, 5 s, separation voltage 15 kV and a temperature of 15°C), complete enantioresolution of the analyte was obtained. It is worth mentioning that the design of experiments (DOE) protocol employed showed a significant interaction between CDs, highlighting the utility of DOE in method development. Finally, small variations in the ionic-polymer concentrations did not significantly influence the EOF, confirming the robustness of the coating method.

  19. Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-1α (SDF) Generates an Effective and Translatable Angiogenic Polypeptide Analog

    PubMed Central

    Hiesinger, William; Perez-Aguilar, Jose Manuel; Atluri, Pavan; Marotta, Nicole A.; Frederick, John R.; Fitzpatrick, J. Raymond; McCormick, Ryan C.; Muenzer, Jeffrey R.; Yang, Elaine C.; Levit, Rebecca D.; Yuan, Li-Jun; MacArthur, John W.; Saven, Jeffery G.; Woo, Y. Joseph

    2014-01-01

    BACKGROUND After ischemic injury, cardiac secretion of the potent endothelial progenitor stem cell (EPC) chemokine SDF stimulates endogenous neovascularization and myocardial repair, a process insufficiently robust to repair major infarcts. Experimentally, exogenous administration of recombinant SDF enhances neovasculogenesis and cardiac function after MI. However, SDF has a short half-life, is bulky, and very expensive. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a more efficient evolution of the native SDF protein. METHODS and RESULTS Protein structure model was used to engineer an SDF polypeptide analog (ESA) that splices the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline segment designed to limit the conformational flexibility of the peptide backbone and retain the relative orientation of these segments observed in the native structure of SDF. EPCs in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared to both SDF and control gradients (ESA 567±74 cells/HPF vs SDF 438±46 p=0.037; vs Control 156±45 p=0.001). EPC receptor activation was evaluated by quantifying phosphorylated AKT. ESA had significantly greater pAKT levels than SDF and control (1.64±0.24 vs 1.26±0.187, p=0.01; vs. 0.95±0.08, p<0.001). Angiogenic growth factor assays revealed a distinct increase in Angiopoietin-1 expression in the ESA and SDF treated hearts. Also, CD-1 mice (n=30) underwent LAD ligation and peri-infarct intramyocardial injection of ESA, SDF-1α, or saline. At 2 weeks, echocardiography demonstrated a significant gain in EF, CO, SV, and Fractional Area Change (FAC) in mice treated with ESA when compared to controls and significant improvement in FAC when compared to SDF treated

  20. Atomic insight into designed carbamate-based derivatives as acetylcholine esterase (AChE) inhibitors: a computational study by multiple molecular docking and molecular dynamics simulation.

    PubMed

    Mohammadi, Tecush; Ghayeb, Yousef

    2017-01-11

    Over 100 variants have been designed and studied, using multiple docking methods such as Autodock Vina, ArgusLab, Molegro Virtual Docker, and Hex-Cuda, to study the effect of alteration in the structure of carbamate-based acetylcholyne esterase (AChE) inhibitors. Sixteen selected systems were then subjected to 14 ns molecular dynamics (MD) simulations. Results from all the docking methods are in agreement. Variants that involved biphenyl substituents possess the most negative binding energies in the -37.64 to -39.31 kJ mol(-1) range due to their π-π interactions with AChE aromatic residues. The root mean square deviation values showed that all of these components achieved equilibration after 6 ns. Gyration radius (Rg) and solvent accessibility surface area were calculated to further investigate the AChE conformational changes in the presence of these components. MD simulation results suggested that these components might interact with AChE, possibly with no major changes in AChE secondary and tertiary structures.

  1. Design, synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives containing benzimidazole skeleton as potential anticancer and apoptosis inducing agents.

    PubMed

    Reddy, T Srinivasa; Kulhari, Hitesh; Reddy, V Ganga; Bansal, Vipul; Kamal, Ahmed; Shukla, Ravi

    2015-08-28

    A series of forty different pyrazole containing benzimidazole hybrids (6-45) have been designed, synthesized and evaluated for their potential anti-proliferative activity against three human tumor cell lines - lung (A549), breast (MCF-7), and cervical (HeLa). Some of the compounds, specifically 9, 17, and 28, showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.83-1.81 μM. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis inducing effect of compounds. The morphology, cell migration and long term clonogenic survival of MCF-7 breast cancer cells were severely affected by treatment with these compounds. Flow-cytometry revealed the compounds arrested MCF-7 cells in the G1 phase of the cell cycle via down regulation of cyclin D2 and CDK2. Fluorescent staining and DNA fragmentation studies showed that cell proliferation was inhibited by induction of apoptosis. Moreover, the compounds led to collapse of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) were noted. The ease of synthesis and the remarkable biological activities make these compounds promising new frameworks for the development of cancer therapeutics.

  2. Design, Synthesis and Evaluation of Marinopyrrole Derivatives as Selective Inhibitors of Mcl-1 Binding to Pro-apoptotic Bim and Dual Mcl-1/Bcl-xL Inhibitors

    PubMed Central

    Li, Rongshi; Daniel, Kenyon G.; Li, Jerry; Qin, Yong; Gavathiotis, Evripidis; Sebti, Said M.

    2015-01-01

    Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogues and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13- and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl-1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (±)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel “lead” marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors. PMID:25437618

  3. Strategy to evaluate persistent contaminant hazards resulting from sea-level rise and storm-derived disturbances—Study design and methodology for station prioritization

    USGS Publications Warehouse

    Reilly, Timothy J.; Jones, Daniel K.; Focazio, Michael J.; Aquino, Kimberly C.; Carbo, Chelsea L.; Kaufhold, Erika E.; Zinecker, Elizabeth K.; Benzel, William M.; Fisher, Shawn C.; Griffin, Dale W.; Iwanowicz, Luke R.; Loftin, Keith A.; Schill, William B.

    2015-10-26

    Coastal communities are uniquely vulnerable to sea-level rise (SLR) and severe storms such as hurricanes. These events enhance the dispersion and concentration of natural and anthropogenic chemicals and pathogenic microorganisms that could adversely affect the health and resilience of coastal communities and ecosystems in coming years. The U.S. Geological Survey has developed a strategy to define baseline and post-event sediment-bound environmental health (EH) stressors (hereafter referred to as the Sediment-Bound Contaminant Resiliency and Response [SCoRR] strategy). A tiered, multimetric approach will be used to (1) identify and map contaminant sources and potential exposure pathways for human and ecological receptors, (2) define the baseline mixtures of EH stressors present in sediments and correlations of relevance, (3) document post-event changes in EH stressors present in sediments, and (4) establish and apply metrics to quantify changes in coastal resilience associated with sediment-bound contaminants. Integration of this information provides a means to improve assessment of the baseline status of a complex system and the significance of changes in contaminant hazards due to storm-induced (episodic) and SLR (incremental) disturbances. This report describes the purpose and design of the SCoRR strategy and the methods used to construct a decision support tool to identify candidate sampling stations vulnerable to contaminants that may be mobilized by coastal storms.

  4. Design of biomimetic and bioactive cold plasma-modified nanostructured scaffolds for enhanced osteogenic differentiation of bone marrow-derived mesenchymal stem cells.

    PubMed

    Wang, Mian; Cheng, Xiaoqian; Zhu, Wei; Holmes, Benjamin; Keidar, Michael; Zhang, Lijie Grace

    2014-03-01

    The objective of this study was to design a biomimetic and bioactive tissue-engineered bone construct via a cold atmospheric plasma (CAP) treatment for directed osteogenic differentiation of human bone morrow mesenchymal stem cells (MSCs). Porous nanocrystalline hydroxyapatite/chitosan scaffolds were fabricated via a lyophilization procedure. The nanostructured bone scaffolds were then treated with CAP to create a more favorable surface for cell attachment, proliferation, and differentiation. The CAP-modified scaffolds were characterized via scanning electron microscope, Raman spectrometer, contact angle analyzer, and white light interferometer. In addition, optimal CAP treatment conditions were determined. Our in vitro study shows that MSC adhesion and infiltration were significantly enhanced on CAP modified scaffolds. More importantly, it was demonstrated that CAP-modified nanostructured bone constructs can greatly promote total protein, collagen synthesis, and calcium deposition after 3 weeks of culture, thus making them a promising implantable scaffold for bone regeneration. Moreover, the fibronectin and vitronection adsorption experiments by enzyme-linked immunosorbent assay demonstrated that more adhesion-mediated protein adsorption on the CAP-treated scaffolds. Since the initial specific protein absorption on scaffold surfaces can lead to further recruitment as well as activation of favorable cell functions, it is suggested that our enhanced stem cell growth and osteogenic function may be related to more protein adsorption resulting from surface roughness and wettability modification. The CAP modification method used in this study provides a quick one-step process for cell-favorable tissue-engineered scaffold architecture remodeling and surface property alteration.

  5. DESIGNING AN OPPORTUNITY FUEL WITH BIOMASS AND TIRE-DERIVED FUEL FOR COFIRING AT WILLOW ISLAND GENERATING STATION AND COFIRING SAWDUST WITH COAL AT ALBRIGHT GENERATING STATION

    SciTech Connect

    K. Payette; D. Tillman

    2002-01-01

    During the period October 1, 2001--December 31, 2001, Allegheny Energy Supply Co., LLC (Allegheny) completed construction of the Willow Island cofiring project. This included completion of the explosion proof electrical wiring, the control system, and the control software. Procedures for system checkout, shakedown, and initial operation were initiated during this period. During this time period the 100-hour test of the Albright Generating Station cofiring facility was completed. The testing demonstrated that cofiring at the Albright Generating Station could reliably contribute to a ''4P Strategy''--reduction of SO{sub 2}, NO{sub x}, mercury, and greenhouse gas emissions over a significant load range. During this period of time Allegheny Energy conducted facility tours of both Albright and Willow Island for the Biomass Interest Group of the Electric Power Research Institute. This report summarizes the activities associated with the Designer Opportunity Fuel program, and demonstrations at Willow Island and Albright Generating Stations. It details the completion of construction activities at the Willow Island site along with the 100-hr test at the Albright site.

  6. Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents.

    PubMed

    Chou, Li-Chen; Tsai, Meng-Tung; Hsu, Mei-Hua; Wang, Sheng-Hung; Way, Tzong-Der; Huang, Chi-Hung; Lin, Hui-Yi; Qian, Keduo; Dong, Yizhou; Lee, Kuo-Hsiung; Huang, Li-Jiau; Kuo, Sheng-Chu

    2010-11-25

    Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.

  7. Adsorption of Disperse Orange 30 dye onto activated carbon derived from Holm Oak (Quercus Ilex) acorns: A 3(k) factorial design and analysis.

    PubMed

    Tezcan Un, Umran; Ates, Funda; Erginel, Nihal; Ozcan, Oznur; Oduncu, Emre

    2015-05-15

    In this study, samples of activated carbon were prepared from Holm Oak acorns by chemical activation with H3PO4, ZnCl2 and KOH as activating agents. The samples were characterized by SEM, BET, FTIR and elemental analysis, and were then evaluated for the removal of Disperse Orange 30 (DO30) dyes from aqueous solutions. A 3(k) factorial design was used to determine the interaction effects of carbonization temperature, pH, dosage of adsorbent and type of activating agent on the amount of dye removal. Also, level of effectiveness factors were determined by conducting regression models for maximum adsorption efficiency. Of all the samples, the sample generated using ZnCl2 as an activating agent showed a maximum dye removal efficiency of 93.5% at a carbonization temperature of 750 °C, a pH of 2 and an adsorbent dosage of 0.15 g/25 ml. The analysis shows that the adsorption process depends significantly on the type of activating agent used in the preparation of activated carbon.

  8. Application of ZnO nanorods loaded on activated carbon for ultrasonic assisted dyes removal: Experimental design and derivative spectrophotometry method.

    PubMed

    Ansari, Fatemeh; Ghaedi, Mehrorang; Taghdiri, Mehdi; Asfaram, Arash

    2016-11-01

    A method based on application of ZnO nanorods loaded on activated carbon (ZnO-NRs-AC) for adsorption of Bromocresol Green (BCG) and Eosin Y (EY) accelerated by ultrasound was described. The present material was synthesized under ultrasound assisted wet-chemical method and subsequently was characterized by FE-SEM, TEM, BET and XRD analysis. The extent of contribution of conventional variables like pH (2.0-10.0), BCG concentration (4-20mgL(-1)), EY concentration (3-23mgL(-1)), adsorbent dosage (0.01-0.03g), sonication time (1-5min) and centrifuge time (2-6min) as main and interaction part were investigated by central composite design under response surface methodology. Analysis of variance (ANOVA) was adapted to experimental data and guide the best operational conditions mass by set at 6.0, 9mgL(-1), 10mgL(-1), 0.02g, 4 and 4min for pH, BCG concentration, EY concentration, adsorbent dosage, sonication and centrifuge time, respectively. At these specified conditions dye adsorption efficiency was higher than 99.5%. The suitability and well prediction of optimum point was tested by conducting five experiments and respective results revel that RSD% was lower than 3% and high quality of fitting was confirmed by t-test. The experimental data were best fitted in Langmuir isotherm equation and the removal followed pseudo second order kinetics. The experimentally obtained maximum adsorption capacities were estimated as 57.80 and 61.73mgg(-1) of ZnO-NRs-AC for BCG and EY respectively from binary dye solutions. The mechanism of removal was explained by boundary layer diffusion via intraparticle diffusion.

  9. DRS: Derivational Reasoning System

    NASA Technical Reports Server (NTRS)

    Bose, Bhaskar

    1995-01-01

    The high reliability requirements for airborne systems requires fault-tolerant architectures to address failures in the presence of physical faults, and the elimination of design flaws during the specification and validation phase of the design cycle. Although much progress has been made in developing methods to address physical faults, design flaws remain a serious problem. Formal methods provides a mathematical basis for removing design flaws from digital systems. DRS (Derivational Reasoning System) is a formal design tool based on advanced research in mathematical modeling and formal synthesis. The system implements a basic design algebra for synthesizing digital circuit descriptions from high level functional specifications. DRS incorporates an executable specification language, a set of correctness preserving transformations, verification interface, and a logic synthesis interface, making it a powerful tool for realizing hardware from abstract specifications. DRS integrates recent advances in transformational reasoning, automated theorem proving and high-level CAD synthesis systems in order to provide enhanced reliability in designs with reduced time and cost.

  10. Design and Investigation of a [(18)F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging.

    PubMed

    Yang, Dongzhi; Comeau, Anthony; Bowen, Wayne D; Mach, Robert H; Ross, Brian D; Hong, Hao; Van Dort, Marcian E

    2017-03-06

    High overexpression of sigma (σ) receptors (σ1 and σ2 subtypes) in a variety of human solid tumors has prompted the development of σ receptor-targeting radioligands, as imaging agents for tumor detection. A majority of these radioligands to date target the σ2 receptor, a potential marker of tumor proliferative status. The identification of approximately equal proportions of both σ receptor subtypes in prostate tumors suggests that a high affinity, dual σ receptor-targeting radioligand could potentially provide enhanced tumor targeting efficacy in prostate cancer. To accomplish this goal, we designed a series of ligands which bind to both σ receptor subtypes with high affinity. Ligand 3a in this series, displaying optimal dual σ receptor subtype affinity (σ1, 6.3 nM; σ2, 10.2 nM) was radiolabeled with fluorine-18 ((18)F) to give [(18)F]3a and evaluated as a σ receptor-targeting radioligand in the mouse PC-3 prostate tumor model. Cellular assays with PC-3 cells demonstrated that a major proportion of [(18)F]3a was localized to cell surface σ receptors, while ∼10% of [(18)F]3a was internalized within cells after incubation for 3.5 h. Serial PET imaging in mice bearing PC-3 tumors revealed that uptake of [(18)F]3a was 1.6 ± 0.8, 4.4 ± 0.3, and 3.6 ± 0.6% ID/g (% injection dose per gram) in σ receptor-positive prostate tumors at 15 min, 1.5 h, and 3.5 h postinjection, respectively (n = 3) resulting in clear tumor visualization. Blocking studies conducted with haloperidol (a nonselective inhibitor for both σ receptor subtypes) confirmed that the uptake of [(18)F]3a was σ receptor-mediated. Histology analysis confirmed similar expression of σ1 and σ2 in PC-3 tumors which was significantly greater than its expression in normal organs/tissues such as liver, kidney, and muscle. Metabolite studies revealed that >50% of radioactivity in PC-3 tumors at 30 min postinjection represented intact [(18)F]3a. Prominent σ receptor-specific uptake of [(18)F]3a in

  11. Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.

    PubMed

    Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd W; Porecca, Frank; Hruby, Victor J

    2016-01-15

    Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results.

  12. Design, synthesis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiol derivatives containing Schiff base formation as FabH inhibitory.

    PubMed

    Zhang, Fei; Wen, Qing; Wang, She-Feng; Shahla Karim, Baloch; Yang, Yu-Shun; Liu, Jia-Jia; Zhang, Wei-Ming; Zhu, Hai-Liang

    2014-01-01

    A series of novel schiff base derivatives (H(1)-H(20)) containing pyrazine and triazole moiety have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH). These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compounds among them were tested for their Escherichia coli FabH inhibitory activity. Based on the biological data, compound H(17) showed the most potent antibacterial activity with MIC values of 0.39-1.56μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 5.2μM, being better than the positive control Kanamycin B with IC50 of 6.3μM. Furthermore, docking simulation was performed to position compound H(17) into the E. coli FabH active site to determine the probable binding conformation. This study indicated that compound H(17) has demonstrated significant E. coli FabH inhibitory activity as a potential antibacterial agent and provides valuable information for the design of E. coli FabH inhibitors.

  13. Construction of peptides with nucleobase amino acids: design and synthesis of the nucleobase-conjugated peptides derived from HIV-1 Rev and their binding properties to HIV-1 RRE RNA.

    PubMed

    Takahashi, T; Hamasaki, K; Ueno, A; Mihara, H

    2001-04-01

    In order to develop a novel molecule that recognizes a specific structure of RNA, we have attempted to design peptides having L-alpha-amino acids with a nucleobase at the side chain (nucleobase amino acid (NBA)), expecting that the function of a nucleobase which can specifically recognize a base in RNA is regulated in a peptide conformation. In this study, to demonstrate the applicability of the NBA units in the peptide to RNA recognition, we designed and synthesized a variety of NBA-conjugated peptides, derived from HIV-1 Rev. Circular dichroism study revealed that the conjugation of the Rev peptide with an NBA unit did not disturb the peptide conformation. RNA-binding affinities of the designed peptides with RRE IIB RNA were dependent on the structure of the nucleobase moieties in the peptides. The peptide having the cytosine NBA at the position of the Asn40 site in the Rev showed a higher binding ability for RRE IIB RNA, despite the diminishing the Asn40 function. Furthermore, the peptide having the guanine NBA at the position of the Arg44 site, which is the most important residue for the RNA binding in the Rev, bound to RRE IIB RNA in an ability similar to Rev34-50 with native sequence. These results demonstrate that an appropriate NBA unit in the peptide plays an important role in the RNA binding with a specific contact such as hydrogen bonding, and the interaction between the nucleobase in the peptide and the base in the RNA can enhance the RNA-binding affinity and specificity.

  14. Quinazoline derivatives: synthesis and bioactivities

    PubMed Central

    2013-01-01

    Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This review summarizes the recent advances in the synthesis and biological activities investigations of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase-transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives also are discussed. PMID:23731671

  15. Rhodamine 123 efflux modulation in the presence of low or high serum from CD56+ hematopoietic cells or CD34+ leukemic blasts by B9309-068, a newly designed pyridine derivative.

    PubMed

    Beck, J F; Buchholz, F; Ulrich, W R; Boer, R; Sanders, K H; Niethammer, D; Gekeler, V

    1998-07-17

    The newly designed pyridine derivative B9309-068 and a series of structurally different compounds were tested for their ability to modulate rhodamine 123 (RHO) efflux from CD56+ hematopoietic cells in the presence of either 10% fetal calf serum or undiluted human AB serum. Furthermore, efflux modulation was investigated on CD34+ blast populations obtained from four patients with relapsed state AML. Target cells were specified throughout by labeling with peridinine chlorophyll protein (PerCP)-conjugated monoclonal antibodies, allowing clear differentiation from RHO emission spectrum by flow cytometry. In the presence of low serum each compound efficiently modulated RHO efflux without significant differences in the range of final concentrations (1.0-3.0 microM). At 0.1 microM, however, RHO efflux was differentially modulated following the series GF120918 approximately B9309-068 > PSC 833 > DNIG approximately DVER. With CD56+ cells in the presence of undiluted human AB serum at a final modulator concentration of 0.1 microM, all chemosensitizers tested were found to be inefficient. At final concentrations of 0.3 microM or higher, distinct RHO efflux modulation was found with the following efficacies: B9309-068 approximately GF120918 > PSC 833 > DVER approximately DNIG. The efficacies seen in undiluted human AB serum at 3.0 microM were comparable to those seen on CD56+ cells at final modulator concentrations of 0.1 microM in low serum. Our results identify the pyridine derivative B9309-068 as a promising compound for modulating P-glycoprotein-mediated drug resistance under conditions resembling the clinical setting. Nonetheless, modulation potencies of a series of structurally very different chemosensitizers was revealed to be substantially diminished at high serum concentrations in vitro.

  16. Anti-AIDS agents 85. Design, synthesis, and evaluation of 1R,2R-dicamphanoyl-3,3-dimethyldihydropyrano-[2,3-c]xanthen-7(1H)-one (DCX) derivatives as novel anti-HIV agents

    PubMed Central

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Huang, Li; Ho, Phong; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

    2011-01-01

    In this study, 1R,2R-dicamphanoyl-3,3-dimethydihydropyrano[2,3-c]xanthen-7(1H)-one (DCX) derivatives were designed and synthesized as novel anti-HIV agents against both wild-type and nonnucleoside reverse transcriptase (RT) inhibitor-resistant HIV-1 (RTMDR-1) strains. Twenty-four DCX analogs (6-29) were synthesized and evaluated against the non-drug-resistant HIV-1 NL4-3 strain, and selected analogs were also screened for their ability to inhibit the RTMDR-1 strain. Compared with the control 2-ethyl-3′,4′-di-O-(-)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (2-EDCP, 2), one of the best anti-HIV coumarin derivatives in our prior study, three DCX compounds (7, 12, and 22) showed better activity against both HIV strains with an EC50 range of 0.062 – 0.081 μM, and five additional compounds (8, 11, 16, 18, and 21) exhibited comparable anti-HIV potency. Six DCX analogs (7, 11-12, 18, and 21-22) also showed enhanced selectivity index (SI) values in comparison to the control. Structure-activity relationship (SAR) information suggested that the extended conjugated system of the pyranoxanthone skeleton facilitates the interaction of the small DCX molecule within the viral binding pocket, consequently leading to enhanced anti-HIV activity and selectivity. Compared to DCP compounds, DCX analogs are a more promising new class of anti-HIV agents. PMID:22063755

  17. Design of a coil satellite centrifuge and its performance on counter-current chromatographic separation of 4-methylumbelliferyl sugar derivatives with polar organic-aqueous two-phase solvent systems.

    PubMed

    Shinomiya, Kazufusa; Tokura, Koji; Kimura, Emiru; Takai, Midori; Harikai, Naoki; Yoshida, Kazunori; Yanagidaira, Kazuhiro; Ito, Yoichiro

    2015-05-01

    A new high-speed counter-current chromatograph, named coil satellite centrifuge (CSC), was designed and fabricated in our laboratory. The CSC apparatus produces the satellite motion such that the coiled column simultaneously rotates around the sun axis (the angular velocity, ω1), the planet axis (ω2) and the satellite axis (the central axis of the column) (ω3). In order to achieve this triplicate rotary motion without twisting of the flow tube, the rotation of each axis was determined by the following formula: ω1=ω2+ω3. This relation enabled to lay out the flow tube without twisting by the simultaneous rotation of three axes. The flow tube was introduced from the bottom side of the apparatus into the sun axis of the first rotary frame reaching the upper side of the planet axis and connected to the column in the satellite axis. The performance of the apparatus was examined on separation of 4-methylumbelliferyl (MU) sugar derivatives as test samples with organic-aqueous two-phase solvent systems composed of ethyl acetate/1-butanol/water (3:2:5, v/v) for lower phase mobile and (1:4:5, v/v) for upper phase mobile. With lower phase mobile, five 4-MU sugar derivatives including β-D-cellobioside (Cel), β-D-glucopyranoside, α-D-mannopyranoside, β-D-fucopyranoside and α-L-fucopyranoside (α-L-Fuc) were separated with the combined rotation around each axis at counterclockwise (CCW) (ω1) - CCW (ω2) - CCW (ω3) by the flow tube distribution. With upper phase mobile, three 4-MU sugar derivatives including α-L-Fuc, β-D-galactopyranoside and Cel were separated with the combined rotation around each axis at clockwise (CW) (ω1) - CW (ω2) - CW (ω3) by the flow tube distribution. A series of experiments on peak resolution and stationary phase retention revealed that better partition efficiencies were obtained at the flow rate of 0.5 mL/min (column 1) and 0.8 mL/min (column 2) for lower phase mobile and 0.2 mL/min (column 1) and 0.4 mL/min (column 2) for upper phase

  18. Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives as Potent Pan Bcr-Abl inhibitors including the threonine(315)→isoleucine(315) mutant.

    PubMed

    Li, Yupeng; Shen, Mengjie; Zhang, Zhang; Luo, Jinfeng; Pan, Xiaofen; Lu, Xiaoyun; Long, Huoyou; Wen, Donghai; Zhang, Fengxiang; Leng, Fang; Li, Yingjun; Tu, Zhengchao; Ren, Xiaomei; Ding, Ke

    2012-11-26

    A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-Abl(WT) and Bcr-Abl(T315I) with IC(50) values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-Abl(WT) or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-Abl(T315I), with IC(50) values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.

  19. Photo-degradation of basic green 1 and basic red 46 dyes in their binary solution by La2O3-Al2O3nanocomposite using first-order derivative spectra and experimental design methodology.

    PubMed

    Fahimirad, Bahareh; Asghari, Alireza; Rajabi, Maryam

    2017-02-10

    In this work, the lanthanum oxide-aluminum oxide (La2O3-Al2O3) nanocomposite is introduced as an efficient photocatalyst for the photo-degradation of the dyes basic green 1 (BG1) and basic red 46 (BR46) in their binary aqueous solution under the UV light irradiation. The properties of this catalyst are determined by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Brunauer-Emmett-Teller (BET), and UV-visible spectrophotometry. The first-order derivative spectra are used for the simultaneous analysis of the dyes in their binary solution. The screening investigations indicate that five parameters including the catalyst dosage, concentration of the dyes, irradiation time, and solution pH have significant effects on the photo-degradation of the dyes. The effects of these variables together with their interactions in the photo-degradation of the dyes are studied using the Box-Behnken design (BBD). Under the optimum experimental conditions, obtained via the desirability function, the photo-catalytic activities of La2O3-Al2O3 and pure Al2O3 are also investigated. The results obtained show an enhancement in the photo-catalytic activity when La2O3 nanoparticles are loaded on the surface of Al2O3 nanoparticles.

  20. Design, synthesis, and biological evaluation of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives as peripheral selective μ opioid receptor Agents.

    PubMed

    Yuan, Yunyun; Elbegdorj, Orgil; Chen, Jianyang; Akubathini, Shashidhar K; Zhang, Feng; Stevens, David L; Beletskaya, Irina O; Scoggins, Krista L; Zhang, Zhenxian; Gerk, Phillip M; Selley, Dana E; Akbarali, Hamid I; Dewey, William L; Zhang, Yan

    2012-11-26

    Peripheral selective μ opioid receptor (MOR) antagonists could alleviate the symptoms of opioid-induced constipation (OIC) without compromising the analgesic effect of opioids. However, a variety of adverse effects were associated with them, partially due to their relatively low MOR selectivity. NAP, a 6β-N-4'-pyridyl substituted naltrexamine derivative, was identified previously as a potent and highly selective MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure-activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED(50) = 0.03 mg/kg). The slight decrease of the ED(50) compared to the original lead was well compensated by the unobserved adverse effect. Hence, this compound seems to be a more promising lead to develop novel therapeutic agents toward OIC.

  1. Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives.

    PubMed

    Eldehna, Wagdy M; Abou-Seri, Sahar M; El Kerdawy, Ahmed M; Ayyad, Rezk R; Hamdy, Abdallah M; Ghabbour, Hazem A; Ali, Mamdouh M; Abou El Ella, Dalal A

    2016-05-04

    A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 μM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).

  2. Design and synthesis of 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase.

    PubMed

    Chen, Yi-Fong; Lin, Yi-Chien; Huang, Po-Kai; Chan, Hsu-Chin; Kuo, Sheng-Chu; Lee, Kuo-Hsiung; Huang, Li-Jiau

    2013-09-01

    Novel 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives 12a-n were designed and prepared through an intramolecular cyclization reaction and evaluated for in vitro anticancer activity. Among the synthesized compounds, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (12e) displayed potent cytotoxicity against several different tumor cell lines at a sub-micromolar level. Furthermore, results of fluorescence-activated cell sorting (FACS) analysis suggested that 12e induced cell cycle arrest in the G2/M phase accompanied by apoptosis in HL-60 and H460 cells. This action was confirmed by Hoechst staining and caspase-3 activation. Due to their easy synthesis and remarkable biological activities, 4-phenylquinolin-2(1H)-one analogs (4-PQs) are promising new anticancer leads based on the quinoline scaffold. Accordingly, compound 12e was identified as a new lead compound that merits further optimization and development as an anticancer candidate.

  3. Design, Synthesis, and Biological Evaluation of 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4’-pyridyl)carboxamido]morphinan Derivatives as Peripheral Selective Mu Opioid Receptor Agents

    PubMed Central

    Yuan, Yunyun; Elbegdorj, Orgil; Chen, Jianyang; Akubathini, Shashidhar K.; Zhang, Feng; Stevens, David L.; Beletskaya, Irina O.; Scoggins, Krista L.; Zhang, Zhenxian; Gerk, Phillip M.; Selley, Dana E.; Akbarali, Hamid I.; Dewey, William L.; Zhang, Yan

    2012-01-01

    Peripheral selective mu opioid receptor (MOR) antagonists could alleviate the symptoms of opioid-induced constipation (OIC) without compromising the analgesic effect of opioids. However, a variety of adverse effects were associated with them, partially due to their relatively low MOR selectivity. NAP, a 6β-N-4'-pyridyl substituted naltrexamine derivative, was identified previously as a potent and highly selective MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED50=0.03 mg/kg). The slight decrease of the ED50 compared to the original lead was well compensated by the unobserved adverse effect. Hence, this compound seems to be a more promising lead to develop novel therapeutic agents toward OIC. PMID:23116124

  4. Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives.

    PubMed

    Tian, Ye; Du, Deping; Rai, Diwakar; Wang, Liu; Liu, Huiqing; Zhan, Peng; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong

    2014-04-01

    In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies.

  5. Design of a novel coil satellite centrifuge and its performance on counter-current chromatographic separation of 4-methylumbelliferyl sugar derivatives with organic-aqueous two-phase solvent systems

    PubMed Central

    Shinomiya, Kazufusa; Tokura, Koji; Kimura, Emiru; Takai, Midori; Harikai, Naoki; Yoshida, Kazunori; Yanagidaira, Kazuhiro; Ito, Yoichiro

    2015-01-01

    A new high-speed counter-current chromatograph, named coil satellite centrifuge (CSC), was designed and fabricated in our laboratory. The CSC apparatus produces the satellite motion such that the coiled column simultaneously rotates around the sun axis (the angular velocity, ω1), the planet axis (ω2) and the satellite axis (the central axis of the column) (ω3). In order to achieve this triplicate rotary motion without twisting of the flow tube, the rotation of each axis was determined by the following formula: ω1 = ω2 + ω3. This relation enabled to lay out the flow tube by two different ways, the SS type and the JS type. In the SS type, the flow tube was introduced from the upper side of the apparatus into the sun axis of the first rotary frame and connected to the planet axis of the second rotary frame like a double letter SS. In the JS type, the flow tube was introduced from the bottom of the apparatus into the sun axis reaching the upper side of the planet axis an inversed letter J, followed by distribution as in the SS type. The performance of the apparatus was examined on separation of 4-methylumbelliferyl (MU) sugar derivatives as test samples with organic-aqueous two-phase solvent systems composed of ethyl acetate/1-butanol/water (3 : 2 : 5, v/v) for lower phase mobile and (1 : 4 : 5, v/v) for upper phase mobile. With lower phase mobile, five 4-MU sugar derivatives including β-D-cellobioside (Cel), β-D-glucopyranoside, α-D-mannopyranoside, β-D-fucopyranoside and α-L-fucopyranoside (α-L-Fuc) were separated with the combined rotation around each axis at counterclockwise (CCW) (ω1) – CCW (ω2) – CCW (ω3) by the JS type flow tube distribution. With upper phase mobile, three 4-MU sugar derivatives including α-L-Fuc, β-D-galactopyranoside and Cel were separated with the combined rotation around each axis at clockwise (CW) (ω1) – CW (ω2) – CW (ω3) by the JS type flow tube distribution. A series of experiments on peak resolution and

  6. Design, synthesis and biological evaluation of a phenyl butyric acid derivative, N-(4-chlorophenyl)-4-phenylbutanamide: A HDAC6 inhibitor with anti-proliferative activity on cervix cancer and leukemia cells.

    PubMed

    Alberto, Rodríguez-Fonseca Rolando; Yudibeth, Sixto-López; Jonathan, Fragoso-Vázquez M; Raúl, Flores-Mejía; Cristina, Cabrera-Pérez Laura; Ismael, Vázquez-Moctezuma; Cecilia, Rosales-Hernández Martha; Martiniano, Bello; Martínez-Archundia, M; Guadalupe, Trujillo-Ferrara José; Elvia, Becerra-Martínez; José, Correa-Basurto

    2017-01-02

    The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc. Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference. The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations. These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM). In conclusion, these results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.

  7. Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents

    PubMed Central

    Ghodsi, Razieh; Azizi, Ebrahim; Zarghi, Afshin

    2016-01-01

    A new group of 4-(Imidazolylmethyl)quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitroanti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in the potent range 0.063-0.090 µM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg513. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells.The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells andCOX-2 inhibitory activity. Among the quinolines 9a-e, 4-((1H-Imidazol-1-yl)methyl) 7,8,9,10-tetrahydro-2-(4-methylsulfonylphenyl)-benzo[h]quinoline (9d)was identified as the most potent andselective COX-2inhibitor as well as the most cytotoxic agent against MCF-7 cells. PMID:27610157

  8. Tilt/Integral/Derivative Compensators For Controllers

    NASA Technical Reports Server (NTRS)

    Lurie, Boris J.

    1995-01-01

    Tilt/integral/derivative (TID) compensators for tunable feedback control systems offer advantages over proportional/integral/derivative compensators. Designed and adjusted more easily, and made to reject disturbances more strongly and less sensitive to variations in parameters of controlled system.

  9. 78 FR 32191 - Derivatives

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-29

    ...This proposed rule permits credit unions to engage in limited derivatives activities for the purpose of mitigating interest rate risk. This proposed rule applies to federal credit unions and any federally insured, state-chartered credit unions that are permitted under applicable state law to engage in derivatives transactions. It requires any credit union seeking derivatives authority to......

  10. Vectors derived from simian immunodeficiency virus (SIV).

    PubMed

    Nègre, Didier; Cosset, François-Loïc

    2002-11-01

    In contrast to other retroviruses, lentiviruses have the unique property of infecting non-proliferating cells. Thus vectors derived from lentiviruses are promising tools for in vivo gene delivery applications. Vectors derived from human primate and non-primate lentiviruses have recently been described and, unlike retroviral vectors derived from murine leukemia viruses, lead to stable integration of the transgene into quiescent cells in various organs. Despite all the safety safeguards that have been progressively introduced in lentiviral vectors, the clinical acceptance of vectors derived from pathogenic lentiviruses is subject to debate. It is therefore essential to design vectors derived from a wide range of lentivirus types and to comparatively examine their properties in terms of transduction efficiency and bio-safety. Here, we review the properties of lentiviral vectors derived from simian immunodeficiency virus (SIV).

  11. Conceptual design optimization study

    NASA Technical Reports Server (NTRS)

    Hollowell, S. J.; Beeman, E. R., II; Hiyama, R. M.

    1990-01-01

    The feasibility of applying multilevel functional decomposition and optimization techniques to conceptual design of advanced fighter aircraft was investigated. Applying the functional decomposition techniques to the conceptual design phase appears to be feasible. The initial implementation of the modified design process will optimize wing design variables. A hybrid approach, combining functional decomposition techniques for generation of aerodynamic and mass properties linear sensitivity derivatives with existing techniques for sizing mission performance and optimization, is proposed.

  12. A study of dinitro-bis-1,2,4-triazole-1,1'-diol and derivatives: design of high-performance insensitive energetic materials by the introduction of N-oxides.

    PubMed

    Dippold, Alexander A; Klapötke, Thomas M

    2013-07-03

    In this contribution we report on the synthesis and full structural as well as spectroscopic characterization of 3,3'-dinitro-5,5'-bis-1,2,4-triazole-1,1'-diol and nitrogen-rich salts thereof. The first synthesis and characterization of an energetic 1-hydroxy-bistriazole in excellent yields and high purity is presented. This simple and straightforward method of N-oxide introduction in triazole compounds using commercially available oxone improves the energetic properties and reveals a straightforward synthetic pathway toward novel energetic 1,2,4-triazole derivatives. X-ray crystallographic measurements were performed and deliver insight into structural characteristics and strong intermolecular interactions. The standard enthalpies of formation were calculated for all compounds at the CBS-4 M level of theory, revealing highly positive heats of formation for all compounds. The energetic properties of all compounds (detonation velocity, pressure, etc.) were calculated using the EXPLO5.05 program, and the ionic derivatives show superior performance in comparison to the corresponding compounds bearing no N-oxide. All substances were characterized in terms of sensitivities (impact, friction, electrostatic) and thermal stabilities, and the ionic derivatives were found to be high thermally stable, insensitive compounds that are exceedingly powerful but safe to handle and prepare.

  13. Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation.

    PubMed

    Schühly, Wolfgang; Hüfner, Antje; Pferschy-Wenzig, Eva M; Prettner, Elke; Adams, Michael; Bodensieck, Antje; Kunert, Olaf; Oluwemimo, Asije; Haslinger, Ernst; Bauer, Rudolf

    2009-07-01

    A set of ten derivatives of methylhonokiol, an anti-inflammatory active biphenyl-type neolignan from Magnolia grandiflora, has been evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified prostaglandin H synthase (PGHS)-1 and PGHS-2 enzymes as well as for their 5-lipoxygenase (5-LOX) mediated LTB(4) formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes. The derivatization reactions included methylation, acetylation, hydrogenation, epoxydation and isomerization. Five of the derivatives are new to science. The most active compound against COX-1 and COX-2 was methylhonokiol with IC(50) values of 0.1 microM, whereas the most active compound against LTB(4) formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC(50) value of 1.0 microM. Structure-activity relationship studies showed that the polarity of the derivatives plays a crucial role in their activity towards COX-1/2 enzyme and 5-LOX mediated LTB(4) formation.

  14. Endohedral Metallofullerene Derivatives

    NASA Technical Reports Server (NTRS)

    Dorn, Harry C. (Inventor); Iezzi, Erick B. (Inventor); Duchamp, James (Inventor)

    2008-01-01

    Trimetallic nitride endohedral metallofullerene derivatives and their preparation are described. The trimetallic nitride endohedral metallofullerene derivatives have the general formula A(sub 3-n)X(sub n)@C(sub m)(R) where n ranges from 0 to 3, A and X may be trivalent metals and may be either rare earth metal or group IIIB metals, m is between about 60 and about 200, and R is preferably an organic group. Derivatives where the R group forms cyclized derivatives with the fullerene cage are also described.

  15. Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents.

    PubMed

    Gnoatto, Simone C B; Susplugas, Sophie; Dalla Vechia, Luciana; Ferreira, Thais B; Dassonville-Klimpt, Alexandra; Zimmer, Karine R; Demailly, Catherine; Da Nascimento, Sophie; Guillon, Jean; Grellier, Philippe; Verli, Hugo; Gosmann, Grace; Sonnet, Pascal

    2008-01-15

    A series of new piperazine derivatives of ursolic acid was synthesized and tested against Plasmodium falciparum strains. They were also tested on their cytotoxicity effects upon MRC-5 cells. Seven new piperazinyl analogues showed significant activity in the nanomolar range (IC(50)=78-167nM) against Plasmodium falciparum CQ-resistant strain FcB1. A possible mechanism of interaction implicating binding of these compounds to beta-hematin was supported by in vitro tests. Moreover, the importance of the hydrophilic framework attached at the terminal nitrogen atom of the bis-(3-aminopropyl)piperazine joined to the triterpene ring was also explored through molecular dynamic simulations.

  16. The Complete Nucleotide Sequence of the Carbapenem Resistance-Conferring Conjugative Plasmid pLD209 from a Pseudomonas putida Clinical Strain Reveals a Chimeric Design Formed by Modules Derived from Both Environmental and Clinical Bacteria

    PubMed Central

    Marchiaro, Patricia M.; Brambilla, Luciano; Morán-Barrio, Jorgelina; Revale, Santiago; Pasteran, Fernando; Vila, Alejandro J.; Viale, Alejandro M.

    2014-01-01

    The complete sequence of the carbapenem-resistance-conferring conjugative plasmid pLD209 from a Pseudomonas putida clinical strain is presented. pLD209 is formed by 3 well-defined regions: an adaptability module encompassing a Tn402-like class 1 integron of clinical origin containing blaVIM-2 and aacA4 gene cassettes, partitioning and transfer modules, and a replication module derived from plasmids of environmental bacteria. pLD209 is thus a mosaic of modules originating in both the clinical and environmental (nonclinical) microbiota. PMID:24395220

  17. Advanced transport design using multidisciplinary design optimization

    NASA Technical Reports Server (NTRS)

    Barnum, Jennifer; Bathras, Curt; Beene, Kirk; Bush, Michael; Kaupin, Glenn; Lowe, Steve; Sobieski, Ian; Tingen, Kelly; Wells, Douglas

    1991-01-01

    This paper describes the results of the first implementation of multidisciplinary design optimisation (MDO) techniques by undergraduates ina design course. The objective of the work was to design a civilian transport aircraft of the Boeing 777 class. The first half of the two semester design course consisted of application of traditional sizing methods and techniques to form a baseline aircraft. MDO techniques were then applied to this baseline design. This paper describes the evolution of the design with special emphasis on the application of MDO techniques, and presents the results of four iterations through the design space. Minimization of take-off gross weight was the goal of the optimization process. The resultant aircraft derived from the MDO procedure weighed approximately 13,382 lbs (2.57 percent) less than the baseline aircraft.

  18. Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

    SciTech Connect

    Kim, Sun Hee; Tran, Martin T.; Ruebsam, Frank; Xiang, Alan X.; Ayida, Benjamin; McGuire, Helen; Ellis, David; Blazel, Julie; Tran, Chinh V.; Murphy, Douglas E.; Webber, Stephen E.; Zhou, Yuefen; Shah, Amit M.; Tsan, Mei; Showalter, Richard E.; Patel, Rupal; Gobbi, Alberto; LeBrun, Laurie A.; Bartkowski, Darian M.; Nolan, Thomas G.; Norris, Daniel A.; Sergeeva, Maria V.; Kirkovsky, Leo; Zhao, Qiang; Han, Qing; Kissinger, Charles R.

    2008-07-28

    A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC{sub 50} values. The most potent compound exhibited IC{sub 50} less than 10 nM against the genotype 1b HCV polymerase and EC{sub 50} of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

  19. Design in Industrial Design Engineering: Teaching Design at the School of IDE at the TU Delft.

    ERIC Educational Resources Information Center

    Schierbeek, Bernd B.

    1988-01-01

    Describes an industrial design course in the Netherlands. Includes a discussion of the school history, integration of various courses, implications from the experience, design process as decision-making, basic design cycle derived from the general problem-solving process, design methodology, creativity, and conclusions. (YP)

  20. Recursive Deadbeat Controller Design

    NASA Technical Reports Server (NTRS)

    Juang, Jer-Nan; Phan, Minh Q.

    1997-01-01

    This paper presents a recursive algorithm for a deadbeat predictive controller design. The method combines together the concepts of system identification and deadbeat controller designs. It starts with the multi-step output prediction equation and derives the control force in terms of past input and output time histories. The formulation thus derived satisfies simultaneously system identification and deadbeat controller design requirements. As soon as the coefficient matrices are identified satisfying the output prediction equation, no further work is required to compute the deadbeat control gain matrices. The method can be implemented recursively just as any typical recursive system identification techniques.