Controlling of N-alkylpolyamine analogue metabolism by selective deuteration.

PubMed

Ucal, Sebahat; Häkkinen, Merja R; Alanne, Aino-Liisa; Alhonen, Leena; Vepsäläinen, Jouko; Keinänen, Tuomo A; Hyvönen, Mervi T

2018-02-14

Replacing protium with deuterium is an efficient method to modulate drug metabolism. N -alkylated polyamine analogues are polyamine antimetabolites with proven anticancer efficacy. We have characterized earlier the preferred metabolic routes of N 1 , N 12 -diethylspermine (DESpm), N 1 -benzyl- N 12 -ethylspermine (BnEtSpm) and N 1 , N 12 -dibenzylspermine (DBSpm) by human recombinant spermine oxidase (SMOX) and acetylpolyamine oxidase (APAO). Here, we studied the above analogues, their variably deuterated counterparts and their metabolites as substrates and inhibitors of APAO, SMOX, semicarbazide-sensitive amine oxidase (SSAO), diamine oxidase (DAO) and monoamine oxidases. We found that targeted deuteration efficiently redirected the preferable cleavage site and suppressed reaction rate by APAO and SMOX in vitro We found a three- to six-fold decline in V max with moderate variable effect on K m when deuterium was located at the preferred hydrogen abstraction site of the analogue. We also found some of the metabolites to be potent inhibitors of DAO and SSAO. Surprisingly, analogue deuteration did not markedly alter the anti-proliferative efficacy of the drugs in DU145 prostate cancer cells, while in mouse embryonic fibroblasts, which had higher basal APAO and SMOX activities, moderate effect was observed. Interestingly, the anti-proliferative efficacy of the analogues did not correlate with their ability to suppress polyamine biosynthetic enzymes, induce spermidine/spermine- N 1 -acetyltransferase or deplete intracellular polyamine levels, but correlated with their ability to induce SMOX. Our data show that selective deuteration of N -alkyl polyamine analogues enables metabolic switching, offering the means for selective generation of bioactive metabolites inhibiting, e.g. SSAO and DAO, thus setting a novel basis for in vivo studies of this class of analogues. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Martian Feeling: An Analogue Study to Simulate a Round-Trip to Mars using the International Space Station

NASA Astrophysics Data System (ADS)

Felix, C. V.; Gini, A.

When talking about human space exploration, Mars missions are always present. It is clear that sooner or later, humanity will take this adventure. Arguably the most important aspect to consider for the success of such an endeavour is the human element. The safety of the crew throughout a Martian mission is a top priority for all space agencies. Therefore, such a mission should not take place until all the risks have been fully understood and mitigated. A mission to Mars presents unique human and technological challenges in terms of isolation, confinement, autonomy, reliance on mission control, communication delays and adaptation to different gravity levels. Analogue environments provide the safest way to simulate these conditions, mitigate the risks and evaluate the effects of long-term space travel on the crew. Martian Feeling is one of nine analogue studies, from the Mars Analogue Path (MAP) report [1], proposed by the TP Analogue group of ISU Masters class 2010. It is an integrated analogue study which simulates the psychological, physiological and operational conditions that an international, six-person, mixed gender crew would experience on a mission to Mars. Set both onboard the International Space Station (ISS) and on Earth, the Martian Feeling study will perform a ``dress rehearsal'' of a mission to Mars. The study proposes to test both human performance and operational procedures in a cost-effective manner. Since Low Earth Orbit (LEO) is more accessible than other space-based locations, an analogue studies in LEO would provide the required level of realism to a simulated transit mission to Mars. The sustained presence of microgravity and other elements of true spaceflight are features of LEO that are neither currently feasible nor possible to study in terrestrial analogue sites. International collaboration, economics, legal and ethical issues were considered when the study was proposed. As an example of international collaboration, the ISS would

Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites.

PubMed

Wong, Michael H L; Bryan, Holly K; Copple, Ian M; Jenkins, Rosalind E; Chiu, Pak Him; Bibby, Jaclyn; Berry, Neil G; Kitteringham, Neil R; Goldring, Christopher E; O'Neill, Paul M; Park, B Kevin

2016-03-24

Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.

Two Active Site Divalent Ions in the Crystal Structure of the Hammerhead Ribozyme Bound to a Transition State Analogue.

PubMed

Mir, Aamir; Golden, Barbara L

2016-02-02

The crystal structure of the hammerhead ribozyme bound to the pentavalent transition state analogue vanadate reveals significant rearrangements relative to the previously determined structures. The active site contracts, bringing G10.1 closer to the cleavage site and repositioning a divalent metal ion such that it could, ultimately, interact directly with the scissile phosphate. This ion could also position a water molecule to serve as a general acid in the cleavage reaction. A second divalent ion is observed coordinated to O6 of G12. This metal ion is well-placed to help tune the pKA of G12. On the basis of this crystal structure as well as a wealth of biochemical studies, we propose a mechanism in which G12 serves as the general base and a magnesium-bound water serves as a general acid.

Comparative experimental/theoretical studies on the EGFR dimerization under the effect of EGF/EGF analogues binding: Highlighting the importance of EGF/EGFR interactions at site III interface.

PubMed

Mehrabi, Masomeh; Mahdiuni, Hamid; Rasouli, Hassan; Mansouri, Kamran; Shahlaei, Mohsen; Khodarahmi, Reza

2018-04-14

Epidermal growth factor receptors (EGFRs) and their cytoplasmic tyrosine kinases play significant roles in cell proliferation and signaling. All the members of the EGFR/ErbB family are primary goals for cancer therapy, particularly for tumors of breast, cervix, ovaries, kidney, esophagus, prostate and non-small-cell lung carcinoma and head and neck tumors. However, the therapeutic ability of accessible anti-ErbB agents is limited. Therefore, recognizing EGF analogues or small organic molecules with high affinity for the extracellular domain of the EGFR is a critical target on cancer research. An effective EGF analogue should have a comparable binding affinity for EGFR in order to create an effective ligand competitive inhibition against circulating wild EGF while fails to transduce appropriate downstream signaling into the cancer cell. In our earlier study we have developed a mutant form of human EGF (mEGF, lacking the four critical amino acid residues; Gln 43 , Tyr 44 , Arg 45 and Asp 46 at the C-terminal of the protein) and its binding properties and mitogenic activity were assessed. The mEGF showed high affinity for EGFR binding domains but caused poor EGFR dimerization and phosphorylation and especially, mEGF induced EGFR internalization. However, underlying mechanism of action of EGF analogues is still unclear and thus considered to be worthwhile for further study. With regard to different effects of the EGF analogue on EGFR activating process, computational analysis of wild EGF/EGFR and mEGF/EGFR complexes (along with EGFt/EGFR complex) were done. Results of the protein dissection identified several interactions within "ligand/EGFR" that are common among EGF and EGFt/mEGF. These results disclose that while several interactions are conserved within EGF/EGFR interfaces, EGF/EGFR interactions on site III interface controls the affinity, EGFR dimerization and subsequent downstream signaling through a heterogeneous set of non-covalent interactions. These findings

Design and Synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (Citalopram) Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites

PubMed Central

Banala, Ashwini K.; Zhang, Peng; Plenge, Per; Cyriac, George; Kopajtic, Theresa; Katz, Jonathan L.; Loland, Claus Juul; Newman, Amy Hauck

2013-01-01

The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N-, 4, 5, and 4’-positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51.) In addition, 8 analogues were identified with similar potencies to S-1 for decreasing the dissociation of [3H]S-1 from the S1 site, via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki=19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [3H]S-1 via S2. PMID:24237160

Field Exploration and Life Detection Sampling for Planetary Analogue Research (FELDSPAR): Variability and Correlation in Biomarker and Mineralogy Measurements from Icelandic Mars Analogues

NASA Technical Reports Server (NTRS)

Gentry, D.; Amador, E.; Cable, M. L.; Cantrell, T.; Chaudry, N.; Cullen, T.; Duca, Z.; Jacobsen, M.; Kirby, J.; McCaig, H.;

Pena blanca natural analogue project: summary of activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levy, Schon S; Goldstein, Steven J; Abdel - Fattah, Amr I

2010-12-08

The inactive Nopal I uranium mine in silicic tuff north of Chihuahua City, Chihuahua, Mexico, was studied as a natural analogue for an underground nuclear-waste repository in the unsaturated zone. Site stratigraphy was confirmed from new drill core. Datafrom site studies include chemical and isotopic compositions of saturated- and unsaturated-zone waters. A partial geochronology of uranium enrichment and mineralization was established. Evidence pertinent to uranium-series transport in the soil zone and changing redox conditions was collected. The investigations contributed to preliminary, scoping-level performance assessment modeling.

Clinical study of a digital vs an analogue hearing aid.

PubMed

Bille, M; Jensen, A M; Kjaerbøl, E; Vesterager, V; Sibelle, P; Nielsen, H

1999-01-01

Digital signal processing in hearing instruments has brought new perspectives to the compensation of hearing impairment and may result in alleviation of the adverse effects of hearing problems. This study compares a commercially available digital signal processing hearing aid (HA) (Senso) with a modern analogue HA with programmable fitting (Logo). The HAs tested are identical in appearance and, in spite of a different mode of operation, the study design ensured blinding of the test subjects. Outcome parameters were: improvements in speech recognition score in noise (deltaSRSN) with the HAs; overall preference for HA; overall satisfaction; and various measures of HA performance evaluated by a self-assessment questionnaire. A total of 28 experienced HA users with sensorineural hearing impairment were included and 25 completed the trial. No significant differences were found in deltaSRSN between the two HAs. Eleven subjects indicated an overall preference for the digital HA, 10 preferred the analogue HA and 4 had no preference. Concerning overall satisfaction, 8 subjects rated the digital HA superior to the analogue one, whereas 7 indicated a superior rating for the analogue HA and 10 rated the HAs equal. Acceptability of noise from traffic was the only outcome parameter which gave a significant difference between the HAs in favour of the digital HA. It is concluded that there are no significant differences in outcome between the digital and analogue signal processing HAs tested by these experienced HA-users.

Two active site divalent ions in the crystal structure of the hammerhead ribozyme bound to a transition state analogue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mir, Aamir; Golden, Barbara L.

2015-11-09

The crystal structure of the hammerhead ribozyme bound to the pentavalent transition state analogue vanadate reveals significant rearrangements relative to the previously determined structures. The active site contracts, bringing G10.1 closer to the cleavage site and repositioning a divalent metal ion such that it could, ultimately, interact directly with the scissile phosphate. This ion could also position a water molecule to serve as a general acid in the cleavage reaction. A second divalent ion is observed coordinated to O6 of G12. This metal ion is well-placed to help tune the p K A of G12. Finally, on the basis ofmore » this crystal structure as well as a wealth of biochemical studies, in this paper we propose a mechanism in which G12 serves as the general base and a magnesium-bound water serves as a general acid.« less

Conformational studies of immunodominant myelin basic protein 1-11 analogues using NMR and molecular modeling

NASA Astrophysics Data System (ADS)

Laimou, Despina; Lazoura, Eliada; Troganis, Anastassios N.; Matsoukas, Minos-Timotheos; Deraos, Spyros N.; Katsara, Maria; Matsoukas, John; Apostolopoulos, Vasso; Tselios, Theodore V.

2011-11-01

Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP1-11) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP1-11[4A]) or a tyrosine residue (Ac-MBP1-11[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-Au was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln3 residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-Au complex, has a different orientation in the mutated analogues especially in the Ac-MBP1-11[4A] peptide. In particular the side chain of Gln3 is not solvent exposed as for the native Ac-MBP1-11 and it is not available for interaction with the TCR.

Mauna Kea, Hawaii as an Analogue Site for Future Planetary Resource Exploration: Results from the 2010 ILSO-ISRU Field-Testing Campaign

NASA Technical Reports Server (NTRS)

ten Kate, I. L.; Armstrong, R.; Bernhardt, B.; Blummers, M.; Boucher, D.; Caillibot, E.; Captain, J.; Deleuterio, G.; Farmer, J. D.; Glavin, D. P.;

Natural analogue study of CO2 storage monitoring using probability statistics of CO2-rich groundwater chemistry

NASA Astrophysics Data System (ADS)

Kim, K. K.; Hamm, S. Y.; Kim, S. O.; Yun, S. T.

2016-12-01

For confronting global climate change, carbon capture and storage (CCS) is one of several very useful strategies as using capture of greenhouse gases like CO2 spewed from stacks and then isolation of the gases in underground geologic storage. CO2-rich groundwater could be produced by CO2 dissolution into fresh groundwater around a CO2 storage site. As consequence, natural analogue studies related to geologic storage provide insights into future geologic CO2 storage sites as well as can provide crucial information on the safety and security of geologic sequestration, the long-term impact of CO2 storage on the environment, and field operation and monitoring that could be implemented for geologic sequestration. In this study, we developed CO2 leakage monitoring method using probability density function (PDF) by characterizing naturally occurring CO2-rich groundwater. For the study, we used existing data of CO2-rich groundwaters in different geological regions (Gangwondo, Gyeongsangdo, and Choongchungdo provinces) in South Korea. Using PDF method and QI (quantitative index), we executed qualitative and quantitative comparisons among local areas and chemical constituents. Geochemical properties of groundwater with/without CO2 as the PDF forms proved that pH, EC, TDS, HCO3-, Ca2+, Mg2+, and SiO2 were effective monitoring parameters for carbonated groundwater in the case of CO2leakage from an underground storage site. KEY WORDS: CO2-rich groundwater, CO2 storage site, monitoring parameter, natural analogue, probability density function (PDF), QI_quantitative index Acknowledgement This study was supported by the "Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (NRF-2013R1A1A2058186)" and the "R&D Project on Environmental Management of Geologic CO2 Storage" from KEITI (Project number: 2014001810003).

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity.

PubMed

Haskell-Luevano, C; Sawyer, T K; Hendrata, S; North, C; Panahinia, L; Stum, M; Staples, D J; Castrucci, A M; Hadley, M F; Hruby, V J

1996-01-01

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity: PEPTIDES 17(6) 995-1002, 1996.-Systematic analysis of fragment derivatives of the superpotent alpha-MSH analogue. Ac-Ser.Tyr-Ser-Nle4-Glu- His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2(NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) "active site." The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereo-chemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His4 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues.

PubMed

Koch, Maximilian F; Harteis, Sabrina; Blank, Iris D; Pestel, Galina; Tietze, Lutz F; Ochsenfeld, Christian; Schneider, Sabine; Sieber, Stephan A

2015-11-09

Analogues of the natural product duocarmycin bearing an indole moiety were shown to bind aldehyde dehydrogenase 1A1 (ALDH1A1) in addition to DNA, while derivatives without the indole solely addressed the ALDH1A1 protein. The molecular mechanism of selective ALDH1A1 inhibition by duocarmycin analogues was unraveled through cocrystallization, mutational studies, and molecular dynamics simulations. The structure of the complex shows the compound embedded in a hydrophobic pocket, where it is stabilized by several crucial π-stacking and van der Waals interactions. This binding mode positions the cyclopropyl electrophile for nucleophilic attack by the noncatalytic residue Cys302, thereby resulting in covalent attachment, steric occlusion of the active site, and inhibition of catalysis. The selectivity of duocarmycin analogues for ALDH1A1 is unique, since only minor alterations in the sequence of closely related protein isoforms restrict compound accessibility. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The novel fluorescent CDP-analogue (Pbeta)MABA-CDP is a specific probe for the NMP binding site of UMP/CMP kinase.

PubMed

Rudolph, M G; Veit, T J; Reinstein, J

1999-12-01

Direct thermodynamic and kinetic investigations of the binding of nucleotides to the nucleoside monophosphate (NMP) site of NMP kinases have not been possible so far because a spectroscopic probe was not available. By coupling a fluorescent N-methylanthraniloyl- (mant) group to the beta-phosphate of CDP via a butyl linker, a CDP analogue [(Pbeta)MABA-CDP] was obtained that still binds specifically to the NMP site of UmpKdicty, because the base and the ribose moieties, which are involved in specific interactions, are not modified. This allows the direct determination of binding constants for its substrates in competition experiments.

The novel fluorescent CDP-analogue (Pbeta)MABA-CDP is a specific probe for the NMP binding site of UMP/CMP kinase.

PubMed Central

Rudolph, M. G.; Veit, T. J.; Reinstein, J.

1999-01-01

Direct thermodynamic and kinetic investigations of the binding of nucleotides to the nucleoside monophosphate (NMP) site of NMP kinases have not been possible so far because a spectroscopic probe was not available. By coupling a fluorescent N-methylanthraniloyl- (mant) group to the beta-phosphate of CDP via a butyl linker, a CDP analogue [(Pbeta)MABA-CDP] was obtained that still binds specifically to the NMP site of UmpKdicty, because the base and the ribose moieties, which are involved in specific interactions, are not modified. This allows the direct determination of binding constants for its substrates in competition experiments. PMID:10631985

Exploration of charge states of balanol analogues acting as ATP-competitive inhibitors in kinases.

PubMed

Hardianto, Ari; Yusuf, Muhammad; Liu, Fei; Ranganathan, Shoba

2017-12-28

(-)-Balanol is an ATP mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is a tumour promoter, PKC isozymes act as tumour promoters or suppressors, depending on the cancer type. In particular, PKCε is frequently implicated in cancer promotion, making it a potential target for anticancer drugs. To improve isozyme selectivity of balanol, exhaustive structural and activity relationship (SAR) studies have been performed in the last two decades, but with limited success. More recently, fluorination on balanol has shown improved selectivity for PKCε, although the fluorine effect is not yet clearly understood. Understanding the origin to this fluorine-based selectivity will be valuable for designing better balanol-based ATP mimicking inhibitors. Computational approaches such as molecular dynamics (MD) simulations can decipher the fluorine effect, provided that correct charges have been assigned to a ligand. Balanol analogues have multiple ionisable functional groups and the effect of fluorine substitutions on the exact charge state of each analogue bound to PKA and to PKCε needs to be thoroughly investigated in order to design highly selective inhibitors for therapeutic applications. We explored the charge states of novel fluorinated balanol analogues using MD simulations. For different potential charge states of these analogues, Molecular Mechanics Generalized Born Surface Area (MMGBSA) binding energy values were computed. This study suggests that balanol and the most potent fluorinated analogue (5S fluorine substitution on the azepane ring), have charges on the azepane ring (N1), and the phenolic (C6''OH) and the carboxylate (C15''O 2 H) groups on the benzophenone moiety, when bound to PKCε as well as PKA. To the best our knowledge, this is the first study showing that the phenolate group is charged in balanol and its analogues binding to the ATP site of PKCε. Correct charge

Structural insights into abasic site for Fpg specific binding and catalysis: comparative high-resolution crystallographic studies of Fpg bound to various models of abasic site analogues-containing DNA

PubMed Central

de Jésus, Karine Pereira; Serre, Laurence; Zelwer, Charles; Castaing, Bertrand

2005-01-01

Fpg is a DNA glycosylase that recognizes and excises the mutagenic 8-oxoguanine (8-oxoG) and the potentially lethal formamidopyrimidic residues (Fapy). Fpg is also associated with an AP lyase activity which successively cleaves the abasic (AP) site at the 3′ and 5′ sides by βδ-elimination. Here, we present the high-resolution crystal structures of the wild-type and the P1G defective mutant of Fpg from Lactococcus lactis bound to 14mer DNA duplexes containing either a tetrahydrofuran (THF) or 1,3-propanediol (Pr) AP site analogues. Structures show that THF is less extrahelical than Pr and its backbone C5′–C4′–C3′ diverges significantly from those of Pr, rAP, 8-oxodG and FapydG. Clearly, the heterocyclic oxygen of THF is pushed back by the carboxylate of the strictly conserved E2 residue. We can propose that the ring-opened form of the damaged deoxyribose is the structure active form of the sugar for Fpg catalysis process. Both structural and functional data suggest that the first step of catalysis mediated by Fpg involves the expulsion of the O4′ leaving group facilitated by general acid catalysis (involving E2), rather than the immediate cleavage of the N-glycosic bond of the damaged nucleoside. PMID:16243784

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

Genie in a blotter: A comparative study of LSD and LSD analogues' effects and user profile.

PubMed

Coney, Leigh D; Maier, Larissa J; Ferris, Jason A; Winstock, Adam R; Barratt, Monica J

2017-05-01

This study aimed to describe self-reported patterns of use and effects of lysergic acid diethylamide (LSD) analogues (AL-LAD, 1P-LSD, and ETH-LAD) and the characteristics of those who use them. An anonymous self-selected online survey of people who use drugs (Global Drug Survey 2016; N = 96,894), which measured perceived drug effects of LSD and its analogues. Most LSD analogue users (91%) had also tried LSD. The proportion of U.K. and U.S. respondents reporting LSD analogue use in the last 12 months was higher than for LSD only. LSD analogue users described the effects as psychedelic (93%), over half (55%) obtained it online, and almost all (99%) reported an oral route of administration. The modal duration (8 hr) and time to peak (2 hr) of LSD analogues were not significantly different from LSD. Ratings for pleasurable high, strength of effect, comedown, urge to use more drugs, value for money, and risk of harm following use were significantly lower for LSD analogues compared with LSD. LSD analogues were reported as similar in time to peak and duration as LSD but weaker in strength, pleasurable high, and comedown. Future studies should seek to replicate these findings with chemical confirmation and dose measurement. Copyright © 2017 John Wiley & Sons, Ltd.

Polyamine analogue antidiarrheals: a structure-activity study.

PubMed

Bergeron, R J; Wiegand, J; McManis, J S; Weimar, W R; Smith, R E; Algee, S E; Fannin, T L; Slusher, M A; Snyder, P S

2001-01-18

The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.

Structure-activity analysis and biological studies of chensinin-1b analogues.

PubMed

Dong, Weibing; Dong, Zhe; Mao, Xiaoman; Sun, Yue; Li, Fei; Shang, Dejing

2016-06-01

Chensinin-1b shows a potent and broad-spectrum bactericidal activity and no hemolytic activity and thus is a potential therapeutic agent against bacterial infection. The NMR structure of chensinin-1b consists of a partially α-helical region (residues 8-14) in a membrane-mimic environment that is distinct from other common antimicrobial peptides. However, further analysis of the structural features of chensinin-1b is required to better understand its bactericidal activity. In this study, a series of N- and C-terminally truncated or amino acid-substituted chensinin-1b analogues were synthesized. Next, the bactericidal activity and bacterial membrane effects of the analogues were investigated. The results indicated that the N-terminal residues play a more significant role than the C-terminal residues in the antimicrobial activity of chensinin-1b. The removal of five amino acids from the C-terminus of chensinin-1b did not affect its biological properties, but helix disruption significantly decreased bactericidal activity. The substitution of positively charged residues increased the helicity and antimicrobial activity of the peptide. We also identified a novel analogue [R(4),R(10)]C1b(3-13) that exhibited similar bactericidal properties with its parent peptide chensinin-1b. Electrostatic interactions between the selected analogues and lipopolysaccharides or cells were detected using isothermal titration calorimetry or zeta potential. The thermodynamic parameters ΔH and ΔS for [R(4),R(10)]C1b(3-13) were -20.48kcalmol(-1) and -0.0408kcalmol(-1)deg(-1), respectively. Chensinin-1b yielded similar results of -26.36kcalmol(-1) and -0.0559kcalmol(-1)deg(-1) for ΔH and ΔS, respectively. These results are consistence with their antimicrobial activities. Lastly, membrane depolarization studies showed that selected analogues exerted bactericidal activity by damaging the cytoplasmic membrane. Antimicrobial peptide chensinin-1b is a candidate for the development of new drugs

The Use of Terrestrial Analogues to Inform Mars Sample Return

NASA Astrophysics Data System (ADS)

Cloutis, E. A.

2018-04-01

Terrestrial Mars analogue sites can provide insights into rover-based biosignature detection, types of biosignatures present in different Mars-relevant terrains, biosignature preservation, and location of biosignature hot spots.

Photophysical Study of Novel Perylene Analogues for Biophysical Applications

NASA Astrophysics Data System (ADS)

Palos-Chávez, Jorge; Penick, Mark; Negrete, George; Brancaleon, Lorenzo

2011-03-01

Perylene and perylene derivatives have been shown to be useful in a variety of photoinitiated applications, such as molecular dyes, organic solar cells, etc. Recently we started the characterization of novel 3,9-perylene analogues which could potentially lead to the synthesis of novel molecules with improved ability to separate charges. We have characterized the basic photophysical properties of these molecules, and we are currently investigating the photochemistry that leads to photoproducts in chlorinated compounds. Spectroscopic measurements show the substantial changes in photophysical parameters consistent with the conversion of the original compounds into photoproducts. SEM and AFM imaging show that these photoproducts form ordered particles. Mass spectrometry studies have confirmed the presence of these photoproducts as well. Additional studies are underway concerning the use of these novel perylene analogues in binding to biological structures such as proteins. It is hoped that these compounds will prove useful for biophysical applications, specifically in studying the manipulation of protein conformation via physical methods. Supported by NIH/NIGMS MBRS RISE GM-60655.

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed

Vora, J P; Owens, D R; Dolben, J; Atiea, J A; Dean, J D; Kang, S; Burch, A; Brange, J

1988-11-12

To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. Study in normal people at a diabetes research unit and a university department of medical physics. Seven healthy male volunteers aged 20-39 not receiving any other drugs. After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

PubMed Central

Vora, J. P.; Owens, D. R.; Dolben, J.; Atiea, J. A.; Dean, J. D.; Kang, S.; Burch, A.; Brange, J.

1988-01-01

OBJECTIVE--To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN--Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING--Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS--Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS--After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT--To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U

THE USE OF PANAX GINSENG AND ITS ANALOGUES AMONG PHARMACY CUSTOMERS IN ESTONIA: A CROSS-SECTIONAL STUDY.

PubMed

Volmer, Dasy; Raal, Ain; Kalle, Raivo; Sõukand, Renata

2016-01-01

The aim of the cross-sectional study was to evaluate the pattern of complementary self-treatment with P. ginseng and its analogues amongst pharmacy customers in Estonia. The study instrument consisted of multiple-choice items related to personal knowledge about and experience with the use of P. ginseng and its analogues. In total, 1233 customers participated in the study. Of study participants, 18.1% reported the use of P. ginseng and its analogues in their lives. P. ginseng preparations were used mostly according to the well- known indications (tiredness, weakness and decreased mental and physical capacity). Of P. ginseng users 44.3% reported positive treatment effects and 12.0% had experienced different side effects. With increase of age (p < 0.01) and at lower levels of education (p = 0.04), the use of ginseng or its analogues decreased. The better the users evaluated their health, the better they perceived the effect of P. ginseng preparations (p < 0.01). This study reported rather frequent use of P. ginseng and its analogues. P. ginseng could be seen in the treatment of conditions, where the use of local medicinal plants has not been established. Further research is needed to learn more about public knowledge and experiences about efficacy and safety of P. ginseng and its analogues.

Variation effect on the insecticide activity of DDT analogues. A chemometric approach

NASA Astrophysics Data System (ADS)

Itoh, S.; Nagashima, U.

2002-08-01

We investigated a variation effect on the insecticide activity of DDT analogues by using the first principles electronic structure calculations and the neural network analysis. It has been found that the charge distribution at the specific atomic sites in the DDT molecule is related to their toxicity. This approach can contribute to designing a new insecticide and a new harmlessness process of the DDT analogues.

Access site complications and puncture site pain following transradial coronary procedures: a correlational study.

PubMed

Cheng, Ka Yan; Chair, Sek Ying; Choi, Kai Chow

2013-10-01

Transradial coronary angiography (CA) and percutaneous coronary intervention (PCI) are gaining worldwide popularity due to the low incidence of major vascular complications and early mobilization of patients post procedures. Although post transradial access site complications are generally considered as minor in nature, they are not being routinely recorded in clinical settings. To evaluate the incidence of access site complications and level of puncture site pain experienced by patients undergoing transradial coronary procedures and to examine factors associated with access site complications occurrence and puncture site pain severity. A cross-sectional correlational study of 85 Chinese speaking adult patients scheduled for elective transradial CA and or PCI. Ecchymosis, bleeding, hematoma and radial artery occlusion (RAO) were assessed through observation, palpation and plethysmographic signal of pulse oximetry after coronary procedures. Puncture site pain was assessed with a 100mm Visual Analogue Scale. Factors that were related to access site complications and puncture site pain were obtained from medical records. Ecchymosis was the most commonly reported transradial access site complication in this study. Paired t-test showed that the level of puncture site pain at 24 h was significantly (p<0.001) lower than that at 3 h after the procedure. Stepwise multivariable regression showed that female gender and shorter sheath time were found to be significantly associated with bleeding during gradual deflation of compression device. Only longer sheath time was significantly associated with RAO. Female gender and larger volume of compression air were associated with the presence of ecchymosis and puncture site pain at 3 h after procedure, respectively. The study findings suggest that common access site complications post transradial coronary procedures among Chinese population are relatively minor in nature. Individual puncture site pain assessment during the period of

Synthesis and biological properties of enzyme-resistant analogues of substance P.

PubMed

Sandberg, B E; Lee, C M; Hanley, M R; Iversen, L L

1981-02-01

Six analogues of substance P were synthesized with the aim of developing a metabolically stable peptide that would retain the biological activity of substance P. A recently isolated and characterized substance-P-degrading enzyme from human brain with a high specificity for substance P described in the preceding paper in this journal was used as a model for the enzymatic inactivation of substance P. The synthetic analogues were designed to protect the peptide bonds on the carboxyl side of residues 6, 7 and 8 of substance P, which represent the sites of cleavage by substance-P-degrading enzyme. To test for increased enzymatic resistance, the analogues were incubated with the enzyme, the digests were separated on a high-performance liquid chromatography reverse-phase column and the peptide fragments were collected and identified by amino acid analysis. Of the analogues described, an heptapeptide analogue of residues 5-11, less than Glu-Gln-Phe-MePhe-MeGly-Leu-MetNH2, showed almost complete resistance both towards substance-P-degrading enzyme and to degradation on exposure to rat hypothalamic slices. This analogue was about a third as potent as substance P in competing for binding to receptor sites for this peptide in rat brain membranes and a tenth as potent in eliciting contractions of the guinea pig ileum. The peptides were synthesized using the solid-phase technique with polydimethylacrylamide as a solid support and the coupling was achieved with pre-formed symmetrical anhydrides in dimethylacetamide. Fluorenylmethyloxycarbonyl was used as an alpha-amino protecting group in conjunction with t-butyloxycarbonyl as an epsilon-amino protecting group. Ammoniolytic cleavage from the resin was followed by stepwise elution from an SP-Sephadex column, deprotection with trifluoroacetic acid and chromatography on a Bio-Rex 70 ion-exchanger. The peptides were finally purified on a semi-preparative reverse-phase column.

Field Exploration and Life Detection Sampling for Planetary Analogue Research (FELDSPAR)

NASA Astrophysics Data System (ADS)

Gentry, D.; Stockton, A. M.; Amador, E. S.; Cable, M. L.; Cantrell, T.; Chaudry, N.; Cullen, T.; Duca, Z. A.; Jacobsen, M. B.; Kirby, J.; McCaig, H. C.; Murukesan, G.; Rennie, V.; Rader, E.; Schwieterman, E. W.; Stevens, A. H.; Sutton, S. A.; Tan, G.; Yin, C.; Cullen, D.; Geppert, W.

2017-12-01

Extraterrestrial studies are typically conducted on mg samples from cm-scale features, while landing sites are selected based on m to km-scale features. It is therefore critical to understand spatial distribution of organic molecules over scales from cm to the km, particularly in geological features that appear homogenous at m to km scales. This is addressed by FELDSPAR, a NASA-funded project that conducts field operations analogous to Mars sample return in its science, operations, and technology [1]. Here, we present recent findings from a 2016 and a 2017 campaign to multiple Martian analogue sites in Iceland. Icelandic volcanic regions are Mars analogues due to desiccation, low nutrient availability, temperature extremes [2], and are relatively young and isolated from anthropogenic contamination [3]. Operationally, many Icelandic analogue sites are remote enough to require that field expeditions address several sampling constraints that are also faced by robotic exploration [1, 2]. Four field sites were evaluated in this study. The Fimmvörðuháls lava field was formed by a basaltic effusive eruption associated with the 2010 Eyjafjallajökull eruption. Mælifellssandur is a recently deglaciated plain to the north of the Myrdalsjökull glacier. Holuhraun is a basaltic spatter and cinder cone formed by 2014 fissure eruptions just north of the Vatnajökull glacier. Dyngjusandur is a plain kept barren by repeated aeolian mechanical weathering. Samples were collected in nested triangular grids from 10 cm to the 1 km scale. We obtained overhead imagery at 1 m to 200 m elevation to create digital elevation models. In-field reflectance spectroscopy was obtained with an ASD spectrometer and chemical composition was measured by a Bruker handheld XRF. All sites chosen were homogeneous in apparent color, morphology, moisture, grain size, and reflectance spectra at all scales greater than 10 cm. Field lab ATP assays were conducted to monitor microbial habitation, and home

Transition States and transition state analogue interactions with enzymes.

PubMed

Schramm, Vern L

2015-04-21

Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

A differential scanning calorimetric study of the effects of metal ions, substrate/product, substrate analogues and chaotropic anions on the thermal denaturation of yeast enolase 1.

PubMed

Brewer, J M; Wampler, J E

2001-03-14

The thermal denaturation of yeast enolase 1 was studied by differential scanning calorimetry (DSC) under conditions of subunit association/dissociation, enzymatic activity or substrate binding without turnover and substrate analogue binding. Subunit association stabilizes the enzyme, that is, the enzyme dissociates before denaturing. The conformational change produced by conformational metal ion binding increases thermal stability by reducing subunit dissociation. 'Substrate' or analogue binding additionally stabilizes the enzyme, irrespective of whether turnover is occurring, perhaps in part by the same mechanism. More strongly bound metal ions also stabilize the enzyme more, which we interpret as consistent with metal ion loss before denaturation, though possibly the denaturation pathway is different in the absence of metal ion. We suggest that some of the stabilization by 'substrate' and analogue binding is owing to the closure of moveable polypeptide loops about the active site, producing a more 'closed' and hence thermostable conformation.

The Need for Analogue Missions in Scientific Human and Robotic Planetary Exploration

NASA Technical Reports Server (NTRS)

Snook, K. J.; Mendell, W. W.

2004-01-01

With the increasing challenges of planetary missions, and especially with the prospect of human exploration of the moon and Mars, the need for earth-based mission simulations has never been greater. The current focus on science as a major driver for planetary exploration introduces new constraints in mission design, planning, operations, and technology development. Analogue missions can be designed to address critical new integration issues arising from the new science-driven exploration paradigm. This next step builds on existing field studies and technology development at analogue sites, providing engineering, programmatic, and scientific lessons-learned in relatively low-cost and low-risk environments. One of the most important outstanding questions in planetary exploration is how to optimize the human and robotic interaction to achieve maximum science return with minimum cost and risk. To answer this question, researchers are faced with the task of defining scientific return and devising ways of measuring the benefit of scientific planetary exploration to humanity. Earth-based and spacebased analogue missions are uniquely suited to answer this question. Moreover, they represent the only means for integrating science operations, mission operations, crew training, technology development, psychology and human factors, and all other mission elements prior to final mission design and launch. Eventually, success in future planetary exploration will depend on our ability to prepare adequately for missions, requiring improved quality and quantity of analogue activities. This effort demands more than simply developing new technologies needed for future missions and increasing our scientific understanding of our destinations. It requires a systematic approach to the identification and evaluation of the categories of analogue activities. This paper presents one possible approach to the classification and design of analogue missions based on their degree of fidelity in ten

Natural analogue studies as supplements to biomineralization research

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNeil, M.B.

1995-09-01

Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usuallymore » overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].« less

Design of insulin analogues for meal-related therapy.

PubMed

Brange, J

1993-01-01

The human insulin in replacement therapy has a hexameric structure. Hexamerization of the insulin molecule facilitates biosynthesis and beta-cell storage of insulin, but is unnecessary for biologic activity and appears to contribute to delayed absorption of exogenous insulin from the subcutis. Insulin analogues with reduced self-association that are produced through recombinant DNA techniques have been shown to have in vivo activity comparable to that of human insulin and absorption kinetics characterized by higher and more constant rates of disappearance from the subcutaneous injection site. In preliminary studies in patients receiving insulin therapy, monomeric insulin analogues have been found to provide glycemic control in the postprandial period that is at least equivalent to that of human insulin. Findings in these studies suggest that the use of such analogues may provide meal-related insulin effects closer to those observed in the physiologic state by limiting excessive postprandial glucose excursions and decreasing the risk of late hypoglycemia. Banting and Best revolutionized diabetes therapy 70 years ago with the extraction of insulin from animal pancreas glands (J Lab Clin Med 7:464-472, 1922). Since that time, many refinements of the therapeutic properties of pharmaceutical preparations of the hormone have been introduced. Until recently, however, such advances have been limited to improvements in insulin purity, insulin species, and adjustment of the composition of the vehicle with respect to auxiliary substances and other additives. With the advent of recombinant DNA techniques, it has become possible to optimize the insulin molecule itself for purposes of replacement therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

PubMed

Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

2014-12-15

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Medical judgement analogue studies with applications to spaceflight crew medical officer.

PubMed

McCarroll, Michele L; Ahmed, Rami A; Schwartz, Alan; Gothard, Michael David; Atkinson, Steven Scott; Hughes, Patrick; Brito, Jose Cepeda; Assad, Lori; Myers, Jerry; George, Richard L

2017-10-01

The National Aeronautics and Space Administration (NASA) developed plans for potential emergency conditions from the Exploration Medical Conditions List. In an effort to mitigate conditions on the Exploration Medical Conditions List, NASA implemented a crew medical officer (CMO) designation for eligible astronauts. This pilot study aims to add knowledge that could be used in the Integrated Medical Model. An analogue population was recruited for two categories: administrative physicians (AP) representing the physician CMOs and technical professionals (TP) representing the non-physician CMOs. Participants completed four medical simulations focused on abdominal pain: cholecystitis (CH) and renal colic (RC) and chest pain: cardiac ischaemia (STEMI; ST-segment elevation myocardial infarction) and pneumothorax (PX). The Medical Judgment Metric (MJM) was used to evaluate medical decision making. There were no significant differences between the AP and TP groups in age, gender, race, ethnicity, education and baseline heart rate. Significant differences were noted in MJM average rater scores in AP versus TP in CH: 13.0 (±2.25), 4.5 (±0.48), p=<0.001; RC: 12.3 (±2.66), 4.8 (±0.94); STEMI: 12.1 (±3.33), 4.9 (±0.56); and PX: 13.5 (±2.53), 5.3 (±1.01), respectively. There could be a positive effect on crew health risk by having a physician CMO. The MJM demonstrated the ability to quantify medical judgement between the two analogue groups of spaceflight CMOs. Future studies should incorporate the MJM in a larger analogue population study to assess the medical risk for spaceflight crewmembers.

[Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

PubMed

Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

2016-08-01

Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

FMR thermomagnetic studies up to 900 C of lunar soils and potential magnetic analogues. [Ferromagnetic Resonance studies

NASA Technical Reports Server (NTRS)

Morris, R. V.; Gibbons, R. V.; Hoerz, F.

1975-01-01

Using a recently developed furnace, ferromagnetic resonance (FMR) thermomagnetic studies up to 900 C were employed to measure the Curie points of the superparamagnetic (SP) and single domain (SD) particles in lunar soils and potential magnetic analogue materials. Based on measured Curie points of 775 C, the SP and SD particles in lunar soils 10084-853, 12070-29, 14161-46, and 67010-4 are essentially pure metallic Fe. Synthetic and terrestrial samples containing magnetite, titanomaghemites, and magnetite-like particles have measured Curie points below 600 C are thus not magnetic analogues of lunar soils.

Role of the Zn1 and Zn2 sites in metallo-beta-lactamase L1.

PubMed

Hu, Zhenxin; Periyannan, Gopalraj; Bennett, Brian; Crowder, Michael W

2008-10-29

In an effort to probe the role of the Zn(II) sites in metallo-beta-lactamase L1, mononuclear metal ion containing and heterobimetallic analogues of the enzyme were generated and characterized using kinetic and spectroscopic studies. Mononuclear Zn(II)-containing L1, which binds Zn(II) in the consensus Zn1 site, was shown to be slightly active; however, this enzyme did not stabilize a nitrocefin-derived reaction intermediate that had been previously detected. Mononuclear Co(II)- and Fe(III)-containing L1 were essentially inactive, and NMR and EPR studies suggest that these metal ions bind to the consensus Zn2 site in L1. Heterobimetallic analogues (ZnCo and ZnFe) analogues of L1 were generated, and stopped-flow kinetic studies revealed that these enzymes rapidly hydrolyze nitrocefin and that there are large amounts of the reaction intermediate formed during the reaction. The heterobimetallic analogues were reacted with nitrocefin, and the reactions were rapidly freeze quenched. EPR studies on these samples demonstrate that Co(II) is 5-coordinate in the resting state, proceeds through a 4-coordinate species during the reaction, and is 5-coordinate in the enzyme-product complex. These studies demonstrate that the metal ion in the Zn1 site is essential for catalysis in L1 and that the metal ion in the Zn2 site is crucial for stabilization of the nitrocefin-derived reaction intermediate.

Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors.

PubMed

Jensen, Anders A; Gharagozloo, Parviz; Birdsall, Nigel J M; Zlotos, Darius P

2006-06-06

Strychnine and brucine from the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors, including some members of the superfamily of ligand-gated ion channels. In this study, we have characterised the pharmacological properties of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain of the 5-HT3A serotonin receptor. Although the majority of the analogues displayed significantly increased Ki values at the glycine receptors compared to strychnine and brucine, a few retained the high antagonist potencies of the parent compounds. However, mirroring the pharmacological profiles of strychnine and brucine, none of the analogues displayed significant selectivity between the alpha1 and alpha1beta subtypes. The structure-activity relationships for the compounds at the alpha7/5-HT3 chimera were significantly different from those at the glycine receptors. Most strikingly, quaternization of strychnine and brucine with substituents possessing different steric and electronic properties completely eliminated the activity at the glycine receptors, whereas binding affinity to the alpha7/5-HT3 chimera was retained for the majority of the quaternary analogues. This study provides an insight into the structure-activity relationships for strychnine and brucine analogues at these ligand-gated ion channels.

Assessment of six dissimilarity metrics for climate analogues

NASA Astrophysics Data System (ADS)

Grenier, Patrick; Parent, Annie-Claude; Huard, David; Anctil, François; Chaumont, Diane

2013-04-01

Spatial analogue techniques consist in identifying locations whose recent-past climate is similar in some aspects to the future climate anticipated at a reference location. When identifying analogues, one key step is the quantification of the dissimilarity between two climates separated in time and space, which involves the choice of a metric. In this communication, spatial analogues and their usefulness are briefly discussed. Next, six metrics are presented (the standardized Euclidean distance, the Kolmogorov-Smirnov statistic, the nearest-neighbor distance, the Zech-Aslan energy statistic, the Friedman-Rafsky runs statistic and the Kullback-Leibler divergence), along with a set of criteria used for their assessment. The related case study involves the use of numerical simulations performed with the Canadian Regional Climate Model (CRCM-v4.2.3), from which three annual indicators (total precipitation, heating degree-days and cooling degree-days) are calculated over 30-year periods (1971-2000 and 2041-2070). Results indicate that the six metrics identify comparable analogue regions at a relatively large scale, but best analogues may differ substantially. For best analogues, it is also shown that the uncertainty stemming from the metric choice does generally not exceed that stemming from the simulation or model choice. A synthesis of the advantages and drawbacks of each metric is finally presented, in which the Zech-Aslan energy statistic stands out as the most recommended metric for analogue studies, whereas the Friedman-Rafsky runs statistic is the least recommended, based on this case study.

Medical judgement analogue studies with applications to spaceflight crew medical officer

PubMed Central

McCarroll, Michele L; Ahmed, Rami A; Schwartz, Alan; Gothard, Michael David; Atkinson, Steven Scott; Hughes, Patrick; Brito, Jose Cepeda; Assad, Lori; Myers, Jerry; George, Richard L

2017-01-01

Background The National Aeronautics and Space Administration (NASA) developed plans for potential emergency conditions from the Exploration Medical Conditions List. In an effort to mitigate conditions on the Exploration Medical Conditions List, NASA implemented a crew medical officer (CMO) designation for eligible astronauts. This pilot study aims to add knowledge that could be used in the Integrated Medical Model. Methods An analogue population was recruited for two categories: administrative physicians (AP) representing the physician CMOs and technical professionals (TP) representing the non-physician CMOs. Participants completed four medical simulations focused on abdominal pain: cholecystitis (CH) and renal colic (RC) and chest pain: cardiac ischaemia (STEMI; ST-segment elevation myocardial infarction) and pneumothorax (PX). The Medical Judgment Metric (MJM) was used to evaluate medical decision making. Results There were no significant differences between the AP and TP groups in age, gender, race, ethnicity, education and baseline heart rate. Significant differences were noted in MJM average rater scores in AP versus TP in CH: 13.0 (±2.25), 4.5 (±0.48), p=<0.001; RC: 12.3 (±2.66), 4.8 (±0.94); STEMI: 12.1 (±3.33), 4.9 (±0.56); and PX: 13.5 (±2.53), 5.3 (±1.01), respectively. Discussion There could be a positive effect on crew health risk by having a physician CMO. The MJM demonstrated the ability to quantify medical judgement between the two analogue groups of spaceflight CMOs. Future studies should incorporate the MJM in a larger analogue population study to assess the medical risk for spaceflight crewmembers. PMID:29354280

Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin

[AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that inmore » all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.« less

Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.

PubMed

Burlison, Joseph A; Avila, Christopher; Vielhauer, George; Lubbers, Donna J; Holzbeierlein, Jeffrey; Blagg, Brian S J

2008-03-21

Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.

Engineering Silicone Rubbers for In vitro Studies: Creating AAA Models and ILT Analogues with Physiological Properties

PubMed Central

Corbett, T.J.; Doyle, B.J.; Callanan, A.; Walsh, M.T.; McGloughlin, T.M

2010-01-01

Background In vitro studies of abdominal aortic aneurysm (AAA) have been widely reported. Frequently mock artery models with intraluminal thrombus (ILT) analogues are used to mimic the AAA in vivo. While the models used may be physiological, their properties are frequently either not reported or investigated. Method of Approach This study is concerned with the testing and characterisation of previously used vessel analogue materials and the development of new materials for the manufacture of AAA models. These materials were used in conjunction with a previously validated injection moulding technique to manufacture AAA models of ideal geometry. To determine the model properties (stiffness (β) and compliance) the diameter change of each AAA model was investigated under incrementally increasing internal pressures and compared to published in vivo studies to determine if the models behaved physiologically. A FEA study was implemented to determine if the pressure – diameter change behaviour of the models could be predicted numerically. ILT analogues were also manufactured and characterised. Ideal models were manufactured with ILT analogue internal to the aneurysm region and the effect of the ILT analogue on the model compliance and stiffness was investigated. Results The wall materials had similar properties to aortic tissue at physiological pressures (Einit 2.22MPa and 1.57MPa (aortic tissue: 1.8MPa)). ILT analogues had similar Young’s modulus to the medial layer of ILT (0.24 and 0.33MPa (ILT: 0.28MPa)). All models had aneurysm sac compliance in the physiological range (2.62 – 8.01×10-4/mmHg (AAA in vivo: 1.8 – 9.4×10-4/mmHg)). The necks of our AAA models had similar stiffness to healthy aortas (20.44 – 29.83 (healthy aortas in vivo: 17.5±5.5)). Good agreement was seen between the diameter changes due to pressurisation in the experimental and FEA wall models with a maximum error of 7.3% at 120mmHg. It was also determined that the inclusion of ILT analogue

Structure of Mandelate Racemase with Bound Intermediate Analogues Benzohydroxamate and Cupferron†

PubMed Central

Lietzan, Adam D.; Nagar, Mitesh; Pellmann, Elise A.; Bourque, Jennifer R.; Bearne, Stephen L.; St Maurice, Martin

2012-01-01

Mandelate racemase (MR, EC 5.1.2.2) from Pseudomonas putida catalyzes the Mg2+-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we solved the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and cupferron, to 2.2-Å resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state/intermediate since its binding affinity to 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, cupferron, and the ground state analogue (S)-atrolacatate reveal that the para-carbon of the substrate phenyl ring moves by 0.8–1.2 Å between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to MR with bound (S)-atrolactate, the intermediate-Mg2+ distance shortens, suggesting a tighter complex with the catalytic Mg2+. In addition, Tyr 54 moves nearer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme

A novel lunar bed rest analogue.

PubMed

Cavanagh, Peter R; Rice, Andrea J; Licata, Angelo A; Kuklis, Matthew M; Novotny, Sara C; Genc, Kerim O; Englehaupt, Ricki K; Hanson, Andrea M

2013-11-01

Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system. We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated. A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%. The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

Synthesis and binding studies of some epibatidine analogues.

PubMed

Rádl, S; Hezký, P; Hafner, W; Budesínský, M; Hejnová, L

2000-01-03

A series of epibatidine analogues and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety is described. Some of the compounds, especially those containing 8-azabicyclo[3.2.1]oct-2-ene moiety show high affinity for the nicotinic cholinergic receptor.

Characterization and comparison of perezone with some analogues. Experimental and theoretical study

NASA Astrophysics Data System (ADS)

Escobedo-González, Rene Gerardo; Bahena, Luis; Arias Tellez, José Luis; Hinojosa Torres, Jaime; Ruvalcaba, Rene Miranda; Aceves-Hernández, Juan Manuel

2015-10-01

Perezone had been used for centuries in the traditional Mexican medicine, it is useful and a handful of illness. Perezone and other derivatives also present activity against certain lines of cancer, such as the myeloblastoid leukemia cell line K-562 and carcinoma cell lines (PC-3 and SKLU-1) with IC50 <10 μM. Perezone and isoperezone have shown the major cytotoxic potency. Characterization of perezone was carried out by UV-Visible, IR, DSC, TGA and powder X-ray diffraction, as well as docking studies using caspase-3 structures as receptors. Theoretical studies for optimizing the geometry of perezone were carried out and the results compared with values of single crystal X-ray diffraction. The experimental values of atomic distances, angles and dihedral angles are in good agreement with the theoretical values. Interaction of perezone with the cysteine catalytic site with the caspase-3 was found in the docking studies. A docking study of perezone, with horminone, thymoquinone and isoperezone as ligands and the protein apoptein, caspase-3 as receptor, was carried to demonstrate that the hindrance steric factor, chemical structure and the functional groups are important in the biological activity of these natural products. The docking score energetic values are in good agreement with the experimental cytotoxic results obtained from the experiments when perezone and analogues were studied in different types of cancer.

Synthesis, biological evaluation and molecular modeling of GW 501516 analogues.

PubMed

Ciocoiu, Calin C; Ravna, Aina W; Sylte, Ingebrigt; Hansen, Trond Vidar

2010-11-01

Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPARδ and a moderate agonist against PPARα. Docking of compound 2e into PPARδ revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473.

Dronedarone: an amiodarone analogue.

PubMed

Doggrell, Sheila A; Hancox, Jules C

2004-04-01

Of the antiarrhythmic drugs in current use, amiodarone is one of the most effective and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is associated with significant extra-cardiac side effects and this has driven development of amiodarone analogues. These analogues include short acting analogues (e.g., AT-2001) with similar acute effects to amiodarone, the thyroid receptor antagonist KB-130015 and dronedarone. Dronedarone, (SR-33589; Sanofi-Synthelabo), is a non-iodinated amiodarone derivative that inhibits Na +, K + and Ca 2+ currents. It is a potent inhibitor of the acetylcholine-activated K + current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K + currents and inhibits L-type calcium current. Dronedarone is an antagonist at alpha- and beta-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors. Dronedarone is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias. In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) clinical trial, dronedarone 800 mg/day appeared to be effective and safe for the prevention of atrial fibrillation relapses after cardioversion. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was stopped due to a potential increased risk of death in the dronedarone group. Trials of dronedarone in the maintenance of sinus rhythm in patients with atrial fibrillation and a safety and tolerability study in patients with an implantable cardioverter defibrillator are ongoing. Further experimental and clinical studies are required before we have a definitive answer to whether dronedarone has advantages over amiodarone and

Simulation and preparation of surface EVA in reduced gravity at the Marseilles Bay subsea analogue sites

NASA Astrophysics Data System (ADS)

Weiss, P.; Gardette, B.; Chirié, B.; Collina-Girard, J.; Delauze, H. G.

2012-12-01

Extravehicular activity (EVA) of astronauts during space missions is simulated nowadays underwater in neutral buoyancy facilities. Certain aspects of weightlessness can be reproduced underwater by adding buoyancy to a diver-astronaut, therefore exposing the subject to the difficulties of working without gravity. Such tests were done at the COMEX' test pool in Marseilles in the 1980s to train for a French-Russian mission to the MIR station, for the development of the European HERMES shuttle and the COLUMBUS laboratory. However, space agencies are currently studying missions to other destinations than the International Space Station in orbit, such as the return to the Moon, NEO (near-Earth objects) or Mars. All these objects expose different gravities: Moon has one sixth of Earth's gravity, Mars has a third of Earth's gravity and asteroids have virtually no surface gravity; the astronaut "floats" above the ground. The preparation of such missions calls for a new concept in neutral buoyancy training, not on man-made structures, but on natural terrain, underwater, to simulate EVA operations such as sampling, locomotion or even anchoring in low gravity. Underwater sites can be used not only to simulate the reduced gravity that astronauts will experience during their field trips, also human factors like stress are more realistically reproduced in such environment. The Bay of Marseille hosts several underwater sites that can be used to simulate various geologic morphologies, such as sink-holes which can be used to simulate astronaut descends into craters, caves where explorations of lava tubes can be trained or monolithic rock structures that can be used to test anchoring devices (e.g., near Earth objects). Marseilles with its aerospace and maritime/offshore heritage hosts the necessary logistics and expertise that is needed to perform such simulations underwater in a safe manner (training of astronaut-divers in local test pools, research vessels, subsea robots and

Environment sensitive fluorescent analogue of biologically active oxazoles differentially recognizes human serum albumin and bovine serum albumin: Photophysical and molecular modeling studies

NASA Astrophysics Data System (ADS)

Maiti, Jyotirmay; Biswas, Suman; Chaudhuri, Ankur; Chakraborty, Sandipan; Chakraborty, Sibani; Das, Ranjan

2017-03-01

An environment sensitive fluorophore, 4-(5-(4-(dimethylamino)phenyl)oxazol-2-yl)benzoic acid (DMOBA), that closely mimics biologically active 2,5-disubstituited oxazoles has been designed to probe two homologous serum proteins, human serum albumin (HSA) and bovine serum albumin (BSA) by means of photophysical and molecular modeling studies. This fluorescent analogue exhibits solvent polarity sensitive fluorescence due to an intramolecular charge transfer in the excited state. In comparison to water, the steady state emission spectra of DMOBA in BSA is characterized by a greater blue shift ( 10 nm) and smaller Stokes' shift ( 5980 cm- 1) in BSA than HSA (Stokes'shift 6600 cm- 1), indicating less polar and more hydrophobic environment of the dye in the former than the latter. The dye-protein binding interactions are remarkably stronger for BSA than HSA which is evident from higher value of the association constant for the DMOBA-BSA complex (Ka 5.2 × 106 M- 1) than the DMOBA-HSA complex (Ka 1.0 × 106 M- 1). Fӧrster resonance energy transfer studies revealed remarkably less efficient energy transfer (8%) between the donor tryptophans in BSA and the acceptor DMOBA dye than that (30%) between the single tryptophan moiety in HSA and the dye, which is consistent with a much larger distance between the donor (tryptophan)-acceptor (dye) pair in BSA (34.5 Å) than HSA (25.4 Å). Site specific competitive binding assays have confirmed on the location of the dye in Sudlow's site II of BSA and in Sudlow's site I of HSA, respectively. Molecular modeling studies have shown that the fluorescent analogue is tightly packed in the binding site of BSA due to strong steric complementarity, where, binding of DMOBA to BSA is primarily dictated by the van der Waals and hydrogen bonding interactions. In contrast, in HSA the steric complementarity is less significant and binding is primarily guided by polar interactions and van der Waals interactions appear to be less significant in the

Zampanolide Binding to Tubulin Indicates Cross-Talk of Taxane Site with Colchicine and Nucleotide Sites.

PubMed

Field, Jessica J; Pera, Benet; Gallego, Juan Estévez; Calvo, Enrique; Rodríguez-Salarichs, Javier; Sáez-Calvo, Gonzalo; Zuwerra, Didier; Jordi, Michel; Andreu, José M; Prota, Andrea E; Ménchon, Grégory; Miller, John H; Altmann, Karl-Heinz; Díaz, J Fernando

2018-03-23

The marine natural product zampanolide and analogues thereof constitute a new chemotype of taxoid site microtubule-stabilizing agents with a covalent mechanism of action. Zampanolide-ligated tubulin has the switch-activation loop (M-loop) in the assembly prone form and, thus, represents an assembly activated state of the protein. In this study, we have characterized the biochemical properties of the covalently modified, activated tubulin dimer, and we have determined the effect of zampanolide on tubulin association and the binding of tubulin ligands at other binding sites. Tubulin activation by zampanolide does not affect its longitudinal oligomerization but does alter its lateral association properties. The covalent binding of zampanolide to β-tubulin affects both the colchicine site, causing a change of the quantum yield of the bound ligand, and the exchangeable nucleotide binding site, reducing the affinity for the nucleotide. While these global effects do not change the binding affinity of 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MTC) (a reversible binder of the colchicine site), the binding affinity of a fluorescent analogue of GTP (Mant-GTP) at the nucleotide E-site is reduced from 12 ± 2 × 10 5 M -1 in the case of unmodified tubulin to 1.4 ± 0.3 × 10 5 M -1 in the case of the zampanolide tubulin adduct, indicating signal transmission between the taxane site and the colchicine and nucleotide sites of β-tubulin.

Template properties of mutagenic cytosine analogues in reverse transcription

PubMed Central

Suzuki, Tetsuya; Moriyama, Kei; Otsuka, Chie; Loakes, David; Negishi, Kazuo

2006-01-01

We have studied the mutagenic properties of ribonucleotide analogues by reverse transcription to understand their potential as antiretroviral agents by mutagenesis of the viral genome. The templating properties of nucleotide analogues including 6-(β-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido[4,5-c](1,2)oxazin-7-one, N4-hydroxycytidine, N4-methoxycytidine, N4-methylcytidine and 4-semicarbazidocytidine, which have been reported to exhibit ambiguous base pairing properties, were examined. We have synthesized RNA templates using T3 RNA polymerase, and investigated the specificity of the incorporation of deoxyribonucleoside triphosphates opposite these cytidine analogues in RNA by HIV and AMV reverse transcriptases. Except for N4-methylcytidine, both enzymes incorporated both dAMP and dGMP opposite these analogues in RNA. This indicates that they would be highly mutagenic if present in viral RNA. To study the basis of the differences among the analogues in the incorporation ratios of dAMP to dGMP, we have carried out kinetic analysis of incorporation opposite the analogues at a defined position in RNA templates. In addition, we examined whether the triphosphates of these analogues were incorporated competitively into RNA by human RNA polymerase II. Our present data supports the view that these cytidine analogues are mutagenic when incorporated into RNA, and that they may therefore be considered as candidates for antiviral agents by causing mutations to the retroviral genome. PMID:17130163

Policy issues in space analogues

NASA Astrophysics Data System (ADS)

Auger, Robin N.; Facktor, Debra D.

Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

Heterogeneous seepage at the Nopal I natural analogue site, Chihuahua, Mexico

NASA Astrophysics Data System (ADS)

Dobson, Patrick F.; Ghezzehei, Teamrat A.; Cook, Paul J.; Rodríguez-Pineda, J. Alfredo; Villalba, Lourdes; de La Garza, Rodrigo

2012-02-01

A study of seepage occurring in an adit at the Nopal I uranium mine in Chihuahua, Mexico, was conducted as part of an integrated natural analogue study to evaluate the effects of infiltration and seepage on the mobilization and transport of radionuclides. An instrumented seepage collection system and local automated weather station permit direct correlation between local precipitation events and seepage. Field observations recorded between April 2005 and December 2006 indicate that seepage is highly heterogeneous with respect to time, location, and quantity. Seepage, precipitation, and fracture data were used to test two hypotheses: (1) that fast flow seepage is triggered by large precipitation events, and (2) that an increased abundance of fractures and/or fracture intersections leads to higher seepage volumes. A few zones in the back adit recorded elevated seepage volumes immediately following large (>20 mm/day) precipitation events, with transit times of less than 4 h through the 8-m thick rock mass. In most locations, there is a 1-6 month time lag between the onset of the rainy season and seepage, with longer times observed for the front adit. There is a less clear-cut relation between fracture abundance and seepage volume; processes such as evaporation and surface flow along the ceiling may also influence seepage.

Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

DOE PAGES

Pereira, Jose H.; Petchprayoon, Chutima; Hoepker, Alexander C.; ...

2014-07-22

The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region tomore » the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.« less

Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues

PubMed Central

Born, G. V. R.; Juengjaroen, Kanchana; Michal, F.

1972-01-01

1. The specificity of platelet receptor sites for 5-HT uptake and for the rapid morphological change and aggregation was investigated with 5-hydroxy-tryptamine (5-HT) and seventeen analogues as well as with some antagonists of 5-HT. 2. The analogues, with the exception of 5-hydroxy-N'N'-dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0.05-2.0 μM), these analogues themselves inhibited competitively the shape change caused by 5-HT. 3. The velocity of change in shape caused by 5-HT was reduced in low Na media. 4. Ten analogues produced platelet aggregation; three of these, viz. 5-methoxy-α-methyltryptamine, 5-hydroxy-α-methyltryptamine and 5-hydroxy-N'N'-diisopropyltryptamine), were approximately equipotent with 5-HT. Six analogues did not induce platelet aggregation. 5. All the analogues which prevented the initial change in shape of platelets caused by 5-HT also inhibited its aggregating effect, apparently competitively with low Ki values (0.02-1.6 μM). 6. As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site. 7. Methysergide was a potent inhibitor of shape change and aggregation (Ki∼0.03 μM); imipramine was much less inhibitory (Ki∼5-10 μM). 8. Only one analogue (5-hydroxy-α-methyltryptamine) was taken up like 5-HT by platelets. All the other analogues inhibited the uptake of 5-HT by platelets (Ki=0.2-2.7 μM). 9. Methysergide was a weak inhibitor of 5-HT uptake (Ki∼125 μM) whereas imipramine was very effective (Ki∼0.3 μM). 10. Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5-HT appears low whereas the uptake mechanism is a highly specific one. The uptake probably proceeds through more than one step, the

Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

NASA Astrophysics Data System (ADS)

Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

1998-03-01

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi

2014-02-01

The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalentlymore » through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.« less

Fungal growth inhibitory properties of new phytosphingolipid analogues.

PubMed

Mormeneo, D; Manresa, A; Casas, J; Llebaria, A; Delgado, A

2008-04-01

To study the growth inhibitory properties of a series of phytosphingosine (PHS) and phytoceramide (PHC) analogues. A panel of two yeast (Candida albicans and Saccharomyces cerevisiae) and six moulds (Aspergillus repens, Aspergillus niger, Penicillium chrysogenum, Cladosporium cladosporioides, Arthroderma uncinatum and Penicillium funiculosum) has been used in this study. A series of new PHS and PHC analogues differing at the sphingoid backbone and the functional group at C1 position were synthesized. Among PHS analogues, 1-azido derivative 1c, bearing the natural D-ribo stereochemistry, showed a promising growth inhibitory profile. Among PHC analogues, compound 12, with a bulky N-pivaloyl group and a Z double bond at C3 position of the sphingoid chain, was the most active growth inhibitor. Minimal inhibitory concentration values were in the range of 23-48 micromol l(-1) for 1c and 44-87 micromol l(-1) for 12. Only scattered data on the antifungal activity of phytosphingolipids have been reported in the literature. This is the first time that a series of analogues of this kind are tested and compared to discern their structural requirements for antifungal activity.

Can concreteness training buffer against the negative effects of rumination on PTSD? An experimental analogue study.

PubMed

Schaich, Anja; Watkins, Edward R; Ehring, Thomas

2013-12-01

Trauma-related rumination has been found to be an important maintaining factor for PTSD. On the background of the processing mode account of ruminative thinking, this study tested whether the relationship between rumination and analogue PTSD symptoms can be modified by training participants in a concrete mode of processing. Healthy participants were trained in either an abstract or a concrete style of processing. Afterwards, they watched a stressful film. The interactive effect of training condition and trait rumination on intrusive memories of the film was examined. Following abstract training, a positive relationship between trait rumination and intrusive memories of the film emerged. As hypothesized, this relationship disappeared following concrete training. include the lack of a no-training control group and the analogue paradigm used. The study provides preliminary evidence that the relationship between trait rumination and analogue PTSD symptoms can be modified. If replicated in future studies, it may be promising to examine the value of concreteness training for prevention and/or treatment of PTSD. Copyright © 2013 Elsevier Ltd. All rights reserved.

8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase.

PubMed

Strydom, Belinda; Bergh, Jacobus J; Petzer, Jacobus P

2011-08-01

Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC(50) values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC(50) = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC(50) value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Final report of the Peña Blanca natural analogue project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levy, Schön S.; Goldstein, Steven Joel; Abdel-Fattah, Amr I.

2016-10-04

The Peña Blanca region, 50 km north of Chihuahua City, Chihuahua, México, was a target of uranium exploration and mining by the Mexican government. After mining ceased in 1981, researchers became interested in this region as a study area for subsurface uranium migration with relevance to geologic disposal of nuclear waste. Many studies related to this concept were conducted at the Nopal I mine site located on a cuesta (hill) of the Sierra Peña Blanca. This site has geologic, tectonic, hydrologic, and geochemical similarities to Yucca Mountain, Nevada, a formerly proposed site for a high-level nuclear-waste repository in the unsaturatedmore » zone. The U.S. Department of Energy (U.S. DOE), Office of Civilian Radioactive Waste Management (OCRWM), sponsored studies at Nopal I in the 1990s and supported the drilling of three research wells – PB1, PB2, and PB3 – at the site in 2003. Beginning in 2004, the Peña Blanca Natural Analogue Project was undertaken by U.S. DOE, OCRWM to develop a three-dimensional conceptual model of the transport of uranium and its radiogenic daughter products at the Nopal I site.« less

Active Site and Remote Contributions to Catalysis in Methylthioadenosine Nucleosidases

DOE PAGES

Thomas, Keisha; Cameron, Scott A.; Almo, Steven C.; ...

2015-03-25

5'-Methylthioadenosine/S-adenosyl-l-homocysteine nucleosidases (MTANs) catalyze the hydrolysis of 5'-methylthioadenosine to adenine and 5-methylthioribose. The amino acid sequences of the MTANs from Vibrio cholerae (VcMTAN) and Escherichia coli (EcMTAN) are 60% identical and 75% similar. Protein structure folds and kinetic properties are similar. However, binding of transition-state analogues is dominated by favorable entropy in VcMTAN and by enthalpy in EcMTAN. Catalytic sites of VcMTAN and EcMTAN in contact with reactants differ by two residues; Ala113 and Val153 in VcMTAN are Pro113 and Ile152, respectively, in EcMTAN. Here, we mutated the VcMTAN catalytic site residues to match those of EcMTAN in anticipation ofmore » altering its properties toward EcMTAN. Inhibition of VcMTAN by transition-state analogues required filling both active sites of the homodimer. However, in the Val153Ile mutant or double mutants, transition-state analogue binding at one site caused complete inhibition. Therefore, a single amino acid, Val153, alters the catalytic site cooperativity in VcMTAN. The transition-state analogue affinity and thermodynamics in mutant VcMTAN became even more unlike those of EcMTAN, the opposite of expectations from catalytic site similarity; thus, catalytic site contacts in VcMTAN are unable to recapitulate the properties of EcMTAN. X-ray crystal structures of EcMTAN, VcMTAN, and a multiple-site mutant of VcMTAN most closely resembling EcMTAN in catalytic site contacts show no major protein conformational differences. In conclusion, the overall protein architectures of these closely related proteins are implicated in contributing to the catalytic site differences.« less

Active Site and Remote Contributions to Catalysis in Methylthioadenosine Nucleosidases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Keisha; Cameron, Scott A.; Almo, Steven C.

5'-Methylthioadenosine/S-adenosyl-l-homocysteine nucleosidases (MTANs) catalyze the hydrolysis of 5'-methylthioadenosine to adenine and 5-methylthioribose. The amino acid sequences of the MTANs from Vibrio cholerae (VcMTAN) and Escherichia coli (EcMTAN) are 60% identical and 75% similar. Protein structure folds and kinetic properties are similar. However, binding of transition-state analogues is dominated by favorable entropy in VcMTAN and by enthalpy in EcMTAN. Catalytic sites of VcMTAN and EcMTAN in contact with reactants differ by two residues; Ala113 and Val153 in VcMTAN are Pro113 and Ile152, respectively, in EcMTAN. Here, we mutated the VcMTAN catalytic site residues to match those of EcMTAN in anticipation ofmore » altering its properties toward EcMTAN. Inhibition of VcMTAN by transition-state analogues required filling both active sites of the homodimer. However, in the Val153Ile mutant or double mutants, transition-state analogue binding at one site caused complete inhibition. Therefore, a single amino acid, Val153, alters the catalytic site cooperativity in VcMTAN. The transition-state analogue affinity and thermodynamics in mutant VcMTAN became even more unlike those of EcMTAN, the opposite of expectations from catalytic site similarity; thus, catalytic site contacts in VcMTAN are unable to recapitulate the properties of EcMTAN. X-ray crystal structures of EcMTAN, VcMTAN, and a multiple-site mutant of VcMTAN most closely resembling EcMTAN in catalytic site contacts show no major protein conformational differences. In conclusion, the overall protein architectures of these closely related proteins are implicated in contributing to the catalytic site differences.« less

Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues.

PubMed

Liu, H; Ji, M; Jiang, H; Liu, L; Hua, W; Chen, K; Ji, R

2000-10-02

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in microM of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable.

Radiation-Driven Formation of Reactive Oxygen Species in Oxychlorine-Containing Mars Surface Analogues.

PubMed

Georgiou, Christos D; Zisimopoulos, Dimitrios; Kalaitzopoulou, Electra; Quinn, Richard C

2017-04-01

The present study demonstrates that γ-radiolyzed perchlorate-containing Mars soil salt analogues (in a CO 2 atmosphere) generate upon H 2 O wetting the reactive oxygen species (ROS) superoxide radical (O 2 •- ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals ( • OH). This study also validates that analogue radiolysis forms oxychlorine species that, in turn, can UV-photolyze to • OH upon UV photolysis. This investigation was made possible by the development of a new assay for inorganic-origin O 2 •- and H 2 O 2 determination and by the modification of a previous assay for soil • OH. Results show that radiolyzed Mg(ClO 4 ) 2 generates H 2 O 2 and • OH; and when included as part of a mixture analogous to the salt composition of samples analyzed at the Mars Phoenix site, the analogue generated O 2 •- , H 2 O 2 , and • OH, with • OH levels 150-fold higher than in the radiolyzed Mg(ClO 4 ) 2 samples. Radiolyzed Mars Phoenix site salt analogue that did not contain Mg(ClO 4 ) 2 generated only • OH also at 150-fold higher concentration than Mg(ClO 4 ) 2 alone. Additionally, UV photolysis of the perchlorate γ radiolysis product chlorite (ClO 2 - ) generated the oxychlorine products trihalide (Cl 3 - ), chlorine dioxide (ClO 2 • ), and hypochlorite (ClO - ), with the formation of • OH by UV photolysis of ClO - . While the generation of ROS may have contributed in part to 14 CO 2 production in the Viking Labeled Release (LR) experiment and O 2 (g) release in the Viking Gas Exchange (GEx) experiment, our results indicate that they are not likely to be the major contributor to the LR and GEx results. However, due to their highly reactive nature, they are expected to play a significant role in the alteration of organics on Mars. Additionally, experiments with hypochlorite show that the thermal stability of NaClO is in the range of the thermal stability observed for thermally liable oxidant responsible for the Viking LR results. Key Words: Mars

Radiation-Driven Formation of Reactive Oxygen Species in Oxychlorine-Containing Mars Surface Analogues

NASA Astrophysics Data System (ADS)

Georgiou, Christos D.; Zisimopoulos, Dimitrios; Kalaitzopoulou, Electra; Quinn, Richard C.

2017-04-01

The present study demonstrates that γ-radiolyzed perchlorate-containing Mars soil salt analogues (in a CO2 atmosphere) generate upon H2O wetting the reactive oxygen species (ROS) superoxide radical (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH). This study also validates that analogue radiolysis forms oxychlorine species that, in turn, can UV-photolyze to •OH upon UV photolysis. This investigation was made possible by the development of a new assay for inorganic-origin O2•- and H2O2 determination and by the modification of a previous assay for soil •OH. Results show that radiolyzed Mg(ClO4)2 generates H2O2 and •OH; and when included as part of a mixture analogous to the salt composition of samples analyzed at the Mars Phoenix site, the analogue generated O2•-, H2O2, and •OH, with •OH levels 150-fold higher than in the radiolyzed Mg(ClO4)2 samples. Radiolyzed Mars Phoenix site salt analogue that did not contain Mg(ClO4)2 generated only •OH also at 150-fold higher concentration than Mg(ClO4)2 alone. Additionally, UV photolysis of the perchlorate γ radiolysis product chlorite (ClO2-) generated the oxychlorine products trihalide (Cl3-), chlorine dioxide (ClO2•), and hypochlorite (ClO-), with the formation of •OH by UV photolysis of ClO-. While the generation of ROS may have contributed in part to 14CO2 production in the Viking Labeled Release (LR) experiment and O2 (g) release in the Viking Gas Exchange (GEx) experiment, our results indicate that they are not likely to be the major contributor to the LR and GEx results. However, due to their highly reactive nature, they are expected to play a significant role in the alteration of organics on Mars. Additionally, experiments with hypochlorite show that the thermal stability of NaClO is in the range of the thermal stability observed for thermally liable oxidant responsible for the Viking LR results.

Antifreeze glycopeptide analogues: microwave-enhanced synthesis and functional studies.

PubMed

Heggemann, Carolin; Budke, Carsten; Schomburg, Benjamin; Majer, Zsuzsa; Wissbrock, Marco; Koop, Thomas; Sewald, Norbert

2010-01-01

Antifreeze glycoproteins enable life at temperatures below the freezing point of physiological solutions. They usually consist of the repetitive tripeptide unit (-Ala-Ala-Thr-) with the disaccharide alpha-D-galactosyl-(1-3)-beta-N-acetyl-D-galactosamine attached to each hydroxyl group of threonine. Monoglycosylated analogues have been synthesized from the corresponding monoglycosylated threonine building block by microwave-assisted solid phase peptide synthesis. This method allows the preparation of analogues containing sequence variations which are not accessible by other synthetic methods. As antifreeze glycoproteins consist of numerous isoforms they are difficult to obtain in pure form from natural sources. The synthetic peptides have been structurally analyzed by CD and NMR spectroscopy in proton exchange experiments revealing a structure as flexible as reported for the native peptides. Microphysical recrystallization tests show an ice structuring influence and ice growth inhibition depending on the concentration, chain length and sequence of the peptides.

Insulin analogues for type 1 diabetes in children and adolescents.

PubMed

Galli-Tsinopoulou, A; Stergidou, D

2012-12-01

Since insulin is the unique and life-long therapy in type 1 diabetes and classical insulin preparations have certain limitations due to their pharmacokinetic and pharmacodynamic properties, the new insulin analogues aim to eliminate these limitations. Five insulin analogues are commercially available and approved for individuals with type 1 diabetes: three rapid-acting (insulin lispro, insulin aspart and insulin glulisine) and two long-acting insulin analogues (insulin glargine and insulin detemir). According to several studies conducted in children with type 1 diabetes, insulin analogues, due to their structural alterations, offer flexibility, reduction of nocturnal hypoglycemic episodes and decrease in postprandial hyperglycemic events, resulting in improved quality of life for diabetic children and their families. However, diabetes control measured with glycosylated hemoglobin A1c has been reported to be similar to conventional insulin preparations. Evidence-based medical reports indicate that insulin analogues are safe and effective, and therefore approved for children even from the age of 2 years. Moreover, suspicions and reports on the association of insulin analogues with carcinogenesis have not been established, requiring further investigation. This review reports the properties and characteristics of insulin analogues, as well as the results of current studies concerning pediatric patients with type 1 diabetes. Copyright 2012 Prous Science, S.A.U. or its licensors. All rights reserved.

Attributions about Perpetrators and Victims of Interpersonal Abuse: Results from an Analogue Study

ERIC Educational Resources Information Center

Langhinrichsen-Rohling, Jennifer; Shlien-Dellinger, Rania K.; Huss, Matthew T.; Kramer, Vertrie L.

2004-01-01

This analogue study (written vignettes and videotapes) examines the influence of victim-perpetrator relationship (spouse or acquaintance), sex of perceiver, and type of abuse (psychological vs. physical) on attributions about victims and perpetrators of domestic abuse. College student participants (73 men, 108 women) were randomly assigned to…

Therapeutic uses of vitamin D analogues.

PubMed

Brown, A J

2001-11-01

The vitamin D endocrine system has been implicated in numerous biological activities throughout the body. The breadth and magnitude of vitamin D activity suggest potential therapeutic applications for the treatment of several diseases and disorders, including hyperproliferative diseases, immune dysfunction, endocrine disorders, and metabolic bone diseases. However, therapy using natural vitamin D hormone, 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) has been precluded in most cases because of the potent calcemic activity shown by this hormone. Newly developed vitamin D analogues with lower calcemic activity have been shown to retain many therapeutic properties of 1,25(OH)(2)D(3). Molecular studies discussed in this article provide insights into the unique target cell specificity afforded by these analogues. In particular, the importance of the nuclear vitamin D receptor (VDR), serum vitamin D-binding protein, 24-hydroxylase, and membrane receptor is noted because analogue selectivity, specificity, and potency are afforded through their molecular interactions. The nuclear VDR has been isolated from a variety of target cells and tissues, suggesting that vitamin D compounds may have therapeutic potential throughout several body systems. Five vitamin D analogues have been approved for use in patients: calcipotriol (Dovonex; Leo Pharmaceuticals, Copenhagen, Denmark) for the treatment of psoriasis, 19-nor-1,25(OH)(2)D(2) (Zemplar; Abbott Laboratories, Abbott Park, IL) for secondary hyperparathyroidism, doxercalciferol (Hectorol; Bone Care Int, Madison, WI) for reduction of elevated parathyroid hormone levels, 22-oxacalcitriol (Maxacalcitol; Chugai Pharmaceuticals, Tokyo, Japan), and alfacalcidol. Several other analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis, as well as immunosuppression. Understanding how analogues exert their selective actions may allow for the design of more effective

Late Pleniglacial vegetation in eastern-central Europe: are there modern analogues in Siberia?

NASA Astrophysics Data System (ADS)

Magyari, Enikő Katalin; Kuneš, Petr; Jakab, Gusztáv; Sümegi, Pál; Pelánková, Barbora; Schäbitz, Frank; Braun, Mihály; Chytrý, Milan

2014-07-01

To characterize Late Pleniglacial (LPG: 26.5-15 ka cal BP) and particularly Last Glacial Maximum (LGM: 21 ± 2 ka cal BP) vegetation and climate, fossil pollen assemblages are often compared with modern pollen assemblages. Given the non-analogue climate of the LPG, a key question is how glacial pollen assemblages and thereby vegetation compare with modern vegetation. In this paper we present three LPG pollen records from the Carpathian Basin and the adjoining Carpathian Mountains to address this question and provide a concise compositional characterization of the LPG vegetation. Fossil pollen assemblages were compared with surface pollen spectra from the Altai-Sayan Mountains in southern Siberia. This area shows many similarities with the LPG vegetation of eastern-central Europe, and has long been considered as its best modern analogue. Ordination and analogue matching were used to characterize vegetation composition and find the best analogues. Our results show that few LPG pollen assemblages have statistically significant analogues in southern Siberia. When analogue pairings occur they suggest the predominance of wet and mesic grasslands and dry steppe in the studied region. Wooded vegetation types (continental and suboceanic hemiboreal forest, continental taiga) appear as significant analogues only in a few cases during the LGM and more frequently after 16 ka cal BP. These results suggest that the LPG landscape of the Carpathian Basin was dominated by dry steppe that occurred outside the river floodplains, while wet and mesic grasslands occurred in the floodplains and on other sites influenced by ground water. Woody vegetation mainly occurred in river valleys, on wet north-facing hillsides, and scattered trees were likely also present on the loess plateaus. The dominant woody species were Larix, Pinus sylvestris, Pinus mugo, Pinus cembra, Picea abies, Betula pendula/pubescens, Betula nana, Juniperus, Hippophaë rhamnoides, Populus, Salix and Alnus. The pollen

Environment sensitive fluorescent analogue of biologically active oxazoles differentially recognizes human serum albumin and bovine serum albumin: Photophysical and molecular modeling studies.

PubMed

Maiti, Jyotirmay; Biswas, Suman; Chaudhuri, Ankur; Chakraborty, Sandipan; Chakraborty, Sibani; Das, Ranjan

2017-03-15

An environment sensitive fluorophore, 4-(5-(4-(dimethylamino)phenyl)oxazol-2-yl)benzoic acid (DMOBA), that closely mimics biologically active 2,5-disubstituited oxazoles has been designed to probe two homologous serum proteins, human serum albumin (HSA) and bovine serum albumin (BSA) by means of photophysical and molecular modeling studies. This fluorescent analogue exhibits solvent polarity sensitive fluorescence due to an intramolecular charge transfer in the excited state. In comparison to water, the steady state emission spectra of DMOBA in BSA is characterized by a greater blue shift (~10nm) and smaller Stokes' shift (~5980cm -1 ) in BSA than HSA (Stokes'shift~6600cm -1 ), indicating less polar and more hydrophobic environment of the dye in the former than the latter. The dye-protein binding interactions are remarkably stronger for BSA than HSA which is evident from higher value of the association constant for the DMOBA-BSA complex (K a ~5.2×10 6 M -1 ) than the DMOBA-HSA complex (K a ~1.0×10 6 M -1 ). Fӧrster resonance energy transfer studies revealed remarkably less efficient energy transfer (8%) between the donor tryptophans in BSA and the acceptor DMOBA dye than that (30%) between the single tryptophan moiety in HSA and the dye, which is consistent with a much larger distance between the donor (tryptophan)-acceptor (dye) pair in BSA (34.5Å) than HSA (25.4Å). Site specific competitive binding assays have confirmed on the location of the dye in Sudlow's site II of BSA and in Sudlow's site I of HSA, respectively. Molecular modeling studies have shown that the fluorescent analogue is tightly packed in the binding site of BSA due to strong steric complementarity, where, binding of DMOBA to BSA is primarily dictated by the van der Waals and hydrogen bonding interactions. In contrast, in HSA the steric complementarity is less significant and binding is primarily guided by polar interactions and van der Waals interactions appear to be less significant in the

Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4.

PubMed

Ty, Nancy; Pontikis, Renée; Chabot, Guy G; Devillers, Emmanuelle; Quentin, Lionel; Bourg, Stéphane; Florent, Jean-Claude

2013-03-01

To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities. Copyright © 2013. Published by Elsevier Ltd.

Substituted Phosphonic Analogues of Phenylglycine as Inhibitors of Phenylalanine Ammonia Lyase from Potatoes.

PubMed

Wanat, Weronika; Talma, Michał; Hurek, Józef; Pawełczak, Małgorzata; Kafarski, Paweł

2018-06-08

A series of phosphonic acid analogues of phenylglycine variously substituted in phenyl ring have been synthesized and evaluated for their inhibitory activity towards potato L-phenylalanine ammonia lyase. Most of the compounds appeared to act as moderate (micromolar) inhibitors of the enzyme. Analysis of their binding performed using molecular modeling have shown that they might be bound either in active site of the enzyme or in the non-physiologic site. The latter one is located in adjoining deep site nearby the to the entrance channel for substrate into active site. Copyright © 2018. Published by Elsevier B.V.

Recent developments in naturally derived antimalarials: cryptolepine analogues.

PubMed

Wright, Colin W

2007-06-01

Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues.

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer.

PubMed

Thomas, T J; Thomas, Thresia

2018-03-13

Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N ¹-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

PubMed Central

Thomas, Thresia

2018-01-01

Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents. PMID:29533973

Inhibition of ATP Synthase by Chlorinated Adenosine Analogue

PubMed Central

Chen, Lisa S.; Nowak, Billie J.; Ayres, Mary L.; Krett, Nancy L.; Rosen, Steven T.; Zhang, Shuxing; Gandhi, Varsha

2009-01-01

8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing α and β subunits. Crystal structures of both α and β subunits that bind to the substrate, ADP, are known in tight binding (αdpβdp) and loose binding (αtpβtp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the αtpβtp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (αdpβdp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 −. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase. PMID:19477165

3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKenna, D.J.; Guan, X.M.; Shulgin, A.T.

1991-03-01

The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, alsomore » show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives {plus minus}fenfluramine, {plus minus}norfenfluramine, {plus minus}MDE, {plus minus}PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.« less

Balanol analogues probe specificity determinants and the conformational malleability of the cyclic 3',5'-adenosine monophosphate-dependent protein kinase catalytic subunit.

PubMed

Akamine, Pearl; Madhusudan; Brunton, Laurence L; Ou, Horng D; Canaves, Jaume M; Xuong, Nguyen-huu; Taylor, Susan S

2004-01-13

The protein kinase family is a prime target for therapeutic agents, since unregulated protein kinase activities are linked to myriad diseases. Balanol, a fungal metabolite consisting of four rings, potently inhibits Ser/Thr protein kinases and can be modified to yield potent inhibitors that are selective-characteristics of a desirable pharmaceutical compound. Here, we characterize three balanol analogues that inhibit cyclic 3',5'-adenosine monophosphate-dependent protein kinase (PKA) more specifically and potently than calcium- and phospholipid-dependent protein kinase (PKC). Correlation of thermostability and inhibition potency suggests that better inhibitors confer enhanced protection against thermal denaturation. Crystal structures of the PKA catalytic (C) subunit complexed to each analogue show the Gly-rich loop stabilized in an "intermediate" conformation, disengaged from important phosphoryl transfer residues. An analogue that perturbs the PKA C-terminal tail has slightly weaker inhibition potency. The malleability of the PKA C subunit is illustrated by active site residues that adopt alternate rotamers depending on the ligand bound. On the basis of sequence homology to PKA, a preliminary model of the PKC active site is described. The balanol analogues serve to test the model and to highlight differences in the active site local environment of PKA and PKC. The PKA C subunit appears to tolerate balanol analogues with D-ring modifications; PKC does not. We attribute this difference in preference to the variable B helix and C-terminal tail. By understanding the details of ligand binding, more specific and potent inhibitors may be designed that differentiate among closely related AGC protein kinase family members.

Life detection at a Mars analogue site of present-day serpentinization in the Tablelands Ophiolite of Newfoundland (Invited)

NASA Astrophysics Data System (ADS)

Morrill, P. L.; Szponar, N.; Brazelton, W. J.; Woodruff, Q.; Schrenk, M. O.; Bower, D. M.; Steele, A.

2010-12-01

The Tableland Ophiolite was created during the collision of Laurentia and Gondwana continents ca. 470 million years ago. Ultramafic mantle rocks, from the ancient sea bed that once separated these continents, were thrusted westward onto the old continental margin, which is now Western Newfoundland. Weathering due to recent glaciations has left large areas of ultramafic rock at the surface and created fissures for fluid flow. As a result serpentinization is occurring as fresh water penetrates the unaltered ultramafic rock. Serpentinization is of particular interest because, through hydration of ultramafic rock, this reaction produces H2 and the reducing conditions necessary for abiogenic hydrocarbon synthesis, while also producing conditions amenable for chemolithotrophic life. Therefore sites of active serpentinization can be the source of either abiogenic or biogenic organics, or both. Serpentinization is a suspected (past or present) source of (detected or putative) hydrocarbons on Mars, Titan and Europa, hence these astrobodies may be potentially habitable or once habitable environments. The Tablelands Ophiolite is an analogue site that is ideal for testing methods of life detection in an extreme environment of high pH and low microbial biomass characteristic of sites of serpentinization. Multiple ultrabasic reducing springs characteristic of present-day serpentinization have been identified and characterized based on their geochemistry and microbiology. Field-based instruments were deployed for the detection of microbial activity (ATP), microbial cell wall material, and mineralogy, in yet untested high pH and low biomass environment. In this talk I will give an overview of the in situ measurements of life detection and put these measurements in context of geochemistry, microbiology, carbon source and reaction pathways, and I will discuss what we have learned that will help us plan for future mission measurements.

The effects of dissociation on information processing for analogue trauma and neutral stimuli: a laboratory study.

PubMed

Olsen, Shira A; Beck, J Gayle

2012-01-01

This study investigated the effects of high and low levels of dissociation on information processing for analogue trauma and neutral stimuli. Fifty-four undergraduate females who reported high and low levels of trait dissociation were presented with two films, one depicting traumatic events, the other containing neutral material. Participants completed a divided attention task (yielding a proxy measure of attention), as well as explicit memory (free-recall) and implicit memory (word-stem completion) tasks for both films. Results indicated that the high DES group showed less attention and had poorer recall for the analogue trauma stimuli, relative to the neutral stimuli and the low DES group. These findings suggest that high levels of trait dissociation are associated with reductions in attention and memory for analogue trauma stimuli, relative to neutral stimuli and relative to low trait dissociation. Implications for the role of cognitive factors in the etiology of negative post-trauma responses are discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Historical space psychology: Early terrestrial explorations as Mars analogues

NASA Astrophysics Data System (ADS)

Suedfeld, Peter

2010-03-01

The simulation and analogue environments used by psychologists to circumvent the difficulties of conducting research in space lack many of the unique characteristics of future explorations, especially the mission to Mars. This paper suggests that appropriate additional analogues would be the multi-year maritime and terrestrial explorations that mapped the surface of the Earth in previous centuries. These, like Mars, often involved a hazardous trek through unknown territory, flanked by extended, dangerous voyages to and from the exploration sites. Characteristic issues included interpersonal relationships under prolonged stress, stretches of boredom interspersed with intense work demands, the impossibility of rescue, resupply, or other help from home, chronic danger, physical discomfort and lack of privacy, and the crucial role of the leader. Illustrative examples of one important factor, leadership style, are discussed. The examination of such expeditions can help to identify the psychological stressors that are likely to be experienced by Mars explorers, and can also indicate countermeasures to reduce the damaging impact of those stressors.

Chemical tailoring of teicoplanin with site-selective reactions.

PubMed

Pathak, Tejas P; Miller, Scott J

2013-06-05

Semisynthesis of natural product derivatives combines the power of fermentation with orthogonal chemical reactions. Yet, chemical modification of complex structures represents an unmet challenge, as poor selectivity often undermines efficiency. The complex antibiotic teicoplanin eradicates bacterial infections. However, as resistance emerges, the demand for improved analogues grows. We have discovered chemical reactions that achieve site-selective alteration of teicoplanin. Utilizing peptide-based additives that alter reaction selectivities, certain bromo-teicoplanins are accessible. These new compounds are also scaffolds for selective cross-coupling reactions, enabling further molecular diversification. These studies enable two-step access to glycopeptide analogues not available through either biosynthesis or rapid total chemical synthesis alone. The new compounds exhibit a spectrum of activities, revealing that selective chemical alteration of teicoplanin may lead to analogues with attenuated or enhanced antibacterial properties, in particular against vancomycin- and teicoplanin-resistant strains.

Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.

PubMed

Le Coq, Johanne; Pavlovsky, Alexander; Malik, Radhika; Sanishvili, Ruslan; Xu, Chengfu; Viola, Ronald E

2008-03-18

Canavan disease is a fatal neurological disorder caused by the malfunctioning of a single metabolic enzyme, aspartoacylase, that catalyzes the deacetylation of N-acetyl-L-aspartate to produce L-aspartate and acetate. The structure of human brain aspartoacylase has been determined in complex with a stable tetrahedral intermediate analogue, N-phosphonomethyl-L-aspartate. This potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed within the active site. The binding of the catalytic intermediate analogue induces the conformational ordering of several substrate binding groups, thereby setting up the active site for catalysis. The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate.

Incorporation of Methionine Analogues Into Bombyx mori Silk Fibroin for Click Modifications.

PubMed

Teramoto, Hidetoshi; Kojima, Katsura

2015-05-01

Bombyx mori silk fibroin incorporating three methionine (Met) analogues-homopropargylglycine (Hpg), azidohomoalanine (Aha), and homoallylglycine (Hag)-can be produced simply by adding them to the diet of B. mori larvae. The Met analogues are recognized by methionyl-tRNA synthetase, bound to tRNA(Met), and used for the translation of adenine-uracil-guanine (AUG) codons competitively with Met. In the presence of the standard amount of Met in the diet, incorporation of these analogues remains low. Lowering the amount of Met in the diet drastically improves incorporation efficiencies. Alkyne and azide groups in Hpg and Aha incorporated into silk fibroin can be selectively modified with Cu-catalyzed azide-alkyne cycloaddition reactions (click chemistry). Since Met residues exist only at the N-terminal domain of the fibroin heavy chain and in the fibroin light chain, good access to the reactive sites is expected and domain-selective modifications are possible without perturbing other major domains, including repetitive domains. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Backbone modified TBA analogues endowed with antiproliferative activity.

PubMed

Esposito, Veronica; Russo, Annapina; Amato, Teresa; Varra, Michela; Vellecco, Valentina; Bucci, Mariarosaria; Russo, Giulia; Virgilio, Antonella; Galeone, Aldo

2017-05-01

The thrombin binding aptamer (TBA) is endowed with antiproliferative properties but its potential development is counteracted by the concomitant anticoagulant activity. Five oligonucleotides (ODNs) based on TBA sequence (GGTTGGTGTGGTTGG) and containing l-residues or both l-residues and inversion of polarity sites have been investigated by NMR and CD techniques for their ability to form G-quadruplex structures. Furthermore, their anticoagulant (PT assay) and antiproliferative properties (MTT assay), and their resistance in fetal bovine serum have been tested. CD and NMR data suggest that the investigated ODNs are able to form right- and left-handed G-quadruplex structures. All ODNs do not retain the anticoagulant activity characteristic of TBA but are endowed with a significant antiproliferative activity against two cancerous cell lines. Their resistance in biological environment after six days is variable, depending on the ODN. A comparison between results and literature data suggests that the antiproliferative activity of the TBA analogues investigated could depends on two factors: a) biological pathways and targets different from those already identified or proposed for other antiproliferative G-quadruplex aptamers, and b) the contribution of the guanine-based degradation products. Modified TBA analogues containing l-residues and inversion of polarity sites lose the anticoagulant activity but gain antiproliferative properties against two cancer cell lines. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. Copyright © 2016 Elsevier B.V. All rights reserved.

The western Qaidam Basin as a potential Martian environmental analogue: An overview

NASA Astrophysics Data System (ADS)

Anglés, Angélica; Li, Yiliang

2017-05-01

The early Martian environment is interpreted as warmer and wetter, before a significant change in its global climatic conditions irreversibly led to the current hyperarid environments. This transition is one of the most intriguing processes of Martian history. The extreme climatic change is preserved in the salt deposits, desiccated landscapes, and geomorphological structures that were shaped by the evaporation of water. However, until a manned journey to Mars is feasible, many Martian materials, morphological structures, and much of its evolutionary history will continue to be poorly understood. In this regard, searching and investigating Martian analogues are still meaningful. To find an Earth environment with a whole set of Martian structures distributed at a scale comparable to Mars is even more important to test landing crafts and provide optimized working parameters for rovers. The western Qaidam Basin in North Tibetan Plateau is such a Martian analogue. The area harbors one of the most extreme hyperarid environments on Earth and contains a series of ancient lakes that evaporated at different evolutionary stages during the rise of the Tibetan Plateau. Large quantities of salts and geomorphological features formed during the transition of warmer-and-wet to colder-and-dry conditions provide unique references to study the modern Martian surface and interpret the orbital data. We present numerous similarities and results of investigations that suggest the Qaidam Basin as a potential analogue to study modern geomorphic processes on Mars, and suggest that this is an essential site to test future Mars sample return missions.

Desferrithiocin Analogue Uranium Decorporation Agents

PubMed Central

Bergeron, Raymond J.; Wiegand, Jan; Singh, Shailendra

2010-01-01

Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue. PMID:19399680

Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study

NASA Astrophysics Data System (ADS)

Soriano-Correa, Catalina; Raya, A.; Esquivel, Rodolfo O.

American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

Biological Synthesis of a Protein Analogue of Acetylcholinesterase: Monoclonal Anti-Idiotype Antibody Analogue of the Esteratic Site.

DTIC Science & Technology

1986-07-10

site- directed inhibitor DFP, the reversible site-directed inhibitors neostigmine, carbachol , edrophonium, and BW284c51; and the allosteric site...Esteratic 10-6 10 -7 - I0-2 Neostigmine Esteratic 10- 7 10- 6 - 10 5 Anionic PI Carbachol Esteratic 10- 4 10 3 10-1 Anionic PI Edrophonium Anionic 10

In Silico Study and Cytotoxicity of the Synthesized Open-chain Analogues of Antimycin A3 Against HEP-2 Laryngeal Cancer Cells

PubMed Central

Arsianti, Ade; Fadilah, Fadilah; Kusmardi, Kusmardi; Sugiarta, Gede Y.; Tanimoto, Hiroki; Kakiuchi, Kiyomi

2017-01-01

Background: Laryngeal cancers affect one quarter of all head and neck cancers. Chemotherapy is a standard method in treatment laryngeal carcinoma. How-ever, cancer chemotherapy is often a failure due to the appearance of drug resistance. This fact suggests that the search for novel, safe, and more effective laryngeal cancer drugs are required. Antimycin A3 is a fit ligand of anti-apoptotic Bcl-2. While Bcl-2 is known to be over-expressed in laryngeal cancer cell, it is quite reasonable to expect an-timycin A3 and its analogue to induce apoptosis in those cells. Methods: With this viewpoint, we decided to conduct research that is aimed to evaluate cytotoxic activity of the synthesized open-chain analogues of antimycin A3 against HEP-2 laryngeal cancer cells, as well as to conduct in silico study of the analogues on receptor binding target Bcl-2 of laryngeal cancer. Results and Conclusion: Open-chain analogues of antimycin A3 were successfully syn-thesized in a good yield from Boc-L-Threonine by esterification, amidation, and Sharp-less asymmetric dihydroxylation. Consistent with in silico study, the analogues exhibited a greater anticancer activity against laryngeal HEP-2 cells than the original antimycin A3 with IC50 ranging of 31.6 µM to 46.3 µM. Our results clearly demonstrate that the open-chain analogues of an-timycin A3 as a promising candidates of new anti-laryngeal cancer agents.

Reactions of trimethylphosphine analogues of auranofin with bovine serum albumin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Isab, A.A.; Shaw, C.F. III; Hoeschele, J.D.

1988-10-05

The reactions of bovine serum albumin (BSA) with (trimethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I), Me/sub 3/PAuSAtg, and its chloro analogue, Me/sub 3/PAuCl, were studied to develop insights into the role of the phosphine ligand in the serum chemistry of the related antiarthritic drug auranofin (triethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I). /sup 31/P NMR spectroscopy, protein modification, and gel-exclusion chromatography methods were employed. Comparison of the reactions of the methyl derivatives to the previously reported reactions of auranofin and Et/sub 3/PAuCl with BSA demonstrated that similar chemical species are formed but revealed three major differences. Despite these differences, the results for the methyl analogues provide important confirmation for previously developed chemicalmore » models of auranofin reactions in serum. Me/sub 3/PO was not observed in reaction mixtures lacking tetraacetylthioglucose (AtgSH); this result affirms the role of AtgSH, displaced by the reaction of Me/sub 3/PAuSAtg at Cys-34, in the generation of the phosphine oxide (an important metabolite in vivo). The weak binding sites on albumin react with Me/sub 3/PAuCl, but not Me/sub 3/PAuSAtg, demonstrating the importance of the strength and reactivity of the anionic ligand-gold bond on the reactions of auranofin analogues. The gold binding capacity of albumin is enhanced after Me/sub 3/PO is formed, consistent with reductive cleavage of albumin disulfide bonds by trimethylphosphine. 24 references, 2 figures, 3 tables.« less

3D-QSAR study and design of 4-hydroxyamino α-pyranone carboxamide analogues as potential anti-HCV agents

NASA Astrophysics Data System (ADS)

Li, Wenlian; Xiao, Faqi; Zhou, Mingming; Jiang, Xuejin; Liu, Jun; Si, Hongzong; Xie, Meng; Ma, Xiuting; Duan, Yunbo; Zhai, Honglin

2016-09-01

The three dimensional-quantitative structure activity relationship (3D-QSAR) study was performed on a series of 4-hydroxyamino α-pyranone carboxamide analogues using comparative molecular similarity indices analysis (COMSIA). The purpose of the present study was to develop a satisfactory model providing a reliable prediction based on 4-hydroxyamino α-pyranone carboxamide analogues as anti-HCV (hepatitis C virus) inhibitors. The statistical results and the results of validation of this optimum COMSIA model were satisfactory. Furthermore, analysis of the contour maps helped to provide guidelines for finding structural requirement. Therefore, the satisfactory results from this study may provide useful guidelines for drug development of anti-HCV inhibitors.

Highly active anticancer curcumin analogues.

PubMed

Mosley, Cara A; Liotta, Dennis C; Snyder, James P

2007-01-01

Curcumin, a compound in the human food supply, represents a near-perfect starting point for drug discovery. Consequently, a number of research groups have taken the natural product as a starting point to prepare and biologically evaluate a wide variety of curcumin analogues. One widely used structural modification truncates the central conjugated beta-diketone in curcumin to the monocarbonyl dienone. A diverse array of the latter compounds exhibit cytotoxicities against an equally diverse set of cancer-related cell lines. Importantly, these compounds still retain toxicity profiles in rodents comparable to the parent natural product, whereas some analogues (e.g., EF-24, 41) exhibit good oral bioavailability and good pharmacokinetics in mice. Thiol conjugates of EF-24 analogues have been prepared that address stability and solubility issues while demonstrating cellular activities similar to the unmodified dienones. In parallel experiments, the factor VIIa-tissue factor complex (fVIIa-TF) has been exploited to develop a targeting strategy for the analogues. In particular, the EF24-FFRck-fVIIa protein conjugate is not only somewhat more effective relative to the drug alone against breast cancer and melanocyte cells. Both simple curcumin analogues and the protein conjugate evidence antiangiogenic activity in cell culture. The implication is that the fVIIa-TF targeting process, like the dienone drugs, permits a double-pronged attack with the potential to destroy a tumor directly by apoptosis.

Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950.

PubMed

Salla, Manohar; Butler, Mark S; Massey, Nicholas L; Reid, Janet C; Cooper, Matthew A; Robertson, Avril A B

2018-02-15

This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC 50  = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quantum analogue computing.

PubMed

Kendon, Vivien M; Nemoto, Kae; Munro, William J

2010-08-13

We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

[Positioning of mRNA 3' of the a site bound codon on the human 80S ribosome].

PubMed

Molotkov, M V; Graĭfer, D M; Demeshkina, N A; Repkova, M N; Ven'iaminova, A G; Karpova, G G

2005-01-01

Short mRNA analogues carrying a UUU triplet at the 5'-termini and a perfluorophenylazide group at either the N7 atom of the guanosine or the C5 atom of the uridine 3' of the triplet were applied to study positioning of mRNA 3' of the A site codon. Complexes of 80S ribosomes with the mRNA analogues were obtained in the presence of tRNAPhe that directed UUU codon to the P site and consequently provided placement of the nucleotide with cross-linker in positions +9 or +12 with respect to the first nucleotide of the P site bound codon. Both types mRNA analogues cross-linked to the 18S rRNA and 40S proteins under mild UV-irradiation. Cross-linking patterns in the complexes where modified nucleotides of the mRNA analogues were in position +7 were analyzed for comparison (cross-linking to the 18S rRNA in such complexes has been studied previously). The efficiency of cross-linking to the ribosomal components depended on the nature of the modified nucleotide in the mRNA analogue and its position on the ribosome, extent of cross-linking to the 18S rRNA being decreased drastically when the modified nucleotide was moved from position +7 to position +12. The nucleotides of 18S rRNA cross-linked to mRNA analogues were determined. Modified nucleotides in positions +9 and +12 cross-linked to the invariant dinucleotide A1824/A1825 and to variable A1823 in the 3'-minidomain of 18S rRNA as well as to protein S15. The same ribosomal components have been found earlier to cross-link to modified mRNA nucleotides in positions from +4 to +7. Besides, all mRNA analogues cross-linked to the invariant nucleotide c1698 in the 3'-minidomain and to and the conserved region 605-620 closing helix 18 in the 5'-domain.

Intestinal P-glycoprotein inhibitors, benzoxanthone analogues.

PubMed

Chae, Song Wha; Lee, Jaeok; Park, Jung Hyun; Kwon, Youngjoo; Na, Younghwa; Lee, Hwa Jeong

2018-02-01

The inhibitors of P-glycoprotein (P-gp) which limits an access of exogenous compounds in the luminal membrane of the intestine have been studied to enhance the intestinal P-gp-mediated absorption of anticancer drugs. Inhibition of the efflux pump by synthesized benzoxanthone derivatives was investigated in vitro and in vivo. MCF-7/ADR cell line was used for cytotoxicity assay and [ 3 H]-daunomycin (DNM) accumulation/efflux study. Eight benzoxanthone analogues were tested for their effects on DNM cytotoxicity. Among them, three analogues were selected for the accumulation/efflux and P-gp ATPase studies. Paclitaxel (PTX), a P-gp substrate anticancer drug, was orally administered to rats with/without compound 1 (8,10-bis(thiiran-2-ylmethoxy)-7H-benzo[c]xanthen-7-one). The pharmacokinetic parameters of PTX in the presence/absence of compound 1 were evaluated from the plasma concentration-time profiles. Compound 1 increased the DNA accumulation to 6.5-fold and decreased the DNM efflux to approximately 1/2 in the overexpressing P-gp cell line. Relative bioavailability (RB) of PTX in rats was significantly increased up to 3.2-fold by compound 1 (0.5 or 2 mg/kg). Benzoxanthone analogue, compound 1 is strongly suggested to be a promising inhibitor of P-gp to improve an oral absorption of compounds for cancer therapy. © 2017 Royal Pharmaceutical Society.

Synthetic Neurotensin Analogues Are Nontoxic Analgesics for the Rabbit Cornea

PubMed Central

Kim, Charles; Barbut, Denise; Heinemann, Murk H.; Pasternak, Gavril; Rosenblatt, Mark I.

2014-01-01

Purpose. To characterize the analgesic potency and toxicity of topical synthetic neurotensin analogues, and localize neurotensin receptors in the cornea and trigeminal ganglion. Methods. Cochet-Bonnet esthesiometry was performed on the rabbit cornea to test the analgesic dose response and duration of effect for two synthetic neurotensin analogues: NT71 and NT72. Receptors for neurotensin were localized in the murine cornea and trigeminal ganglion using quantitative PCR (qPCR), Western blotting, and immunohistochemistry. In vitro toxicity of NT71, NT72, and sodium channel blockers was evaluated using cytotoxicity, single-cell migration, and scratch closure assays performed on rabbit corneal epithelial cells. In vivo toxicity of these agents was assessed using a rabbit laser phototherapeutic keratectomy (PTK) model and histology. Results. NT71 and NT72 induced potent analgesic effects on the rabbit cornea at concentrations between 1.0 and 2.5 mg/mL, lasting up to 180 minutes. A site-specific distribution of neurotensin receptors was observed in the murine cornea and trigeminal ganglion. NT71 and NT72 did not cause any significant in vitro or in vivo toxicity, in contrast to sodium channel blockers. Conclusions. Synthetic neurotensin analogues are potent analgesics that avoid the toxicities associated with established topical analgesic agents. Receptors for neurotensin are present in both the cornea and trigeminal ganglion. PMID:24825106

Synthetic neurotensin analogues are nontoxic analgesics for the rabbit cornea.

PubMed

Kim, Charles; Barbut, Denise; Heinemann, Murk H; Pasternak, Gavril; Rosenblatt, Mark I

2014-05-13

To characterize the analgesic potency and toxicity of topical synthetic neurotensin analogues, and localize neurotensin receptors in the cornea and trigeminal ganglion. Cochet-Bonnet esthesiometry was performed on the rabbit cornea to test the analgesic dose response and duration of effect for two synthetic neurotensin analogues: NT71 and NT72. Receptors for neurotensin were localized in the murine cornea and trigeminal ganglion using quantitative PCR (qPCR), Western blotting, and immunohistochemistry. In vitro toxicity of NT71, NT72, and sodium channel blockers was evaluated using cytotoxicity, single-cell migration, and scratch closure assays performed on rabbit corneal epithelial cells. In vivo toxicity of these agents was assessed using a rabbit laser phototherapeutic keratectomy (PTK) model and histology. NT71 and NT72 induced potent analgesic effects on the rabbit cornea at concentrations between 1.0 and 2.5 mg/mL, lasting up to 180 minutes. A site-specific distribution of neurotensin receptors was observed in the murine cornea and trigeminal ganglion. NT71 and NT72 did not cause any significant in vitro or in vivo toxicity, in contrast to sodium channel blockers. Synthetic neurotensin analogues are potent analgesics that avoid the toxicities associated with established topical analgesic agents. Receptors for neurotensin are present in both the cornea and trigeminal ganglion. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Poly(propyleneimine) glycodendrimers non-covalently bind ATP in a pH- and salt-dependent manner - model studies for adenosine analogue drug delivery.

PubMed

Gorzkiewicz, Michał; Buczkowski, Adam; Appelhans, Dietmar; Voit, Brigitte; Pułaski, Łukasz; Pałecz, Bartłomiej; Klajnert-Maculewicz, Barbara

2018-06-10

Adenosine analogue drugs (such as fludarabine or cladribine) require transporter-mediated uptake into cells and subsequent phosphorylation for anticancer activity. Therefore, application of nanocarrier systems for direct delivery of active triphosphate forms has been proposed. Here, we applied isothermal titration calorimetry and zeta potential titration to determine the stoichiometry and thermodynamic parameters of interactions between 4th generation poly(propyleneimine) dendrimers (unmodified or sugar-modified for increased biocompatibility) and ATP as a model adenosine nucleotide. We showed that glycodendrimers have the ability to efficiently interact with nucleoside triphosphates and to form stable complexes via electrostatic interactions between the ionized phosphate and amino groups on the nucleotide and the dendrimer, respectively. The complexation process is spontaneous, enthalpy-driven and depends on buffer composition (strongest interactions in organic buffer) and pH (more binding sites in acidic pH). These properties allow us to consider maltose-modified dendrimers as especially promising carriers for adenosine analogues. Copyright © 2018 Elsevier B.V. All rights reserved.

Synthesis and evaluation of heterocyclic analogues of bromoxynil.

PubMed

Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

2014-01-15

One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential

Monitoring CCS Sites: Lessons Learned Studying Natural Laboratories.

NASA Astrophysics Data System (ADS)

Tartarello, M. C.; Beaubien, S. E.; Graziani, S.; Lombardi, S.; Ruggiero, L.

2016-12-01

Monitoring is one of the most important aspects of Carbon Capture and Storage (CCS), both for early recognition of leaks from the reservoir and for public safety. Natural analogues could be useful to understand the potential impact of a leakage on the local ecosystem and to develop new techniques of monitoring. These sites, called also "natural laboratories", are characterized by natural, geologically-produced CO2 constantly leaking from the seafloor or from the groundsurface. In the last 10 years, our group as partner of some EC funded projects focused on CCS (NASCENT (2000-2003), CO2GeoNet (2004-2009), CO2ReMoVe (2006-2011), RISCS (2010-2013), and ECO2 (2011-2015)), studied gas migration mechanisms in these "natural laboratories", applying near-surface geochemistry to monitoring. This method provides one of the most powerful tools to assess whether a CCS site is leaking and, if it is, to quantify that leakage. This is because rather than being a remote method that estimates amounts based on proxy associations, such as some geophysical tools, it is an exact measurement of the item of interest (in this case CO2) in the accessible biosphere where there is concern regarding its potential impact. In particular, we have been studied two sites in Italy, characterized by significant emissions of CO2, related to volcanic emissions: the Latera Caldera (in Central Italy) and the offshore emissions near Panarea Island. We combined continuous and discontinuous monitoring, structural surveys and gas flux measurements. The results show a strong correlation between fault architecture and leakage rates. Moreover, the monitoring of an area for long periods allows defining the baseline, which is the fluctuation of gas concentrations both spatially and temporally as a function of biological, chemical, geological, land-use and meteorological processes.

Metric optimisation for analogue forecasting by simulated annealing

NASA Astrophysics Data System (ADS)

Bliefernicht, J.; Bárdossy, A.

2009-04-01

It is well known that weather patterns tend to recur from time to time. This property of the atmosphere is used by analogue forecasting techniques. They have a long history in weather forecasting and there are many applications predicting hydrological variables at the local scale for different lead times. The basic idea of the technique is to identify past weather situations which are similar (analogue) to the predicted one and to take the local conditions of the analogues as forecast. But the forecast performance of the analogue method depends on user-defined criteria like the choice of the distance function and the size of the predictor domain. In this study we propose a new methodology of optimising both criteria by minimising the forecast error with simulated annealing. The performance of the methodology is demonstrated for the probability forecast of daily areal precipitation. It is compared with a traditional analogue forecasting algorithm, which is used operational as an element of a hydrological forecasting system. The study is performed for several meso-scale catchments located in the Rhine basin in Germany. The methodology is validated by a jack-knife method in a perfect prognosis framework for a period of 48 years (1958-2005). The predictor variables are derived from the NCEP/NCAR reanalysis data set. The Brier skill score and the economic value are determined to evaluate the forecast skill and value of the technique. In this presentation we will present the concept of the optimisation algorithm and the outcome of the comparison. It will be also demonstrated how a decision maker should apply a probability forecast to maximise the economic benefit from it.

Astrobiology Field Research in Moon/Mars Analogue Environments: Preface

NASA Technical Reports Server (NTRS)

Foing, B. H.; Stoker, C.; Ehrenfreund, P.

2011-01-01

Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

Non-robust numerical simulations of analogue extension experiments

NASA Astrophysics Data System (ADS)

Naliboff, John; Buiter, Susanne

2016-04-01

Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

Cross-reactivity of insulin analogues with three insulin assays.

PubMed

Dayaldasani, A; Rodríguez Espinosa, M; Ocón Sánchez, P; Pérez Valero, V

2015-05-01

Immunometric assays have recently shown higher specificity in the detection of human insulin than radioimmunoassays with almost no cross-reaction with proinsulin or C peptide. The introduction of the new insulin analogues on the market, however, has raised the need to define their cross-reactivity in these assays. Several studies have been published in this regard with different results. The analogues studied were insulins lispro, aspart, glargine, detemir, and glulisine. Insulin concentrations were measured in Immulite(®) 2000 and Advia Centaur(®) XP (Siemens Healthcare Diagnostics), and Elecsys(®) Modular Analytics E170 (Roche). All samples were processed 15 times in the same analytical run following a random sequence. Those samples which showed statistically and clinically significant changes in insulin concentration were reprocessed using increasing concentrations of analogue, and this was done twice, using two different serum pools, one with a low concentration of insulin and one with a high concentration of insulin. In the Elecsys(®) E170 analyser, glargine showed statistical changes (comparison of mean concentrations with p < 0.05) and clinically significant changes in measured insulin (percentage difference 986.2% > reference change value: 59.8%), and the interference increased with increasing concentrations of analogue; the differences were not significant in the case of the other analogues. In the Advia Centaur(®) and Immulite(®) 2000 only the results for glulisine did not present significance (percentage difference 44.7% < reference change value 103.5%). Increasing concentrations of aspart, glargine, and lispro showed increased interference in Immulite(®) 2000. In the Elecsys(®) E170 assay, relevant cross-reactivity was only detected with insulin glargine, whereas in the other analysers all analogues except glulisine showed significant interference. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Synthesis and preliminary antileukemic studies of cyclic mitoguazone analogues.

PubMed

Krezel, I; Graczyk, J

1998-03-01

Analogues of mitoguazone bearing a terminal amidino group as a part of the seven-membered ring of 1,3-diazepine and six-membered ring of pyrimidine were prepared in order to evaluate in vivo antileukemic action towards L1210 leukemia in mice. Preliminary pharmacological screening showed that the investigated compounds increase the life span (T/C%) of the treated mice in comparison with the untreated animals. The strongest antineoplastic effect was exhibited by compound 8.

Using stressful films to analyze risk factors for PTSD in analogue experimental studies--which film works best?

PubMed

Weidmann, Anke; Conradi, Ania; Groger, Kathrin; Fehm, Lydia; Fydrich, Thomas

2009-10-01

To understand mental disorders, analogue paradigms provide an indispensable contribution. In posttraumatic stress disorder (PTSD), the stressful film paradigm is a frequently used analogue approach: Films depicting traumatic events are shown to non-clinical participants in order to elicit stress responses analogue to responses to traumatic events in real life. Previous studies used a large variety of films, which is problematic with regard to the comparability of results. The main goal of this study was to identify a film clip that (a) consistently provokes stress reactions and (b) provokes reactions that are as similar as possible to traumatic stress. We randomly exposed 105 male and female participants to one of four stressful films, differing, e.g., in content and origin. Intrusive memories of the film, reported immediately after the film and during a diary phase of three days, as well as distress, heart rate, and several mood states were measured. A film clip depicting rape elicited the most consistent reactions that were characterized by a higher heart rate, more distress and more intrusive memories, compared to the other three clips. Intrusive memories across all films were especially related to an increase in heart rate and disgust in response to the film.

Computational study of the activity, dynamics, energetics and conformations of insulin analogues using molecular dynamics simulations: Application to hyperinsulinemia and the critical residue B26.

PubMed

Papaioannou, Anastasios; Kuyucak, Serdar; Kuncic, Zdenka

2017-09-01

Due to the increasing prevalence of diabetes, finding therapeutic analogues for insulin has become an urgent issue. While many experimental studies have been performed towards this end, they have limited scope to examine all aspects of the effect of a mutation. Computational studies can help to overcome these limitations, however, relatively few studies that focus on insulin analogues have been performed to date. Here, we present a comprehensive computational study of insulin analogues-three mutant insulins that have been identified with hyperinsulinemia and three mutations on the critical B26 residue that exhibit similar binding affinity to the insulin receptor-using molecular dynamics simulations with the aim of predicting how mutations of insulin affect its activity, dynamics, energetics and conformations. The time evolution of the conformers is studied in long simulations. The probability density function and potential of mean force calculations are performed on each insulin analogue to unravel the effect of mutations on the dynamics and energetics of insulin activation. Our conformational study can decrypt the key features and molecular mechanisms that are responsible for an enhanced or reduced activity of an insulin analogue. We find two key results: 1) hyperinsulinemia may be due to the drastically reduced activity (and binding affinity) of the mutant insulins. 2) Y26 B S and Y26 B E are promising therapeutic candidates for insulin as they are more active than WT-insulin. The analysis in this work can be readily applied to any set of mutations on insulin to guide development of more effective therapeutic analogues.

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues.

PubMed

Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

2017-01-01

The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening.

Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

PubMed Central

Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

2017-01-01

Background The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. Materials and methods In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. Results The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. Discussion The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening. PMID:28053504

The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.

PubMed

Pankiewicz, Krzysztof W; Watanabe, Kyoichi A; Lesiak-Watanabe, Krystyna; Goldstein, Barry M; Jayaram, Hiremagalur N

2002-04-01

Oncolytic C-nucleosides, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and benzamide riboside (3-beta-D-ribofuranosylbenzamide) are converted in cell into active metabolites thiazole-4-carboxamide- and benzamide adenine dinucleotide, TAD and BAD, respectively. TAD and BAD as NAD analogues were found to bind at the nicotinamide adenine dinucleotide (cofactor NAD) site of inosine monophosphate dehydrogenase (IMPDH), an important target in cancer treatment. The synthesis and evaluation of anticancer activity of a number of C-nucleosides related to tiazofurin and nicotinamide riboside then followed and are reviewed herein. Interestingly, pyridine C-nucleosides (such as C-nicotinamide riboside) are not metabolized into the corresponding NAD analogues in cell. Their conversion by chemical methods is described. As dinucleotides these compounds show inhibition of IMPDH in low micromolar level. Also, the synthesis of BAD in metabolically stable bis(phosphonate) form is discussed indicating the usefulness of such preformed inhibitors in drug development. Among tiazofurin analogues, Franchetti and Grifantini found, that the replacement of the sulfur by oxygen (as in oxazafurin) but not the removal of nitrogen (tiophenfurin) of the thiazole ring resulted in inactive compounds. The anti cancer activity of their synthetic dinucleotide analogues indicate that inactive compounds are not only poorly metabolized in cell but also are weak inhibitors of IMPDH as dinucleotides.

A peptidases-resistant glycosylated analogue of substance P-(5-11). Specificity towards substance P receptors.

PubMed

Poujade, C; Lavielle, S; Torrens, Y; Beaujouan, J C; Glowinski, J; Marquet, A

1984-09-01

Glycosylated analogues of the C-terminal heptapeptide of substance P either free or blocked on the N-terminal glutamine were synthesized in order to develop a metabolically stable peptide that would have an increased specificity for one type of receptor. Of the analogue described, (N-alpha-Boc-beta-D-Glc-p (1----5) Gln) -Gln-Phe-Phe-Gly-Leu-Met-NH2 is highly resistant to degradation on exposure to rat hypothalamic slices. This glycosylated peptide is about one third as potent as substance P in eliciting contractions of the guinea-pig ileum and is almost devoided of affinity for the 125I-Bolton Hunter-SP specific binding sites on rat brain synaptosomes.

Monocarbonyl curcumin analogues: heterocyclic pleiotropic kinase inhibitors that mediate anticancer properties.

PubMed

Brown, Andrew; Shi, Qi; Moore, Terry W; Yoon, Younghyoun; Prussia, Andrew; Maddox, Clinton; Liotta, Dennis C; Shim, Hyunsuk; Snyder, James P

2013-05-09

Curcumin is a biologically active component of curry powder. A structurally related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for 10 of the enzymes at 5 μM, while 22 of the proteins were blocked at ≥40%. IC50 values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogues are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways.

Surfactin analogues produced by Bacillus subtilis strains grown on rapeseed cake

NASA Astrophysics Data System (ADS)

Jajor, Paweł; Piłakowska-Pietras, Dorota; Krasowska, Anna; Łukaszewicz, Marcin

2016-12-01

Microbiologically produced surface acting compounds (biosurfactants) have very interesting properties with many potential industrial applications. Lipopeptides is a particularly promising group of biosurfactants in respect to the potentially huge number of various chemical structures. The chemical diversity results from fatty acid moiety (e.g. length, saturation, branching or hydroxylation) and type and sequence of the amino acids in the peptide chain. The limiting factor for the design and analysis of various lipopeptides is the ability of the targeted biosynthesis. Biosynthesis of particular lipopeptides may be potentially achieved by strain selection, culture conditions, or molecular engineering. The well-known lipopeptedes (surfactins, iturins, and fengycins) producer is B. subtilis. The aim of this study was to study targeted surfactin structural analogues biosynthesis in response to culture conditions in view of the design and production of tailor-made lipopeptides. Two B. subtilis strains (KB1 and #309) were tested for surfactin production. Both strains produced a mixture of five major surfactin analogues with the number of carbons in an alkyl chain ranging from 12 to 16. The two strains differed with respect to their oxygen demand for optimal surfactin biosynthesis (lower oxygen demand for KB1). The amount of air influenced the relative ratios of surfactin analogues. Lower oxygen amount decreased the share of C15 analogues while it increased the share of C12 analogues. Thus, the biosynthesis of a desired surfactin analogue may controlled by both strain and culture conditions.

Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

PubMed Central

Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

2015-01-01

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

Synthesis, antimycobacterial evaluation and pharmacophore modeling of analogues of the natural product formononetin.

PubMed

Mutai, Peggoty; Pavadai, Elumalai; Wiid, Ian; Ngwane, Andile; Baker, Bienyameen; Chibale, Kelly

2015-06-15

The synthesis and antimycobacterial activity of formononetin analogues is hereby reported. Formononetin and its analogue 11E showed 88% and 95% growth inhibition, respectively, against the H37Rv strain of Mycobacterium tuberculosis. Pharmacophore modeling studies indicated that the presence of a hydroxyl group in formononetin and its analogues, is crucial for maintaining activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

From BPA to its analogues: Is it a safe journey?

PubMed

Usman, Afia; Ahmad, Masood

2016-09-01

Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful? Copyright © 2016. Published by Elsevier Ltd.

PTAL Database and Website: Developing a Novel Information System for the Scientific Exploitation of the Planetary Terrestrial Analogues Library

NASA Astrophysics Data System (ADS)

Veneranda, M.; Negro, J. I.; Medina, J.; Rull, F.; Lantz, C.; Poulet, F.; Cousin, A.; Dypvik, H.; Hellevang, H.; Werner, S. C.

2018-04-01

The PTAL website will store multispectral analysis of samples collected from several terrestrial analogue sites and pretend to become a cornerstone tool for the scientific community interested in deepening the knowledge on Mars geological processes.

Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study.

PubMed

Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J; Guan, Lan; Byrne, Bernadette; Chae, Pil Seok

2015-05-07

Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, n-dodecyl-β-D-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation.

Systematic Review of the Cost Effectiveness of Insulin Analogues in Type 1 and Type 2 Diabetes Mellitus.

PubMed

Shafie, Asrul Akmal; Ng, Chin Hui; Tan, Yui Ping; Chaiyakunapruk, Nathorn

2017-02-01

Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required. Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses. Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin

3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor.

PubMed

Liu, Ming; He, Lin; Hu, Xiaopeng; Liu, Peiqing; Luo, Hai-Bin

2010-12-01

The nociceptin/orphanin FQ receptor (NOP) has been implicated in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have a great potential to be developed into anxiolytics. However, the crystal structure of NOP is still not available. In the present work, both structure-based and ligand-based modeling methods have been used to achieve a comprehensive understanding on 67N-substituted spiropiperidine analogues as NOP agonists. The comparative molecular-field analysis method was performed to formulate a reasonable 3D-QSAR model (cross-validated coefficient q(2)=0.819 and conventional r(2)=0.950), whose robustness and predictability were further verified by leave-eight-out, Y-randomization, and external test-set validations. The excellent performance of CoMFA to the affinity differences among these compounds was attributed to the contributions of electrostatic/hydrogen-bonding and steric/hydrophobic interactions, which was supported by the Surflex-Dock and CDOCKER molecular-docking simulations based on the 3D model of NOP built by the homology modeling method. The CoMFA contour maps and the molecular docking simulations were integrated to propose a binding mode for the spiropiperidine analogues at the binding site of NOP. Copyright © 2010 Elsevier Ltd. All rights reserved.

Study of Geological Analogues for Understanding the Radar Sounder Response of the RIME Targets

NASA Astrophysics Data System (ADS)

Thakur, S.; Bruzzone, L.

2017-12-01

Radar for Icy Moon Exploration (RIME), the radar sounder onboard the Jupiter Icy Moons Explorer (JUICE), is aimed at characterizing the ice shells of the Jovian moons - Ganymede, Europa and Callisto. RIME is optimized to operate at 9 MHz central frequency with bandwidth of 1 MHz and 2.7 MHz to achieve a penetration depth up to 9 km through ice. We have developed an approach to the definition of a database of simulated RIME radargrams by leveraging the data available from airborne and orbital radar sounder acquisitions over geological analogues of the expected icy moon features. These simulated radargrams are obtained by merging real radar sounder data with models of the subsurface of the Jupiter icy moons. They will be useful for geological interpretation of the RIME radargrams and for better predicting the performance of RIME. The database will also be useful in developing pre-processing and automatic feature extraction algorithms to support data analysis during the mission phase of RIME. Prior to the JUICE mission exploring the Jovian satellites with RIME, there exist radar sounders such as SHARAD (onboard MRO) and MARSIS (onboard MEX) probing Mars, the LRS (onboard SELENE) probing the Moon, and many airborne sounders probing the polar regions of Earth. Analogues have been identified in these places based on similarity in geo-morphological expression. Moreover, other analogues have been identified on the Earth for possible dedicated acquisition campaigns before the RIME operations. By assuming that the subsurface structure of the RIME targets is approximately represented in the analogue radargrams, the difference in composition is accounted for by imposing different dielectric and subsurface attenuation models. The RIME radargrams are simulated from the analogue radargrams using the radar equation and the RIME processing chain and accounting for different possible scenarios in terms of subsurface structure, dielectric properties and instrument parameters. For

Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents.

PubMed

Aroonkit, Pasuk; Thongsornkleeb, Charnsak; Tummatorn, Jumreang; Krajangsri, Suppachai; Mungthin, Mathirut; Ruchirawat, Somsak

2015-04-13

Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Synthesis and antioxidant activity of peptide-based ebselen analogues.

PubMed

Satheeshkumar, Kandhan; Mugesh, Govindasamy

2011-04-18

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration. Copyright �

Space analogue studies in Antarctica

NASA Technical Reports Server (NTRS)

Lugg, D.; Shepanek, M.

1999-01-01

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Space analogue studies in Antarctica

NASA Astrophysics Data System (ADS)

Lugg, D.; Shepanek, M.

1999-09-01

Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

Comparative study of the interactions between bisphenol-A and its endocrine disrupting analogues with bovine serum albumin using multi-spectroscopic and molecular docking studies.

PubMed

Ikhlas, Shoeb; Usman, Afia; Ahmad, Masood

2018-04-24

Interaction studies of bisphenol analogues; biphenol-A (BPA), bisphenol-B (BPB), and bisphenol-F (BPF) with bovine serum albumin (BSA) were performed using multi-spectroscopic and molecular docking studies at the protein level. The mechanism of binding of bisphenols with BSA was dynamic in nature. SDS refolding experiments demonstrated no stabilization of BSA structure denatured by BPB, however, BSA denatured by BPA and BPF was found to get stabilized. Also, CD spectra and molecular docking studies revealed that BPB bound more strongly and induced more conformational changes in BSA in comparison to BPA. Hence, this study throws light on the replacement of BPA by its analogues and whether the replacement is associated with a possible risk, raising a doubt that perhaps BPB is not a good substitute of BPA.

Synthesis and biological evaluation of febrifugine analogues.

PubMed

Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

2014-12-01

A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity.

Bisphenol Analogues Other Than BPA: Environmental Occurrence, Human Exposure, and Toxicity-A Review.

PubMed

Chen, Da; Kannan, Kurunthachalam; Tan, Hongli; Zheng, Zhengui; Feng, Yong-Lai; Wu, Yan; Widelka, Margaret

2016-06-07

Numerous studies have investigated the environmental occurrence, human exposure, and toxicity of bisphenol A (BPA). Following stringent regulations on the production and usage of BPA, several bisphenol analogues have been produced as a replacement for BPA in various applications. The present review outlines the current state of knowledge on the occurrence of bisphenol analogues (other than BPA) in the environment, consumer products and foodstuffs, human exposure and biomonitoring, and toxicity. Whereas BPA was still the major bisphenol analogue found in most environmental monitoring studies, BPF and BPS were also frequently detected. Elevated concentrations of BPAF, BPF, and BPS (i.e., similar to or greater than that of BPA) have been reported in the abiotic environment and human urine from some regions. Many analogues exhibit endocrine disrupting effects, cytotoxicity, genotoxicity, reproductive toxicity, dioxin-like effects, and neurotoxicity in laboratory studies. BPAF, BPB, BPF, and BPS have been shown to exhibit estrogenic and/or antiandrogenic activities similar to or even greater than that of BPA. Knowledge gaps and research needs have been identified, which include the elucidation of environmental occurrences, persistence, and fate of bisphenol analogues (other than BPA), sources and pathways for human exposure, effects on reproductive systems and the mammary gland, mechanisms of toxicity from coexposure to multiple analogues, metabolic pathways and products, and the impact of metabolic modification on toxicity.

Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9GluB27, AspB10, AspB28) in healthy subjects.

PubMed

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (AspB9GluB27, monomeric; AspB28, mixture of monomers and dimers; and AspB10, dimeric) and soluble human insulin were evaluated. Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol.kg-1 s.c. 125I-labeled AspB10 or soluble human insulin (Novolin R, Novo, Copenhagen); 1st study and 0.6 nmol.kg-1 s.c. 125I-labeled AspB28, AspB9GluB27 or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations. The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for AspB10 compared with 184 +/- 10 min for human insulin (P less than 0.001), 83 +/- 8 min for AspB28 (P less than 0.005), and 63 +/- 9 min for AspB9GluB27 (P less than 0.001) compared with 182 +/- 21 min for human insulin. delta Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P less than 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P less than 0.005). The magnitude of the hypoglycemic nadir was greater after AspB9GluB27 (P less than 0.05) and AspB28 (P less than 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P less than 0.05). The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short

Aspartame and Its Analogues

NASA Astrophysics Data System (ADS)

Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

1981-04-01

The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

Lobatamide C: total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies.

PubMed

Shen, Ruichao; Lin, Cheng Ting; Bowman, Emma Jean; Bowman, Barry J; Porco, John A

2003-07-02

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.

Mechanism of MenE Inhibition by Acyl-Adenylate Analogues and Discovery of Novel Antibacterial Agents

PubMed Central

Sharma, Indrajeet; Lavaud, Lubens J.; Ngo, Stephen C.; Shek, Roger; Rajashankar, Kanagalaghatta R.; French, Jarrod B.; Tan, Derek S.; Tonge, Peter J.

2015-01-01

MenE is an o-succinylbenzoyl-CoA (OSB-CoA) synthetase in the bacterial menaquinone biosynthesis pathway and is a promising target for the development of novel antibacterial agents. The enzyme catalyzes CoA ligation via an acyl-adenylate intermediate, and we have previously reported tight-binding inhibitors of MenE based on stable acyl-sulfonyladenosine analogues of this intermediate, including OSB-AMS (1) which has an IC50 value of ≤ 25 nM for the Escherichia coli MenE. Herein, we show that OSB-AMS reduces menaquinone levels in S. aureus, consistent with its proposed mechanism of action, despite the observation that the antibacterial activity of OSB-AMS is ~1000-fold lower than the IC50 for enzyme inhibition. To inform the synthesis of MenE inhibitors with improved antibacterial activity, we have undertaken a structure–activity relationship (SAR) study stimulated by the knowledge that OSB-AMS can adopt two isomeric forms in which the OSB side chain exists either as an open-chain keto acid or a cyclic lactol. These studies revealed that negatively charged analogues of the keto-acid form bind, while neutral analogues do not, consistent with the hypothesis that the negatively-charged keto-acid form of OSB-AMS is the active isomer. X-ray crystallography and site-directed mutagenesis confirm the importance of a conserved arginine for binding the OSB carboxylate. Although most lactol isomers tested were inactive, a novel difluoroindanediol inhibitor (11) with improved antibacterial activity was discovered, providing a pathway toward the development of optimized MenE inhibitors in the future. PMID:26394156

Mechanism of MenE inhibition by acyl-adenylate analogues and discovery of novel antibacterial agents.

PubMed

Matarlo, Joe S; Evans, Christopher E; Sharma, Indrajeet; Lavaud, Lubens J; Ngo, Stephen C; Shek, Roger; Rajashankar, Kanagalaghatta R; French, Jarrod B; Tan, Derek S; Tonge, Peter J

2015-10-27

MenE is an o-succinylbenzoyl-CoA (OSB-CoA) synthetase in the bacterial menaquinone biosynthesis pathway and is a promising target for the development of novel antibacterial agents. The enzyme catalyzes CoA ligation via an acyl-adenylate intermediate, and we have previously reported tight-binding inhibitors of MenE based on stable acyl-sulfonyladenosine analogues of this intermediate, including OSB-AMS (1), which has an IC50 value of ≤25 nM for Escherichia coli MenE. Herein, we show that OSB-AMS reduces menaquinone levels in Staphylococcus aureus, consistent with its proposed mechanism of action, despite the observation that the antibacterial activity of OSB-AMS is ∼1000-fold lower than the IC50 for enzyme inhibition. To inform the synthesis of MenE inhibitors with improved antibacterial activity, we have undertaken a structure-activity relationship (SAR) study stimulated by the knowledge that OSB-AMS can adopt two isomeric forms in which the OSB side chain exists either as an open-chain keto acid or a cyclic lactol. These studies revealed that negatively charged analogues of the keto acid form bind, while neutral analogues do not, consistent with the hypothesis that the negatively charged keto acid form of OSB-AMS is the active isomer. X-ray crystallography and site-directed mutagenesis confirm the importance of a conserved arginine for binding the OSB carboxylate. Although most lactol isomers tested were inactive, a novel difluoroindanediol inhibitor (11) with improved antibacterial activity was discovered, providing a pathway toward the development of optimized MenE inhibitors in the future.

Restoration of estuarine wetlands via "managed realignment": the use of natural analogues.

NASA Astrophysics Data System (ADS)

Cundy, A.

2003-04-01

A proposed management response to rising sea-levels for low-relief coastal areas is the managed-realignment approach, where existing coastal defences are repositioned landward, and protective wetlands allowed to develop on the abandoned land. This technique has been applied with varying degrees of success at a number of coastal sites, and, in the U.K. at least, its use is increasing as coastal management authorities move away from hard engineering approaches towards more "natural" coastal and floodplain management. Studies of the response of low-lying coastal areas to the managed-realignment approach, and the subsequent restoration of intertidal wetlands, have tended to rely on short-term (< 5 years) studies of erosion and accretion, vegetation change, and changes in sediment chemistry. While the short-term response to breaching is important, it is essential to complement these studies with an understanding of the medium-term (decadal) response of low-lying coasts to sudden inundation to allow effective site selection and management. This medium-term response may be assessed using sedimentary and geomorphological studies at coastal sites which have been historically breached and flooded, which provide natural analogues for the managed realignment process. This paper illustrates this approach using data from two contrasting sites in southern England (Pagham Harbour and part of the Hamble estuary), which were flooded in the early 20th century following breaching of flood defences. Sediments at both sites retain a record of environmental change following marine inundation, and sedimentary studies, combined with documentary evidence, have been used to examine post-breaching marsh stability, variations in sediment accumulation rate, and vegetation colonisation and dieback over varying timescales. Historically-breached sites such as Pagham Harbour and the Hamble estuary are relatively common around European coasts, and these provide important natural laboratories within

Inhibitory Effects of Lysine Analogues on t-PA Induced Whole Blood Clot Lysis

DTIC Science & Technology

1994-01-01

aminocaproic acid (EACA) and trans-4-amino- methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with... aminocaproic acid (EACA) and the others have lower affinity binding sites (K&=5 mM) (5). The lysine analogues EACA and trans-4-aniinomethyl...JL, Wissler FC. Quantitative determination of the binding of epsilon- aminocaproic acid to native plasminogen. J Biol Chem 253, 727-732, 1978. 6

Structural Analogues of Selfotel.

PubMed

Dziuganowska, Zofia A; Ślepokura, Katarzyna; Volle, Jean-Noël; Virieux, David; Pirat, Jean-Luc; Kafarski, Paweł

2016-06-17

A small library of phosphonopiperidylcarboxylic acids, analogues of NMDA antagonist selfotel (CGS 19755), was synthesized. First, the series of aromatic esters was obtained via a palladium-catalyzed cross-coupling reaction (Hirao coupling) of dialkyl phosphites with bromopyridinecarboxylates, followed by their hydrolysis. Then, hydrogenation of the resulting phosphonopyridylcarboxylic acids over PtO2 yielded the desired phosphonopiperidylcarboxylic acids. NMR studies indicated that the hydrogenation reaction proceeds predominantly by cis addition. Several compounds were obtained as monocrystal structures. Preliminary biological studies performed on cultures of neurons suggest that the obtained compounds possess promising activity toward NMDA receptors.

Rheological and physical characteristics of crustal-scaled materials for centrifuge analogue modelling

NASA Astrophysics Data System (ADS)

Waffle, Lindsay; Godin, Laurent; Harris, Lyal B.; Kontopoulou, M.

2016-05-01

We characterize a set of analogue materials used for centrifuge analogue modelling simulating deformation at different levels in the crust simultaneously. Specifically, we improve the rheological characterization in the linear viscoelastic region of materials for the lower and middle crust, and cohesive synthetic sands without petroleum-binding agents for the upper crust. Viscoelastic materials used in centrifuge analogue modelling demonstrate complex dynamic behaviour, so viscosity alone is insufficient to determine if a material will be an effective analogue. Two series of experiments were conducted using an oscillating bi-conical plate rheometer to measure the storage and loss moduli and complex viscosities of several modelling clays and silicone putties. Tested materials exhibited viscoelastic and shear-thinning behaviour. The silicone putties and some modelling clays demonstrated viscous-dominant behaviour and reached Newtonian plateaus at strain rates < 0.5 × 10-2 s-1, while other modelling clays demonstrated elastic-dominant power-law relationships. Based on these results, the elastic-dominant modelling clay is recommended as an analogue for basement cratons. Inherently cohesive synthetic sands produce fine-detailed fault and fracture patterns, and developed thrust, strike-slip, and extensional faults in simple centrifuge test models. These synthetic sands are recommended as analogues for the brittle upper crust. These new results increase the accuracy of scaling analogue models to prototype. Additionally, with the characterization of three new materials, we propose a complete lithospheric profile of analogue materials for centrifuge modelling, allowing future studies to replicate a broader range of crustal deformation behaviours.

Ring size of somatostatin analogues (ODT-8) modulates receptor selectivity and binding affinity

PubMed Central

Erchegyi, Judit; Grace, Christy Rani R.; Samant, Manoj; Cescato, Renzo; Piccand, Veronique; Riek, Roland; Reubi, Jean Claude; Rivier, Jean E.

2009-01-01

The synthesis, biological testing and NMR studies of several analogues of H-c[Cys3-Phe6-Phe7-dTrp8-Lys9-Thr10-Phe11-Cys14]-OH (ODT-8, a pan-somatostatin analogue) (1), have been performed to assess the effect of changing the stereochemistry and the number of the atoms in the disulfide bridge on binding affinity. Cysteine at positions 3 and/or 14 (SRIF numbering) were/was substituted with d-cysteine, Nor-cysteine, d-Nor-cysteine, Homo-cysteine and/or d-Homo-cysteine. The 3D structures of selected partially selective, bioactive analogues (3, 18, 19 and 21) were carried out in DMSO. Interestingly and not unexpectedly, the 3D structures of these analogues comprised the pharmacophore for which the analogues had the highest binding affinities (i.e., sst4 in all cases). PMID:18410084

Maltose Neopentyl Glycol-3 (MNG-3) Analogues for Membrane Protein Study

PubMed Central

Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J.; Guan, Lan; Byrne, Bernadette

2015-01-01

Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayer and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs behaved superior to a conventional detergent, n–dodecyl–β–D–maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation. PMID:25813698

Flexibility of rapid-acting insulin analogues in children and adolescents with diabetes mellitus.

PubMed

Danne, Thomas

2007-01-01

Every year, approximately 70,000 children aged<15 years develop type 1 diabetes mellitus (DM) worldwide. Achieving glycosylated hemoglobin control is a very important aim, but quality-of-life concerns for the child and the family should also have high priority in the management of pediatric DM. This review outlines some of the issues involved in treating type 1 DM in children and adolescents, as well as the use of rapid-acting insulin analogues in basal-bolus therapy and continuous subcutaneous insulin infusion pumps. This review article was based on a presentation at a satellite symposium entitled "Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues "that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Treating children and adolescents with DM is a challenge that should not be ignored. Furthermore, DM in children is quite different from that in adults. Numerous factors have to be taken into account when evaluating treatment for children with DM in comparison with treatment for adult DM: sleep patterns; unpredictable activities, especially eating behaviors; limited size of injection sites, making it difficult to rotate injections; higher insulin sensitivity; and frequent infectious diseases. In addition, achieving normal psychosocial development may be just as important as achieving strict metabolic control in this population. Rapid-acting insulin analogues can be used effectively in these individuals with type 1 DM. The pharmacokinetic profile of insulin aspart suggests that it is suitable for flexible mealtime administration in children and adolescents. Indeed, clinical studies in children and adolescents have shown the efficacy and tolerability of postprandial administration of insulin aspart, particularly in comparison with soluble human insulin. Postprandial administration of insulin aspart, compared with preprandial soluble human insulin, has also been studied in

The anti-inflammatory activity of dillapiole and some semisynthetic analogues.

PubMed

Parise-Filho, Roberto; Pastrello, Michelli; Pereira Camerlingo, Carla Emygdio; Silva, Gisele Juni; Agostinho, Leonardo Aguiar; de Souza, Thaís; Motter Magri, Fátima Maria; Ribeiro, Roberto Rodrigues; Brandt, Carlos Alberto; Polli, Michelle Carneiro

2011-11-01

Piper aduncum L. (Piperaceae) produces an essential oil (dillapiole) with great exploitative potential and it has proven effects against traditional cultures of phytopathogens, such as fungi, bacteria and mollusks, as well as analgesic action with low levels of toxicity. This study investigated the in vivo anti-inflammatory activity of dillapiole. Furthermore, in order to elucidate its structure-anti-inflammatory activity relationship (SAR), semisynthetic analogues were proposed by using the molecular simplification strategy. Dillapiole and safrole were isolated and purified using column chromatography. The semisynthetic analogues were obtained by using simple organic reactions, such as catalytic reduction and isomerization. All the analogues were purified by column chromatography and characterized by (1)H and (13)C NMR. The anti-inflammatory activities of dillapiole and its analogues were studied in carrageenan-induced rat paw edema model. Dillapiole and di-hydrodillapiole significantly (p<0.05) inhibited rat paw edema. All the other substances tested, including safrole, were less powerful inhibitors with activities inferior to that of indomethacin. These findings showed that dillapiole and di-hydrodillapiole have moderate anti-phlogistic properties, indicating that they can be used as prototypes for newer anti-inflammatory compounds. Structure-activity relationship studies revealed that the benzodioxole ring is important for biological activity as well as the alkyl groups in the side chain and the methoxy groups in the aromatic ring.

5'-Phosphorothiolate Dinucleotide Cap Analogues: Reagents for Messenger RNA Modification and Potent Small-Molecular Inhibitors of Decapping Enzymes.

PubMed

Wojtczak, Blazej A; Sikorski, Pawel J; Fac-Dabrowska, Kaja; Nowicka, Anna; Warminski, Marcin; Kubacka, Dorota; Nowak, Elzbieta; Nowotny, Marcin; Kowalska, Joanna; Jemielity, Jacek

2018-05-09

The 5' cap consists of 7-methylguanosine (m 7 G) linked by a 5'-5'-triphosphate bridge to messenger RNA (mRNA) and acts as the master regulator of mRNA turnover and translation initiation in eukaryotes. Cap analogues that influence mRNA translation and turnover (either as small molecules or as part of an RNA transcript) are valuable tools for studying gene expression, which is often also of therapeutic relevance. Here, we synthesized a series of 15 dinucleotide cap (m 7 GpppG) analogues containing a 5'-phosphorothiolate (5'-PSL) moiety (i.e., an O-to-S substitution within the 5'-phosphoester) and studied their biological properties in the context of three major cap-binding proteins: translation initiation factor 4E (eIF4E) and two decapping enzymes, DcpS and Dcp2. While the 5'-PSL moiety was neutral or slightly stabilizing for cap interactions with eIF4E, it significantly influenced susceptibility to decapping. Replacing the γ-phosphoester with the 5'-PSL moiety (γ-PSL) prevented β-γ-pyrophosphate bond cleavage by DcpS and conferred strong inhibitory properties. Combining the γ-PSL moiety with α-PSL and β-phosphorothioate (PS) moiety afforded first cap-derived hDcpS inhibitor with low nanomolar potency. Susceptibility to Dcp2 and translational properties were studied after incorporation of the new analogues into mRNA transcripts by RNA polymerase. Transcripts containing the γ-PSL moiety were resistant to cleavage by Dcp2. Surprisingly, superior translational properties were observed for mRNAs containing the α-PSL moiety, which were Dcp2-susceptible. The overall protein expression measured in HeLa cells for this mRNA was comparable to mRNA capped with the translation augmenting β-PS analogue reported previously. Overall, our study highlights 5'-PSL as a synthetically accessible cap modification, which, depending on the substitution site, can either reduce susceptibility to decapping or confer superior translational properties on the mRNA. The 5'-PSL-analogues

A computational study of open-chain epothilone analogue

NASA Astrophysics Data System (ADS)

Kamel, Karol; Rusinska-Roszak, Danuta

Molecular mechanics (MM/Ambers) calculations were applied to probe the conformational profile of open-chain epothilone analogue [Org Lett 2006, 8, 685], cytotoxic against some cell lines. Geometries of the most stable conformers were optimized at DFT level using the B3LYP functional and then compared to known both experimental and virtual conformers of epothilone. One of the most stable structures is III (1.47 kcal/mol above global minimum) which represents high similarity to the appropriate fragment of the Taylor's model of epothilone A, but two other conformers: XIV and XX, although they have almost the same conformation as the mother structure, are very unstable (6.7 and 12.4 kcal/mol above the global minimum).0

NMR studies of multiple conformations in complexes of Lactobacillus casei dihydrofolate reductase with analogues of pyrimethamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Birdsall, B.; Tendler, S.J.B.; Feeney, J.

1990-10-01

{sup 1}H and {sup 19}F NMR signals from bound ligands have been assigned in one- and two-dimensional NMR spectra of complexes of Lactobacillus casei dihydrofolate reductase with various pyrimethamine analogues. The signals were identified mainly by correlating signals from bound and free ligands by using 2D exchange experiments. Analogues with symmetrically substituted phenyl rings give rise to {sup 1}H signals from four nonequivalent aromatic protons, clearly indicating the presence of hindered rotation about the pyrimidine-phenyl bond. Analogues with symmetrically substituted phenyl rings give rise to {sup 1}H signals from four nonequivalent aromatic protons, clearly indicating the presence of hindered rotationmore » about the pyrimidine-phenyl bond. Analogues containing asymmetrically substituted aromatic rings exist as mixtures of two rotational isomers (an enantiomeric pair) because of this hindered rotation and the NMR spectra revealed that both isomers (forms A and B) bind to the enzyme with comparable, though unequal, binding energies. In this case two complete sets of bound proton signals were observed. The relative orientations of the two forms have been determined from NOE through-space connections between protons on the ligand and protein. Ternary complexes with NADP{sup {plus}} were also examined.« less

Uncovering mass segregation with galaxy analogues in dark-matter simulations

NASA Astrophysics Data System (ADS)

Joshi, Gandhali D.; Parker, Laura C.; Wadsley, James

2016-10-01

We investigate mass segregation in group and cluster environments by identifying galaxy analogues in high-resolution dark-matter simulations. Subhaloes identified by the Amiga's Halo Finder (AHF) and ROCKSTAR halo finders have similar mass functions, independent of resolution, but different radial distributions due to significantly different subhalo hierarchies. We propose a simple way to classify subhaloes as galaxy analogues. The radial distributions of galaxy analogues agree well at large halocentric radii for both AHF and ROCKSTAR but disagree near parent halo centres where the phase-space information used by ROCKSTAR is essential. We see clear mass segregation at small radii (within 0.5 rvir) with average galaxy analogue mass decreasing with radius. Beyond the virial radius, we find a mild trend where the average galaxy analogue mass increases with radius. These mass segregation trends are strongest in small groups and dominated by the segregation of low-mass analogues. The lack of mass segregation in massive galaxy analogues suggests that the observed trends are driven by the complex accretion histories of the parent haloes rather than dynamical friction.

Making Connections in Math: Activating a Prior Knowledge Analogue Matters for Learning

ERIC Educational Resources Information Center

Sidney, Pooja G.; Alibali, Martha W.

2015-01-01

This study investigated analogical transfer of conceptual structure from a prior-knowledge domain to support learning in a new domain of mathematics: division by fractions. Before a procedural lesson on division by fractions, fifth and sixth graders practiced with a surface analogue (other operations on fractions) or a structural analogue (whole…

Comparison of medication adherence in diabetes mellitus patients on human versus analogue insulins.

PubMed

Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro; Echeverri-Cataño, Luis Felipe

2017-02-01

Objetive: This study evaluated the results of treatment adherence scales in two cohorts of patients with diabetes mellitus treated either with human or analogue insulins. A cohort study was conducted in diabetes mellitus patients older than 18 that were being treated with human or analogue insulins. Two instruments were applied to each patient [medication possession ratio, Morisky-Green test] to evaluate treatment adherence. A total of 238 patients, were included. The majority (69.4%) of the subjects had human insulin and 30.6% had insulin analogue prescriptions. Out of the total, 163 (68.5%) cases were classified as adherent to therapy, according to the type of insulin, as follows: 69.9% for conventional and 65.3% for analogues; without differences between the groups (CI95%:0.450-1.458). The adherence to treatment was more probable in patients with elementary-secondary education (OR:2.341; CI95%:1.199-4.568) and less probable for those in the age range of 31-45 years (OR:0.427; CI95%:0.187-0.971). The results of this study show that there are no significant statistical differences in adherence when comparing human with analogue insulin therapy. Strategies to improve treatment adherence are particularly important since they improve the clinical results.

How Analogue Research Can Advance Descriptive Evaluation Theory: Understanding (and Improving) Stakeholder Dialogue

ERIC Educational Resources Information Center

Campbell, Bernadette; Mark, Melvin M.

2015-01-01

Evaluation theories can be tested in various ways. One approach, the experimental analogue study, is described and illustrated in this article. The approach is presented as a method worthy to use in the pursuit of what Alkin and others have called descriptive evaluation theory. Drawing on analogue studies conducted by the first author, we…

New AdoMet Analogues as Tools for Enzymatic Transfer of Photo-Cross-Linkers and Capturing RNA-Protein Interactions.

PubMed

Muttach, Fabian; Mäsing, Florian; Studer, Armido; Rentmeister, Andrea

2017-05-02

Elucidation of biomolecular interactions is of utmost importance in biochemistry. Photo-cross-linking offers the possibility to precisely determine RNA-protein interactions. However, despite the inherent specificity of enzymes, approaches for site-specific introduction of photo-cross-linking moieties into nucleic acids are scarce. Methyltransferases in combination with synthetic analogues of their natural cosubstrate S-adenosyl-l-methionine (AdoMet) allow for the post-synthetic site-specific modification of biomolecules. We report on three novel AdoMet analogues bearing the most widespread photo-cross-linking moieties (aryl azide, diazirine, and benzophenone). We show that these photo-cross-linkers can be enzymatically transferred to the methyltransferase target, that is, the mRNA cap, with high efficiency. Photo-cross-linking of the resulting modified mRNAs with the cap interacting protein eIF4E was successful with aryl azide and diazirine but not benzophenone, reflecting the affinity of the modified 5' caps. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conformationally restrained aromatic analogues of fosmidomycin and FR900098.

PubMed

Kurz, Thomas; Schlüter, Katrin; Pein, Miriam; Behrendt, Christoph; Bergmann, Bärbel; Walter, Rolf D

2007-07-01

The synthesis and in-vitro antimalarial activity of conformationally restrained bis(pivaloyloxymethyl) ester analogues of the natural product fosmidomycin is presented. In contrast to alpha-aryl-substituted analogues, conformationally restrained aromatic analogues exhibit only moderate in-vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The most active derivative displays an IC(50) value of 47 microM.

Evaluation of meteorites as habitats for terrestrial microorganisms: Results from the Nullarbor Plain, Australia, a Mars analogue site

NASA Astrophysics Data System (ADS)

Tait, Alastair W.; Wilson, Siobhan A.; Tomkins, Andrew G.; Gagen, Emma J.; Fallon, Stewart J.; Southam, Gordon

2017-10-01

Unambiguous identification of biosignatures on Mars requires access to well-characterized, long-lasting geochemical standards at the planet's surface that can be modified by theoretical martian life. Ordinary chondrites, which are ancient meteorites that commonly fall to the surface of Mars and Earth, have well-characterized, narrow ranges in trace element and isotope geochemistry compared to martian rocks. Given that their mineralogy is more attractive to known chemolithotrophic life than the basaltic rocks that dominate the martian surface, exogenic rocks (e.g., chondritic meteorites) may be good places to look for signs of prior life endemic to Mars. In this study, we show that ordinary chondrites, collected from the arid Australian Nullarbor Plain, are commonly colonized and inhabited by terrestrial microorganisms that are endemic to this Mars analogue site. These terrestrial endolithic and chasmolithic microbial contaminants are commonly found in close association with hygroscopic veins of gypsum and Mg-calcite, which have formed within cracks penetrating deep into the meteorites. Terrestrial bacteria are observed within corrosion cavities, where troilite (FeS) oxidation has produced jarosite [KFe3(SO4)2(OH)6]. Where terrestrial microorganisms have colonized primary silicate minerals and secondary calcite, these mineral surfaces are heavily etched. Our results show that inhabitation of meteorites by terrestrial microorganisms in arid environments relies upon humidity and pH regulation by minerals. Furthermore, microbial colonization affects the weathering of meteorites and production of sulfate, carbonate, Fe-oxide and smectite minerals that can preserve chemical and isotopic biosignatures for thousands to millions of years on Earth. Meteorites are thus habitable by terrestrial microorganisms, even under highly desiccating environmental conditions of relevance to Mars. They may therefore be useful as chemical and isotopic ;standards; that preserve evidence of

Transport characteristics of endomorphin-2 analogues in brain capillary endothelial cells.

PubMed

Mallareddy, Jayapal Reddy; Tóth, Géza; Fazakas, Csilla; Molnár, Judit; Nagyőszi, Péter; Lipkowski, Andrzej W; Krizbai, István A; Wilhelm, Imola

2012-04-01

Because of their poor metabolic stability and limited blood-brain barrier permeability, endomorphins have a low analgesic efficacy when administered systemically. Therefore, it is of great importance to design analogues with improved peptidase resistance and better delivery to the central nervous system. Recently, novel endomorphin-2 analogues have been synthesized, which proved to bind with high affinity and selectivity to the μ-opioid receptors and showed proteolytic resistance. In this study, we have analysed the transport characteristics of endomorphin-2 and three of its analogues [Dmt-Pro-Phe-Phe-NH(2) , Tyr-(1S,2R)Acpc-Phe-Phe-NH(2) and Tyr-(1S,2R)Achc-Phe-Phe-NH(2) ] using an in vitro blood-brain barrier model. The lipophilicity of the analogues, as assessed by their octanol/water partition coefficients, was higher than that of endomorphin-2. The flux of all four peptides from the apical (blood) side to the basolateral (brain) side was not saturable in the 10nm-1mm concentration range, suggesting that a passive mechanism plays a major role in their transport. The permeability coefficient of the analogues was significantly higher than that of endomorphin-2, suggesting increased blood-brain barrier penetration properties. We conclude that because of their good peptidase resistance and improved transport through brain endothelial cells, these endomorphin-2 analogues will have better analgesic properties in vivo. © 2011 John Wiley & Sons A/S.

Synthesis and biological evaluation of Santacruzamate-A based analogues.

PubMed

Randino, Rosario; Gazzerro, Patrizia; Mazitschek, Ralph; Rodriquez, Manuela

2017-12-15

Several derivatives of Santacruzamate-A, a natural product that is structurally related to SAHA, were synthesized to explore the potential of carbamates and oxalylamides as novel biasing element for targeting the catalytic site of zinc-dependent histone deacetylases (HDACs). An additional class of Santacruzamate-A derivatives was synthesized to investigate the influence of the cap group and the linker element on HDAC inhibitory activity. All compounds were evaluated in dose response for their in vitro cytotoxic activity in MTT assay in HCT116 cells. HDAC inhibitory activity was evaluated in vitro by western blot analysis for histone hyperacetylation assay and biochemically for representative human HDACs isoforms. Two novel compounds were identified to exhibit potent time dependent anti proliferative activity. However, unlike hydroxamic acid analogues, the tested Santacruzamate-A derivatives showed no noticeable HDAC inhibitory activity. The ethylcarbamate moiety as unusual zinc-binding group displayed no ability to coordinate the zinc ion and thus, presumably, was not able to reproduce known inhibitor-substrate zinc-binding group interactions with the HDAC catalytic site. This study confirmed that the accommodation of the zinc-binding group is deeply critical of the positioning of the linker and the projection of the cap group toward the different surface pockets of the enzyme. Copyright © 2017 Elsevier Ltd. All rights reserved.

U.S. Nuclear Regulatory Commission natural analogue research program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kovach, L.A.; Ott, W.R.

1995-09-01

This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

Using Geothermal Play Types as an Analogue for Estimating Potential Resource Size

DOE Office of Scientific and Technical Information (OSTI.GOV)

Terry, Rachel; Young, Katherine

Blind geothermal systems are becoming increasingly common as more geothermal fields are developed. Geothermal development is known to have high risk in the early stages of a project development because reservoir characteristics are relatively unknown until wells are drilled. Play types (or occurrence models) categorize potential geothermal fields into groups based on geologic characteristics. To aid in lowering exploration risk, these groups' reservoir characteristics can be used as analogues in new site exploration. The play type schemes used in this paper were Moeck and Beardsmore play types (Moeck et al. 2014) and Brophy occurrence models (Brophy et al. 2011). Operatingmore » geothermal fields throughout the world were classified based on their associated play type, and then reservoir characteristics data were catalogued. The distributions of these characteristics were plotted in histograms to develop probability density functions for each individual characteristic. The probability density functions can be used as input analogues in Monte Carlo estimations of resource potential for similar play types in early exploration phases. A spreadsheet model was created to estimate resource potential in undeveloped fields. The user can choose to input their own values for each reservoir characteristic or choose to use the probability distribution functions provided from the selected play type. This paper also addresses the United States Geological Survey's 1978 and 2008 assessment of geothermal resources by comparing their estimated values to reported values from post-site development. Information from the collected data was used in the comparison for thirty developed sites in the United States. No significant trends or suggestions for methodologies could be made by the comparison.« less

Invariom based electron density studies on the C/Si analogues haloperidol/sila-haloperidol and venlafaxine/sila-venlafaxine.

PubMed

Luger, Peter; Dittrich, Birger; Tacke, Reinhold

2015-09-14

The subjects of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1a·HCl), haloperidol hydropicrate (1a·HPic) and sila-haloperidol hydrochloride (1b·HCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2a·HCl; as orthorhombic (2a·HCl-ortho) and monoclinic polymorph (2a·HCl-mono)) and sila-venlafaxine hydrochloride (2b·HCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader's quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues.

The effects of the phyllolitorin analogue [desTrp3,Leu8]phyllolitorin on scratching induced by bombesin and related peptides in rats

PubMed Central

Johnson, Mark D.; Ko, Mei-Chuan; Choo, Kevin S.; Traynor, John R.; Mosberg, Henry I.; Naughton, Norah N.; Woods, James H.

2010-01-01

Bombesin along with several closely related neuropeptides elicit scratching behavior when administered centrally. The first part of the study was designed to determine the antagonistic effects of a novel phyllolitorin analogue wdesTrp3,Leu8]phyllolitorin (DTP) on scratching induced by three peptides (bombesin, neuromedin-C, and [Leu8]phyllolitorin). In addition, the binding affinity of each peptide for the bombesin receptor site was determined. DTP (30 μg) inhibited scratching induced by these peptides, but unlike the peptides, DTP had no affinity for the bombesin site, thereby suggesting that DTP is displaying physiological antagonism through an unknown mechanism. PMID:10482814

Novel nicotine analogues with potential anti-mycobacterial activity.

PubMed

Gandhi, Paresh T; Athmaram, Thimmasandra Narayanappa; Arunkumar, Gundaiah Ramesh

2016-04-15

Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Harmony of computational quantum chemistry and experimental chemistry: Comprehensive DFT studies, microsynthesis, and characterization of mustard gas polysulfide analogues

NASA Astrophysics Data System (ADS)

Saeidian, Hamid; Faraz, Sajjad Mousavi; Mirjafary, Zohreh; Babri, Mehran

2018-05-01

After microsynthesis, structures of mustard gas polysulfide analogues were characterized using electron impact (EI) mass spectrometry. General EI fragmentation pathways for such compounds are proposed. The structure of sulfur mustard (HD) and its two other polysulfide analogues have been examined through B3LYP/6-311++G(2d, 2p) calculations. Geometrical analysis of HD shows that the calculated bond distances are satisfactorily comparable with experimental results. Calculated NMR chemical shifts for HD also were compared with experimental data, indicating good agreement both for 1H and 13C atoms. The vibrational frequencies of HD and polysulfide analogues have been precisely assigned. At the end, based on visual inspection of lowest unoccupied molecular orbitals and the relative difference in the total energies of their episulfonium ions, relative reactivity of HD and its polysulfide analogues were investigated.

mRNA 3' of the A site bound codon is located close to protein S3 on the human 80S ribosome.

PubMed

Molotkov, Maxim V; Graifer, Dmitri M; Popugaeva, Elena A; Bulygin, Konstantin N; Meschaninova, Maria I; Ven'yaminova, Aliya G; Karpova, Galina G

2006-07-01

Ribosomal proteins neighboring the mRNA downstream of the codon bound at the decoding site of human 80S ribosomes were identified using three sets of mRNA analogues that contained a UUU triplet at the 5' terminus and a perfluorophenylazide cross-linker at guanosine, adenosine or uridine residues placed at various locations 3' of this triplet. The positions of modified mRNA nucleotides on the ribosome were governed by tRNA(Phe) cognate to the UUU triplet targeted to the P site. Upon mild UV-irradiation, the mRNA analogues cross-linked preferentially to the 40S subunit, to the proteins and to a lesser extent to the 18S rRNA. Cross-linked nucleotides of 18S rRNA were identified previously. In the present study, it is shown that among the proteins the main target for cross-linking with all the mRNA analogues tested was protein S3 (homologous to prokaryotic S3, S3p); minor cross-linking to protein S2 (S5p) was also detected. Both proteins cross-linked to mRNA analogues in the ternary complexes as well as in the binary complexes (without tRNA). In the ternary complexes protein S15 (S19p) also cross-linked, the yield of the cross-link decreased significantly when the modified nucleotide moved from position +5 to position +12 with respect to the first nucleotide of the P site bound codon. In several ternary complexes minor cross-linking to protein S30 was likewise detected. The results of this study indicate that S3 is a key protein at the mRNA binding site neighboring mRNA downstream of the codon at the decoding site in the human ribosome.

Aminopropyl carbazole analogues as potent enhancers of neurogenesis.

PubMed

Yoon, Hye Jin; Kong, Sun-Young; Park, Min-Hye; Cho, Yongsung; Kim, Sung-Eun; Shin, Jae-Yeon; Jung, Sunghye; Lee, Jiyoun; Farhanullah; Kim, Hyun-Jung; Lee, Jeewoo

2013-11-15

Neural stem cells are multipotent and self-renewing cells that can differentiate into new neurons and hold great promise for treating various neurological disorders including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Small molecules that can trigger neurogenesis and neuroprotection are particularly useful not only because of their therapeutic implications but also because they can provide an invaluable tool to study the mechanisms of neurogenesis. In this report, we have developed and screened 25 aminopropyl carbazole derivatives that can enhance neurogenesis of cultured neural stem cells. Among these analogues, compound 9 demonstrated an excellent proneurogenic and neuroprotective activity with no apparent toxicity. We believe that compound 9 can serve as an excellent lead to develop various analogues and to study the underlying mechanisms of neurogenesis. Copyright © 2013 Elsevier Ltd. All rights reserved.

Insulin analogues with improved absorption characteristics.

PubMed

Brange, J; Hansen, J F; Langkjaer, L; Markussen, J; Ribel, U; Sørensen, A R

1992-01-01

The insulin preparations available today are not ideal for therapy as s.c. injection does not provide a physiological insulin profile. With the aim to improve the absorption properties recombinant DNA technology has been utilized to design novel insulin molecules with changed physico-chemical characteristics and hence altered subcutaneous absorption kinetics. Soluble, long-acting human insulin analogues in which the isoelectric point has been increased from 5.4 to approx. 7 are absorbed very slowly, providing a more constant basal insulin delivery with lower day-to-day variation than present protracted preparations. In addition they have better storage stability. Rapid-acting human insulin analogues with largely reduced self-association are absorbed substantially faster from subcutaneous tissue than current regular insulin and thus are better suited for bolus injection. The absorption kinetics of these analogues have been able to explain the mechanism behind the dose effect on insulin absorption rate.

Photoaffinity labelling of the ATP-binding site of the epidermal growth factor-dependent protein kinase.

PubMed

Kudlow, J E; Leung, Y

1984-06-15

Epidermal growth factor (EGF), after binding to its receptor, activates a tyrosine-specific protein kinase which phosphorylates several substrates, including the EGF receptor itself. The effects of a photoaffinity analogue of ATP, 3'-O-(3-[N-(4-azido-2-nitrophenyl)amino]propionyl)adenosine 5'-triphosphate (arylazido-beta-alanyl-ATP) on the EGF-dependent protein kinase in A431 human tumour cell plasma membrane vesicles was investigated. This analogue was capable of inactivating the EGF-receptor kinase in a photodependent manner. Partial inactivation occurred at an analogue concentration of 1 microM and complete inactivation occurred at 10 microM when a 2 min light exposure was used. Arylazido-beta-alanine at 100 microM and ATP at 100 microM were incapable of inactivating the enzyme with 2 min of light exposure. The photodependent inactivation of the enzyme by the analogue could be partially blocked by 20 mM-ATP and more effectively blocked by either 20 mM-adenosine 5'-[beta gamma-imido]triphosphate or 20 mM-guanosine 5'-[beta gamma-imido]triphosphate, indicating nucleotide-binding site specificity. Arylazido-beta-alanyl-[alpha-32P]ATP was capable of labelling membrane proteins in a photodependent manner. Numerous proteins were labelled, the most prominent of which ran with an apparent Mr of 53000 on polyacrylamide-gel electrophoresis. A band of minor intensity was seen of Mr corresponding to the EGF receptor (170000). Immunoprecipitation of affinity-labelled and solubilized membranes with an anti-(EGF receptor) monoclonal antibody demonstrated that the Mr 170000 receptor protein was photoaffinity labelled by the analogue. The Mr 53000 peptide was not specifically bound by the anti-receptor antibody. The affinity labelling of the receptor was not enhanced by EGF, suggesting that EGF stimulation of the kinase activity does not result from changes in the affinity of the kinase for ATP. These studies demonstrate that arylazido-beta-alanyl-ATP interacts with the ATP

Imaging, biodistribution and therapy potential of halogenated tamoxifen analogues.

PubMed

Yang, D J; Li, C; Kuang, L R; Price, J E; Buzdar, A U; Tansey, W; Cherif, A; Gretzer, M; Kim, E E; Wallace, S

1994-01-01

Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

Fetal bovine serum influences the stability and bioactivity of resveratrol analogues: A polyphenol-protein interaction approach.

PubMed

Tang, Fen; Xie, Yixi; Cao, Hui; Yang, Hua; Chen, Xiaoqing; Xiao, Jianbo

2017-03-15

Fetal bovine serum (FBS) is a universal growth supplement of cell and tissue culture media. Herein, the influences of FBS on the stability and antioxidant activity of 21 resveratrol analogues were investigated using a polyphenol-protein interaction approach. The structure-stability relationships of resveratrol analogues in FBS showed a clear decrease in the stability of hydroxylated resveratrol analogues in the order: resorcinol-type>pyrogallol-type>catechol-type. The glycosylation and methoxylation of resveratrol analogues enhanced their stability. A linear relationship between the stability of resveratrol analogues in FBS and the affinity of resveratrol analogues-FBS interaction was found. The oxidation process is not the only factor governing the stability of resveratrol analogues in FBS. These results facilitated the insightful investigation of the role of polyphenol-protein interactions in serum, thereby providing some fundamental clues for future clinical research and pharmacological studies on natural small molecules. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

PubMed

Satishkumar, Sakilam; Vuram, Prasanna K; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J; Montemayor, Michelle M Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K

2015-10-09

Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

PubMed

Segal, Meirav; Fischer, Bilha

2012-02-28

Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

Variation of Geochemical Signatures and Correlation of Biomarkers in Icelandic Mars Analogue Environments

NASA Astrophysics Data System (ADS)

Gentry, D.; Amador, E. S.; Cable, M. L.; Cantrell, T.; Chaudry, N.; Cullen, T.; Duca, Z. A.; Jacobsen, M. B.; McCaig, H. C.; Murukesan, G.; Rennie, V.; Schwieterman, E. W.; Stevens, A. H.; Tan, G.; Yin, C.; Stockton, A.; Cullen, D.; Geppert, W.

2015-12-01

Exploration missions to Mars rely on rovers to perform deep analyses over small sampling areas; however, landing site selection is done using large-scale but low-resolution remote sensing data. Using Earth analogue environments to estimate the small-scale spatial and temporal distributions of key geochemical signatures and (for habitability studies) biomarkers helps ensure that the chosen sampling strategies meet mission science goals. We conducted two rounds of analogue expeditions to recent Icelandic lava fields. In July 2013, we tested correlation between three common biomarker assays: cell quantification via fluorescence microscopy, ATP quantification via bioluminescence, and quantitative PCR with universal primer sets. Sample sites were nested at four spatial scales (1 m, 10 m, 100 m, and > 1 km) and homogeneous at 'remote imaging' resolution (overall temperature, apparent moisture content, and regolith grain size). All spatial scales were highly diverse in ATP, bacterial 16S, and archaeal 16S DNA content; nearly half of sites were statistically different in ATP content at α = 0.05. Cell counts showed significant variation at the 10 m and 100 m scale; at the > 1 km scale, the mean counts were not distinguishable, but the median counts were, indicating differences in underlying distribution. Fungal 18S DNA content similarly varied at 1 m, 10 m, and 100 m scales only. Cell counts were not correlated with ATP or DNA content at any scale. ATP concentration and DNA content for all three primer sets were positively correlated. Bacterial DNA content was positively correlated with archaeal and fungal DNA content, though archaeal correlation was weak. Fungal and archaeal correlation was borderline. In July 2015, we repeated the sampling strategy, with the addition of a smaller-scale sampling grid of 10 cm and a third > 1 km location. This expedition also measured reflectance of the tephra cover and preserved mineral samples for future Raman spectroscopy in order to

Synthesis of the biologically active natural product cyclodepsipeptides apratoxin A and its analogues.

PubMed

Doi, Takayuki

2014-01-01

This paper describes the synthetic studies conducted on a marine natural product, cyclodepsipeptide apratoxin A. Total synthesis of the oxazoline analogue of apratoxin A was achieved. The conversion of oxazoline to thioamide, as well as thioamide formation from a serine-derived compound, were both unsuccessful. However, thiazoline formation from a cysteine-derived compound led to the total synthesis of apratoxin A. An in vivo study on synthetic apratoxin A revealed that it has potent antitumor activity, but with significant toxicity. Solid-phase synthesis of apratoxin A was accomplished using a preformed thiazoline derivative as a coupling unit. This method was used to synthesize several azido-containing analogues as precursors of molecular probes, and these analogues exhibited potent biological activity.

Chromophoric Nucleoside Analogues: Synthesis and Characterization of 6-Aminouracil-Based Nucleodyes.

PubMed

Freeman, Noam S; Moore, Curtis E; Wilhelmsson, L Marcus; Tor, Yitzhak

2016-06-03

Nucleodyes, visibly colored chromophoric nucleoside analogues, are reported. Design criteria are outlined and the syntheses of cytidine and uridine azo dye analogues derived from 6-aminouracil are described. Structural analysis shows that the nucleodyes are sound structural analogues of their native nucleoside counterparts, and photophysical studies demonstrate that the nucleodyes are sensitive to microenvironmental changes. Quantum chemical calculations are presented as a valuable complementary tool for the design of strongly absorbing nucleodyes, which overlap with the emission of known fluorophores. Förster critical distance (R0) calculations determine that the nucleodyes make good FRET pairs with both 2-aminopurine (2AP) and pyrrolocytosine (PyC). Additionally, unique tautomerization features exhibited by 5-(4-nitrophenylazo)-6-oxocytidine (8) are visualized by an extraordinary crystal structure.

5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nichols, D.E.; Johnson, M.P.; Oberlender, R.

1991-01-01

A rigid analogue, 5-iodo-2-aminoindan (5-IAI), of the serotonin neurotoxic halogenated amphetamine p-iodoamphetamine (PIA) was pharmacologically evaluated for production of serotonin neurotoxicity. A comparison was also made between 5-IAI and PIA in the two-lever drug discrimination paradigm in rats trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA) or saline from the alpha-ethyl homologue of MDMA, MBDB. PIA and 5-IAI were both behaviorally active, and fully substituted in both groups of animals, but were considerably less potent than p-chloroamphetamine (PCA). PIA had about twice the potency of PCA as an inhibitor of {sup 3}H-5-HT uptake in rat brain cortical synaptosomes, while 5-IAI wasmore » only about 75% as potent as PCA in this assay. A single 40 mg/kg dose of PIA resulted in a 40% reduction of 5-HT and 5-HIAA levels and in the number of 5-HT uptake sites in rat cortex at one week sacrifice. The same dose of 5-IAI with one week sacrifice led to about a 15% decrease in 5-HIAA levels and number of 5-HT uptake sites, but only the latter was statistically significant. In rat hippocampus, PIA gave significant decreases in all serotonin markers examined, while 5-IAI slightly but significantly decreased only 5-HT levels. Neither compound produced any change in catecholamine or catecholamine metabolite levels. The results confirm earlier reports of the selective serotonin neurotoxicity of PIA, which is less severe than that of PCA, and also demonstrate that its rigid analogue 5-IAI does not appear to cause significant serotonin deficits in the rat.« less

[Ocular Surface Evaluation in Patients Treated with Prostaglandin Analogues Considering Preservative Agent].

PubMed

Mlčáková, E; Mlčák, P; Karhanová, M; Langová, K; Marešová, K

The aim of this study was to evaluate the ocular surface in patients treated with prostaglandin analogues considering contained preservative agent. 60 patients with glaucoma or ocular hypertension treated with prostaglandin analogue monotherapy were enrolled in this observational study. 20 patients with glaucoma suspect or ocular hypertension without local or systemic glaucoma medication formed the control group. Demographic data and medical history were recorded for each participant. Patients filled in the Ocular surface disease index© (OSDI) questionnaire and underwent an ophthalmological examination including assessment of conjunctival hyperaemia according to Efron, tear film break up time (BUT) and fluorescein staining according to the Oxford grading scheme. Treated participants were divided into 3 groups according to the preservative contained in the currently used prostaglandin analogue: the preservative-free group (18 patients), the polyquaternium group (17 patients) and the benzalkonium chloride (BAK) group (25 patients). The control group had significantly lower fluorescein staining than the preservative-free group (p=0.001), the polyquaternium group (p=0.007) and the BAK group (p=0.002). The conjunctival hyperaemia was significantly lower in the preservative-free group compared to the polyquaternium group (p=0.011). There was no significant difference among the other groups. The difference neither in the OSDI score nor in the BUT was statistically important. This study confirmed that the ocular surface is worse in patients treated with prostaglandin analogue monotherapy than in people without glaucoma medication. A significant difference among treated patients depending on a preservative agent was not proved.Key words: benzalkonium chloride, glaucoma, ocular surface disease, preservatives, prostaglandin analogues.

Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent.

PubMed

Cochrane, Rachel V K; Sanichar, Randy; Lambkin, Gareth R; Reiz, Béla; Xu, Wei; Tang, Yi; Vederas, John C

2016-01-11

The antimalarial agent cladosporin is a nanomolar inhibitor of the Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood- and liver-stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it is biosynthesized by a highly reducing (HR) and a non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analogue indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. Advanced-intermediate analogues were synthesized and incorporated by Cla3 to furnish new cladosporin analogues. A putative lysyl-tRNA synthetase resistance gene was identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-activity relationship of tryptamine analogues on the heart of venus mercenaria

PubMed Central

Greenberg, M. J.

1960-01-01

A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor. ImagesFIG. 7 PMID:13708259

In vitro and in vivo potency of insulin analogues designed for clinical use.

PubMed

Vølund, A; Brange, J; Drejer, K; Jensen, I; Markussen, J; Ribel, U; Sørensen, A R; Schlichtkrull, J

1991-11-01

Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.

Cholecystokinin octapeptide analogues stable to brain proteolysis.

PubMed

Knight, M; Barone, P; Tamminga, C A; Steardo, L; Chase, T N

1985-01-01

Based on recent findings identifying the initial degradative cleavage of CCK-8 at the Met3-Gly4 bond by a metalloendopeptidase, two analogues of CCK-8 with D-Ala and D-Trp substitutions at the Gly4 position were synthesized as stable analogues. Their stability to proteolysis by brain membranes and their binding potency at central CCK receptors were quantified. Both peptides are stable to degradation by peptidases in cortical synaptic membrane preparations. The analogues are nearly equipotent to CCK-8 in their affinities for inhibition of 125I-CCK-33 binding to guinea pig cortical membranes. L-Ala and L-Trp substituted peptides were synthesized for comparison. Both these peptides are degraded by synaptic membranes and the L-Trp substituted peptide possesses a greatly reduced affinity for central CCK receptors. Therefore, the structure of CCK due to the D conformation of Gly is more capable of interacting with brain CCK receptors. Further conformational analysis will establish whether the stabilized structure is a beta-bend or a beta-turn. Since these peptides are highly potent and stable to brain proteolysis they may be useful as stable CCK analogues for in vivo application.

Biological activity of silylated amino acid containing substance P analogues.

PubMed

Cavelier, F; Marchand, D; Martinez, J; Sagan, S

2004-03-01

The need to replace natural amino acids in peptides with nonproteinogenic counterparts to obtain new medicinal agents has stimulated a great deal of innovation on synthetic methods. Here, we report the incorporation of non-natural silylated amino acids in substance P (SP), the binding affinity for the two hNK-1 binding sites and, the potency to stimulate phospholipase C (PLC) and adenylate cyclase of the resulting peptide. We also assess the improvement of their stability towards enzyme degradation. Altogether, we found that replacing glycine with silaproline (Sip) in position 9 of SP leads to a potent analogue exhibiting an increased resistance to angiotensin-converting enzyme hydrolysis.

Conformational analysis of compstatin analogues with molecular dynamics simulations in explicit water.

PubMed

Tamamis, Phanourios; Skourtis, Spiros S; Morikis, Dimitrios; Lambris, John D; Archontis, Georgios

2007-09-01

The cyclic 13-residue peptide compstatin is a potential therapeutic agent against the unregulated activation of the complement system. A thorough knowledge of its structural and dynamical properties in solution may assist the design of improved complement inhibitors. NMR studies have suggested that the 5-8 segment of free compstatin folds into a critical for activity 5-8 beta turn and the rest of the peptide is mainly disordered. Earlier computational studies of compstatin analogues with a polar-hydrogen/generalized-Born approximation reproduced the 5-8 turn, but also indicated the formation of beta-hairpin or alpha-helical elements and the existence of interactions between certain charged or aromatic sidechains. However, these features are absent or partly present in the NMR spectra, due to extensive conformational averaging. In order to check the compstatin properties with a more rigorous model of the intra- and intermolecular interactions, we conduct here 98-ns all-atom/explicit-water simulations of three compstatin analogues with variable activity; a native analogue, the more active mutant V4W/H9A and the inactive mutant Q5G. The 5-8 beta-turn population is in good accord with NMR. For the systems studied here, the simulations suggest that the 5-8 turn population does not correlate strictly with activity, in agreement with earlier mutational studies. Furthermore, they show structural differences among the analogues outside the 5-8 region. The possible role of these differences in activity is discussed. The probability of beta-hairpin or alpha-helix elements is much smaller with respect to the polar-hydrogen/GB simulations, and the persistent Trp4-Trp7 or Asp6-Arg11 sidechain interactions of the earlier GB studies are not reproduced. The present simulations extend the NMR data and improve our understanding of the properties of compstatin and related analogues.

3D-QSAR studies on the inhibitory activity of trimethoprim analogues against Escherichia coli dihydrofolate reductase.

PubMed

Vijayaraj, Ramadoss; Devi, Mekapothula Lakshmi Vasavi; Subramanian, Venkatesan; Chattaraj, Pratim Kumar

2012-06-01

Three-dimensional quantitative structure activity relationship (3D-QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4-diamino-5-(substituted-benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. To construct highly predictive 3D-QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models show statistically significant cross-validated and non-cross-validated correlation coefficient of r2 CV and r2 nCV, respectively. The final 3D-QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the substitution of electronegative groups at the first and second position along with electropositive group at the third position of R2 substitution significantly increases the potency of the derivatives. The results obtained from the CoMFA and CoMSIA study delineate the substituents on the trimethoprim analogues responsible for the enhanced potency and also provide valuable directions for the design of new trimethoprim analogues with improved affinity. © 2012 John Wiley & Sons A/S.

Behavior of a fluorescent analogue of calmodulin in living 3T3 cells.

PubMed

Luby-Phelps, K; Lanni, F; Taylor, D L

1985-10-01

with intracellular components with a range of affinities. The mobility of LRB-CM in the cytoplasm was sensitive to treatment of the cells with trifluoperazine, which suggests that at least some of the intracellular binding sites are specific for calmodulin in the calcium-bound form. FRAP of LRB-CM in the nuclei of living 3T3 cells indicated that the analogue was highly mobile within the nucleus but entered the nucleus from the cytoplasm much more slowly than fluorescein isothiocyanate-dextran of comparable molecular size and much more slowly than predicted from its mobility in cytoplasm.

Behavior of a fluorescent analogue of calmodulin in living 3T3 cells

PubMed Central

1985-01-01

interacts with intracellular components with a range of affinities. The mobility of LRB-CM in the cytoplasm was sensitive to treatment of the cells with trifluoperazine, which suggests that at least some of the intracellular binding sites are specific for calmodulin in the calcium-bound form. FRAP of LRB-CM in the nuclei of living 3T3 cells indicated that the analogue was highly mobile within the nucleus but entered the nucleus from the cytoplasm much more slowly than fluorescein isothiocyanate-dextran of comparable molecular size and much more slowly than predicted from its mobility in cytoplasm. PMID:4044638

Ab initio study of the binding of Trichostatin A (TSA) in the active site of histone deacetylase like protein (HDLP).

PubMed

Vanommeslaeghe, Kenno; Van Alsenoy, Christian; De Proft, Frank; Martins, José C; Tourwé, Dirk; Geerlings, Paul

2003-08-21

Histone deacetylase (HDAC) inhibitors have recently attracted considerable interest because of their therapeutic potential for the treatment of cell proliferative diseases. An X-ray structure of a very potent inhibitor, Trichostatin A (TSA), bound to HDLP (an HDAC analogue isolated from Aquifex aeolicus), is available. From this structure, an active site model (322 atoms), relevant for the binding of TSA and structural analogues, has been derived, and TSA has been minimized in this active site at HF 3-21G* level. The resulting conformation is in excellent accordance with the X-ray structure, and indicates a deprotonation of the hydroxamic acid in TSA by His 131. Also, a water molecule was minimized in the active site. In addition to a similar deprotonation, in accordance with a possible catalytic mechanism of HDAC as proposed by Finnin et al. (M. S. Finnin, J. R. Donigian, A. Cohen, V. M. Richon, R. A. Rifkind and P. A. Marks, Nature, 1999, 401, 188-193), a displacement of the resulting OH- ion in the active site was observed. Based on these results, the difference in energy of binding between TSA and water was calculated. The resulting value is realistic in respect to experimental binding affinities. Furthermore, the mechanism of action of the His 131-Asp 166 charge relay system was investigated. Although the Asp residue in this motif is known to substantially increase the basicity of the His residue, no proton transfer from His 131 to Asp 166 was observed on binding of TSA or water. However, in the empty protonated active site, this proton transfer does occur.

The discovery of a novel antagonist - Manduca sexta allatotropin analogue - as an insect midgut active ion transport inhibitor.

PubMed

Deng, Xi-le; Kai, Zhen-Peng; Chamberlin, Mary E; Horodyski, Frank M; Yang, Xin-Ling

2016-11-01

The midgut is an important site for both nutrient absorption and ionic regulation in lepidopteran larvae, major pests in agriculture. The larval lepidopteran midgut has become a potent insecticide target over the past few decades. Recent studies have shown that an insect neuropeptide, Manduca sexta allatotropin (Manse-AT), exhibits inhibition of active ion transport (AIT) across the larval midgut epithelium. The full characteristic of the AIT inhibition capacity of Manse-AT is essential to assay. In this study, AIT inhibition across the M. sexta midgut by Manse-AT and its analogues in a range of concentrations was assayed. The structure-activity relationship of Manse-AT was also studied by truncated and alanine-replacement strategies. Our results identified three residues, Thr4, Arg6 and Phe8, as the most important components for activity on the midgut. Replacement of Glu1, Met2 and Met3 reduced the potency of the analogues. The conservative substitution of Gly7 with alanine had little effect on the potency of the analogues. We demonstrated for the first time that Manse-AT (10-13) behaves as a potent antagonist in vitro on active ion transport across the epithelium of the posterior midgut in M. sexta. Structure-activity studies of Manse-AT are useful in developing lead compounds for the design and testing of synthetic antagonists, ultimately to develop potent and specific pest control strategies. Manse-AT (10-13) has been discovered as the first Manse-AT antagonist, with a significant effect and a short sequence compared with other insect neuropeptides. It may be a new potential pest control agent in the future. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Occurrence and profiles of bisphenol analogues in municipal sewage sludge in China.

PubMed

Song, Shanjun; Song, Maoyong; Zeng, Luzhe; Wang, Thanh; Liu, Runzeng; Ruan, Ting; Jiang, Guibin

2014-03-01

Extensive use of bisphenol A and its analogues has caused increasing concern over the potential adverse health impacts of these chemicals. In this study, the presence and profiles of 13 bisphenols (BPs) were investigated in 52 municipal sewage sludge samples collected from 30 cities in China. Tetrabromobisphenol A was the most frequently observed analogue (geometric mean: 20.5 ng/g dw). Bisphenol A (4.69 ng/g dw), bisphenol S (3.02 ng/g dw), and bisphenol F (3.84 ng/g dw) were found with similar frequency. Other BP analogues such as tetrachlorobisphenol A, bisphenol AF, bisphenol E, and dihydroxybiphenyl were identified for the first time in sewage sludge in China. Significant correlations were found among BP concentrations, but no relationships were found with wastewater treatment plant characteristics. Profiles of the relative estradiol equivalents suggested that the estrogenic potential of BP mixtures may be associated with the occurrence and contributions of specific analogues. Copyright © 2013 Elsevier Ltd. All rights reserved.

Computer-aided rational design of novel EBF analogues with an aromatic ring.

PubMed

Wang, Shanshan; Sun, Yufeng; Du, Shaoqing; Qin, Yaoguo; Duan, Hongxia; Yang, Xinling

2016-06-01

Odorant binding proteins (OBPs) are important in insect olfactory recognition. These proteins bind specifically to insect semiochemicals and induce their seeking, mating, and alarm behaviors. Molecular docking and molecular dynamics simulations were performed to provide computational insight into the interaction mode between AgamOBP7 and novel (E)-β-farnesene (EBF) analogues with an aromatic ring. The ligand-binding cavity in OBP7 was found to be mostly hydrophobic due to the presence of several nonpolar residues. The interactions between the EBF analogues and the hydrophobic residues in the binding cavity increased in strength as the distance between them decreased. The EBF analogues with an N-methyl formamide or ester linkage had higher docking scores than those with an amide linkage. Moreover, delocalized π-π and electrostatic interactions were found to contribute significantly to the binding between the ligand benzene ring and nearby protein residues. To design new compounds with higher activity, four EBF analogues D1-D4 with a benzene ring were synthesized and evaluated based on their docking scores and binding affinities. D2, which had an N-methyl formamide group linkage, exhibited stronger binding than D1, which had an amide linkage. D4 exhibited particularly strong binding due to multiple hydrophobic interactions with the protein. This study provides crucial foundations for designing novel EBF analogues based on the OBP structure. Graphical abstract The design strategy of new EBF analogues based on the OBP7 structure.

Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calamini, Barbara; Santarsiero, Bernard D.; Boutin, Jean A.

Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certainmore » cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 {angstrom} (1 {angstrom} = 0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K{sub i} = 7.2 {mu}M) and uncompetitive against menadione (K{sub i} = 92 {mu}M), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2.« less

An assessment of soil-to-plant concentration ratios for some natural analogues of the transuranic elements.

PubMed

Linsalata, P; Morse, R S; Ford, H; Eisenbud, M; Franca, E P; de Castro, M B; Lobao, N; Sachett, I; Carlos, M

1989-01-01

A field study was conducted in an area of enhanced, natural radioactivity to assess the soil to edible vegetable concentration ratios (CR = concentration in dry vegetable/concentration in dry soil) of 232Th, 230Th, 226Ra, 228Ra, and the light rare earth elements (REE's) La, Ce and Nd. Twenty-nine soil and 42 vegetable samples consisting of relatively equal numbers of seven varieties were obtained from 11 farms on the Pocos de Caldas Plateau in the state of Minas Gerais, Brazil. This region is the site of a major natural analogue study to assess the mobilization and retardation processes affecting Th and the REE's at the Morro do Ferro ore body and U series radionuclides at a nearby open pit U mine. Thorium (IV) serves as a chemical analogue for quadrivalent Pu and the light REE's (III) as chemical analogues for trivalent Am and Cm. The geometric mean CR's (all times 10(-4] decreased as 228Ra (148) greater than 226Ra (76) greater than La (5.4) greater than Nd (3.0) = Ce (2.6) greater than 232Th (0.6), or simply as M (II) greater than M (III) greater than M (IV). These differences may reflect the relative availability of these metals for plant uptake. Significant differences were found in the CR's (for any given analyte) among many of the vegetables sampled. The CR's for the different analytes were also highly correlated. The reasons for the correlations in CR's seen among elements with such diverse chemistries as Ra-REE or Ra-Th are not clear but are apparently related to the essential mineral requirements or mineral status of the different vegetables sampled. This conclusion is based on the significant correlations obtained between the Ca content of the dried vegetables and the CR's for all of the elements studied.

Circular dichroism study of the interaction between mutagens and bilirubin bound to different binding sites of serum albumins

NASA Astrophysics Data System (ADS)

Orlov, Sergey; Goncharova, Iryna; Urbanová, Marie

Although recent investigations have shown that bilirubin not only has a negative role in the organism but also exhibits significant antimutagenic properties, the mechanisms of interactions between bilirubin and mutagens are not clear. In this study, interaction between bilirubin bound to different binding sites of mammalian serum albumins with structural analogues of the mutagens 2-aminofluorene, 2,7-diaminofluorene and mutagen 2,4,7-trinitrofluorenone were investigated by circular dichroism and absorption spectroscopy. Homological human and bovine serum albumins were used as chiral matrices, which preferentially bind different conformers of bilirubin in the primary binding sites and make it observable by circular dichroism. These molecular systems approximated a real system for the study of mutagens in blood serum. Differences between the interaction of bilirubin bound to primary and to secondary binding sites of serum albumins with mutagens were shown. For bilirubin bound to secondary binding sites with low affinity, partial displacement and the formation of self-associates were observed in all studied mutagens. The associates of bilirubin bound to primary binding sites of serum albumins are formed with 2-aminofluorene and 2,4,7-trinitrofluorenone. It was proposed that 2,7-diaminofluorene does not interact with bilirubin bound to primary sites of human and bovine serum albumins due to the spatial hindrance of the albumins binding domains. The spatial arrangement of the bilirubin bound to serum albumin along with the studied mutagens was modelled using ligand docking, which revealed a possibility of an arrangement of the both bilirubin and 2-aminofluorene and 2,4,7-trinitrofluorenone in the primary binding site of human serum albumin.

Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

PubMed

Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

2017-01-01

3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT 2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT 2a,b,c and NE α2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT 2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT 2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC 50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT 2a,c receptors as compared to MDMA.

The role of safety signals in fear extinction: An analogue study.

PubMed

Restrepo-Castro, Juan C; Castro-Camacho, Leonidas; Javier Labrador, Francisco

2017-12-01

Safety signals are conditioned inhibitory stimuli that indicate the absence of unconditioned stimuli. It is not clear whether the presence of safety signals is detrimental or beneficial in extinction-based interventions. The purpose of this study was to evaluate the effect of safety signals on autonomic and expectancy fear-related responses. Following the conditional discrimination paradigm (AX +, BX-), undergraduate students (N = 48) underwent an aversive conditioning procedure, while safety signals were experimentally created. Participants were randomly assigned to one of two conditions during extinction: presence or absence of safety signals. Significant reductions of fear-related responses were found in both groups. Expectancy measures showed that the presence of safety signals did not interfere with reduction of fear related responses at follow-up. The analogue nature of the study affects its ecological validity. There are some methodological issues. Safety signals did not interfere with extinction learning. Attention may be a mechanism associated with the maintenance of fear responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Combining molecular docking and QSAR studies for modeling the anti-tyrosinase activity of aromatic heterocycle thiosemicarbazone analogues

NASA Astrophysics Data System (ADS)

Dong, Huanhuan; Liu, Jing; Liu, Xiaoru; Yu, Yanying; Cao, Shuwen

2018-01-01

A collection of thirty-six aromatic heterocycle thiosemicarbazone analogues presented a broad span of anti-tyrosinase activities were designed and obtained. A robust and reliable two-dimensional quantitative structure-activity relationship model, as evidenced by the high q2 and r2 values (0.848 and 0.893, respectively), was gained based on the analogues to predict the quantitative chemical-biological relationship and the new modifier direction. Inhibitory activities of the compounds were found to greatly depend on molecular shape and orbital energy. Substituents brought out large ovality and high highest-occupied molecular orbital energy values helped to improve the activity of these analogues. The molecular docking results provided visual evidence for QSAR analysis and inhibition mechanism. Based on these, two novel tyrosinase inhibitors O04 and O05 with predicted IC50 of 0.5384 and 0.8752 nM were designed and suggested for further research.

Human versus animal: contrasting decomposition dynamics of mammalian analogues in experimental taphonomy.

PubMed

Stokes, Kathryn L; Forbes, Shari L; Tibbett, Mark

2013-05-01

Taphonomic studies regularly employ animal analogues for human decomposition due to ethical restrictions relating to the use of human tissue. However, the validity of using animal analogues in soil decomposition studies is still questioned. This study compared the decomposition of skeletal muscle tissues (SMTs) from human (Homo sapiens), pork (Sus scrofa), beef (Bos taurus), and lamb (Ovis aries) interred in soil microcosms. Fixed interval samples were collected from the SMT for microbial activity and mass tissue loss determination; samples were also taken from the underlying soil for pH, electrical conductivity, and nutrient (potassium, phosphate, ammonium, and nitrate) analysis. The overall patterns of nutrient fluxes and chemical changes in nonhuman SMT and the underlying soil followed that of human SMT. Ovine tissue was the most similar to human tissue in many of the measured parameters. Although no single analogue was a precise predictor of human decomposition in soil, all models offered close approximations in decomposition dynamics. © 2013 American Academy of Forensic Sciences.

Analogues to features and processes of a high-level radioactive waste repository proposed for Yucca Mountain, Nevada

USGS Publications Warehouse

Simmons, Ardyth M.; Stuckless, John S.; with a Foreword by Abraham Van Luik, U.S. Department of Energy

2010-01-01

Natural analogues are defined for this report as naturally occurring or anthropogenic systems in which processes similar to those expected to occur in a nuclear waste repository are thought to have taken place over time periods of decades to millennia and on spatial scales as much as tens of kilometers. Analogues provide an important temporal and spatial dimension that cannot be tested by laboratory or field-scale experiments. Analogues provide one of the multiple lines of evidence intended to increase confidence in the safe geologic disposal of high-level radioactive waste. Although the work in this report was completed specifically for Yucca Mountain, Nevada, as the proposed geologic repository for high-level radioactive waste under the U.S. Nuclear Waste Policy Act, the applicability of the science, analyses, and interpretations is not limited to a specific site. Natural and anthropogenic analogues have provided and can continue to provide value in understanding features and processes of importance across a wide variety of topics in addressing the challenges of geologic isolation of radioactive waste and also as a contribution to scientific investigations unrelated to waste disposal. Isolation of radioactive waste at a mined geologic repository would be through a combination of natural features and engineered barriers. In this report we examine analogues to many of the various components of the Yucca Mountain system, including the preservation of materials in unsaturated environments, flow of water through unsaturated volcanic tuff, seepage into repository drifts, repository drift stability, stability and alteration of waste forms and components of the engineered barrier system, and transport of radionuclides through unsaturated and saturated rock zones.

Role of circulation in European heatwaves using flow analogues

NASA Astrophysics Data System (ADS)

Jézéquel, Aglaé; Yiou, Pascal; Radanovics, Sabine

2018-02-01

The intensity of European heatwaves is connected to specific synoptic atmospheric circulation. Given the relatively small number of observations, estimates of the connection between the circulation and temperature require ad hoc statistical methods. This can be achieved through the use of analogue methods, which allow to determine a distribution of temperature conditioned to the circulation. The computation of analogues depends on a few parameters. In this article, we evaluate the influence of the variable representing the circulation, the size of the domain of computation, the length of the dataset, and the number of analogues on the reconstituted temperature anomalies. We tested the sensitivity of the reconstitution of temperature to these parameters for four emblematic recent heatwaves: June 2003, August 2003, July 2006 and July 2015. The paper provides general guidelines for the use of flow analogues to investigate European summer heatwaves. We found that Z500 is better suited than SLP to simulate temperature anomalies, and that rather small domains lead to better reconstitutions. The dataset length has an important influence on the uncertainty. We conclude by a set of recommendations for an optimal use of analogues to probe European heatwaves.

Esterified Trehalose Analogues Protect Mammalian Cells from Heat Shock.

PubMed

Bragg, Jack T; D'Ambrosio, Hannah K; Smith, Timothy J; Gorka, Caroline A; Khan, Faraz A; Rose, Joshua T; Rouff, Andrew J; Fu, Terence S; Bisnett, Brittany J; Boyce, Michael; Khetan, Sudhir; Paulick, Margot G

2017-09-19

Trehalose is a disaccharide produced by many organisms to better enable them to survive environmental stresses, including heat, cold, desiccation, and reactive oxygen species. Mammalian cells do not naturally biosynthesize trehalose; however, when introduced into mammalian cells, trehalose provides protection from damage associated with freezing and drying. One of the major difficulties in using trehalose as a cellular protectant for mammalian cells is the delivery of this disaccharide into the intracellular environment; mammalian cell membranes are impermeable to the hydrophilic sugar trehalose. A panel of cell-permeable trehalose analogues, in which the hydrophilic hydroxyl groups of trehalose are masked as esters, have been synthesized and the ability of these analogues to load trehalose into mammalian cells has been evaluated. Two of these analogues deliver millimolar concentrations of free trehalose into a variety of mammalian cells. Critically, Jurkat cells incubated with these analogues show improved survival after heat shock, relative to untreated Jurkat cells. The method reported herein thus paves the way for the use of esterified analogues of trehalose as a facile means to deliver high concentrations of trehalose into mammalian cells for use as a cellular protectant. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of glutamate-104 in generating a transition state analogue inhibitor at the active site of cytidine deaminase.

PubMed

Carlow, D C; Short, S A; Wolfenden, R

1996-01-23

The 19F-NMR resonance of 5-[19F]fluoropyrimidin-2-one ribonucleoside moves upfield when it is bound by wild-type cytidine deaminase from Escherichia coli, in agreement with UV and X-ray spectroscopic indications that this inhibitor is bound as the rate 3,4-hydrated species 5-fluoro-3,4-dihydrouridine, a transition state analogue inhibitor resembling an intermediate in direct water attack on 5-fluorocytidine. Comparison of pKa values of model compounds indicates that the equilibrium constant for 3,4-hydration of this inhibitor in free solution is 3.5 x 10(-4) M, so that the corrected dissociation constant of 5-fluoro-3,4-dihydrouridine from the wild-type enzyme is 3.9 x 10(-11) M. Very different behavior is observed for a mutant enzyme in which alanine replaces Glu-104 at the active site, and kcat has been reduced by a factor of 10(8). 5-[19F]Fluoropyrimidin-2-one ribonucleoside is strongly fluorescent, making it possible to observe that the mutant enzyme binds this inhibitor even more tightly (Kd = 4.4 x 10(-8) M) than does the native enzyme (Kd = 1.1 x 10(-7) M). 19F-NMR indicates, however, that the E104A mutant enzyme binds the inhibitor without modification, in a form that resembles the substrate in the ground state. These results are consistent with a major role for Glu-104, not only in stabilizing the ES++ complex in the transition state, but also in destabilizing the ES complex in the ground state.

Rapid actions of calcitriol and its side chain analogues CB1093 and GS1500 on intracellular calcium levels in skeletal muscle cells: a comparative study

PubMed Central

Vazquez, Guillermo; Sellés, Juana; de Boland, Ana Russo; Boland, Ricardo

1999-01-01

The ability of synthetic analogues of the secosteroid hormone 1α,25-dihydroxy-vitamin-D3 [calcitriol, CT; 1,25(OH)2D3] to exert non-genomic (rapid) effects on target cells has been scarcely studied. To evaluate the pharmacological potential of the CT side-chain analogues CB1093 and GS1500, we compared their fast effects on intracellular calcium concentration ([Ca2+]i) in chick skeletal muscle cells with those elicited by the natural hormone.Both analogues, similarly to CT, specifically induced rapid (30–60 s) and sustained rises in [Ca2+]i levels. CB1093 and GS1500 were more potent than the natural hormone at concentrations as low as 10−13 M (4.5 fold stimulation) and 10−12 M (2.5 fold), respectively, whereas higher concentrations (10−9–10−8 M) of CT were more effective than the analogues in elevating [Ca2+]i. Cyclic AMP was markedly increased by both analogues pointing for a role of this messenger in the fast actions of the synthetic compounds.In Ca2+ free medium CT and analogues elicited a transient elevation in [Ca2+]i. The PLC inhibitors U73122 (2 μM) and neomycin (0.5 mM), as well as depletion of intracellular stores with thapsigargin (1 μM), completely prevented CB1093/GS1500-dependent changes in [Ca2+]i suggesting that, similarly to CT, these analogues mobilized Ca2+ from an IP3/thapsigargin-sensitive store.The voltage-dependent calcium channel (VDCC) blocker nifedipine (2 μM) reduced by 50–60% the influx phase of the [Ca2+]i response to CB1093 and GS1500, indicating that VDCC contributed partially to Ca2+ entry. The Ca2+ readdition protocol suggested that analogue-dependent activation of a SOC entry pathway accounted, to the same extent as for CT, for the remaining non-VDCC mediated Ca2+ influx. PMID:10372825

Interval-level measurement with visual analogue scales in Internet-based research: VAS Generator.

PubMed

Reips, Ulf-Dietrich; Funke, Frederik

2008-08-01

The present article describes VAS Generator (www.vasgenerator.net), a free Web service for creating a wide range of visual analogue scales that can be used as measurement devices in Web surveys and Web experimentation, as well as for local computerized assessment. A step-by-step example for creating and implementing a visual analogue scale with visual feedback is given. VAS Generator and the scales it generates work independently of platforms and use the underlying languages HTML and JavaScript. Results from a validation study with 355 participants are reported and show that the scales generated with VAS Generator approximate an interval-scale level. In light of previous research on visual analogue versus categorical (e.g., radio button) scales in Internet-based research, we conclude that categorical scales only reach ordinal-scale level, and thus visual analogue scales are to be preferred whenever possible.

[Protein S3 in the human 80S ribosome adjoins mRNA from 3'-side of the A-site codon].

PubMed

Molotkov, M V; Graĭfer, D M; Popugaeva, E A; Bulygin, K N; Meshchaninova, M I; Ven'iaminova, A G; Karpova, G G

2007-01-01

The protein environment of mRNA 3' of the A-site codon (the decoding site) in the human 80S ribosome was studied using a set of oligoribonucleotide derivatives bearing a UUU triplet at the 5'-end and a perfluoroarylazide group at one of the nucleotide residues at the 3'-end of this triplet. Analogues of mRNA were phased into the ribosome using binding at the tRNAPhe P-site, which recognizes the UUU codon. Mild UV irradiation of ribosome complexes with tRNAPhe and mRNA analogues resulted in the predominant crosslinking of the analogues with the 40S subunit components, mainly with proteins and, to a lesser extent, with rRNA. Among the 40S subunit ribosomal proteins, the S3 protein was the main target for modification in all cases. In addition, minor crosslinking with the S2 protein was observed. The crosslinking with the S3 and S2 proteins occurred both in triple complexes and in the absence of tRNA. Within triple complexes, crosslinking with S15 protein was also found, its efficiency considerably falling when the modified nucleotide was moved from positions +5 to +12 relative to the first codon nucleotide in the P-site. In some cases, crosslinking with the S30 protein was observed, it was most efficient for the derivative containing a photoreactive group at the +7 adenosine residue. The results indicate that the S3 protein in the human ribosome plays a key role in the formation of the mRNA binding site 3' of the codon in the decoding site.

A Computational Study of Structure and Reactivity of N-Substitued-4-Piperidones Curcumin Analogues and Their Radical Anions.

PubMed

Martínez-Cifuentes, Maximiliano; Weiss-López, Boris; Araya-Maturana, Ramiro

2016-12-02

In this work, a computational study of a series of N -substitued-4-piperidones curcumin analogues is presented. The molecular structure of the neutral molecules and their radical anions, as well as their reactivity, are investigated. N -substituents include methyl and benzyl groups, while substituents on the aromatic rings cover electron-donor and electron-acceptor groups. Substitutions at the nitrogen atom do not significantly affect the geometry and frontier molecular orbitals (FMO) energies of these molecules. On the other hand, substituents on the aromatic rings modify the distribution of FMO. In addition, they influence the capability of these molecules to attach an additional electron, which was studied through adiabatic (AEA) and vertical electron affinities (VEA), as well as vertical detachment energy (VDE). To study electrophilic properties of these structures, local reactivity indices, such as Fukui ( f ⁺) and Parr ( P ⁺) functions, were calculated, and show the influence of the aromatic rings substituents on the reactivity of α,β-unsaturated ketones towards nucleophilic attack. This study has potential implications for the design of curcumin analogues based on a 4-piperidone core with desired reactivity.

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

PubMed Central

Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

2016-01-01

Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

Theoretical study on the influence of different para-substituents on 13C NMR of the single carbonyl curcumin analogues

NASA Astrophysics Data System (ADS)

Jia, Fei-yun; Ran, Ming; Zhang, Bo

2015-12-01

The structure of eight kinds of different para-substituents curcumin analogues has been optimized at the level of B3LYP/6-31G( d, p), under which the stability has been verified by means of vibration analysis. Moreover, NMR spectra of curcumin analogues compounds have been studied at the level of B3LYP/6-311G( d, p) by GIAO method. The results show that the structure of eight compounds, a larger conjugated system, has good planarity. The effect of ortho-substituents on bond lengths and bond angles is greater than para and meta. Different substituents and different positions of substituents all have different influence on NMR of the single carbonyl curcumin analogues. In general, after the hydrogen atom on the benzene ring is substituted by other groups, the δ value of α-C changes significantly, the δ value of ortho-carbon atom may also have great change, but the δ value change of meta-carbon atoms is not too obvious. The effect of substituent electronegativity on α-C atoms presents obvious regularity, while the influence of conjugate effect on carbon atoms of benzene ring is more complex. Finally, the bigger substituted alkyl is, the more the δ value of α-C increases.

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

PubMed

Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

1992-02-01

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

PubMed Central

Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

1992-01-01

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

Characterization of resistance gene analogues (RGAs) in Apple (Malus 6domestica Borkh.) and their evolutionary history of the Rosaceae family

USDA-ARS?s Scientific Manuscript database

The family of resistance gene analogues (RGAs) with a nucleotide-binding site (NBS) domain accounts for the largest number of disease resistance genes and is one of the largest gene families in plants. We have identified 868 RGAs in the genome of the apple (Malus × domestica Borkh.) cultivar ‘Golden...

Human factors research as part of a Mars exploration analogue mission on Devon Island

NASA Astrophysics Data System (ADS)

Binsted, Kim; Kobrick, Ryan L.; Griofa, Marc Ó.; Bishop, Sheryl; Lapierre, Judith

2010-06-01

Human factors research is a critical element of space exploration as it provides insight into a crew's performance, psychology and interpersonal relationships. Understanding the way humans work in space-exploration analogue environments permits the development and testing of countermeasures for and responses to potential hazardous situations, and can thus help improve mission efficiency and safety. Analogue missions, such as the one described here, have plausible mission constraints and operational scenarios, similar to those that a real Mars crew would experience. Long duration analogue studies, such as those being conducted at the Flashline Mars Arctic Research Station (FMARS) on Devon Island, Canada, offer an opportunity to study mission operations and human factors in a semi-realistic environment, and contribute to the design of missions to explore the Moon and Mars. The FMARS XI Long Duration Mission (F-XI LDM) was, at four months, the longest designed analogue Mars mission conducted to date, and thus provides a unique insight into human factors issues for long-duration space exploration. Here, we describe the six human factors studies that took place during F-XI LDM, and give a summary of their results, where available. We also present a meta-study, which examined the impact of the human-factors research itself on crew schedule and workload. Based on this experience, we offer some lessons learnt: some aspects (perceived risk and crew motivation, for example) of analogue missions must be realistic for study results to be valid; human factors studies are time-consuming, and should be fully integrated into crew schedules; and crew-ground communication and collaboration under long-term exploration conditions can present serious challenges.

A computational approach for predicting off-target toxicity of antiviral ribonucleoside analogues to mitochondrial RNA polymerase.

PubMed

Freedman, Holly; Winter, Philip; Tuszynski, Jack; Tyrrell, D Lorne; Houghton, Michael

2018-06-22

In the development of antiviral drugs that target viral RNA-dependent RNA polymerases, off-target toxicity caused by the inhibition of the human mitochondrial RNA polymerase (POLRMT) is a major liability. Therefore, it is essential that all new ribonucleoside analogue drugs be accurately screened for POLRMT inhibition. A computational tool that can accurately predict NTP binding to POLRMT could assist in evaluating any potential toxicity and in designing possible salvaging strategies. Using the available crystal structure of POLRMT bound to an RNA transcript, here we created a model of POLRMT with an NTP molecule bound in the active site. Furthermore, we implemented a computational screening procedure that determines the relative binding free energy of an NTP analogue to POLRMT by free energy perturbation (FEP), i.e. a simulation in which the natural NTP molecule is slowly transformed into the analogue and back. In each direction, the transformation was performed over 40 ns of simulation on our IBM Blue Gene Q supercomputer. This procedure was validated across a panel of drugs for which experimental dissociation constants were available, showing that NTP relative binding free energies could be predicted to within 0.97 kcal/mol of the experimental values on average. These results demonstrate for the first time that free-energy simulation can be a useful tool for predicting binding affinities of NTP analogues to a polymerase. We expect that our model, together with similar models of viral polymerases, will be very useful in the screening and future design of NTP inhibitors of viral polymerases that have no mitochondrial toxicity. © 2018 Freedman et al.

Differential Top10 promoter regulation by six tetracycline analogues in plant cells

NASA Technical Reports Server (NTRS)

Love, John; Allen, George C.; Gatz, Christiane; Thompson, William F.; Brown, C. S. (Principal Investigator)

2002-01-01

The effects of five tetracycline analogues, anhydrotetracycline, doxycycline, minocycline, oxytetracycline, and tetracycline, on Top10 promoter activity in NT1 tobacco tissue culture cells have been analysed. The concentration that repressed Top10 promoter activity, the level of transgene repression and the kinetics of transgene de-repression were determined for each analogue, and could not be predicted from in vitro binding affinity to the tetracycline repressor or from comparison with animal cells. Doxycycline had the most potent effect on the Top10 promoter and completely inhibited transgene expression at 4 nmol l(-1). Tetracycline was the most versatile of the analogues tested; tetracycline inhibited the Top10 promoter at 10 nmol l(-1) and was easily washed out to restore Top10-driven expression in 12-24 h. A study was also made of the suitability for plant research of a novel tetracycline analogue, GR33076X. In animal cells, GR33076X de-repressed Top10 promoter activity in the presence of inhibitory concentrations of anhydrotetracycline. In NT1, it is shown that GR 33076X can antagonize repression of the Top10 promoter in the presence of tetracycline, but not of anhydrotetracycline or of doxycycline. Different tetracycline analogues can therefore be used to regulate the Top10 promoter in plant cells and this property may be exploited in planning an optimum course of transgene regulation.

Differential Top10 promoter regulation by six tetracycline analogues in plant cells.

PubMed

Love, John; Allen, George C; Gatz, Christiane; Thompson, William F

2002-09-01

The effects of five tetracycline analogues, anhydrotetracycline, doxycycline, minocycline, oxytetracycline, and tetracycline, on Top10 promoter activity in NT1 tobacco tissue culture cells have been analysed. The concentration that repressed Top10 promoter activity, the level of transgene repression and the kinetics of transgene de-repression were determined for each analogue, and could not be predicted from in vitro binding affinity to the tetracycline repressor or from comparison with animal cells. Doxycycline had the most potent effect on the Top10 promoter and completely inhibited transgene expression at 4 nmol l(-1). Tetracycline was the most versatile of the analogues tested; tetracycline inhibited the Top10 promoter at 10 nmol l(-1) and was easily washed out to restore Top10-driven expression in 12-24 h. A study was also made of the suitability for plant research of a novel tetracycline analogue, GR33076X. In animal cells, GR33076X de-repressed Top10 promoter activity in the presence of inhibitory concentrations of anhydrotetracycline. In NT1, it is shown that GR 33076X can antagonize repression of the Top10 promoter in the presence of tetracycline, but not of anhydrotetracycline or of doxycycline. Different tetracycline analogues can therefore be used to regulate the Top10 promoter in plant cells and this property may be exploited in planning an optimum course of transgene regulation.

Affinity alkylation of the active site of C/sub 21/ steroid side-chain cleavage cytochrome P-450 from neonatal porcine testis: a unique cysteine residue alkylated by 17-(bromoacetoxy)progesterone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Onoda, M.; Haniu, M.; Yanagibashi, K.

1987-01-27

The affinity alkylating progesterone analogue 17-(bromoacetoxy)progesterone has been used to label the active site of a microsomal cytochrome P-450 enzyme from neonatal pig testis. The enzyme causes removal of the C/sub 20/ and C/sub 21/ side chains from the substrates progesterone and pregnenolone by catalyzing both 17-hydroxylase and C/sub 17,20/-lyase reactions, which produce the corresponding C/sub 1//sup 9/ steroidal precursors of testosterone. The progesterone analogue causes simultaneous inactivation of the two catalytic activities of the enzyme by a first-order kinetic process that obeys saturation kinetics. Progesterone and 17-hydroxyprogesterone each protect the enzyme against inactivation. The progesterone analogue is a competitivemore » inhibitor of the enzyme with K/sub i/ values of 8.4 ..mu..M and 7.8 ..mu..M for progesterone and 17-hydroxyprogesterone, respectively. The enzyme inactivation and kinetic data are consistent with a theory proposing that the analogue and the two substrates compete for the same active site. The radioactive analogue 17-((/sup 14/C)bromoacetoxy)progesterone causes inactivation of the enzyme with incorporation of 1.5-2.2 mol of the analogue per mole of inactivated enzyme. When this experiment is carried out in the presence of a substrate, then 0.9-1.2 mol of radioactive analogue is incorporated per mole of inactivated enzyme. The data suggest that the analogue can bind to two different sites, one of which is related to the catalytic site. Radiolabeled enzyme samples, from reactions of the /sup 14/C-labeled analogue with the enzyme alone or with enzyme in the presence of a substrate, were subjected to amino acid analysis and also in tryptic digestion and peptide mapping.« less

Substance P analogues potentiate the pressor response to microinjection of L-glutamate into laminas I and II of the cat dorsal horn.

PubMed

Beyaert, C A; Hill, J M; Kaufman, M P

1997-06-06

Microinjection of a substance P analogue (1 mM; 7 or 10 nl) into laminae I and II of the L7 dorsal horn of decerebrate cats significantly potentiated (P < 0.05) the increase in arterial pressure evoked by microinjection of L-glutamate (109 mM; 7 or 10 nl) into these spinal sites. Microinjection of the substance P analogues (i.e., GR73638 and [Sar9,Met(O2)11]-substance P) which were selective NK-1 receptor agonists, had no impact on the cardioacceleration evoked by microinjection of L-glutamate (P > 0.05). In addition, microinjection of these analogues had no effect on the modest and non-significant increase in phrenic nerve discharge evoked by L-glutamate. We conclude that stimulation of NK-1 receptors in the superficial laminae of the dorsal horn potentiates the pressor responses to microinjection of L-glutamate.

Emotions and Habitability study in Moon Mars Analogue.

NASA Astrophysics Data System (ADS)

Mertens, Alexandre; Lia Schlacht, Irene

Euro Moon Mars mission have been conducted by students and field researchers in the Mars Desert Research Station (MDRS) a habitat installed by the Mars Society (MS) in the Utah desert. The campaign was supported by ILEWG International Lunar Exploration Working Group, ESTEC, NASA Ames, and partners. It investigated human aspects of isolation in a Mars analogue base. The project is in line with the ILEWG which coordinates several MDRS missions, and contributes to the preparation of future Mars sample return missions. The objective is to study and improve the habitat dynamics in a closed and small environment. Investigation cover different fields as emotional, sociological and psychological aspects and a food study but also habitability aspects. The study has been conducted by asking to the crew members to perform task and fill in questionnaires before, during and after the simulation. Video recovering, pictures and heart rate counting will also be used. One of the main study subject, conducted by Bernard Rimé, concerns the sharing of emotions in an isolated environ-e ment. Another is "Mars Habitability Experiment", which responsible is Irene Schlacht, will try to determine whether humans need variability of stimuli such as it happens in the natural environment -e.g. seasonal changing -to gain efficiency, reliability and well-being. This study have been conducted from February 19 to April 19 on two crews presenting different aspects that could lead to various behaviours. The first crew is made of people from different countries that don't know each other very well. On the opposite, the second crew members have the same cultural background -they come from the same country, university -and they know each other for at least six months. This allow studying how the extreme conditions of the isolation affect the crew efficiency, creativity and sanity according to its homogeneity. Report on the science and technical results, and implications for Earth-Mars comparative stud-ies

Isolation and characterization of NBS–LRR resistance gene analogues from mango

PubMed Central

Lei, Xintao; Yao, Quansheng; Xu, Xuerong; Liu, Yang

2014-01-01

The nucleotide-binding site (NBS)–leucine-rich repeat (LRR) gene family is a class of R genes in plants. NBS genes play a very important role in disease defence. To further study the variation and homology of mango NBS–LRR genes, 16 resistance gene analogues (RGAs) (GenBank accession number HM446507-22) were isolated from the polymerase chain reaction fragments and sequenced by using two degenerate primer sets. The total nucleotide diversity index Pi was 0.362, and 236 variation sites were found among 16 RGAs. The degree of homology between the RGAs varied from 44.4% to 98.5%. Sixteen RGAs could be translated into amino sequences. The high level of this homology in the protein sequences of the P-loop and kinase-2 of the NBS domain between the RGAs isolated in this study and previously characterized R genes indicated that these cloned sequences belonged to the NBS–LRR gene family. Moreover, these 16 RGAs could be classified into the non-TIR–NBS–LRR gene family because only tryptophan (W) could be claimed as the final residual of the kinase-2 domain of all RGAs isolated here. From our results, we concluded that our mango NBS–LRR genes possessed a high level of variation from the mango genome, which may allow mango to recognize many different pathogenic virulence factors. PMID:26740762

Synthesis of indolizidinone analogues of cytotoxic alkaloids: monocyclic precursors are also active.

PubMed

Boto, Alicia; Miguélez, Javier; Marín, Raquel; Díaz, Mario

2012-05-15

Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission-oxidation-alkylation process, which yields 2-substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure-activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives. Copyright © 2012 Elsevier Ltd. All rights reserved.

Membrane-Targeting DCAP Analogues with Broad-Spectrum Antibiotic Activity against Pathogenic Bacteria

PubMed Central

2015-01-01

We performed a structure–activity relationship study of 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), which is an antibacterial agent that disrupts the membrane potential and permeability of bacteria. The stereochemistry of DCAP had no effect on the biological activity of DCAP. The aromaticity and electronegativity of the chlorine-substituted carbazole was required for activity, suggesting that its planar and dipolar characteristics orient DCAP in membranes. Increasing the hydrophobicity of the tail region of DCAP enhanced its antibiotic activity. Two DCAP analogues displayed promising antibacterial activity against the BSL-3 pathogens Bacillus anthracis and Francisella tularensis. Codosing DCAP analogues with ampicillin or kanamycin increased their potency. These studies demonstrate that DCAP and its analogues may be a promising scaffold for developing chemotherapeutic agents that bind to bacterial membranes and kill strains of slow-growing or dormant bacteria that cause persistent infections. PMID:25941556

The monoamine oxidase inhibition properties of selected structural analogues of methylene blue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Delport, Anzelle

The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, themore » present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC{sub 50} = 0.0037 μM), Nile blue (IC{sub 50} = 0.0077 μM) and 1,9-dimethyl methylene blue (IC{sub 50} = 0.018 μM) exhibiting higher potency inhibition compared to MB (IC{sub 50} = 0.07 μM). Nile blue also represents a potent MAO-B inhibitor with an IC{sub 50} value of 0.012 μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. - Highlights: • MB analogues, cresyl violet and Nile blue, are high potency MAO-A inhibitors. • Nile blue also represents a potent MAO-B inhibitor. • Potent MAO-A inhibition should alert to potential serotonin toxicity.« less

Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues

PubMed Central

Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W.; Shears, Stephen B.

2016-01-01

The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. PMID:27460418

The monoamine oxidase inhibition properties of selected structural analogues of methylene blue.

PubMed

Delport, Anzelle; Harvey, Brian H; Petzer, Anél; Petzer, Jacobus P

2017-06-15

The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC 50 =0.0037μM), Nile blue (IC 50 =0.0077μM) and 1,9-dimethyl methylene blue (IC 50 =0.018μM) exhibiting higher potency inhibition compared to MB (IC 50 =0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC 50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST. Copyright © 2017 Elsevier Inc. All rights reserved.

Lead optimization of antimalarial propafenone analogues.

PubMed

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

2012-07-12

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

Sensing of hydrophobic cavity of serum albumin by an adenosine analogue: fluorescence correlation and ensemble spectroscopic studies.

PubMed

Nag, Moupriya; Bera, Kallol; Chakraborty, Sandipan; Basak, Soumen

2013-10-05

Adenosine is a naturally occurring purine nucleoside that plays important role in various biochemical processes. We have studied the binding of TNP-Ado (trinitrophenylated-adenosine), a fluorescent analogue of adenosine (which itself is a weak fluorophore), with a model transport protein, bovine serum albumin (BSA). The binding affinity was determined using Fluorescence correlation spectroscopy (FCS) and compared with its value obtained from macroscopic fluorescence spectroscopic studies. Fluorescence and circular dichroism (CD) spectroscopies were employed together with molecular docking study to locate the probable binding site of TNP-Ado on BSA and its effect on the conformation and stability of BSA. Fluorescence studies showed that TNP-Ado binds to BSA in 1:1 stoichiometry via an entropically favoured process. Induced CD spectra revealed that a chiro-optical switching of TNP-Ado occurs upon binding to BSA. Results on urea-induced denaturation of BSA and docking study suggested that the binding site for the ligand is in the hydrophobic subdomain IIA of BSA, consistent with the results of other measurements. This study establishes TNP-Ado as a sensor of hydrophobic regions in proteins like serum albumin, having the capability of detecting a minimum concentration of 140ng/ml protein. FCS measurement of binding interaction of rhodamine-labeled TNP-Ado (RTNP-Ado) with BSA yielded an association constant of KFCS=(1.03±0.06) × 10(4)M(-1). The association constants (Ka) obtained for binding of BSA with rhodamine-free (i.e. TNP-Ado) and rhodamine-labeled (RTNP-Ado) ligands, obtained using the ensemble spectroscopic technique, were (2.3±0.06) × 10(5)M(-1) and (3.4±0.03) × 10(4)M(-1), respectively. The difference between the values of Ka for the free and labeled ligands suggests that fluorescent labeling of small molecules perceptibly interferes with the binding process. On the other hand, the difference in Ka obtained by FCS and ensemble techniques is due to the

Structure-based design of novel quinoxaline-2-carboxylic acids and analogues as Pim-1 inhibitors.

PubMed

Oyallon, Bruno; Brachet-Botineau, Marie; Logé, Cédric; Bonnet, Pascal; Souab, Mohamed; Robert, Thomas; Ruchaud, Sandrine; Bach, Stéphane; Berthelot, Pascal; Gouilleux, Fabrice; Viaud-Massuard, Marie-Claude; Denevault-Sabourin, Caroline

2018-05-11

We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC 50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues.

PubMed

Nuti, Elisa; Bassani, Barbara; Camodeca, Caterina; Rosalia, Lea; Cantelmo, AnnaRita; Gallo, Cristina; Baci, Denisa; Bruno, Antonino; Orlandini, Elisabetta; Nencetti, Susanna; Noonan, Douglas M; Albini, Adriana; Rossello, Armando

2017-09-29

Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 μM concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R 2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin

PubMed Central

Holden, Sarah E; Poole, Chris D; Morgan, Christopher Ll

2011-01-01

Introduction Insulin analogues have become increasingly popular despite their greater cost compared with human insulin. The aim of this study was to calculate the incremental cost to the National Health Service (NHS) of prescribing analogue insulin preparations instead of their human insulin alternatives. Methods Open-source data from the four UK prescription pricing agencies from 2000 to 2009 were analysed. Cost was adjusted for inflation and reported in UK pounds at 2010 prices. Results Over the 10-year period, the NHS spent a total of £2732 million on insulin. The total annual cost increased from £156 million to £359 million, an increase of 130%. The annual cost of analogue insulin increased from £18.2 million (12% of total insulin cost) to £305 million (85% of total insulin cost), whereas the cost of human insulin decreased from £131 million (84% of total insulin cost) to £51 million (14% of total insulin cost). If it is assumed that all patients using insulin analogues could have received human insulin instead, the overall incremental cost of analogue insulin was £625 million. Conclusion Given the high marginal cost of analogue insulin, adherence to prescribing guidelines recommending the preferential use of human insulin would have resulted in considerable financial savings over the period. PMID:22021891

[Cloning, expressing of exendin-4 analogue and bioactivity analysis in vivo].

PubMed

Li, Taiming; Gu, Chunjiao; Ge, Xiaoyu; Li, Zhezhe; Wang, Dan; Ma, Yanhong; Liu, Tao; Zhang, Meiyou; Li, Li; Liu, Jingjing

2012-07-01

To construct, express and purify Exendin-4 analogue and detect its biological activity in vivo. Insert gene sequence into fusion partner ofpED plasmid which is helped to purification, entitled the new recombinant plasmid 5 Exendin-4 analogue polypeptide gene and fusion partner gene was linked by acid hydrolysisgene, transformed to E. coli BL21 and the fusion protein was induced by lactose. After acid hydrolysis, the Exendin-4 analogue polypeptide separated from fusion chaperon. Anion charge chromatography were used to further purification. 6 to 8 week-old ICR mice were injected (s.c) with Exendin-4 analogue, blood glucose and plasma insulin level was detected in different period after oral glucose tolerance test. The results show that high expression of inclusion body was induced by lactose, which accounted for 40% of germ proteins, the Exendin-4 analogue was obtained with the purity of 91.8% after being purified by anion charge chromatography. Bioactivity assay showed that the level of blood glucose of mouse which treated with exendin-4 analogue was obviously decreased to normal (P < 0.01), and the level of plasma insulin was increased obviously (P < 0.01).

A Cross-Sectional Survey of the Association between Bilateral Topical Prostaglandin Analogue Use and Ocular Adnexal Features

PubMed Central

Shah, Mamta; Lee, Grace; Lefebvre, Daniel R.; Kronberg, Benjamin; Loomis, Stephanie; Brauner, Stacey C.; Turalba, Angela; Rhee, Douglas J.; Freitag, Suzanne K.; Pasquale, Louis R.

2013-01-01

We studied the relation between prostaglandin analogue use and ocular adnexal features. We used a prospective, cross-sectional study involving 157 current, 15 past, and 171 never users of prostaglandin analogues. Patients 50 years of age or older and without conditions affecting ocular adnexal anatomy underwent glaucoma medication use history, external digital photography and systematic external adnexal exam. Two masked readers assessed the digital photos for upper lid dermatochalasis and lower lid steatoblepharon using a validated grading scheme. Another masked clinical examiner also assessed upper lid ptosis, levator muscle function, and inferior scleral show. We performed ordinal logistic regression analysis accounting for multiple covariates to assess the relation between prostaglandin analogue use and adnexal features. Multivariable analyses indicated there was a 230-fold increased risk of incremental involution of dermatochalasis (odds ratio (OR)  =  2.30; 95% confidence interval (CI) 1.43–3.69; p = 5.44E-04) and a 249-fold increased risk of incremental loss of lower lid steatoblepharon (OR  =  2.49; 95% CI, 1.54–4.03; p =  1.98E-04) associated with current prostaglandin analogue use (bimatoprost 0.03%, travoprost 0.005%, or latanoprost 0.004%) versus prostaglandin analogue never or past users. Upper lid ptosis (OR  =  4.04; 95% CI, 2.43–6.72; p = 7.37E-08), levator dysfunction (OR =  7.51; 95% CI, 3.39–16.65; p = 6.74E-07) and lower lid retraction (OR = 2.60; 95% CI, 1.58–4.28; p = 1.72E-04) were highly associated with current prostaglandin analogue use versus prostaglandin analogue never or past users. The associations between prostaglandin analogue use and deepening of the upper lid sulci and between prostaglandin analogue use and loss of inferior periorbital fat are confirmed in this multivariable analysis. The associations between prostaglandin analogue use and levator muscle dysfunction and between

Mediation by SRIF1 receptors of the contractile action of somatostatin in rat isolated distal colon; studies using some novel SRIF analogues.

PubMed Central

McKeen, E S; Feniuk, W; Humphrey, P P

1994-01-01

1. The motor effects of somatostatin-14 (SRIF), and several SRIF peptide analogues were investigated on the rat isolated distal colon. The objective of these studies was to characterize the receptor mediating the contractile action of SRIF by comparing the relative agonist potencies of a range of SRIF analogues. 2. SRIF (1 nM-1 microM) produced concentration-dependent contractions with an EC50 value of approximately 10 nM. Contractile responses induced by SRIF were insensitive to atropine (1 microM) or naloxone (1 microM) but abolished by tetrodotoxin (1 microM). Somatostatin-28 (SRIF28), also induced concentration-dependent contractions and was equipotent with SRIF. Phosphoramidon (1 microM) and amastatin (10 microM) did not increase the potency of either SRIF or SRIF28. 3. The SRIF peptide analogues, octreotide, SRIF25, seglitide, angiopeptin and CGP23996 (1 nM-1 microM) produced contractile responses in the rat distal colon, each having similar potency and maximal activity relative to SRIF. The SSTR2 receptor-selective hexapeptide, BIM23027 (0.1 nM-1 microM), and the SRIF stereoisomer, D-Trp8-SRIF (0.1 nM-1 microM), were the most potent agonists examined being approximately 12 and 7 times more potent than SRIF, respectively. In contrast, the SSTR5 receptor-selective analogue, L362,855, was approximately 120 times weaker than SRIF, whilst the SSTR3 receptor-selective analogue, BIM23056, was inactive at concentrations up to 3 microM. 4. The putative SRIF receptor antagonist, (cyclo(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[Bzl]))(CPP) (1 microM), had no agonist activity and had no effect on contractions induced by SRIF. 5. The contractile actions of BIM23027 and seglitide were subject to pronounced desensitization.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7834217

Bioluminescence of beetle luciferases with 6'-amino-D-luciferin analogues reveals excited keto-oxyluciferin as the emitter and phenolate/luciferin binding site interactions modulate bioluminescence colors.

PubMed

Viviani, Vadim R; Neves, Deimison Rodrigues; Amaral, Danilo Trabuco; Prado, Rogilene A; Matsuhashi, Takuto; Hirano, Takashi

2014-08-19

Beetle luciferases produce different bioluminescence colors from green to red using the same d-luciferin substrate. Despite many studies of the mechanisms and structural determinants of bioluminescence colors with firefly luciferases, the identity of the emitters and the specific active site interactions responsible for bioluminescence color modulation remain elusive. To address these questions, we analyzed the bioluminescence spectra with 6'-amino-D-luciferin (aminoluciferin) and its 5,5-dimethyl analogue using a set of recombinant beetle luciferases that naturally elicit different colors and different pH sensitivities (pH-sensitive, Amydetes vivianii λmax=538 nm, Macrolampis sp2 λmax=564 nm; pH-insensitive, Phrixotrix hirtus λmax=623 nm, Phrixotrix vivianii λmax=546 nm, and Pyrearinus termitilluminans λmax=534 nm), a luciferase-like enzyme (Tenebrionidae, Zophobas morio λmax=613 nm), and mutants of C311 (S314). The green-yellow-emitting luciferases display red-shifted bioluminescence spectra with aminoluciferin in relation to those with D-luciferin, whereas the red-emitting luciferases displayed blue-shifted spectra. Bioluminescence spectra with 5,5-dimethylaminoluciferin, in which enolization is blocked, were almost identical to those of aminoluciferin. Fluorescence probing using 2-(4-toluidino)naphthalene-6-sulfonate and inference with aminoluciferin confirm that the luciferin binding site of the red-shifted luciferases is more polar than in the case of the green-yellow-emitting luciferases. Altogether, the results show that the keto form of excited oxyluciferin is the emitter in beetle bioluminescence and that bioluminescence colors are essentially modulated by interactions of the 6'-hydroxy group of oxyluciferin and basic moieties under the influence of the microenvironment polarity of the active site: a strong interaction between a base moiety and oxyluciferin phenol in a hydrophobic microenvironment promotes green-yellow emission, whereas a more polar

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed Central

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-01-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells. PMID:2548207

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

Evolving a polymerase for hydrophobic base analogues.

PubMed

Loakes, David; Gallego, José; Pinheiro, Vitor B; Kool, Eric T; Holliger, Philipp

2009-10-21

Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favorable substrate properties, their discovery has remained challenging. Here we describe a complementary strategy for improving HBA substrate properties by directed evolution of a dedicated polymerase using compartmentalized self-replication (CSR) with the archetypal HBA 5-nitroindole (d5NI) and its derivative 5-nitroindole-3-carboxamide (d5NIC) as selection substrates. Starting from a repertoire of chimeric polymerases generated by molecular breeding of DNA polymerase genes from the genus Thermus, we isolated a polymerase (5D4) with a generically enhanced ability to utilize HBAs. The selected polymerase. 5D4 was able to form and extend d5NI and d5NIC (d5NI(C)) self-pairs as well as d5NI(C) heteropairs with all four bases with efficiencies approaching, or exceeding, those of the cognate Watson-Crick pairs, despite significant distortions caused by the intercalation of the d5NI(C) heterocycles into the opposing strand base stack, as shown by nuclear magnetic resonance spectroscopy (NMR). Unlike Taq polymerase, 5D4 was also able to extend HBA pairs such as Pyrene: varphi (abasic site), d5NI: varphi, and isocarbostyril (ICS): 7-azaindole (7AI), allowed bypass of a chemically diverse spectrum of HBAs, and enabled PCR amplification with primers comprising multiple d5NI(C)-substitutions, while maintaining high levels of catalytic activity and fidelity. The selected polymerase 5D4 promises to expand the range of nucleobase analogues amenable to replication and should find numerous applications, including the synthesis and replication of nucleic acid polymers with expanded chemical and functional diversity.

The mucosal toxicity of different benzalkonium chloride analogues evaluated with an alternative test using slugs.

PubMed

Adriaens, E; Dierckens, K; Bauters, T G; Nelis, H J; van Goethem, F; Vanparys, P; Remon, J P

2001-07-01

The objective of this study was to evaluate the mucosal toxicity of different benzalkonium chloride (BAC) analogues using slugs as the alternative test organism. The effect of different BAC analogues on the mucosal tissue of slugs was determined from the protein, lactate dehydrogenase, and alkaline phosphatase released from the foot mucosa after treatment. Additionally, mucus production and reduction in body weight of the slugs were measured. The eye irritation potency of the molecules was evaluated with the Bovine Corneal Opacity and Permeability (BCOP) assay. The antimicrobial activity of the different BAC analogues was also assessed. All BAC analogues induced severe damage to the mucosal epithelium of the slugs, and the irritation increased with decreasing alkyl chain length: BAC-C16 < BAC-C14 < BAC-C12 approximately BAC-mix. A similar ranking was obtained with the BCOP assay for eye irritation. The relative order of activities among the three BAC analogues was the same, i.e., BAC-C14 > or = BAC-C16 > BAC-C12. The BAC-C14 exhibited higher activity than the BAC-mix. The toxicity and activity of BAC analogues depend on the alkyl chain length. The use of BAC-C14 as a conservative agent in pharmaceutical preparations instead of the BAC-mix should be considered.

Trends in the use and cost of human and analogue insulins in a Colombian population, 2011-2015.

PubMed

Torres, D R; Portilla, A; Machado-Duque, M E; Machado-Alba, J E

2017-12-01

Diabetes mellitus is a common disease among the general population and imposes considerable costs on health care systems. Insulin is used to treat type 1 diabetes mellitus and as an adjuvant to oral agents in advanced stages of type 2 diabetes mellitus. The objective was to describe the trends in use and cost of human and analogue insulins for Colombian patients. Descriptive retrospective analysis of prescriptions of human and analogue insulins on a monthly basis for the period from July 1, 2011 to February 2, 2015. Information was collected for the database population of two insurance companies. Frequencies and proportions were calculated; estimated economic impact was expressed as net cost and cost per thousand inhabitants per day. During the observation period, there was continuous growth in use of insulin, mainly in analogue forms (34.0% growth). At the start of the study, 10.4% of subjects were using an analogue insulin; this figure was 62.6% at the end of the study. In 2012, the average cost per 1000 inhabitants/day was US$1.7 for analogue and US$0.8 for human insulins. At the end of the observation period these costs had risen to US$9.2 for analogue (441.1% increase) and fallen to US$0.5 for human insulin (58.3% decrease). There has been an increase in the unit cost and frequency of use of insulin analogues for anti-diabetic therapy in Colombian patients. Moreover, there is controversy over whether insulin analogues are a more cost-effective treatment than human insulins for the general diabetic population. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

NASA Astrophysics Data System (ADS)

Greenidge, Paulette A.; Merz, Alfred; Folkers, Gerd

1995-12-01

A representative range of pyrimidine nucleoside analogues that are known to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV), thymidine kinase (TK) and human TK1. Given a set of interacting ligands, superimposed in such a manner as to define a pharmacophore, the pseudoreceptor modelling technique Yak provides a means of building binding site models of macromolecules for which no three-dimensional experimental structures are available. Once the models have been evaluated by their ability to reproduce experimental binding data [Vedani et al., J. Am. Chem. Soc., 117 (1995) 4987], they can be used for predictive purposes. Calculated and experimental values of relative binding affinity are compared. Our models suggest that the substitution of one residue may be sufficient to determine ligand subtype affinity.

Biological evaluation and 3D-QSAR studies of curcumin analogues as aldehyde dehydrogenase 1 inhibitors.

PubMed

Wang, Hui; Du, Zhiyun; Zhang, Changyuan; Tang, Zhikai; He, Yan; Zhang, Qiuyan; Zhao, Jun; Zheng, Xi

2014-05-16

Aldehyde dehydrogenase 1 (ALDH1) is reported as a biomarker for identifying some cancer stem cells, and down-regulation or inhibition of the enzyme can be effective in anti-drug resistance and a potent therapeutic for some tumours. In this paper, the inhibitory activity, mechanism mode, molecular docking and 3D-QSAR (three-dimensional quantitative structure activity relationship) of curcumin analogues (CAs) against ALDH1 were studied. Results demonstrated that curcumin and CAs possessed potent inhibitory activity against ALDH1, and the CAs compound with ortho di-hydroxyl groups showed the most potent inhibitory activity. This study indicates that CAs may represent a new class of ALDH1 inhibitor.

Antimicrobial activity of antihypertensive food-derived peptides and selected alanine analogues.

PubMed

McClean, Stephen; Beggs, Louise B; Welch, Robert W

2014-03-01

This study evaluated four food-derived peptides with known antihypertensive activities for antimicrobial activity against pathogenic microorganisms, and assessed structure-function relationships using alanine analogues. The peptides (EVSLNSGYY, barley; PGTAVFK, soybean; TTMPLW, α-casein; VHLPP, α-zein) and the six alanine substitution peptides of PGTAVFK were synthesised, characterised and evaluated for antimicrobial activity using the bacteria, Escherichia coli, Staphylococcus aureus, and Micrococcus luteus and the yeast, Candida albicans. The peptides TTMPLW and PGTAVFK inhibited growth of all four microorganisms tested, with activities of a similar order of magnitude to ampicillin and ethanol controls. EVSLNSGYY inhibited the growth of the bacteria, but VHLPP showed no antimicrobial activity. The alanine analogue, PGAAVFK showed the highest overall antimicrobial activity and PGTAVFA showed no activity; overall, the activities of the analogues were consistent with their structures. Some peptides with antihypertensive activity also show antimicrobial activity, suggesting that food-derived peptides may exert beneficial effects via a number of mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparison of insulin analogue B9AspB27Glu and soluble human insulin in insulin-treated diabetes.

PubMed

Kang, S; Owens, D R; Vora, J P; Brange, J

1990-02-10

Postprandial plasma glucose excursions and plasma levels of free insulin after subcutaneous bolus injection of a rapidly absorbed monomeric insulin analogue (B9AspB27Glu) or soluble human insulin ('Actrapid HM' U100) were studied in six insulin-treated diabetic subjects. 10 U actrapid or an equimolar amount of the analogue were injected, in random order with an interval of 1 week, immediately before a 500 kcal test meal. Basal insulin levels were similar on the 2 study days (mean 74.1 [SE 5.1] pmol/l, actrapid; 79.7 [13.0] pmol/l, analogue). After injection of actrapid plasma free insulin levels rose slowly, reaching a plateau by 105 min at 222 (19) pmol/l. Injection of the analogue resulted in a rapid early peak at 30 min (798 [112] pmol/l), and levels were significantly higher than those after actrapid between 15 and 210 min. The more physiological plasma insulin levels achieved with the analogue were accompanied by a substantial reduction in postprandial plasma glucose excursions; the integrated area under the incremental plasma glucose curve was 45% lower after the analogue than after actrapid.

Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues.

PubMed

Meints, Lisa M; Poston, Anne W; Piligian, Brent F; Olson, Claire D; Badger, Katherine S; Woodruff, Peter J; Swarts, Benjamin M

2017-02-17

Chemically modified versions of trehalose, or trehalose analogues, have applications in biology, biotechnology, and pharmaceutical science, among other fields. For instance, trehalose analogues bearing detectable tags have been used to detect Mycobacterium tuberculosis and may have applications as tuberculosis diagnostic imaging agents. Hydrolytically stable versions of trehalose are also being pursued due to their potential for use as non-caloric sweeteners and bioprotective agents. Despite the appeal of this class of compounds for various applications, their potential remains unfulfilled due to the lack of a robust route for their production. Here, we report a detailed protocol for the rapid and efficient one-step biocatalytic synthesis of trehalose analogues that bypasses the problems associated with chemical synthesis. By utilizing the thermostable trehalose synthase (TreT) enzyme from Thermoproteus tenax, trehalose analogues can be generated in a single step from glucose analogues and uridine diphosphate glucose in high yield (up to quantitative conversion) in 15-60 min. A simple and rapid non-chromatographic purification protocol, which consists of spin dialysis and ion exchange, can deliver many trehalose analogues of known concentration in aqueous solution in as little as 45 min. In cases where unreacted glucose analogue still remains, chromatographic purification of the trehalose analogue product can be performed. Overall, this method provides a "green" biocatalytic platform for the expedited synthesis and purification of trehalose analogues that is efficient and accessible to non-chemists. To exemplify the applicability of this method, we describe a protocol for the synthesis, all-aqueous purification, and administration of a trehalose-based click chemistry probe to mycobacteria, all of which took less than 1 hour and enabled fluorescence detection of mycobacteria. In the future, we envision that, among other applications, this protocol may be applied to

Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

PubMed

de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

2012-01-01

For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

NASA Astrophysics Data System (ADS)

Dechristopher, Brian A.; Loy, Brian A.; Marsden, Matthew D.; Schrier, Adam J.; Zack, Jerome A.; Wender, Paul A.

2012-09-01

Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.

PubMed

Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong

2013-07-15

Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Efficient synthesis of RITA and its analogues: derivation of analogues with improved antiproliferative activity via modulation of p53/miR-34a pathway.

PubMed

Lin, Jinshun; Jin, Xiuli; Bu, Yiwen; Cao, Deliang; Zhang, Nannan; Li, Shangfu; Sun, Qinsheng; Tan, Chunyan; Gao, Chunmei; Jiang, Yuyang

2012-12-28

A novel approach to synthesize RITA by practical palladium-catalyzed C-C bond-forming Suzuki reactions at room temperature was developed, which was used for deriving a series of substituted tricyclic α-heteroaryl (furan/thiophene) analogues of RITA under mild conditions. These novel analogues showed notable antiproliferative activity against cancer cell lines with wild-type p53 (i.e., HCT116, A549, MCF-7 and K562), but much less activity in HCT116/p53(-/-) cells. In particular, compound 1f demonstrated promising antiproliferative activity compared to RITA, with IC(50) = 28 nM in MCF-7 vs. 54 nM for RITA, and cancer cell selectivity. Compound 1f markedly activated p53 in HCT116 cells at 100 nM, triggering apoptosis. Importantly, we found that both RITA and compound 1f induced G(0)/G(1) cell cycle arrest by up-regulating miR-34a, which in turn down-regulated the expression of cell cycle-related proteins CDK4 and E2F1. In summary, this study reports an effective synthetic approach for RITA and its analogues, and elucidates a novel antiproliferative mechanism of these compounds.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bajusz, S.; Janaky, T.; Csernus, V.J.

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Ofmore » the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.« less

Aqueous extracts of a Mars analogue regolith that mimics the Phoenix landing site do not inhibit spore germination or growth of model spacecraft contaminants Bacillus subtilis 168 and Bacillus pumilus SAFR-032

NASA Astrophysics Data System (ADS)

Nicholson, Wayne L.; McCoy, Lashelle E.; Kerney, Krystal R.; Ming, Douglas W.; Golden, D. C.; Schuerger, Andrew C.

2012-08-01

Because Mars is a primary target for life detection and habitability assessment missions, its exploration is also by necessity a Planetary Protection issue. The recent finding of significant levels of perchlorate (ClO4-) in regolith sampled from the Phoenix landing site raises the question of its potential biotoxicity to putative indigenous martian life, microbial forward contaminants from Earth, or future human visitors. To address this issue, an analogue regolith was constructed based on regolith chemistry data from the Phoenix landing site. A Mars Aqueous Regolith Extract (MARE) was prepared from the Phoenix analogue regolith and analyzed by ion chromatography. The MARE contained (mg/L) the cations Na+ (1411 ± 181), Mg2+ (1051 ± 160), Ca2+ (832 ± 125), and K+ (261 ± 29), and the anions SO42-(5911±993), ClO4-(5316±1767), Cl(171±25) and F- (2.0 ± 0.4). Nitrogen-containing species NO3-(773±113) and NO2-(6.9±2.3) were also present as a result of regolith preparation procedures, but their relevance to Mars is at present unknown. The MARE was tested for potential toxic effects on two model spacecraft contaminants, the spore-forming bacteria Bacillus subtilis strain 168 and Bacillus pumilus strain SAFR-032. In B. subtilis, spore germination and initial vegetative growth (up to ˜5 h) was not inhibited in a rich complex medium prepared with the MARE, but growth after 5 h was significantly suppressed in medium prepared using the MARE. Both B. subtilis and B. pumilus exhibited significantly higher rates of spore germination and growth in the MARE vs. DW with no additions (likely due to endogenous spore nutrients), but germination and growth was further stimulated by addition of glucose and a combination of buffered inorganic salts (K2HPO4, KH2PO4, (NH4)2SO4, and MgSO4). The data indicate that the aqueous environment in the regolith from the Phoenix landing site containing high levels of perchlorate does not pose a significant barrier to growth of putative

Space Analogue Environments: Are the Populations Comparable?

NASA Astrophysics Data System (ADS)

Sandal, G. M.

Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

Phospholipid analogues of Porphyromonas gingivalis.

PubMed

Tavana, A M; Korachi, M; Boote, V; Hull, P S; Love, D N; Drucker, D B

2000-05-01

Porphyromonas has lipids containing hydroxy acids and C16:0 and iso-C15:0 major monocarboxylic acids among others. Nothing is known of its individual phospholipid molecular species. The aim of this study was to determine molecular weights and putative identities of individual phospholipid molecular species extracted from Porphyromonas gingivalis (seven strains), P. asaccharolytica (one strain) and P. endodontalis (two strains). Cultures on Blood-Fastidious Anaerobe Agar were harvested, washed and freeze-dried. Phospholipids were extracted and separated by fast atom bombardment mass spectrometry (FAB MS) in negative-ion mode. Phospholipid classes were also separated by thin layer chromatography (TLC). The major anions in the range m/z 209-299 were consistent with the presence of the C13: 0, C15: 0, C16: 0 and C18: 3 mono-carboxylate anions. Major polar lipid anion peaks in the range m/z 618-961 were consistent with the presence of molecular species of phosphatidylethanolamine, phosphatidylglycerol and with unidentified lipid analogues. Porphyromonas gingivalis differed from comparison strains of other species by having major anions with m/z 932, 946 and 960. Unusually, a feline strain of P. gingivalis had a major peak of m/z 736. Selected anions were studied by tandem FAB MS which revealed that peaks with m/z 653 and 946 did not correspond to commonly occurring classes of polar lipids. They were however, glycerophosphates. It is concluded that the polar lipid analogue profiles obtained with Porphyromonas are quite different from those of the genera Prevotella and Bacteroides but reveal heterogeneity within P. gingivalis.

Cysteine analogues potentiate glucose-induced insulin release in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ammon, H.P.; Hehl, K.H.; Enz, G.

1986-12-01

In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhancemore » insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.« less

Algicidal Activity of Bacillamide Alkaloids and Their Analogues against Marine and Freshwater Harmful Algae.

PubMed

Wang, Bo; Tao, Yuanyuan; Liu, Qisheng; Liu, Na; Jin, Zhong; Xu, Xiaohua

2017-08-07

Harmful algal blooms have become a great challenge to global aquatic ecosystems over the past decades. Given their low toxicity, high selectivity, and environment-friendly properties, the use of natural products and their analogues as algicides has proven to be particularly efficient. In the present study, algicidal activity of naturally occurring bacillamides A-C, alkaloid ( 1 ), and neobacillamide A, as well as their synthetic analogues were investigated intensively. Bioassay results showed that, relative to natural bacillamide alkaloids, aniline-derived analogue ( 10d ) exhibited higher algicidal potential against three freshwater harmful algae Mycrocyctis aeruginosa, Scenedesmus obliquus, and Chlorella pyrenoidosa , suggesting that it could be used as a promising lead compound to develop novel algicide for controlling harmful algal blooms.

Studies on G-protein alpha.betagamma heterotrimer formation reveal a putative S-prenyl-binding site in the alpha subunit.

PubMed Central

Dietrich, Alexander; Scheer, Alexander; Illenberger, Daria; Kloog, Yoel; Henis, Yoav I; Gierschik, Peter

2003-01-01

The alpha and betagamma subunits of heterotrimeric G-proteins contain specific lipid modifications, which are required for their biological function. However, the relevance of these modifications to the interactions within the heterotrimeric G-protein is not fully understood. In order to explore the role of the S-prenyl moiety of the isoprenylated betagamma dimer of retinal transducin, betagamma(t), in the formation of the heterotrimeric complex with the corresponding N-acylated alpha subunit, alpha(t), we employed purified fully processed subunits, which are soluble in aqueous solutions without detergents. Pertussis-toxin-mediated [(32)P]ADP-ribosylation of alpha(t) is strongly stimulated (approximately 10-fold) in the presence of betagamma(t) and can thus serve as a measure for heterotrimer formation. Using this assay, preincubation of alpha(t) with S-prenyl analogues containing farnesyl or geranylgeranyl moieties was found to inhibit heterotrimer formation in a dose-dependent manner. The inhibition was competitive and reversible, as indicated by its reversal upon increase of the betagamma(t) dimer concentration or by removal of the S-prenyl analogue using gel filtration. The competitive nature of the inhibition is supported by the marked attenuation of the inhibition when the S-prenyl analogue was added to alpha(t) together with or after betagamma(t). The inhibition does not involve interaction with the alpha(t) acyl group, since an S-prenyl analogue inhibited the [(32)P]ADP-ribosylation of an unlipidated alpha(t) mutant. These data suggest the existence of a hitherto unrecognized S-prenyl-binding site in alpha(t), which is critical for its interaction with prenylated betagamma(t). PMID:12952523

Synthesis, fungicidal activity, structure-activity relationships (SARs) and density functional theory (DFT) studies of novel strobilurin analogues containing arylpyrazole rings.

PubMed

Liu, Yuanyuan; Lv, Kunzhi; Li, Yi; Nan, Qiuli; Xu, Jinyuan

2018-05-18

A series of novel strobilurin analogues (1a-1f, 2a-2e, 3a-3e) containing arylpyrazole rings were synthesized and characterized by NMR spectroscopy. The structures of 1f, 2b and 3b were also determined by single crystal X-ray diffraction analysis. These analogues were collected together with other twenty-eight similar compounds 4a-4f, 5a-5h, 6a-6h and 7a-7f from our previous studies, for in vitro bioassays and thorough structure-activity relationships (SARs) studies. Most compounds exhibited excellent-to-good fungicidal activity against Rhizoctonia solani, especially 5c, 7a, 6c, and 3b with 98.94%, 83.40%, 71.40% and 65.87% inhibition rates at 0.1 μg mL -1 , respectively, better than commercial pyraclostrobin. Comparative molecular field analysis (CoMFA) was employed to study three-dimensional quantitative structure-activity relationships (3D-QSARs). Density functional theory (DFT) calculation was also carried out to provide more information regarding SARs. The present work provided some hints for developing novel strobilurin fungicides.

[C-terminal fragment of ribosomal protein S15 is located at the decoding site of the human ribosome].

PubMed

Khaĭrulina, Iu S; Molotkov, M V; Bulygin, K N; Graĭfer, D M; Ven'iaminova, A G; Karpova, G G

2008-01-01

Protein S15 is a characteristic component of the mammalian 80S ribosome that neighbors mRNA codon at the decoding site and the downstream triplets. In this study we determined S15 protein fragments located close to mRNA positions +4 to +12 with respect to the first nucleotide of the P site codon on the human ribosome. For cross-linking to ribosomal protein S15, a set of mRNA was used that contained triplet UUU/UUC at the 5'-termini and a perfluorophenyl azide-modified uridine in position 3' of this triplet. The locations of mRNA analogues on the ribosome were governed by tRNAPhe cognate to the UUU/UUC triplet targeted to the P site. Cross-linked S15 protein was isolated from the irradiated with mild UV light complexes of 80S ribosomes with tRNAPhe and mRNA analogues with subsequent cleavage with CNBr that splits polypeptide chain after methionines. Analysis of modified oligopeptides resulted from the cleavage revealed that in all cases cross-linking site was located in C-terminal fragment 111-145 of protein S15 indicating that this fragment is involved in formation of decoding site of the eukaryotic ribosome.

GnRH Analogues in the Prevention of Ovarian Hyperstimulation Syndrome

PubMed Central

Alama, Pilar; Bellver, Jose; Vidal, Carmen; Giles, Juan

2013-01-01

The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article. PMID:23825982

Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

PubMed

Singh, Vijay P; Poon, Jia-fei; Engman, Lars

2013-12-20

In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

Analyzing surface features on icy satellites using a new two-layer analogue model

NASA Astrophysics Data System (ADS)

Morales, K. M.; Leonard, E. J.; Pappalardo, R. T.; Yin, A.

2017-12-01

The appearance of similar surface morphologies across many icy satellites suggests potentially unified formation mechanisms. Constraining the processes that shape the surfaces of these icy worlds is fundamental to understanding their rheology and thermal evolution—factors that have implications for potential habitability. Analogue models have proven useful for investigating and quantifying surface structure formation on Earth, but have only been sparsely applied to icy bodies. In this study, we employ an innovative two-layer analogue model that simulates a warm, ductile ice layer overlain by brittle surface ice on satellites such as Europa and Enceladus. The top, brittle layer is composed of fine-grained sand while the ductile, lower viscosity layer is made of putty. These materials were chosen because they scale up reasonably to the conditions on Europa and Enceladus. Using this analogue model, we investigate the role of the ductile layer in forming contractional structures (e.g. folds) that would compensate for the over-abundance of extensional features observed on icy satellites. We do this by simulating different compressional scenarios in the analogue model and analyzing whether the resulting features resemble those on icy bodies. If the resulting structures are similar, then the model can be used to quantify the deformation by calculating strain. These values can then be scaled up to Europa or Enceladus and used to quantity the observed surface morphologies and the amount of extensional strain accommodated by certain features. This presentation will focus on the resulting surface morphologies and the calculated strain values from several analogue experiments. The methods and findings from this work can then be expanded and used to study other icy bodies, such as Triton, Miranda, Ariel, and Pluto.

Active-site-directed irreversible inhibitors of isopentenyl diphosphate isomerase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muhlbacher, M.

1987-01-01

Seven analogues of isopentenyl diphosphate, containing fluorine, epoxy, or ammonium functionalities were found to irreversibly inhibit isopentenyl diphosphate:dimethylallyl diphosphate isomerase isolated from the mold Claviceps purpurea. The mechanism of their inhibition of isomerase was studied. Syntheses of 3-(fluoromethyl)-3-buten-1-yl diphosphate, 2-dimethylamino-1-ethyl diphosphate, 3,4-epoxy-3-methyl-1-butyl diphosphate, 3,4,-epoxy-1-butyl diphosphate, and 2,3-epoxy-3-methyl-1-butyl diphosphate were developed and carried out in high overall yield affording 100 mg quantities of the triammonium diphosphate salts. Radiolabeled materials of these analogues with {sup 3}H, {sup 14}C, and {sup 32}P at appropriate positions were also prepared. Inactivation kinetics, substrate protection studies, and labeling experiments demonstrated that the analogues interact stoichiometrically withmore » the active-site of isomerase. Radioactive enzyme-inactivator complexes were isolated, that are stable to extended dialysis and chaotropic reagents. The complexes resulting from inactivation of the enzyme by 3-(fluoromethyl)-3-buten-1-yl diphosphate and 3,4-epoxy-3-methyl-1-butyl diphosphate are stable to ion exchange chromatography and gel electrophoresis. Stoichiometric fluoride ion release occurs during inactivation of isomerase with 3-(fluoromethyl)-3-buten-1-yl diphosphate. The complexes are not stable to high concentrations of mixtures of 2-mercaptoethanol-sodium dodecyl sulfate. The radiolabeled 2-dimethylamino-1-ethyl diphosphate isomerase complex loses radioactivity almost instantaneously when treated with base. Partial fragmentation of the inactivator molecule was observed.« less

Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation.

PubMed

Grimm, Marcus O W; Thiel, Andrea; Lauer, Anna A; Winkler, Jakob; Lehmann, Johannes; Regner, Liesa; Nelke, Christopher; Janitschke, Daniel; Benoist, Céline; Streidenberger, Olga; Stötzel, Hannah; Endres, Kristina; Herr, Christian; Beisswenger, Christoph; Grimm, Heike S; Bals, Robert; Lammert, Frank; Hartmann, Tobias

2017-12-19

Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

PubMed Central

Tutton, P. J.; Barkla, D. H.

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours. PMID:7362778

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

PubMed

Tutton, P J; Barkla, D H

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours.

A-site ordered quadruple perovskite oxides

NASA Astrophysics Data System (ADS)

Youwen, Long

2016-07-01

The A-site ordered perovskite oxides with chemical formula display many intriguing physical properties due to the introduction of transition metals at both A‧ and B sites. Here, research on the recently discovered intermetallic charge transfer occurring between A‧-site Cu and B-site Fe ions in LaCu3Fe4O12 and its analogues is reviewed, along with work on the magnetoelectric multiferroicity observed in LaMn3Cr4O12 with cubic perovskite structure. The Cu-Fe intermetallic charge transfer leads to a first-order isostructural phase transition accompanied by drastic variations in magnetism and electrical transport properties. The LaMn3Cr4O12 is a novel spin-driven multiferroic system with strong magnetoelectric coupling effects. The compound is the first example of cubic perovskite multiferroics to be found. It opens up a new arena for studying unexpected multiferroic mechanisms. Project supported by the National Basic Research Program of China (Grant No. 2014CB921500), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB07030300), and the National Natural Science Foundation of China (Grant No. 11574378).

Application of molecular docking and ONIOM methods for the description of interactions between anti-quorum sensing active (AHL) analogues and the Pseudomonas aeruginosa LasR binding site.

PubMed

Ahumedo, Maicol; Drosos, Juan Carlos; Vivas-Reyes, Ricardo

2014-05-01

Molecular docking methods were applied to simulate the coupling of a set of nineteen acyl homoserine lactone analogs into the binding site of the transcriptional receptor LasR. The best pose of each ligand was explored and a qualitative analysis of the possible interactions present in the complex was performed. From the results of the protein-ligand complex analysis, it was found that residues Tyr-64 and Tyr-47 are involved in important interactions, which mainly determine the antagonistic activity of the AHL analogues considered for this study. The effect of different substituents on the aromatic ring, the common structure to all ligands, was also evaluated focusing on how the interaction with the two previously mentioned tyrosine residues was affected. Electrostatic potential map calculations based on the electron density and the van der Waals radii were performed on all ligands to graphically aid in the explanation of the variation of charge density on their structures when the substituent on the aromatic ring is changed through the elements of the halogen group series. A quantitative approach was also considered and for that purpose the ONIOM method was performed to estimate the energy change in the different ligand-receptor complex regions. Those energy values were tested for their relationship with the corresponding IC50 in order to establish if there is any correlation between energy changes in the selected regions and the biological activity. The results obtained using the two approaches may contribute to the field of quorum sensing active molecules; the docking analysis revealed the role of some binding site residues involved in the formation of a halogen bridge with ligands. These interactions have been demonstrated to be responsible for the interruption of the signal propagation needed for the quorum sensing circuit. Using the other approach, the structure-activity relationship (SAR) analysis, it was possible to establish which structural characteristics

Glycosylation and intracellular transport of membrane glycoproteins encoded by murine leukemia viruses. Inhibition by amino acid analogues and by tunicamycin.

PubMed

Polonoff, E; Machida, C A; Kabat, D

1982-12-10

Addition of asparagine-linked oligosaccharides to nascent murine leukemia virus (MuLV)-encoded membrane glycoproteins was inhibited either completely by tunicamycin or specifically at Asn-X-Thr glycosylation sites by incorporation of the threonine analogue beta-hydroxynorvaline. In conditions of partial analogue substitution, a series of subglycosylated components is formed which are related by a constant apparent Mr difference when assayed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The total number of asparagine-linked oligosaccharides is then estimated by dividing the measured apparent Mr of one oligosaccharide into the total apparent Mr difference between the complete glycoprotein and the polypeptide chain that is synthesized in cells incubated with tunicamycin. Correct results were obtained using glycoproteins with known numbers of oligosaccharides. Our analyses indicate that the gp70 membrane envelope glycoproteins of certain ecotropic MuLVs contain seven oligosaccharides, whereas the GIX+ antigen-containing variant gp70 contains one fewer Asn-X-Thr-linked oligosaccharide. The membrane glycoprotein encoded by the gag gene of Friend MuLV contains only one asparagine-linked oligosaccharide. Similarly, the gp55 membrane glycoprotein encoded by Friend erythroleukemia virus contains four asparagine-linked oligosaccharides. Pulse-chase and cell surface iodination analyses indicate that MuLV membrane envelope glycoprotein processing by partial proteolysis and transport to the cell surface can be efficiently blocked by structural perturbations caused by incorporation of different amino acid analogues or by loss of oligosaccharides. Our data also suggest that loss of oligosaccharides may expose new antigenic sites in viral membrane glycoproteins and increase their susceptibility to intracellular proteolysis.

Climatic Forecasting of Net Infiltration at Yucca Montain Using Analogue Meteororological Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

B. Faybishenko

At Yucca Mountain, Nevada, future changes in climatic conditions will most likely alter net infiltration, or the drainage below the bottom of the evapotranspiration zone within the soil profile or flow across the interface between soil and the densely welded part of the Tiva Canyon Tuff. The objectives of this paper are to: (a) develop a semi-empirical model and forecast average net infiltration rates, using the limited meteorological data from analogue meteorological stations, for interglacial (present day), and future monsoon, glacial transition, and glacial climates over the Yucca Mountain region, and (b) corroborate the computed net-infiltration rates by comparing themmore » with the empirically and numerically determined groundwater recharge and percolation rates through the unsaturated zone from published data. In this paper, the author presents an approach for calculations of net infiltration, aridity, and precipitation-effectiveness indices, using a modified Budyko's water-balance model, with reference-surface potential evapotranspiration determined from the radiation-based Penman (1948) formula. Results of calculations show that net infiltration rates are expected to generally increase from the present-day climate to monsoon climate, to glacial transition climate, and then to the glacial climate. The forecasting results indicate the overlap between the ranges of net infiltration for different climates. For example, the mean glacial net-infiltration rate corresponds to the upper-bound glacial transition net infiltration, and the lower-bound glacial net infiltration corresponds to the glacial transition mean net infiltration. Forecasting of net infiltration for different climate states is subject to numerous uncertainties-associated with selecting climate analogue sites, using relatively short analogue meteorological records, neglecting the effects of vegetation and surface runoff and runon on a local scale, as well as possible anthropogenic climate

q-bosons and the q-analogue quantized field

NASA Technical Reports Server (NTRS)

Nelson, Charles A.

1995-01-01

The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues.

PubMed

Bharate, Sandip B; Bhutani, Kamlesh K; Khan, Shabana I; Tekwani, Babu L; Jacob, Melissa R; Khan, Ikhlas A; Singh, Inder Pal

2006-03-15

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.

The development and validation of the Visual Analogue Self-Esteem Scale (VASES).

PubMed

Brumfitt, S M; Sheeran, P

1999-11-01

To develop a visual analogue measure of self-esteem and test its psychometric properties. Two correlational studies involving samples of university students and aphasic speakers. Two hundred and forty-three university students completed multiple measures of self-esteem, depression and anxiety as well as measures of transitory mood and social desirability (Study 1). Two samples of aphasic speakers (N = 14 and N = 20) completed the Visual Analogue Self-Esteem Scale (VASES), the Rosenberg (1965) self-esteem scale and measures of depression and anxiety. (Study 2). Study 1 found evidence of good internal and test-retest reliability, construct validity and convergent and discriminant validity for a 10-item VASES. Study 2 demonstrated good internal reliability among aphasic speakers. The VASES is a short and easy to administer measure of self-esteem that possesses good psychometric properties.

[Synthesis and cytotoxicity of novel phosphorusless analogues of edelfosine].

PubMed

Romanova, S G; Shtil', A A; Serebrennikova, G A

2008-01-01

Modified series of phosphorusless edelfosine analogues bearing the polar heads of aliphatic bases, N,N-dimethylethanolamine and N,N,N(1),N(1)-tetramethylethylenediamine, were synthesized, with the length of the spacer varying from three to four methylene units. The cytotoxic characteristics of the compounds synthesized were studied.

Calpha methylation in molecular recognition. Application to substance P and the two neurokinin-1 receptor binding sites.

PubMed

Sagan, S; Lequin, O; Frank, F; Convert, O; Ayoub, M; Lavielle, S; Chassaing, G

2001-05-01

Two binding sites NK-1M (major, more abundant) and NK-1m (minor) are associated with the neurokinin-1 receptor. For the first time with a bioactive peptide, the Calpha methylation constraint, shown to be a helix stabiliser in model peptides, was systematically used to probe the molecular requirements of NK-1M and NK-1m binding sites and the previously postulated bioactive helical conformation of substance P (SP). Seven Calpha methylated analogues of the undecapeptide SP (from position 5-11) have been assayed for their affinities and their potencies to stimulate second messenger production. The consequences of Calpha methylation on the structure of SP have been analysed by circular dichroism and nuclear magnetic resonance combined with restrained molecular dynamics. The decreased potencies of six out of these seven Calpha methylated SP analogues do not allow the identification of any clear-cut differences in the structural requirements between the two binding sites. Strikingly, the most active analogue, [alphaMeMet5]SP, leads to variable subnanomolar affinity and potency when interacting with the NK-1m binding site. The conformational analyses show that the structural consequences associated with Calpha methylation of SP are sequence dependent. Moreover, a single Calpha methylation is not sufficient by itself to drastically stabilize a helical structure even pre-existing in solution, except when Gly9 is substituted by an alpha-aminoisobutyric acid. Furthermore, Calpha methylation of residues 5 and 6 of SP in the middle of the postulated helix does not stabilize, but decreases (to different extents) the stability of the helical structure previously observed in the 4-8 domain of other potent SP analogues.

Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation

PubMed Central

Evans, Elizabeth L; Cuthbertson, Kevin; Endesh, Naima; Rode, Baptiste; Blythe, Nicola M; Hyman, Adam J; Hall, Sally J; Gaunt, Hannah J; Ludlow, Melanie J

2018-01-01

Background and Purpose The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small‐molecule agonist, but the pharmacology of these channels is otherwise limited. Experimental Approach Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ and Tl+ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta. Key Results Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 μM Yoda1‐induced Ca2+‐entry with IC50s of 1.3 μM (HEK 293 cells) and 1.5 μM (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP‐evoked Ca2+ elevation or store‐operated Ca2+ entry in HEK 293 cells or Ca2+ entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose‐dependent relaxation of aortic rings, which was mediated by an endothelium‐ and NO‐dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1. Conclusion and Implications Chemical antagonism of Yoda1‐evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains. PMID:29498036

The Planetary Terrestrial Analogues Library (PTAL)

NASA Astrophysics Data System (ADS)

Werner, S. C.; Dypvik, H.; Poulet, F.; Rull Perez, F.; Bibring, J.-P.; Bultel, B.; Casanova Roque, C.; Carter, J.; Cousin, A.; Guzman, A.; Hamm, V.; Hellevang, H.; Lantz, C.; Lopez-Reyes, G.; Manrique, J. A.; Maurice, S.; Medina Garcia, J.; Navarro, R.; Negro, J. I.; Neumann, E. R.; Pilorget, C.; Riu, L.; Sætre, C.; Sansano Caramazana, A.; Sanz Arranz, A.; Sobron Grañón, F.; Veneranda, M.; Viennet, J.-C.; PTAL Team

2018-04-01

The Planetary Terrestrial Analogues Library project aims to build and exploit a spectral data base for the characterisation of the mineralogical and geological evolution of terrestrial planets and small solar system bodies.

Neurological Effects of Bisphenol A and its Analogues

PubMed Central

Inadera, Hidekuni

2015-01-01

The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

(D-Phe/sup 12/)bombesin analogues: a new class of bombesin receptor antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heinz-Erian, P.; Coy, D.H.; Tamura, M.

1987-03-01

Previous attempts to develop analogues of bombesin that function as specific receptor antagonists have been unsuccessful. Alteration of the histidine in luteinizing hormone releasing factor has resulted in analogues that function as competitive antagonists. In the present study the authors have used a similar strategy and altered the histidine in bombesin. (D-Phe/sup 12/)bombesin, (D-Phe/sup 12/,Leu/sup 14/)bombesin, and (Try/sup 4/, D-)je/sup 12/) bombesin did not stimulate amylase release from guinea pig pancreatic acini when present alone, but each analog inhibited bombesin-stimulated secretion. For each analog, detectable inhibition occurred at 1 ..mu..M and half-maximal inhibition at 4 ..mu..M. Each analog inhibited amylasemore » release by bombesin and other agonists that stimulate secretion by interacting with bombesin receptors. The analogues of bombesin did not alter stimulation by substance P or other agonists that interact with other receptors. The inhibition of the action of bombesin was competitive with Schild plots having slopes of 1.0. Each analog also inhibited binding of /sup 125/I-labeled (Try/sup 4/) bombesin but not /sup 125/I-labeled substance P. These results demonstrate that (D-Phe/sup 12/) analogues of bombesin function as bombesin receptor antagonists and are the only bombesin receptor antagonists that interact only with the bombesin receptor. Because of their specificity, these analogues may prove useful for defining the role of bombesin in various physiological or pathological processes.« less

Synthesis, structural studies and biological properties of new TBA analogues containing an acyclic nucleotide.

PubMed

Coppola, Teresa; Varra, Michela; Oliviero, Giorgia; Galeone, Aldo; D'Isa, Giuliana; Mayol, Luciano; Morelli, Elena; Bucci, Maria-Rosaria; Vellecco, Valentina; Cirino, Giuseppe; Borbone, Nicola

2008-09-01

A new modified acyclic nucleoside, namely N(1)-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-thymidine, was synthesized and transformed into a building block useful for oligonucleotide (ON) automated synthesis. A series of modified thrombin binding aptamers (TBAs) in which the new acyclic nucleoside replaces, one at the time, the thymidine residues were then synthesized and characterized by UV, CD, MS, and (1)H NMR. The biological activity of the resulting TBAs was tested by Prothrombin Time assay (PT assay) and by purified fibrinogen clotting assay. From a structural point of view, nearly all the new TBA analogues show a similar behavior as the unmodified counterpart, being able to fold into a bimolecular or monomolecular quadruplex structure depending on the nature of monovalent cations (sodium or potassium) coordinated in the quadruplex core. From the comparison of structural and biological data, some important structure-activity relationships emerged, particularly when the modification involved the TT loops. In agreement with previous studies we found that the folding ability of TBA analogues is more affected by modifications involving positions 4 and 13, rather than positions 3 and 12. On the other hand, the highest anti-thrombin activities were detected for aptamers containing the modification at T13 or T12 positions, thus indicating that the effects produced by the introduction of the acyclic nucleoside on the biological activity are not tightly connected with structure stabilities. It is noteworthy that the modification at T7 produces an ON being more stable and active than the natural TBA.

Hawai'i and Gale Crater: A Mars Analogue Study of Igneous, Sedimentary, Weathering, and Alteration Trends in Geochemistry

NASA Technical Reports Server (NTRS)

Berger, J. A.; Flemming, R. L.; Schmidt, M. E.; Gellert, R.; Morris, R. V.; Ming, D. W.

2017-01-01

Sedimentary rocks in Gale Crater on Mars indicate a varied provenance with a range of alteration and weathering [1, 2]. Geochemical trends identified in basaltic and alkalic sedimentary rocks by the Alpha Particle X-ray Spectrometer (APXS) on the Mars rover Curiosity represent a complex interplay of igneous, sedimentary, weathering, and alteration processes. Assessing the relative importance of these processes is challenging with unknown compositions for parent sediment sources and with the constraints provided by Curiosity's instruments. We therefore look to Mars analogues on Earth where higher-resolution analyses and geologic context can constrain interpretations of Gale Crater geochemical observations. We selected Maunakea (AKA Mauna Kea) and Kohala volcanoes, Hawai'i, for an analogue study because they are capped by post-shield transitional basalts and alkalic lavas (hawaiites, mugearites) with compositions similar to Gale Crater [1, 3]. Our aim was to characterize Hawaiian geochemical trends associated with igneous processes, sediment transport, weathering, and alteration. Here, we present initial results and discuss implications for selected trends observed by APXS in Gale Crater.

Some fluorescence properties of dimethylaminochalcone and its novel cyclic analogues

NASA Astrophysics Data System (ADS)

Tomečková, Vladimíra; Poškrobová, Martina; Štefanišinová, Miroslava; Perjési, Pál

2009-12-01

This paper demonstrates the basic character (polarity, solubility, colour, absorption and fluorescence quantum yield) of synthetic dimethylaminochalcone ( 1) and its cyclic analogues measured in toluene, chloroform, dimethylsulfoxide and ethanol, which have been studied by absorption and fluorescence spectroscopy. The biologically active dye 4'-dimethylaminochalcone ( 1b) and its less flexible analogues 4-dimethylaminoindanone ( 2b), -tetralone ( 3b), and -benzosuberone ( 4b) are lipophilic molecules that displayed the best solubility in toluene and chloroform. The highest fluorescence and quantum yields of compounds 1 and 2 have been obtained in DMSO and chloroform. Quenching effect of fluorescence compounds ( 1- 4) has been studied in the mixture of the most polar organic solvents DMSO and water. In the presence of water, fluorescence of compound 1 has been quenched the best from all studied chalcones and emission maxima of molecules 1- 4 have been shifted to the longer wavelengths. Quenching effect of fluorescence by water was in order 1 > 2 > 3 > 4.

Algicidal Activity of Bacillamide Alkaloids and Their Analogues against Marine and Freshwater Harmful Algae

PubMed Central

Wang, Bo; Tao, Yuanyuan; Liu, Qisheng; Liu, Na; Jin, Zhong; Xu, Xiaohua

2017-01-01

Harmful algal blooms have become a great challenge to global aquatic ecosystems over the past decades. Given their low toxicity, high selectivity, and environment-friendly properties, the use of natural products and their analogues as algicides has proven to be particularly efficient. In the present study, algicidal activity of naturally occurring bacillamides A–C, alkaloid (1), and neobacillamide A, as well as their synthetic analogues were investigated intensively. Bioassay results showed that, relative to natural bacillamide alkaloids, aniline-derived analogue (10d) exhibited higher algicidal potential against three freshwater harmful algae Mycrocyctis aeruginosa, Scenedesmus obliquus, and Chlorella pyrenoidosa, suggesting that it could be used as a promising lead compound to develop novel algicide for controlling harmful algal blooms. PMID:28783131

ATP analogues at a glance.

PubMed

Bagshaw, C

2001-02-01

ATP has long been known to play a central role in the energetics of cells both in transduction mechanisms and in metabolic pathways, and is involved in regulation of enzyme, channel and receptor activities. Numerous ATP analogues have been synthesised to probe the role of ATP in biosystems (Yount, 1975; Jameson and Eccleston, 1997; Bagshaw, 1998). In general, two contrasting strategies are employed. Modifications may be introduced deliberately to change the properties of ATP (e.g. making it non-hydrolysable) so as to perturb the chemical steps involved in its action. Typically these involve modification of the phosphate chain. Alternatively, derivatives (e.g. fluorescent probes) are designed to report on the action of ATP but have a minimal effect on its properties. ATP-utilising systems vary enormously in their specificity; so what acts as a good analogue in one case may be very poor in another. The accompanying poster shows a representative selection of derivatives that have been synthesised and summarises their key properties.

Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

PubMed Central

Tijono, S M; Guo, K; Henare, K; Palmer, B D; Wang, L-C S; Albelda, S M; Ching, L-M

2013-01-01

Background: Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models. Methods: Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts. Results: Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems. Conclusion: Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds. PMID:23481185

Validity and reproducibility of cephalometric measurements obtained from digital photographs of analogue headfilms.

PubMed

Grybauskas, Simonas; Balciuniene, Irena; Vetra, Janis

2007-01-01

The emerging market of digital cephalographs and computerized cephalometry is overwhelming the need to examine the advantages and drawbacks of manual cephalometry, meanwhile, small offices continue to benefit from the economic efficacy and ease of use of analogue cephalograms. The use of modern cephalometric software requires import of digital cephalograms or digital capture of analogue data: scanning and digital photography. The validity of digital photographs of analogue headfilms rather than original headfilms in clinical practice has not been well established. Digital photography could be a fast and inexpensive method of digital capture of analogue cephalograms for use in digital cephalometry. The objective of this study was to determine the validity and reproducibility of measurements obtained from digital photographs of analogue headfilms in lateral cephalometry. Analogue cephalometric radiographs were performed on 15 human dry skulls. Each of them was traced on acetate paper and photographed three times independently. Acetate tracings and digital photographs were digitized and analyzed in cephalometric software. Linear regression model, paired t-test intergroup analysis and coefficient of repeatability were used to assess validity and reproducibility for 63 angular, linear and derivative measurements. 54 out of 63 measurements were determined to have clinically acceptable reproducibility in the acetate tracing group as well as 46 out of 63 in the digital photography group. The worst reproducibility was determined for measurements dependent on landmarks of incisors and poorly defined outlines, majority of them being angular measurements. Validity was acceptable for all measurements, and although statistically significant differences between methods existed for as many as 15 parameters, they appeared to be clinically insignificant being smaller than 1 unit of measurement. Validity was acceptable for 59 of 63 measurements obtained from digital photographs

Luciferase-Specific Coelenterazine Analogues for Optical Contamination-Free Bioassays.

PubMed

Nishihara, Ryo; Abe, Masahiro; Nishiyama, Shigeru; Citterio, Daniel; Suzuki, Koji; Kim, Sung Bae

2017-04-19

Spectral overlaps among the multiple optical readouts commonly cause optical contamination in fluorescence and bioluminescence. To tackle this issue, we created five-different lineages of coelenterazine (CTZ) analogues designed to selectively illuminate a specific luciferase with unique luciferase selectivity. In the attempt, we found that CTZ analogues with ethynyl or styryl groups display dramatically biased bioluminescence to specific luciferases and pHs by modifying the functional groups at the C-2 and C-6 positions of the imidazopyradinone backbone of CTZ. The optical contamination-free feature was exemplified with the luciferase-specific CTZ analogues, which illuminated anti-estrogenic and rapamycin activities in a mixture of optical probes. This unique bioluminescence platform has great potential for specific and high throughput imaging of multiple optical readouts in bioassays without optical contamination.

Spectroscopic characterization of metal bound phytochelatin analogue (Glu-Cys)4-Gly.

PubMed

Cheng, Yongsheng; Yan, Yong-Bin; Liu, Jinyuan

2005-10-01

The metal ion binding properties of a phytochelatin (PC) analogue, (Glu-Cys)4-Gly (named as EC4), have been studied by a divalent metal ion binding assay monitored by UV-visible spectroscopy, circular dichroism and NMR spectroscopy. Spectro- photometric titration with different divalent metal ions have revealed that the stiochoimetry of metal-bound EC4 was 1:1, and its metal binding affinities with different divalent metal ions in the order of Cd(II)>Cu(II)>Zn(II)>Pb(II)>Ni(II)>Co(II). UV-visible spectroscopic analysis of metal complexes indicated that four sulfur atoms in cysteine residues are attributable to ligand-to-metal charge transfer (LMCT) between divalent metal ions and EC4, and further confirmed by 1D H1 NMR study and Circular Dichroism. In addition, Circular Dichroism spectra of both free and metal-bound forms of EC4 revealed that metal coordination drives the nonapeptide chain to fold into a turned conformation. The comprehensive analysis of spectroscopic properties of the nonapeptide complexed with metal ions not only provides a fundamental description of the metal ion binding properties of PC analogue, but also shows a correlation between metal binding affinity of PC analogue and the induction activity of metal ions.

Neoglycolipid analogues of ganglioside G sub M1 as functional receptors of cholera toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pacuszka, T.; Bradley, R.M.; Fishman, P.H.

1991-03-12

The authors synthesized several lipid analogues of ganglioside G{sub M1} by attaching its oligosaccharide moiety (G{sub M1}OS) to aminophospholipids, aliphatic amines, and cholesteryl hemisuccinate. They incubated G{sub M1}-deficient rat glioma C6 cells with each of the derivatives as well as native G{sub M1} and assayed the cells for their ability to bind and respond to cholera toxin. On the basis of the observed increase in binding of {sup 125}I-labeled cholera toxin, it was apparent that the cells took up and initially incorporated most of the derivatives into the plasma membrane. In the case of the aliphatic amine derivatives, the abilitymore » to generate new toxin binding sites was dependent on chain length; whereas the C{sub 10} derivative was ineffective, C{sub 12} and higher analogues were effective. Increased binding was dependent on both the concentration of the neoglycolipid in the medium and the time of exposure. Cells pretreated with the various derivatives accumulated cyclic AMP in response to cholera toxin, but there were differences in their effectiveness. The cholesterol and long-chain aliphatic amine derivatives were more effective than native G{sub M1}, whereas the phospholipid derivatives were less effective. The distance between G{sub M1}OS and the phospholipid also appeared to influence its functional activity. The results indicate that although G{sub M1}OS provides the recognition site for the binding of cholera toxin, the nature of the lipid moiety plays an important role in the action of the toxin.« less

A thiamin-bound, pre-decarboxylation reaction intermediate analogue in the pyruvate dehydrogenase E1 subunit induces large scale disorder-to-order transformations in the enzyme and reveals novel structural features in the covalently bound adduct.

PubMed

Arjunan, Palaniappa; Sax, Martin; Brunskill, Andrew; Chandrasekhar, Krishnamoorthy; Nemeria, Natalia; Zhang, Sheng; Jordan, Frank; Furey, William

2006-06-02

The crystal structure of the E1 component from the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc) has been determined with phosphonolactylthiamin diphosphate (PLThDP) in its active site. PLThDP serves as a structural and electrostatic analogue of the natural intermediate alpha-lactylthiamin diphosphate (LThDP), in which the carboxylate from the natural substrate pyruvate is replaced by a phosphonate group. This represents the first example of an experimentally determined, three-dimensional structure of a thiamin diphosphate (ThDP)-dependent enzyme containing a covalently bound, pre-decarboxylation reaction intermediate analogue and should serve as a model for the corresponding intermediates in other ThDP-dependent decarboxylases. Regarding the PDHc-specific reaction, the presence of PLThDP induces large scale conformational changes in the enzyme. In conjunction with the E1-PLThDP and E1-ThDP structures, analysis of a H407A E1-PLThDP variant structure shows that an interaction between His-407 and PLThDP is essential for stabilization of two loop regions in the active site that are otherwise disordered in the absence of intermediate analogue. This ordering completes formation of the active site and creates a new ordered surface likely involved in interactions with the lipoyl domains of E2s within the PDHc complex. The tetrahedral intermediate analogue is tightly held in the active site through direct hydrogen bonds to residues His-407, Tyr-599, and His-640 and reveals a new, enzyme-induced, strain-related feature that appears to aid in the decarboxylation process. This feature is almost certainly present in all ThDP-dependent decarboxylases; thus its inclusion in our understanding of general thiamin catalysis is important.

A comparative study on the crystal structure of bicycle analogues to the natural phytotoxin helminthosporins

NASA Astrophysics Data System (ADS)

Barbosa, Luiz Cláudio de Almeida; Teixeira, Robson Ricardo; Nogueira, Leonardo Brandão; Maltha, Celia Regina Alvares; Doriguetto, Antônio Carlos; Martins, Felipe Terra

2016-02-01

Herein we described structural insights of a series of analogues to helminthosporin phytotoxins. The key reaction used to prepare the compounds corresponded to the [3 + 4] cycloaddition between the oxyallyl cation generated from 2,4-dibromopentan-3-one and different furans. Their structures were confirmed upon IR, NMR and X-ray diffraction analyses. While bicycles 7, 8 and 9 crystallize in the centrosymmetric monoclinic space group P21/c, compound 10 was solved in the noncentrosymmetric orthorhombic space group P212121. The solid materials obtained were shown to be racemic crystals (7, 8, 9) or racemic conglomerate (10). In all compounds, there is formation of a bicycle featured by fused tetrahydropyranone and 2,5-dihydrofuran rings. They adopt chair and envelope conformations, respectively. Crystal packing of all compounds is stabilized through C-H•••O contacts. Conformational aspects as well as similarities and differences among the crystal structures of the synthesized analogues are discussed.

Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue.

PubMed

Shekh-Ahmad, Tawfeeq; Bialer, Meir; Yavin, Eylon

2012-02-01

Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds. New conjugation products between N,N'-dimethylethanolamine to VPA and TMCA to form N,N-dimethylethanolamine valproate (DEVA) and N,N-dimethylethanolamine 2,2,3,3-tetramethylcyclopropionate were synthesized and their anticonvulsant activity was assessed in the maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) seizure tests and the hippocampal kindling model in mice and/or rats. An amide analogue of DEVA (DEVAMIDE) was also synthesized and evaluated. The pharmacokinetics of DEVA and DEVAMIDE was comparatively evaluated in rats. In rats DEVA acted as a prodrug of VPA and had ED(50) values of 73 mg/kg and 158 mg/kg in the MES and the hippocampal kindling models, respectively. At these two anticonvulsant models DEVA was seven-times more potent than VPA. DEVAMIDE was active in the MES test at doses of 100 mg/kg (mice) and its rat-MES-ED(50)=38.6 mg/kg however, its protective index (PI=TD(50)/ED(50)) was twice lower than DEVA's PI. The TMCA analogues were inactive at the mice MES and scMet models. DEVA underwent rapid metabolic hydrolysis to VPA and consequently, in its pharmacokinetic analysis only VPA plasma levels were monitored. In contrast, DEVAMIDE was stable in whole blood. DEVA acts in rats as a prodrug of VPA yet shows a more potent anticonvulsant activity than VPA. DEVAMIDE acted as the drug on its own and was more potent than DEVA at the rat-MES test. Copyright © 2011 Elsevier B.V. All rights reserved.

Divergent strategy for the synthesis of alpha-aryl-substituted fosmidomycin analogues.

PubMed

Devreux, Vincent; Wiesner, Jochen; Jomaa, Hassan; Rozenski, Jef; Van der Eycken, Johan; Van Calenbergh, Serge

2007-05-11

Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin.

Vitual screening and binding mode elucidation of curcumin analogues on Cyclooxygenase-2 using AYO_COX2_V1.1 protocol

NASA Astrophysics Data System (ADS)

Mulatsari, E.; Mumpuni, E.; Herfian, A.

2017-05-01

Curcumin is yellow colored phenolic compounds contained in Curcuma longa. Curcumin is known to have biological activities as anti-inflammatory, antiviral, antioxidant, and anti-infective agent [1]. Synthesis of curcumin analogue compounds has been done and some of them had biological activity like curcumin. In this research, the virtual screening of curcumin analogue compounds has been conducted. The purpose of this research was to determine the activity of these compounds as selective Cyclooxygenase-2inhibitors in in-silico. Binding mode elucidation was made by active and inactive representative compounds to see the interaction of the amino acids in the binding site of the compounds. This research used AYO_COX2_V.1.1, a structure-based virtual screening protocol (SBVS) that has been validated by Mumpuni E et al, 2014 [2]. AYO_COX2_V.1.1 protocol using a variety of integrated applications such as SPORES, PLANTS, BKchem, OpenBabel and PyMOL. The results of virtual screening conducted on 49 curcumin analogue compounds obtained 8 compounds with 4 active amino acid residues (GLY340, ILE503, PHE343, and PHE367) that were considered active as COX-2 inhibitor.

Structure-function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery.

PubMed

Cheng, Jianjun; Zeidan, Ryan; Mishra, Swaroop; Liu, Aijie; Pun, Suzie H; Kulkarni, Rajan P; Jensen, Gregory S; Bellocq, Nathalie C; Davis, Mark E

2006-11-02

To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essential to provide increased gene expression. Further, the enhancements are more dramatically affected by changes to the aromatic ring and are positively correlated to the strength of intercalation between DNA and the CQ analogues. Quinacrine (QC), a CQ analogue with a fused acridinyl structure that can strongly intercalate DNA, enhances transfection similarly to CQ at a concentration 10 times lower, while N(4)-(4-pyridinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CP), a CQ analogue that has a weakly intercalating pyridinyl ring, shows no effect on gene expression. Subtle change on the 7-substituent of the chloroquine aromatic structure can also greatly affect the ability of the CQ analogues to enhance transgene expression. Transfection in the presence of N(4)-(7-trifluoromethyl-4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamin e (CQ7a) shows expression efficiency 10 times higher than in the presence of CQ at same concentration, while transfection in the presence of N(4)-(4-quinolinyl)-N(1),N(1)-diethyl-1,4-pentanediamine (CQ7b) does not reveal any enhancing effects on expression. Through a number of comparative studies with CQ and its analogues, we conclude that there are at least three mechanistic features of CQ that lead to the enhancement in gene expression: (i) pH buffering in endocytic vesicles, (ii) displacement of polycations from the nucleic acids in polyplexes, and (iii) alteration of the biophysical properties of the released nucleic acid.

Novel synthesis of cyclic amide-linked analogues of angiotensins II and III.

PubMed

Matsoukas, J M; Hondrelis, J; Agelis, G; Barlos, K; Gatos, D; Ganter, R; Moore, D; Moore, G J

1994-09-02

Cyclic amide-linked angiotension II (ANGII) analogues have been synthesized by novel strategies, in an attempt to test the ring clustering and the charge relay bioactive conformation recently suggested. These analogues were synthesized by connecting side chain amino and carboxyl groups at positions 1 and 8, 2 and 8, 3 and 8, and 3 and 5, N-terminal amino and C-terminal carboxyl groups at positions 1 and 8, 2 and 8, and 4 and 8, and side chain amino to C-terminal carboxyl group at positions 1 and 8. All these analogues were biologically inactive, except for cyclic [Sar1, Asp3, Lys5]ANGII (analogue 10) which had high contractile activity in the rat uterus assay (30% of ANGII) and [Lys1, Tyr(Me)4, Glu8]ANGII (analogue 7) which had weak antagonist activity (PA2 approximately 6). Precyclic linear peptides synthesized using 2-chlorotrityl chloride resin and N alpha-Fmoc-amino acids with suitable side chain protection were obtained in high yield and purity and were readily cyclized with benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate as coupling reagent. Molecular modeling suggests that the ring structure of the potent analogue can be accommodated in the charge relay conformation proposed for ANGII.

Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation

PubMed Central

Winkler, Jakob; Lehmann, Johannes; Regner, Liesa; Nelke, Christopher; Janitschke, Daniel; Benoist, Céline; Streidenberger, Olga; Stötzel, Hannah; Endres, Kristina; Beisswenger, Christoph; Bals, Robert; Lammert, Frank; Hartmann, Tobias

2017-01-01

Alzheimer’s disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D2 and D3 analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention. PMID:29257109

Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues.

PubMed

Mayo, Bronwen J; Stringer, Andrea M; Bowen, Joanne M; Bateman, Emma H; Keefe, Dorothy M

2017-02-01

A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.

Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.

PubMed

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-05-01

Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (σp ) and lipophilic (πp ) parameters of the para substituents. For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity. © 2014 The British Pharmacological Society.

Quantitative structure–activity relationship analysis of the pharmacology of para-substituted methcathinone analogues

PubMed Central

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-01-01

Background and Purpose Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure–activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents. Experimental Approach For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. Key Results MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Conclusions and Implications Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es) are key determinants of this selectivity. PMID:25438806

Unravelling the binding mechanism and protein stability of human serum albumin while interacting with nefopam analogues: a biophysical and insilico approach.

PubMed

Gokara, Mahesh; Narayana, Vidadala V; Sadarangani, Vineet; Chowdhury, Shatabdi Roy; Varkala, Sreelaxmi; Ramachary, Dhevalapally B; Subramanyam, Rajagopal

2017-08-01

In this study, molecular binding affinity was investigated for Nefopam analogues (NFs), a functionalized benzoxazocine, with human serum albumin (HSA), a major transport protein in the blood. Its binding affinity and concomitant changes in its conformation, binding site and simulations were also studied. Fluorescence data revealed that the fluorescence quenching of HSA upon binding of NFs analogues is based on a static mechanism. The three analogues of NFs binding constants (K A ) are in the order of NF3 > NF2 > NF1 with values of 1.53 ± .057 × 10 4 , 2.16 ± .071 × 10 4 and 3.6 ± .102 × 10 5  M -1 , respectively. Concurrently, thermodynamic parameters indicate that the binding process was spontaneous, and the complexes were stabilized mostly by hydrophobic interactions, except for NF2 has one hydrogen bond stabilizes it along with hydrophobic interactions. Circular dichroism (CD) studies revealed that there is a decrease in α-helix with an increase in β-sheets and random coils signifying partial unfolding of the protein upon binding of NFs, which might be due to the formation of NFs-HSA complexes. Further, molecular docking studies showed that NF1, NF2 and NF3 bound to subdomains IIIA, IB and IIA through hydrophobic interactions. However, NF1 have additionally formed a single hydrogen bond with LYS 413. Furthermore, molecular simulations unveiled that NFs binding was in support with the structural perturbation observed in CD, which is evident from the root mean square deviation and R g fluctuations. We hope our insights will provide ample scope for engineering new drugs based on the resemblances with NFs for enhanced efficacy with HSA.

Structure-based optimization of Cephalothin-analogue boronic acids as β-lactamase inhibitors

PubMed Central

Morandi, Stefania; Morandi, Federica; Caselli, Emilia; Shoichet, Brian K.; Prati, Fabio

2008-01-01

Boronic acids have proved to be promising selective inhibitors of β-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC β-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed. PMID:17997318

Cross-reactivity of amphetamine analogues with Roche Abuscreen radioimmunoassay reagents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cody, J.T.

1990-01-01

Cross-reactivity of amphetamine analogues with the Abuscreen amphetamine radioimmunoassay reagents was determined for both the standard and high specificity antibody systems. Compounds tested included 2-methoxyamphetamine, 4-hydroxymethamphetamine, 2,5-dimethoxyamphetamine (DMA), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-bromo-2,5-dimethoxy-beta-phenethylamine (BDMPEA), 3,4,5-trimethoxyamphetamine (TMA), 3,4-methylenedioxyamphetamine (MDA), N,N-dimethyl-3,4-methylenedioxyamphetamine and N-hydroxy-3,4-methylenedioxyamphetamine (N-OH MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-methylamphetamine (DOM), and 3,4,5-trimethoxyphenethylamine (mescaline). Blank negative reference material was spiked with 1,000 to 100,000 ng/mL of the amphetamine analogue and used as sample in the assays. MDA was the only analogue that showed cross reactivity equal to or greater than that of amphetamine. None of the other analogue compounds demonstrated a positive resultmore » at even the highest concentration; however several showed depressed counts at various concentration levels.« less

A Facile Semi-Synthetic Approach towards Halogen-Substituted Aminobenzoic Acid Analogues of Platensimycin.

PubMed

Qiu, Lin; Tian, Kai; Pan, Jian; Jiang, Lin; Yang, Hu; Zhu, Xiangcheng; Shen, Ben; Duan, Yanwen; Huang, Yong

2017-02-09

Platensimycin (PTM), produced by several strains of Streptomyces platensis, is a promising drug lead for infectious diseases and diabetes. The recent pilot-scale production of PTM from S. platensis SB12026 has set the stage for the facile semi-synthesis of a focused library of PTM analogues. In this study, gram-quantity of platensic acid (PTMA) was prepared by the sulfuric acid-catalyzed ethanolysis of PTM, followed by a mild hydrolysis in aqueous lithium hydroxide. Three PTMA esters were also obtained in near quantitative yields in a single step, suggesting a facile route to make PTMA aliphatic esters. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU)-catalyzed coupling of PTMA and 33 aminobenzoates resulted in the synthesis of 28 substituted aminobenzoate analogues of PTM, among which 26 of them were reported for the first time. Several of the PTM analogues showed weak antibacterial activity against methicillin-resistant Staphylococcus aureus. Our study supported the potential utility to integrate natural product biosynthetic and semi-synthetic approaches for structure diversification.

Physical Properties of Granulates Used in Analogue Experiments of Caprock Failure and Sediment Remobilisation

NASA Astrophysics Data System (ADS)

Kukowski, N.; Warsitzka, M.; May, F.

2014-12-01

Geological systems consisting of a porous reservoir and a low-permeable caprock are prone to hydraulic fracturing, if pore pressure rises to the effective stress. Under certain conditions, hydraulic fracturing is associated with sediment remobilisation, e.g. sand injections or pipes, leading to reduced seal capacity of the caprock. In dynamically scaled analogue experiments using granular materials and air pressure, we intent to investigate strain patterns and deformation mechanisms during caprock failure and fluidisation of shallow over-pressured reservoirs. The aim of this study is to improve the understanding of leakage potential of a sealing formation and the fluidisation potential of a reservoir formation depending on rock properties and effective stress. For reliable interpretation of analogue experiments, physical properties of analogue materials, e.g. frictional strength, cohesion, density, permeability etc., have to be correctly scaled according to those of their natural equivalents. The simulation of caprock requires that the analogue material possess a low permeability and is capable to shear failure and tensional failure. In contrast, materials representing the reservoir have to possess high porosity and low shear strength. In order to find suitable analogue materials, we measured the stress-strain behaviour and the permeability of over 25 different types of natural and artificial granular materials, e.g. glass powder, siliceous microspheres, diatomite powder, loess, or plastic granulate. Here, we present data of frictional parameters, compressibility and permeability of these granular materials characterized as a function of sphericity, grain size, and density. The repertoire of different types of granulates facilitates the adjustment of accurate mechanical properties in the analogue experiments. Furthermore, conditions during seal failure and fluidisation can be examined depending on the wide range of varying physical properties.

Habitability & Astrobiology Research in Mars Terrestrial Analogues

NASA Astrophysics Data System (ADS)

Foing, Bernard

2014-05-01

Journal of Astrobiology , IJA 2011, 10, vol. 3. 137-305 [1] Foing B. et al. (2011) Field astrobiology research at Moon-Mars analogue site: Instruments and methods, IJA 2011, 10 (3), 141;[2] Clarke, J., Stoker, C. Concretions in exhumed & inverted channels near Hanksville Utah: implications for Mars, (IJA 2011, 10 (3), 162;[3] Thiel et al., (2011) PCR-based analysis of microbial communities during the EuroGeoMars campaign at Mars Desert Research Station, Utah. (IJA 2011, 10 (3), 177;[4] Direito et al. (2011). A wide variety of putative extremophiles and large beta-diversity at the Mars Desert Research Station (Utah). (IJA 2011, 10 (3), 191;[5] Orzechowska, G. et al (20110 analysis of Mars Analog soils using solid Phase Microextraction, Organics solvent extraction and GCMS, (IJA 2011, 10 (3), 209; [6] Kotler et al. (2011). Analysis of mineral matrices of planetary soils analogs from the Utah Desert. (IJA 2011, 10 (3), 221; [7] Martins et al. (2011). Extraction of amino acids from soils close to the Mars Desert Research Station (MDRS), Utah. (IJA 2011, 10 (3), 231; [8] Ehrenfreund et al. (2011) Astrobiology and habitability studies in preparation for future Mars missions: trends from investigating minerals, organics and biota. (IJA 2011, 10 (3), 239; [9] Stoker C. et al (2011) Mineralogical, Chemical, Organic & Microbial Properties of Subsurface Soil Cores from Mars Desert Research Station, a Phyllosilicate and Sulfate Rich Mars Analog Site, IJA 2011, 10 (3), 269; [10] Rodrigues L. et al (2014, in preparation) Preventing biocontamination during sterile sampling; [11] Rodrigues L. et al (2014, in preparation) Microbial diversity in MDRS rocks and soils; [12] ILEWG EuroMoonMars Team, (2014, special issue in preparation) Results from ILEWG EuroMoonMars campaign 2013 **Acknowledgements: B.H.Foing (1, 2, 6), C. Stoker (3), P. Ehrenfreund (4, 5), I. Rammos (2), L. Rodrigues (2), A. Svendsen (2), D. Oltheten (2), K. Nebergall (6), M. Battler (6, 7), H. v't Houd (8), A. Bruneau (6

Analogue and digital linear modulation techniques for mobile satellite

NASA Technical Reports Server (NTRS)

Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

1990-01-01

The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

Comparative study of the effect of BPA and its selected analogues on hemoglobin oxidation, morphological alterations and hemolytic changes in human erythrocytes.

PubMed

Maćczak, Aneta; Bukowska, Bożena; Michałowicz, Jaromir

2015-01-01

Bisphenol A (BPA) has been shown to provoke many deleterious impacts on human health, and thus it is now successively substituted by BPA analogues, whose effects have been poorly investigated. Up to now, only one study has been realized to assess the effect of BPA on human erythrocytes, which showed its significant hemolytic and oxidative potential. Moreover, no study has been conducted to evaluate the effect of BPA analogues on red blood cells. The purpose of the present study was to compare the impact of BPA and its selected analogues such as bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF) on hemolytic and morphological changes and hemoglobin oxidation (methemoglobin formation) of human erythrocytes. The erythrocytes were incubated with different bisphenols concentrations ranging from 0.5 to 500μg/ml for 1, 4 and 24h. The compounds examined caused hemolysis in human erythrocytes with BPAF exhibiting the strongest effect. All bisphenols examined caused methemoglobin formation with BPA inducing the strongest oxidative potential. Flow cytometry analysis showed that all bisphenols (excluding BPS) induced significant changes in erythrocytes size. Changes in red blood cells shape were conducted using phase contrast microscopy. It was noticed that BPA and BPAF induced echinocytosis, BPF caused stomatocytosis, while BPS did not provoke significant changes in shape of red blood cells. Generally, the results showed that BPS, which is the main substituent of bisphenol A in polymers and thermal paper production, exhibited significantly lower disturbance of erythrocyte functions than BPA. Copyright © 2015 Elsevier Inc. All rights reserved.

Design of novel analogues of short antimicrobial peptide anoplin with improved antimicrobial activity.

PubMed

Wang, Yang; Chen, Jianbo; Zheng, Xin; Yang, Xiaoli; Ma, Panpan; Cai, Ying; Zhang, Bangzhi; Chen, Yuan

2014-12-01

Currently, novel antibiotics are urgently required to combat the emergence of drug-resistant bacteria. Antimicrobial peptides with membrane-lytic mechanism of action have attracted considerable interest. Anoplin, a natural α-helical amphiphilic antimicrobial peptide, is an ideal research template because of its short sequence. In this study, we designed and synthesized a group of analogues of anoplin. Among these analogues, anoplin-4 composed of D-amino acids displayed the highest antimicrobial activity due to increased charge, hydrophobicity and amphiphilicity. Gratifyingly, anoplin-4 showed low toxicity to host cells, indicating high bacterial selectivity. Furthermore, the mortality rate of mice infected with Escherichia coli was significantly reduced by anoplin-4 treatment relative to anoplin. In conclusion, anoplin-4 is a novel anoplin analogue with high antimicrobial activity and enzymatic stability, which may represent a potent agent for the treatment of infection. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.

Production of fumonisin B and C analogues by several fusarium species.

PubMed

Sewram, Vikash; Mshicileli, Ndumiso; Shephard, Gordon S; Vismer, Hester F; Rheeder, John P; Lee, Yin-Won; Leslie, John F; Marasas, Walter F O

2005-06-15

Six strains of Fusarium verticillioides, two of F. oxysporum, one strain of F. proliferatum, and a strain of an unidentified species were cultured on maize patties and rice and evaluated for their ability to simultaneously produce fumonisin B (FB) and C (FC) series analogues. Fumonisins were quantified by LC-MS-MS using positive ion electrospray ionization. FC1 provided characteristic fragment ions at m/z 690, 672, 654, 532, 514, and 338 corresponding to sequential loss of H2O and tricarboxylic acid moieties from the alkyl backbone, while FC3 and FC4 provided equivalent product ions 16 and 32 amu lower than the corresponding FC1 fragments, respectively. All isolates cultured on maize produced FC4. All isolates except for that of F. proliferatum also produced FC1, and three of the six strains of F. verticillioides produced FC3. All isolates except those of F. oxysporum produced detectable amounts of FB1, FB2, and FB3. Isolates that produced fumonisin B analogues produced at least 10 fold more of the B series analogues than they did of the C series analogues. The results confirm that at least some strains of F. oxysporum produce FC, but not FB, fumonisin analogues and also suggest that the genetics and physiological regulation of fumonisin production may be more complicated than previously envisaged since some strains of F. verticillioides and F. proliferatum as well as the strain of the unidentified species can simultaneously produce both FB and FC analogues.

Structure-based design of potent histatin analogues.

PubMed

Brewer, Dyanne; Lajoie, Gilles

2002-04-30

Conformational studies of human salivary peptide, histatin 3 (Hst3), were performed by nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy in a membrane-mimicking environment. The structural information that was obtained was used in the design of peptide analogues with improved antifungal activity. In the presence of increasing concentrations of L-alpha-dimyristoylphosphatidylcholine (L-alpha-DMPC) lipid vesicles, a dramatic increase in a minimum at 198 nm is observed in the CD spectra of Hst3. The NMR data of Hst3 in the presence of L-alpha-DMPC lipid vesicles reveal the proximity of residues Y(10) and S(20), indicating the existence of a more compact structure. Peptide analogues were designed on the basis of this observation, which incorporated a disulfide bond to stabilize an extended loop in this region of the sequence. One of these, peptide 4, was 100 times more potent than Hst5 against Saccharomyces cerevisiae cells. Conformational analysis of peptide 4 revealed a looped structure with charged residues protruding on the outside surface, while a combination of aromatic residues and histidines are packed into an internal core.

Spontaneous translocation of antitumor oxaliplatin, its enantiomeric analogue, and Cisplatin from one strand to another in double-helical DNA.

PubMed

Malina, Jaroslav; Natile, Giovanni; Brabec, Viktor

2013-09-02

Oxaliplatin and cisplatin belong to the class of platinum-based anticancer agents. Formation of DNA adducts by these complexes and the consequences for its structure and function, is the mechanistic paradigm by which these drugs exert their antitumor activity. We show that employing short oligonucleotide duplexes containing single, site-specific 1,3-intrastrand cross-links of oxaliplatin, its enantiomeric analogue, or cisplatin and by using gel electrophoresis that under physiological conditions the coordination bonds between platinum and the N7 position of guanine residues involved in the cross-links of the Pt(II) complexes can be cleaved. This cleavage may lead to linkage isomerization reactions between these metallodrugs and double-helical DNA. For instance, approximately 25 % 1,3-intrastrand cross-links of the platinum complexes isomerized after 192 h (at 310 K in 200 mM NaClO4). Differential scanning calorimetry of duplexes containing single, site-specific cross-links of oxaliplatin, its enantiomeric analogue, and cisplatin reveals that one of the driving forces that leads to the lability of DNA cross-links of these metallodrugs is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of the DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule. In addition, the differences in the kinetics of the rearrangement reactions and the thermodynamic destabilization of DNA observed for adducts of oxaliplatin and its enantiomeric analogue confirm that the chirality at the carrier 1,2-diaminocyclohexane ligand can considerably affect structural and other physical properties of DNA adducts and consequently their biological effects. In aggregate, interesting generalization of the results described in this work

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue.

PubMed

Fiebrich, H-B; Van Den Berg, G; Kema, I P; Links, T P; Kleibeuker, J H; Van Beek, A P; Walenkamp, A M E; Sluiter, W J; De Vries, E G E

2010-12-01

Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels remains unknown. To investigate the prevalence of fat-soluble vitamin deficiencies in long-term somatostatin analogue users. All acromegaly and carcinoid patients using somatostatin analogues for ≥ 18 months visiting the University Medical Center Groningen between December 2008 and April 2009 were eligible. Vitamin levels of fat-soluble vitamins in blood, clinical and vitamin-dependent laboratory parameters were collected. In all, 19 acromegaly and 35 carcinoid patients were included. Twelve patients experienced steatorrhoea; two carcinoid patients experienced night blindness. Forty-two (78%) were deficient for one or more vitamins, and 32% (n = 17) had multiple deficiencies. Deficiencies for vitamin A, D, E, K1 and E in erythrocytes occurred in 6%, 28%, 15%, 63% and 58% of the patients. Prevalence of vitamin D, E and K1 deficiencies was similar in both patient groups. Treatment duration did not influence vitamin levels. The length of intestinal resection and age correlated negatively with vitamin A levels. Fat-soluble vitamin deficiencies are frequent during long-term somatostatin analogue treatment. Therefore, fat-soluble vitamins should be monitored in these patients. © 2010 Blackwell Publishing Ltd.

Thymidine analogue-sparing highly active antiretroviral therapy (HAART).

PubMed

Nolan, David; Mallal, Simon

2003-02-01

The use of alternative nucleoside reverse transcriptase inhibitors (NRTIs) to the thymidine analogues stavudine (d4T) and zidovudine(ZDV) has been advocated as a means of limiting long-term NRTI-associated toxicity, particularly the development of lipoatrophy or fat wasting. This approach reflects an increasing knowledge of the distinct toxicity profiles of NRTI drugs. However, recent clinical trials have demonstrated that the use of thymidine analogue NRTIs and newer alternative backbone NRTIs, such as tenofovir (TNF) and abacavir (ABC), is associated with comparable short-term efficacy and tolerability. Given the importance of toxicity profile differences in determining clinical management, it is important to recognise that d4T and ZDV cary significantly different risks for long-term NRTI toxicity. Recognising that all NRTIs, including thymidine analogues, have individual toxicity profiles provides a more appropriate basis for selecting optimal antiretroviral therapy. The safety and efficacy of TNF and ABC are also reviewed here, although the available data provide only limited knowledge of the long-term effects of these drugs in terms of toxicity and antiviral durability.

Field Exploration and Life Detection Sampling Through Planetary Analogue Sampling (FELDSPAR).

NASA Technical Reports Server (NTRS)

Stockton, A.; Amador, E. S.; Cable, M. L.; Cantrell, T.; Chaudry, N.; Cullen, T.; Duca, Z.; Gentry, D. M.; Kirby, J.; Jacobsen, M.;

Study site characterization. Chapter 2

Treesearch

Chris Potter; Richard Birdsey

2008-01-01

This chapter is an overview of the main site characterization requirements at landscape-scale sampling locations. The overview is organized according to multiple "Site Attribute" headings that require descriptions throughout a given study site area, leading ultimately to a sufficient overall site characterization. Guidance is provided to describe the major...

Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity

PubMed Central

2016-01-01

Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy. PMID:27035329

Fallon, Nevada FORGE Analogue Outcrop Samples

DOE Data Explorer

Blankenship, Doug; Bauer, Steve J.; Barrow, P.; Robbins, A.; Hileman, M.

2018-03-12

Compilation of results for mechanical and fluid flow properties of analogue outcrop samples - experimental data for compressional and shear wave velocities, tensile strengths, and compressive strengths. Outcrop location and sample orientation data are documented in a separate csv file.

Altered Enthalpy-Entropy Compensation in Picomolar Transition State Analogues of Human Purine Nucleoside Phosphorylase†

PubMed Central

Edwards, Achelle A.; Mason, Jennifer M.; Clinch, Keith; Tyler, Peter C.; Evans, Gary B.; Schramm, Vern L.

2009-01-01

Human purine nucleoside phosphorylase (PNP) belongs to the trimeric class of PNPs and is essential for catabolism of deoxyguanosine. Genetic deficiency of PNP in humans causes a specific T-cell immune deficiency and transition state analogue inhibitors of PNP are in development for treatment of T-cell cancers and autoimmune disorders. Four generations of Immucillins have been developed, each of which contains inhibitors binding with picomolar affinity to human PNP. Full inhibition of PNP occurs upon binding to the first of three subunits and binding to subsequent sites occurs with negative cooperativity. In contrast, substrate analogue and product bind without cooperativity. Titrations of human PNP using isothermal calorimetery indicate that binding of a structurally rigid first-generation Immucillin (K d = 56 pM) is driven by large negative enthalpy values (ΔH = −21.2 kcal/mol) with a substantial entropic (-TΔS) penalty. The tightest-binding inhibitors (K d = 5 to 9 pM) have increased conformational flexibility. Despite their conformational freedom in solution, flexible inhibitors bind with high affinity because of reduced entropic penalties. Entropic penalties are proposed to arise from conformational freezing of the PNP·inhibitor complex with the entropy term dominated by protein dynamics. The conformationally flexible Immucillins reduce the system entropic penalty. Disrupting the ribosyl 5’-hydroxyl interaction of transition state analogues with PNP causes favorable entropy of binding. Tight binding of the seventeen Immucillins is characterized by large enthalpic contributions, emphasizing their similarity to the transition state. By introducing flexibility into the inhibitor structure, the enthalpy-entropy compensation pattern is altered to permit tighter binding. PMID:19425594

The project De Caldas International Project: An example of a large-scale radwaste isolation natural analogue study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shea, M.

1995-09-01

The proper isolation of radioactive waste is one of today`s most pressing environmental issues. Research is being carried out by many countries around the world in order to answer critical and perplexing questions regarding the safe disposal of radioactive waste. Natural analogue studies are an increasingly important facet of this international research effort. The Pocos de Caldas Project represents a major effort of the international technical and scientific community towards addressing one of modern civilization`s most critical environmental issues - radioactive waste isolation.

An analogue conceptual rainfall-runoff model for educational purposes

NASA Astrophysics Data System (ADS)

Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

2016-04-01

Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

The Canadian space agency planetary analogue materials suite

NASA Astrophysics Data System (ADS)

Cloutis, Edward A.; Mann, Paul; Izawa, Matthew R. M.; Applin, Daniel M.; Samson, Claire; Kruzelecky, Roman; Glotch, Timothy D.; Mertzman, Stanley A.; Mertzman, Karen R.; Haltigin, Timothy W.; Fry, Christopher

2015-12-01

The Canadian Space Agency (CSA) recently commissioned the development of a suite of over fifty well-characterized planetary analogue materials. These materials are terrestrial rocks and minerals that are similar to those known or suspected to occur on the lunar or martian surfaces. These include: Mars analogue sedimentary, hydrothermal, igneous and low-temperature alteration rock suites; lunar analogue basaltic and anorthositic rock suites; and a generic impactite rock suite from a variety of terrestrial impact structures. Representative thin sections of the materials have been characterized by optical microscopy and electron probe microanalysis (EPMA). Reflectance spectra have been collected in the ultraviolet, visible, near-infrared and mid-infrared, covering 0.2-25 μm. Thermal infrared emission spectra were collected from 5 to 50 μm. Raman spectra with 532 nm excitation, and laser-induced fluorescence spectra with 405 nm excitation were also measured. Bulk chemical analysis was carried out using X-ray fluorescence, with Fe valence determined by wet chemistry. Chemical and mineralogical data were collected using a field-portable Terra XRD-XRF instrument similar to CheMin on the MSL Curiosity rover. Laser-induced breakdown spectroscopy (LIBS) data similar to those measured by ChemCam on MSL were collected for powdered samples, cut slab surfaces, and as depth profiles into weathered surfaces where present. Three-dimensional laser camera images of rock textures were collected for selected samples. The CSA intends to make available sample powders (<45 μm and 45-1000 μm grain sizes), thin sections, and bulk rock samples, and all analytical data collected in the initial characterisation study to the broader planetary science community. Aiming to complement existing planetary analogue rock and mineral libraries, the CSA suite represents a new resource for planetary scientists and engineers. We envision many potential applications for these materials in the

The costal landslide from analogue experiments: perspectives and limitation

NASA Astrophysics Data System (ADS)

Del Ventisette, C.; Nolesini, T.; Moretti, S.; Fanti, R.

2010-12-01

Understanding the triggering mechanism of coastal landslides (triggered and/or developed at air-water interface) and their evolution is fundamental to evaluate their hazard and, predicting the energy, the associated tsunami risk. The aim of this work is to verify the suitability of analogue modelling to understand the triggering mechanism and the evolution of landslide along the costal line. As a starting case study the Sciara del Fuoco (SdF), northwest flank of the volcanic island of Stromboli (Italy), was chosen. The analogue modelling technique has been proven to represent an useful tool to understand many geological processes, as it allows studying the progressive deformation, providing also useful indications about the role of distinct factors controlling the final deformation pattern. The models simulated at a first approximation the geological geometries observed at Stromboli, a composite volcano forming the northernmost island of the Aeolian Archipelago (Tyrrhenian Sea). The activity of Stromboli volcano is characterized by a persistent mild explosive activity at the summit craters sporadically interrupted by episodes of lava effusion and violent paroxysmal explosions as in 2002-2003 and in 2007. During the 2002 effusion a large landslide occurred on the SdF. The landslide caused a tsunami, which produced severe damages along the island shores. A series of analogue models was performed to investigate the influence of two different types of triggering mechanism and the behaviour of landslides both in air and air-water interface: 1) surface bulging due to the intrusion of a dike; 2) accumulation of material due to an uppermost landslide or due to opening of a new vent. The models, constructed in a Plexiglas tank, were scaled to the natural prototype following the geometrical, rheological, kinematical and dynamical similarities (e.g. Hubbert, 1937; Ramberg, 1981). The modelling material (Fontainbleau sand and rice) was sieved on a slope, inclination of which

Effects of analogues of hydra peptide morphogen on DNA synthesis in the myocardium of newborn albino rats.

PubMed

Sazonova, E N; Yakovenko, I G; Kryzhanovskaya, S Yu; Budylev, A A; Timoshin, S S

2012-01-01

DNA-synthetic activity of myocardial cells was studied by (3)H-thymidine autoradiography in newborn albino rats after intraperitoneal injection of hydra peptide morphogen and its analogues. Administration of hydra peptide morphogen stimulated proliferative activity in the myocardium. Short analogues of hydra peptide morphogen, 6C and 3C peptides, produced a similar effect. Administration of arginine-containing analogue of hydra peptide morphogen significantly reduced the number of DNA-synthesizing nuclei in the ventricular myocardium of newborn albino rats. The role of the structure of the peptide molecule in the realization of the morphogenetic effects of hydra peptide morphogen is discussed.

Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations.

PubMed

Maruyama, Mitsunori; Xiao, Jianmin; Zhou, Qiang; Vembaiyan, Kannan; Chua, Su-Kiat; Rubart-von der Lohe, Michael; Lin, Shien-Fong; Back, Thomas G; Chen, S R Wayne; Chen, Peng-Sheng

2013-01-01

Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2). To test a hypothesis that carvedilol analogue may also prevent triggered activities (TAs) through the suppression of early afterdepolarizations (EADs). Intracellular Ca(2+) and membrane voltage were simultaneously recorded by using optical mapping technique in Langendorff-perfused mouse and rabbit hearts to study the effect of carvedilol analogue VK-II-36, which does not have significant beta-blocking effects. Spontaneous intracellular Ca(2+) elevations (SCaEs) during diastole were induced by rapid ventricular pacing and isoproterenol infusion in intact rabbit ventricles. Systolic and diastolic SCaEs were simultaneously noted in Langendorff-perfused RyR2 R4496(+/-) mouse hearts after creating atrioventricular block. VK-II-36 effectively suppressed SCaEs and eliminated TAs observed in both mouse and rabbit ventricles. We tested the effect of VK-II-36 on EADs by using a rabbit model of acquired long QT syndrome, in which phase 2 and phase 3 EADs were observed in association with systolic SCaEs. VK-II-36 abolished the systolic SCaEs and phase 2 EADs, and greatly decreased the dispersion of repolarization and the amplitude of phase 3 EADs. VK-II-36 completely prevented EAD-mediated TAs in all ventricles studied. A carvedilol analogue, VK-II-36, inhibits ventricular tachyarrhythmias in intact mouse and rabbit ventricles by the suppression of SCaEs, independent of beta-blocking activity. The RyR2 may be a potential target for treating focal ventricular arrhythmias triggered by either EADs or DADs. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Analogue scale modelling of extensional tectonic processes using a large state-of-the-art centrifuge

NASA Astrophysics Data System (ADS)

Park, Heon-Joon; Lee, Changyeol

2017-04-01

Analogue scale modelling of extensional tectonic processes such as rifting and basin opening has been numerously conducted. Among the controlling factors, gravitational acceleration (g) on the scale models was regarded as a constant (Earth's gravity) in the most of the analogue model studies, and only a few model studies considered larger gravitational acceleration by using a centrifuge (an apparatus generating large centrifugal force by rotating the model at a high speed). Although analogue models using a centrifuge allow large scale-down and accelerated deformation that is derived by density differences such as salt diapir, the possible model size is mostly limited up to 10 cm. A state-of-the-art centrifuge installed at the KOCED Geotechnical Centrifuge Testing Center, Korea Advanced Institute of Science and Technology (KAIST) allows a large surface area of the scale-models up to 70 by 70 cm under the maximum capacity of 240 g-tons. Using the centrifuge, we will conduct analogue scale modelling of the extensional tectonic processes such as opening of the back-arc basin. Acknowledgement This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number 2014R1A6A3A04056405).

Conformationally Constrained Analogues of N'-(4-t-Butylbenzyl)-N-(4-Methylsulfonylaminobenzyl)Thiourea as TRPV1 Antagonists

PubMed Central

Ryu, HyungChul; Lim, Ju-Ok; Kang, Dong Wook; Pearce, Larry V.; Tran, Richard; Toth, Attila; Lee, Jeewoo; Blumberg, Peter M.

2012-01-01

A series of bicyclic analogues having indan and tetrahydronaphthalene templates in the A-region were designed as conformationally constrained analogues of our previously reported potent TRPV1 antagonists (1, 3). The activities for rat TRPV1 of the conformationally restricted analogues were moderately or markedly diminished, particularly in the case of the tetrahydronaphthalene analogues. The analysis indicated that steric constraints at the benzylic position in the bicyclic analogues were an important factor for their unfavorable interaction with the receptor. PMID:18406014

Swift heavy ion irradiation of interstellar dust analogues. Small carbonaceous species released by cosmic rays

NASA Astrophysics Data System (ADS)

Dartois, E.; Chabot, M.; Pino, T.; Béroff, K.; Godard, M.; Severin, D.; Bender, M.; Trautmann, C.

2017-03-01

Context. Interstellar dust grain particles are immersed in vacuum ultraviolet (VUV) and cosmic ray radiation environments influencing their physicochemical composition. Owing to the energetic ionizing interactions, carbonaceous dust particles release fragments that have direct impact on the gas phase chemistry. Aims: The exposure of carbonaceous dust analogues to cosmic rays is simulated in the laboratory by irradiating films of hydrogenated amorphous carbon interstellar analogues with energetic ions. New species formed and released into the gas phase are explored. Methods: Thin carbonaceous interstellar dust analogues were irradiated with gold (950 MeV), xenon (630 MeV), and carbon (43 MeV) ions at the GSI UNILAC accelerator. The evolution of the dust analogues is monitored in situ as a function of fluence at 40, 100, and 300 K. Effects on the solid phase are studied by means of infrared spectroscopy complemented by simultaneously recording mass spectrometry of species released into the gas phase. Results: Specific species produced and released under the ion beam are analyzed. Cross sections derived from ion-solid interaction processes are implemented in an astrophysical context.

Rotating black hole solutions in relativistic analogue gravity

NASA Astrophysics Data System (ADS)

Giacomelli, Luca; Liberati, Stefano

2017-09-01

Simulation and experimental realization of acoustic black holes in analogue gravity systems have lead to a novel understanding of relevant phenomena such as Hawking radiation or superradiance. We explore here the possibility of using relativistic systems for simulating rotating black hole solutions and possibly get an acoustic analogue of a Kerr black hole. In doing so, we demonstrate a precise relation between nonrelativistic and relativistic solutions and provide a new class of vortex solutions for relativistic systems. Such solutions might be used in the future as a test bed in numerical simulations as well as concrete experiments.

Synthesis and evaluation of coumermycin A1 analogues that inhibit the Hsp90 protein folding machinery.

PubMed

Burlison, Joseph A; Blagg, Brian S J

2006-10-12

[structure: see text] The coumarin antibiotics are not only potent inhibitors of DNA gyrase but also represent the most effective C-terminal inhibitors of 90 kDa heat shock proteins (Hsp90) reported thus far. In contrast to the N-terminal ATP-binding site, little is known about the Hsp90 C-terminus. In addition, very limited structure-activity relationships exist between this class of natural products and Hsp90. In this letter, the syntheses of dimeric coumarin analogues are presented along with their inhibitory values in breast cancer cell lines.

8-Amido-Bearing pseudomycin B (PSB) analogue: novel antifungal agents.

PubMed

Zhang, Y Z; Sun, X; Zeckner, D J; Sachs, R K; Current, W L; Chen, S H

2001-01-22

During the course of a structure-activity relationship (SAR) study on novel depsinonapeptide pseudomycin B, we synthesized a total of 12 8-amidopseudomycin analogues via standard two-step sequence from either ZPSB 2 or AllocPSB 3. A number of these amides exhibited good in vitro antifungal activities.

Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

PubMed Central

Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

2015-01-01

Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

Identification of quinone analogues as potential inhibitors of picornavirus 3C protease in vitro.

PubMed

Jung, Eunhye; Lee, Joo-Youn; Kim, Ho Jeong; Ryu, Chung-Kyu; Lee, Kee-In; Kim, Meehyein; Lee, Chong-Kyo; Go, Yun Young

2018-05-29

Picornaviruses are non-enveloped viruses that represent a large family of positive-sense single-stranded RNA viruses including a number of causative agents of many human and animal diseases such as coxsackievirus B3 (CVB3) and rhinoviruses (HRV). In this study, we performed a high-throughput screening of a compound library composed of ∼6000 small molecules in search of potential picornavirus 3C protease (3C pro ) inhibitors. As results, we identified quinone analogues that effectively inhibited both CVB3 3C pro and HRV 3C pro with IC 50 values in low micromolar range. Together with predicted binding modes of these compounds to the active site of the viral protease, it is implied that structural features of these non-peptidic inhibitors may act as useful scaffold for further anti-picornavirus drug design and development. Copyright © 2018 Elsevier Ltd. All rights reserved.

Modern Climate Analogues of Late-Quaternary Paleoclimates for the Western United States.

NASA Astrophysics Data System (ADS)

Mock, Cary Jeffrey

This study examined spatial variations of modern and late-Quaternary climates for the western United States. Synoptic climatological analyses of the modern record identified the predominate climatic controls that normally produce the principal modes of spatial climatic variability. They also provided a modern standard to assess past climates. Maps of the month-to-month changes in 500 mb heights, sea-level pressure, temperature, and precipitation illustrated how different climatic controls govern the annual cycle of climatic response. The patterns of precipitation ratios, precipitation bar graphs, and the seasonal precipitation maximum provided additional insight into how different climatic controls influence spatial climatic variations. Synoptic-scale patterns from general circulation model (GCM) simulations or from analyses of climatic indices were used as the basis for finding modern climate analogues for 18 ka and 9 ka. Composite anomaly maps of atmospheric circulation, precipitation, and temperature were compared with effective moisture maps compiled from proxy data to infer how the patterns, which were evident from the proxy data, were generated. The analyses of the modern synoptic climatology indicate that smaller-scale climatic controls must be considered along with larger-scale ones in order to explain patterns of spatial climate heterogeneity. Climatic extremes indicate that changes in the spatial patterns of precipitation seasonality are the exception rather than the rule, reflecting the strong influence of smaller-scale controls. Modern climate analogues for both 18 ka and 9 ka clearly depict the dry Northwest/wet Southwest contrast that is suggested by GCM simulations and paleoclimatic evidence. 18 ka analogues also show the importance of smaller-scale climatic controls in explaining spatial climatic variation in the Northwest and northern Great Plains. 9 ka analogues provide climatological explanations for patterns of spatial heterogeneity over several

Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus.

PubMed

Plank, Johannes; Siebenhofer, Andrea; Berghold, Andrea; Jeitler, Klaus; Horvath, Karl; Mrak, Peter; Pieber, Thomas R

2005-06-27

This article compares the effect of treatment with short-acting insulin (SAI) analogues vs regular insulin on glycemic control, hypoglycemic episodes, quality of life, and diabetes-specific complications. Electronic searches (Cochrane Library, MEDLINE, and EMBASE) and additional searching (pharmaceutical companies, experts, approval agencies, abstracts of diabetology meetings) were performed. Two reviewers independently screened randomized controlled trials to determine inclusion. Forty-two randomized controlled trials that assessed the effect of SAI analogues vs regular insulin in 7933 patients with type 1 diabetes mellitus, type 2 diabetes mellitus, and gestational diabetes mellitus were identified. The weighted mean difference between hemoglobin A(1c) values obtained using SAI analogues and regular insulin was -0.12% (95% confidence interval [CI], -0.17% to -0.07%) for adult patients with type 1 diabetes mellitus and -0.02% (95% CI, -0.10% to 0.07%) for patients with type 2 diabetes mellitus. The standardized mean difference for overall hypoglycemia (episodes per patient per month) was -0.05 (95% CI, -0.22 to 0.11) and -0.04 (95% CI, -0.12 to 0.04) comparing SAI analogues with regular insulin in adult patients with type 1 and type 2 diabetes mellitus, respectively. No differences between treatments were observed in children with type 1 diabetes, pregnant women with type 1 diabetes mellitus, and women with gestational diabetes. Concerning quality of life, improvement was observed only in open-label studies in patients with type 1 diabetes mellitus. No differences were seen in a double-blinded study of patients with type 1 or in the studies of patients with type 2 diabetes mellitus. Our analysis suggests only a minor benefit to hemoglobin A(1c) values in adult patients with type 1 diabetes mellitus but no benefit in the remaining population with type 2 or gestational diabetes from SAI analogue treatment.

High stability and biological activity of the copper(II) complexes of alloferon 1 analogues containing tryptophan.

PubMed

Kadej, Agnieszka; Kuczer, Mariola; Czarniewska, Elżbieta; Urbański, Arkadiusz; Rosiński, Grzegorz; Kowalik-Jankowska, Teresa

2016-10-01

Copper(II) complex formation processes between the alloferon 1 (Allo1) (HGVSGHGQHGVHG) analogues where the tryptophan residue is introducing in the place His residue H1W, H6W, H9W and H12W have been studied by potentiometric, UV-visible, CD and EPR spectroscopic, and MS methods. For all analogues of alloferon 1 complex speciation have been obtained for a 1:1 metal-to-ligand molar ratio and 2:1 of H1W because of precipitation at higher (2:1, 3:1 and 4:1) ratios. At physiological pH7.4 and a 1:1 metal-to-ligand molar ratio the tryptophan analogues of alloferon 1 form the CuH -1 L and/or CuH -2 L complexes with the 4N binding mode. The introduction of tryptophan in place of histidine residues changes the distribution diagram of the complexes formed with the change of pH and their stability constants compared to the respective substituted alanine analogues of alloferon 1. The CuH -1 L, CuH -2 L and CuH -3 L complexes of the tryptophan analogues are more stable from 1 to 5 log units in comparison to those of the alanine analogues. This stabilization of the complexes may result from cation(Cu(II))-π and indole/imidazole ring interactions. The induction of apoptosis in vivo, in Tenebrio molitor cells by the ligands and their copper(II) complexes at pH7.4 was studied. The biological results show that copper(II) ions in vivo did not cause any apparent apoptotic features. The most active were the H12W peptide and Cu(II)-H12W complex formed at pH7.4. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantifying Variability and Correlation in Biomarker and Mineralogical Measurements: Lessons from Five Astrobiological Mars Analogue Expeditions in Iceland

NASA Astrophysics Data System (ADS)

Gentry, D.; Amador, E. S.; Cable, M. L.; Cantrell, T.; Chaudry, N.; Duca, Z. A.; Jacobsen, M. B.; Kirby, J.; McCaig, H. C.; Murukesan, G.; Rader, E.; Cullen, T.; Rennie, V.; Schwieterman, E. W.; Stevens, A. H.; Sutton, S. A.; Tan, G.; Yin, C.; Cullen, D.; Geppert, W.; Stockton, A. M.

2017-12-01

Studies in planetary analogue sites correlating remote imagery, mineralogy, and biomarker assay results help predict biomarker distribution and preservation. The FELDSPAR team has conducted five expeditions (2012-2017) to Icelandic Mars analogue sites with an increasingly refined battery of physicochemical measurements and biomarker assays. Two additional expeditions are planned; here we report intermediate results.The biomarker assays performed represent a diversity of potential biomarker types: ATP, cell counts, qPCR with domain-level primers, and DNA content. Mineralogical, chemical, and physical measurements and observations include temperature, pH, moisture content, and Raman, near-IR reflectance, and X-ray fluorescence spectra. Sites are geologically recent basaltic lava flows (Fimmvörðuháls, Eldfell, Holuhraun) and barren basaltic sand plains (Mælifellssandur, Dyngjusandur). All samples were 'homogeneous' at the 1 m to 1 km scale in apparent color, morphology, and grain size.[1]Sample locations were arranged in hierarchically nested grids at 10 cm, 1 m, 10 m, 100 m, and >1 km scales. Several measures of spatial distribution and variability were derived: unbiased sample variance, F- and pairwise t-tests with Bonferroni correction, and the non-parametric H- and u-tests. All assay results, including preliminary mineralogical information in the form of notable spectral bands, were then tested for correlation using the non-parametric Spearman's rank test.[2] For Fimmvörðuháls, four years of data were also examined for temporal trends.Biomarker quantification (other than cell count) was generally well correlated, although all assays showed notable variability even at the smallest examined spatial scale. Pairwise comparisons proved to be the most intuitive measure of variability; non-parametric characterization indicated trends at the >100 m scale, but required more replicates than were feasible at smaller scales. Future work will integrate additional

Field Comparisons of Three Biomarker Detection Methods in Icelandic Mars Analogue Environments

NASA Astrophysics Data System (ADS)

Gentry, D.; Amador, E. S.; Cable, M. L.; Chaudry, N.; Cullen, T.; Jacobsen, M.; Murusekan, G.; Schwieterman, E.; Stevens, A.; Stockton, A.; Yin, C.; Cullen, D.; Geppert, W.

2014-12-01

The ability to estimate the spatial and temporal distributions of biomarkers has been identified as a key need for planning life detection strategies. In a typical planetary exploration scenario, sampling site selection will be informed only by remote sensing data; however, if a difference of a few tens of meters, or centimeters, makes a significant difference in the results, science objectives may not be met. We conducted an analogue planetary expedition to test the correlation of three common biomarker detection methods -- cell counts through fluorescence microscopy, ATP quantification, and quantitative PCR with universal primer sets (bacteria, archaea, and fungi) -- and their spatial scale representativeness. Sampling sites in recent Icelandic lava fields (Fimmvörđuháls and Eldfell) spanned four nested spatial scales: 1 m, 10 m, 100 m, and > 1 km. Each site was homogeneous at typical 'remote sampling' resolution (overall temperature, apparent moisture content, and regolith grain size). No correlation between cell counts and either ATP or qPCR data was significant at any distance scale; ATP quantification and the archaeal and fungal qPCR data showed a marginal negative correlation at the 1 m level. Visible cell count data was statistically site-dependent for sites 10 m and 100 m apart, but not for sites > 1 km apart, whereas ATP results and qPCR data showed site dependence at all four scales. Distance had no significant effect on variability in cell counts and qPCR data, but was positively correlated with ATP variability. These results highlight the difficulty of choosing a 'good' biomarker: not only may different methods yield conflicting results, but they may also be differentially representative of the overall area. We intend to expand on this work with a follow-up campaign using comprehensive assays of physicochemical site properties to better distinguish between effects of environmental variability and intrinsic biomarker variability.

Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities.

PubMed

Thakkar, Sampark S; Thakor, Parth; Ray, Arabinda; Doshi, Hiren; Thakkar, Vasudev R

2017-10-15

Benzothiazole analogues are of interest due to their potential activity against malarial and microbial infections. In search of suitable antimicrobial and antimalarial agents, we report here the synthesis, characterization and biological activities of benzothiazole analogues (J 1-J 10). The molecules were characterized by IR, Mass, 1 H NMR, 13 C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains; the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds J 1, J 2, J 3, J 5 and J 6 were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR, computational and in vitro studies were carried out to examine their candidatures as lead dihydrofolate reductase inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease.

PubMed

Huy, Pham Dinh Quoc; Yu, Yao-Chung; Ngo, Son Tung; Thao, Tran Van; Chen, Chin-Piao; Li, Mai Suan; Chen, Yi-Cheng

2013-04-01

Aggregation of amyloid-beta (Aβ) has been proposed as the main cause of Alzheimer's disease (AD). Vitamin K deficiency has been linked to the pathogenesis of AD. Therefore, 15 synthesized vitamin K3 (VK3) analogues were studied for their anti-amyloidogenic activity. Biological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of Aβ, such as aggregation, free radical formation, and cell viability. Molecular dynamics simulation was used to calculate the binding affinity and mode of VK3 analogue binding to Aβ. Both numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit Aβ aggregation and conformational conversion. The calculated inhibition constants were in the μM range for VK3-10, VK3-6, and VK3-9 which was similar to the IC50 of curcumin. Cell viability assays indicated that VK3-9 could effectively reduce free radicals and had a protective effect on cytotoxicity induced by Aβ. The results clearly demonstrated that VK3 analogues could effectively inhibit Aβ aggregation and protect cells against Aβ induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD. VK3 analogues effectively inhibit Aβ aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD. Copyright © 2012 Elsevier B.V. All rights reserved.

A prospective comparison of a new, synthetic donor site dressing versus an impregnated gauze dressing.

PubMed

Hickerson, W L; Kealey, G P; Smith, D J; Thomson, P D

1994-01-01

Three institutions enrolled 38 patients who required bilateral skin graft donor sites into a safety and efficacy study of a new synthetic donor site dressing. Bilateral donor sites were randomized to receive either a new, synthetic donor site dressing or an impregnated gauze dressing. Wounds were assessed by time to healing, pain, and patient preference. Synthetic dressing wounds were treated 7.9 days compared with 10.2 days for gauze dressing wounds (p < 0.001), and synthetic dressing wounds were more completely epithelialized. Visual analogue pain analysis revealed significantly less donor site pain with synthetic dressing (2.94) versus gauze dressing (4.64) (p < 0.001). Synthetic dressing had fewer treatment-related adverse experiences than gauze dressing (2 vs 7) and was judged by recipients to be superior to gauze dressing in comfort, pain relief, cosmetic appeal, ease of ambulation, and overall acceptance.

Simulated Milky Way analogues: implications for dark matter direct searches

NASA Astrophysics Data System (ADS)

Bozorgnia, Nassim; Calore, Francesca; Schaller, Matthieu; Lovell, Mark; Bertone, Gianfranco; Frenk, Carlos S.; Crain, Robert A.; Navarro, Julio F.; Schaye, Joop; Theuns, Tom

2016-05-01

We study the implications of galaxy formation on dark matter direct detection using high resolution hydrodynamic simulations of Milky Way-like galaxies simulated within the EAGLE and APOSTLE projects. We identify Milky Way analogues that satisfy observational constraints on the Milky Way rotation curve and total stellar mass. We then extract the dark matter density and velocity distribution in the Solar neighbourhood for this set of Milky Way analogues, and use them to analyse the results of current direct detection experiments. For most Milky Way analogues, the event rates in direct detection experiments obtained from the best fit Maxwellian distribution (with peak speed of 223-289 km/s) are similar to those obtained directly from the simulations. As a consequence, the allowed regions and exclusion limits set by direct detection experiments in the dark matter mass and spin-independent cross section plane shift by a few GeV compared to the Standard Halo Model, at low dark matter masses. For each dark matter mass, the halo-to-halo variation of the local dark matter density results in an overall shift of the allowed regions and exclusion limits for the cross section. However, the compatibility of the possible hints for a dark matter signal from DAMA and CDMS-Si and null results from LUX and SuperCDMS is not improved.

Simulated Milky Way analogues: implications for dark matter direct searches

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bozorgnia, Nassim; Calore, Francesca; Lovell, Mark

2016-05-01

We study the implications of galaxy formation on dark matter direct detection using high resolution hydrodynamic simulations of Milky Way-like galaxies simulated within the EAGLE and APOSTLE projects. We identify Milky Way analogues that satisfy observational constraints on the Milky Way rotation curve and total stellar mass. We then extract the dark matter density and velocity distribution in the Solar neighbourhood for this set of Milky Way analogues, and use them to analyse the results of current direct detection experiments. For most Milky Way analogues, the event rates in direct detection experiments obtained from the best fit Maxwellian distribution (withmore » peak speed of 223–289 km/s) are similar to those obtained directly from the simulations. As a consequence, the allowed regions and exclusion limits set by direct detection experiments in the dark matter mass and spin-independent cross section plane shift by a few GeV compared to the Standard Halo Model, at low dark matter masses. For each dark matter mass, the halo-to-halo variation of the local dark matter density results in an overall shift of the allowed regions and exclusion limits for the cross section. However, the compatibility of the possible hints for a dark matter signal from DAMA and CDMS-Si and null results from LUX and SuperCDMS is not improved.« less

Metal ion interaction with phosphorylated tyrosine analogue monolayers on gold.

PubMed

Petoral, Rodrigo M; Björefors, Fredrik; Uvdal, Kajsa

2006-11-23

Phosphorylated tyrosine analogue molecules (pTyr-PT) were assembled onto gold substrates, and the resulting monolayers were used for metal ion interaction studies. The monolayers were characterized by X-ray photoelectron spectroscopy (XPS), infrared reflection-absorption spectroscopy (IRAS), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS), both prior to and after exposure to metal ions. XPS verified the elemental composition of the molecular adsorbate and the presence of metal ions coordinated to the phosphate groups. Both the angle-dependent XPS and IRAS results were consistent with the change in the structural orientation of the pTyr-PT monolayer upon exposure to metal ions. The differential capacitance of the monolayers upon coordination of the metal ions was evaluated using EIS. These metal ions were found to significantly change the capacitance of the pTyr-PT monolayers in contrast to the nonphosphorylated tyrosine analogue (TPT). CV results showed reduced electrochemical blocking capabilities of the phosphorylated analogue monolayer when exposed to metal ions, supporting the change in the structure of the monolayer observed by XPS and IRAS. The largest change in the structure and interfacial capacitance was observed for aluminum ions, compared to calcium, magnesium, and chromium ions. This type of monolayer shows an excellent capability to coordinate metal ions and has a high potential for use as sensing layers in biochip applications to monitor the presence of metal ions.

Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22.

PubMed

Krause-Heuer, Anwen M; Fraser-Spears, Rheaclare; Dobrowolski, Jeremy C; Ashford, Mark E; Wyatt, Naomi A; Roberts, Maxine P; Gould, Georgianna G; Cheah, Wai-Ching; Ng, Clarissa K L; Bhadbhade, Mohan; Zhang, Bo; Greguric, Ivan; Wheate, Nial J; Kumar, Naresh; Koek, Wouter; Callaghan, Paul D; Daws, Lynette C; Fraser, Benjamin H

2017-09-08

Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

PubMed Central

Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P.; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

2015-01-01

Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

Evaluation of anti-HIV-1 mutagenic nucleoside analogues.

PubMed

Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

2015-01-02

Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of "lethal mutagenesis" that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Strongly enhanced Fenton degradation of organic pollutants by cysteine: An aliphatic amino acid accelerator outweighs hydroquinone analogues.

PubMed

Li, Tuo; Zhao, Zhenwen; Wang, Quan; Xie, Pengfei; Ma, Jiahai

2016-11-15

Quinone-hydroquinone analogues have been proven to be efficient promoters of Fenton reactions by accelerating the Fe(III)/Fe(II) redox cycle along with self-destruction. However, so far there is little information on non-quinone-hydroquinone cocatalyst for Fenton reactions. This study found that cysteine, a common aliphatic amino acid, can strongly enhance Fenton degradation of organic pollutants by accelerating Fe(III)/Fe(II) redox cycle, as quinone-hydroquinone analogues do. Further, cysteine is superior to quinone-hydroquinone analogues in catalytic activity, H 2 O 2 utilization and atmospheric limits. The cocatalysis mechanism based on the cycle of cysteine/cystine was proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Natural analogues for processes affecting disposal of high-level radioactive waste in the vadose zone

NASA Astrophysics Data System (ADS)

Stuckless, J. S.

2003-04-01

Natural analogues can contribute to understanding and predicting the performance of subsystems and processes affecting a mined geologic repository for high-level radioactive waste in several ways. Most importantly, analogues provide tests for various aspects of systems of a repository at dimensional scales and time spans that cannot be attained by experimental study. In addition, they provide a means for the general public to judge the predicted performance of a potential high-level nuclear waste repository in familiar terms such that the average person can assess the anticipated long-term performance and other scientific conclusions. Hydrologists working on the Yucca Mountain Project (currently the U.S. Department of Energy's Office of Repository Development) have modeled the flow of water through the vadose zone at Yucca Mountain, Nevada and particularly the interaction of vadose-zone water with mined openings. Analogues from both natural and anthropogenic examples confirm the prediction that most of the water moving through the vadose zone will move through the host rock and around tunnels. This can be seen both quantitatively where direct comparison between seepage and net infiltration has been made and qualitatively by the excellent degree of preservation of archaeologic artifacts in underground openings. The latter include Paleolithic cave paintings in southwestern Europe, murals and artifacts in Egyptian tombs, painted subterranean Buddhist temples in India and China, and painted underground churches in Cappadocia, Turkey. Natural analogues also suggest that this diversion mechanism is more effective in porous media than in fractured media. Observations from natural analogues are also consistent with the modeled decrease in the percentage of infiltration that becomes seepage with a decrease in amount of infiltration. Finally, analogues, such as tombs that have ben partially filled by mud flows, suggest that the same capillary forces that keep water in the

Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase.

PubMed

Leonetti, Francesco; Capaldi, Carmelida; Pisani, Leonardo; Nicolotti, Orazio; Muncipinto, Giovanni; Stefanachi, Angela; Cellamare, Saverio; Caccia, Carla; Carotti, Angelo

2007-10-04

Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI = 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents. The significantly diverse MAO-B affinities of a number of R and S alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.

Synthesis and Evaluation of Chlorinated Substrate Analogues for Farnesyl Diphosphate Synthase

PubMed Central

Heaps, Nicole A.; Poulter, C. Dale

2011-01-01

Substrate analogues for isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), where the C3 methyl groups were replaced by chlorine, were synthesized and evaluated as substrates for avian farnesyl diphosphate synthase (FPPase). The IPP analogue (3-ClIPP) was a co-substrate when incubated with dimethylallyl diphosphate (DMAPP) or geranyl diphosphate (GPP) to give the corresponding chlorinated analogues of geranyl diphosphate (3-ClGPP) and farnesyl diphosphate (3-ClFPP), respectively. No products were detected in incubations of 3-ClIPP with 3-ClDMAPP. Incubation of IPP with 3-ClDMAPP gave 11-ClFPP as the sole product. Values of KM3-ClIPP (with DMAPP) and KM3-ClDMAPP (with IPP) were similar to those for IPP and DMAPP, however values of kcat for both analogues were substantially lower. These results are consistent with a dissociative electrophilic alkylation mechanism where the rate-limiting step changes from heterolytic cleavage of the carbon-oxygen bond in the allylic substrate to alkylation of the double bond of the homoallylic substrate. PMID:21344952

Optimization of gefitinib analogues with potent anticancer activity.

PubMed

Yin, Kai-Hao; Hsieh, Yi-Han; Sulake, Rohidas S; Wang, Su-Pei; Chao, Jui-I; Chen, Chinpiao

2014-11-15

The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues. Copyright © 2014 Elsevier Ltd. All rights reserved.

B38: an all-boron fullerene analogue

NASA Astrophysics Data System (ADS)

Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

2014-09-01

Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. Electronic supplementary information

Phosphatase-Resistant Analogues of Lysophosphatidic Acid

PubMed Central

Prestwich, Glenn D.; Gajewiak, Joanna; Zhang, Honglu; Xu, Xiaoyu; Yang, Guanghui; Serban, Monica

2008-01-01

Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G protein coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and also biochemical resistance to chemotherapy- and radiotherapy-induced apoptosis. LPA and its analogues also are feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, a.k.a., autotaxin, ATX), a central regulator of invasion and metastasis. For cancer therapy, the optimal therapeutic profile would be a metabolically stabilized, pan-LPA receptor antagonist that also inhibited lysoPLD. For protection of gastrointestinal mucosa and lymphocytes, LPA agonists would be desirable to minimize or reverse radiation or chemical-induced injury. Analogues of lysophosphatidic acid (LPA) that are chemically modified to be less susceptible to phospholipases and phosphatases show activity as long-lived receptor-specific agonists and antagonists for LPA receptors, as well as inhibitors for the lysoPLD activity of ATX. PMID:18454946

Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells

PubMed Central

Dugnani, Silvana; Calastretti, Angela; Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco; Canti, Gianfranco; Scaglione, Francesco; Bevilacqua, Annamaria

2017-01-01

Melatonin plays different physiological functions ranging from the regulation of circadian rhythms to tumor inhibition, owing to its antioxidant, immunomodulatory and anti-aging properties. Due to its pleiotropic functions, melatonin has been shown to elicit cytoprotective processes in normal cells and trigger pro-apoptotic signals in cancer cells. The therapeutic potential of melatonin analogues prompted us to investigate the in vitro and in vivo antitumor activity of new melatonin derivatives and explore the underlying molecular mechanisms. The experiments revealed that the new melatonin analogues inhibited the growth of melanoma and breast cancer cells in a dose- and time-dependent manner. In addition, our results indicated that melatonin derivative UCM 1037 could induce apoptosis in melanoma and breast cancer cells, as well as cell necrosis, in MCF-7. Together, apoptosis and necrosis could be two possible mechanisms to explain the cytotoxic effect of the melatonin analogue against cancer cells. The suppression of tumor growth by the melatonin analogues was further demonstrated in vivo in a xenograft mice model. A decrease in the activation of MAPK pathway was observed in all cancer cells following UCM 1037 treatment. Overall, this study describes a promising antitumor compound showing antiproliferative and cytotoxic activity in melanoma and breast cancer cells. PMID:28978121

Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells.

PubMed

Gatti, Giuliana; Lucini, Valeria; Dugnani, Silvana; Calastretti, Angela; Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco; Canti, Gianfranco; Scaglione, Francesco; Bevilacqua, Annamaria

2017-09-15

Melatonin plays different physiological functions ranging from the regulation of circadian rhythms to tumor inhibition, owing to its antioxidant, immunomodulatory and anti-aging properties. Due to its pleiotropic functions, melatonin has been shown to elicit cytoprotective processes in normal cells and trigger pro-apoptotic signals in cancer cells. The therapeutic potential of melatonin analogues prompted us to investigate the in vitro and in vivo antitumor activity of new melatonin derivatives and explore the underlying molecular mechanisms. The experiments revealed that the new melatonin analogues inhibited the growth of melanoma and breast cancer cells in a dose- and time-dependent manner. In addition, our results indicated that melatonin derivative UCM 1037 could induce apoptosis in melanoma and breast cancer cells, as well as cell necrosis, in MCF-7. Together, apoptosis and necrosis could be two possible mechanisms to explain the cytotoxic effect of the melatonin analogue against cancer cells. The suppression of tumor growth by the melatonin analogues was further demonstrated in vivo in a xenograft mice model. A decrease in the activation of MAPK pathway was observed in all cancer cells following UCM 1037 treatment. Overall, this study describes a promising antitumor compound showing antiproliferative and cytotoxic activity in melanoma and breast cancer cells.

Vasopressin Analogue DDAVP in Diabetes Insipidus: Clinical and Laboratory Studies

PubMed Central

Edwards, C. R. W.; Kitau, M. J.; Chard, T.; Besser, G. M.

1973-01-01

In seven patients with cranial diabetes insipidus an analogue of vasopressin, DDAVP, produced an antidiuresis lasting up to 20 hours after a single intranasal dose. Lysine vasopressin (LVP) in the same dose produced a less potent antidiuresis which lasted for only three to four hours. The plasma half life of DDAVP was 7·8 and 75·5 min for the fast and slow phases, compared with 2·5 and 14·5 min for LVP. Radioiodine-labelled DDAVP was not destroyed by incubation with late pregnancy plasma, which contains an enzyme that inactivates vasopressin. The slow metabolic clearance of DDAVP, its absorption through the nasal mucosa, and its lack of side effects make this the ideal drug for the treatment of vasopressin-sensitive diabetes insipidus. Patients usually require 10 to 20 μg DDAVP given intranasally twice daily for good clinical control of their diabetes insipidus. PMID:4581079

Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

PubMed

Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

2008-03-15

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

PubMed

Parhizgar, Arezoo Rafiee; Tahghighi, Azar

2017-03-01

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

Sharp phase variations from the plasmon mode causing the Rabi-analogue splitting

NASA Astrophysics Data System (ADS)

Wang, Yujia; Sun, Chengwei; Gan, Fengyuan; Li, Hongyun; Gong, Qihuang; Chen, Jianjun

2017-06-01

The Rabi-analogue splitting in nanostructures resulting from the strong coupling of different resonant modes is of importance for lasing, sensing, switching, modulating, and quantum information processes. To give a clearer physical picture, the phase analysis instead of the strong coupling is provided to explain the Rabi-analogue splitting in the Fabry-Pérot (FP) cavity, of which one end mirror is a metallic nanohole array and the other is a thin metal film. The phase analysis is based on an analytic model of the FP cavity, in which the reflectance and the reflection phase of the end mirrors are dependent on the wavelength. It is found that the Rabi-analogue splitting originates from the sharp phase variation brought by the plasmon mode in the FP cavity. In the experiment, the Rabi-analogue splitting is realized in the plasmonic-photonic coupling system, and this splitting can be continually tuned by changing the length of the FP cavity. These experimental results agree well with the analytic and simulation data, strongly verifying the phase analysis based on the analytic model. The phase analysis presents a clear picture to understand the working mechanism of the Rabi-analogue splitting; thus, it may facilitate the design of the plasmonic-photonic and plasmonic-plasmonic coupling systems.

Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.

PubMed

Navarrete-Vázquez, Gabriel; Alaniz-Palacios, Alfredo; Hidalgo-Figueroa, Sergio; González-Acevedo, Cristina; Ávila-Villarreal, Gabriela; Estrada-Soto, Samuel; Webster, Scott P; Medina-Franco, José L; López-Vallejo, Fabian; Guerrero-Álvarez, Jorge; Tlahuext, Hugo

2013-06-01

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+). Copyright © 2013 Elsevier Ltd. All rights reserved.

Rational Synthesis of Hollow Prussian Blue Analogue Through Coordination Replication and Controlled-Etching for Cs-Ion Removal.

PubMed

Xu, Jun; Bu, Fan-Xing; Guo, Yi-Fei; Zhang, Wei; Hu, Ming; Jiang, Ji-Sen

2018-05-01

Radioactive cesium pollution have received considerable attention due to the increasing risks in development of the nuclear power plants in the world. Although various functional porous materials are utilized to adsorb Cs+ ions in water, Prussian blue analogues (PBAs) are an impressive class of candidates because of their super affinity of Cs+ ions. The adsorption ability of the PBAs strongly relate to the mesostructure and interstitial sites. To design a hollow PBA with large number of interstitial sites, the traditional hollowing methods are not suitable owing to the difficulty in processing the specific PBAs with large number of interstitial sites. In this work, we empolyed a rational strategy which was to form a "metal oxide"@"PBA" core-shell structure via coordination replication at first, then utilized a mild etching to remove the metal oxide core, led to hollow PBA finally. The obtained hollow PBAs were of high crystallinity and large number of interstitial sites, showing a super adsorption performance for Cs+ ions (221.6 mg/g) within a short period (10 min).

Correlation of Thermal Stability and Structural Distortion of DNA Interstrand Cross-Links Produced from Oxidized Abasic Sites with Their Selective Formation and Repair.

PubMed

Ghosh, Souradyuti; Greenberg, Marc M

2015-10-13

C4'-oxidized (C4-AP) and C5'-oxidized abasic sites (DOB) that are produced following abstraction of a hydrogen atom from the DNA backbone reversibly form cross-links selectively with dA opposite a 3'-adjacent nucleotide, despite the comparable proximity of an opposing dA. A previous report on UvrABC incision of DNA substrates containing stabilized analogues of the ICLs derived from C4-AP and DOB also indicated that the latter is repaired more readily by nucleotide excision repair [Ghosh, S., and Greenberg, M. M. (2014) Biochemistry 53, 5958-5965]. The source for selective cross-link formation was probed by comparing the reactivity of ICL analogues of C4-AP and DOB that mimic the preferred and disfavored cross-links with that of reagents that indirectly detect distortion by reacting with the nucleobases. The disfavored C4-AP and DOB analogues were each more reactive than the corresponding preferred cross-link substrates, suggesting that the latter are more stable, which is consistent with selective ICL formation. In addition, the preferred DOB analogue is more reactive than the respective C4-AP ICL, which is consistent with its more efficient incision by UvrABC. The conclusions drawn from the chemical probing experiments are corroborated by UV melting studies. The preferred ICLs exhibit melting temperatures higher than those of the corresponding disfavored isomers. These studies suggest that oxidized abasic sites form reversible interstrand cross-links with dA opposite the 3'-adjacent thymidine because these products are more stable and the thermodynamic preference is reflected in the transition states for their formation.

Studies of ATM Kinase Activity Using Engineered ATM Sensitive to ATP Analogues (ATM-AS).

PubMed

Enari, Masato; Matsushima-Hibiya, Yuko; Miyazaki, Makoto; Otomo, Ryo

2017-01-01

Ataxia-telangiectasia mutated (ATM) protein is a member of the phosphatidylinositol 3-phosphate kinase (PI3-K)-related protein kinase (PIKK) family and is implicated in the initiation of signaling pathways following DNA double strand breaks (DSBs) elicited by exposure to ionizing irradiation (IR) or radiomimetic compounds. Loss of function of the ATM gene product results in the human genetic disorder ataxia-telangiectasia (A-T) characterized by neurodegeneration, immunodeficiency, genomic instability, and cancer predisposition. In response to DSBs, ATM is activated and phosphorylates Ser/Thr-Gln (S/T-Q) sequences on numerous proteins participating in DNA-damage responses. Among these proteins, phosphorylation of the tumor suppressor p53 at Ser15 is known as a target for ATM, which leads to the dissociation of MDM2, an E3 ubiquitin ligase, from p53 to prevent MDM2-dependent p53 degradation. Ser46 on p53 is phosphorylated in response to DSBs and contributes to the preferential transactivation of pro-apoptotic genes, such as p53AIP1, Noxa, and PUMA, to prevent tumor formation. Our group have shown that not only ATM preferentially phosphorylates S/T-Q sequences, but also Ser46, which is a noncanonical site with an S-P sequence for ATM. Ser46 on p53 is directly phosphorylated by ATM in a p53 conformation-dependent manner using the ATP analogue-accepting ATM mutant (ATM-AS) system. This protocol summarizes an approach to identify direct numerous targets for ATM kinase and is used to elucidate ATM signaling pathways in the DNA damage responses.

Immediate, non-submerged, root-analogue direct laser metal sintering (DLMS) implants: a 1-year prospective study on 15 patients.

PubMed

Mangano, Francesco Guido; De Franco, Michele; Caprioglio, Alberto; Macchi, Aldo; Piattelli, Adriano; Mangano, Carlo

2014-07-01

This study evaluated the 1-year survival and success rate of root-analogue direct laser metal sintering (DLMS) implants, placed into the extraction sockets of 15 patients. DLMS is a technology which allows solids with complex geometry to be fabricated by annealing metal powder microparticles in a focused laser beam, according to a computer-generated three-dimensional (3D) model; the fabrication process involves the laser-induced fusion of titanium microparticles, in order to build, layer-by-layer, the desired object. Cone-beam computed tomography (CBCT) acquisition and 3D image conversion, combined with the DLMS process, allow the fabrication of custom-made, root-analogue implants (RAIs). CBCT images of 15 non-restorable premolars (eight maxilla; seven mandible) were acquired and transformed into 3D models: from these, custom-made, root-analogue DLMS implants with integral abutment were fabricated. Immediately after tooth extraction, the RAIs were placed in the sockets and restored with a single crown. One year after implant placement, clinical and radiographic parameters were assessed: success criteria included absence of pain, suppuration, and exudation; absence of implant mobility and absence of continuous peri-implant radiolucency; distance between the implant shoulder and the first visible bone-to-implant contact <1.5 mm from initial surgery; and absence of prosthetic complications. At the 1-year follow-up, no implants were lost, for a survival rate of 100 %. All implants were stable, with no signs of infection. The good conditions of the peri-implant tissues were confirmed by the radiographic examination, with a mean DIB of 0.7 mm (±0.2). The possibility of fabricating custom-made, RAI DLMS implants opens new interesting horizons for immediate placement of dental implants.

Photophysical analysis of 1,10-phenanthroline-embedded porphyrin analogues and their magnesium(II) complexes.

PubMed

Ishida, Masatoshi; Lim, Jong Min; Lee, Byung Sun; Tani, Fumito; Sessler, Jonathan L; Kim, Dongho; Naruta, Yoshinori

2012-11-05

The synthesis, characterization, photophysical properties, and theoretical analysis of a series of tetraaza porphyrin analogues (H-Pn: n=1-4) containing a dipyrrin subunit and an embedded 1,10-phenanthroline subunit are described. The meso-phenyl-substituted derivative (H-P1) interacts with a Mg(2+) salt (e.g., MgCl(2), MgBr(2), MgI(2), Mg(ClO(4))(2), and Mg(OAc)(2)) in MeCN solution, thereby giving rise to a cation-dependent red-shift in both the absorbance- and emission maxima. In this system, as well as in the other H-Pn porphyrin analogues used in this study, the four nitrogen atoms of the ligand interact with the bound magnesium cation to form Mg(2+)-dipyrrin-phenanthroline complexes of the general structure MgX-Pn (X=counteranion). Both single-crystal X-ray diffraction analysis of the corresponding zinc-chloride derivative (ZnCl-P1) and fluorescence spectroscopy of the Mg-adducts that are formed from various metal salts provide support for the conclusion that, in complexes such as MgCl-P1, a distorted square-pyramidal geometry persists about the metal cation wherein a chloride anion acts as an axial counteranion. Several analogues (HPn) that contain electron-donating and/or electron-withdrawing dipyrrin moieties were prepared in an effort to understand the structure-property relationships and the photophysical attributes of these Mg-dipyrrin complexes. Analysis of various MgX-Pn (X=anion) systems revealed significant substitution effects on their chemical, electrochemical, and photophysical properties, as well as on the Mg(2+)-cation affinities. The fluorescence properties of MgCl-Pn reflected the effect of donor-excited photoinduced electron transfer (d-PET) processes from the dipyrrin subunit (as a donor site) to the 1,10-phenanthroline acceptor subunit. The proposed d-PET process was analyzed by electron paramagnetic resonance (EPR) spectroscopy and by femtosecond transient absorption (TA) spectroscopy, as well as by theoretical DFT calculations. Taken

Optical analogue of relativistic Dirac solitons in binary waveguide arrays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tran, Truong X., E-mail: truong.tran@mpl.mpg.de; Max Planck Institute for the Science of Light, Günther-Scharowsky str. 1, 91058 Erlangen; Longhi, Stefano

2014-01-15

We study analytically and numerically an optical analogue of Dirac solitons in binary waveguide arrays in the presence of Kerr nonlinearity. Pseudo-relativistic soliton solutions of the coupled-mode equations describing dynamics in the array are analytically derived. We demonstrate that with the found soliton solutions, the coupled mode equations can be converted into the nonlinear relativistic 1D Dirac equation. This paves the way for using binary waveguide arrays as a classical simulator of quantum nonlinear effects arising from the Dirac equation, something that is thought to be impossible to achieve in conventional (i.e. linear) quantum field theory. -- Highlights: •An opticalmore » analogue of Dirac solitons in nonlinear binary waveguide arrays is suggested. •Analytical solutions to pseudo-relativistic solitons are presented. •A correspondence of optical coupled-mode equations with the nonlinear relativistic Dirac equation is established.« less

Legumes and meat analogues consumption are associated with hip fracture risk independently of meat intake among Caucasian men and women: the Adventist Health Study-2.

PubMed

Lousuebsakul-Matthews, Vichuda; Thorpe, Donna L; Knutsen, Raymond; Beeson, W Larry; Fraser, Gary E; Knutsen, Synnove F

2014-10-01

In contrast to non-vegetarians, vegetarians consume more legumes and meat analogues as sources of protein to substitute for meat intake. The present study aimed to assess the association between foods with high protein content (legumes, meat, meat analogues) by dietary pattern (vegetarians, non-vegetarians) and hip fracture incidence, adjusted for selected lifestyle factors. A prospective cohort of Adventist Health Study-2 (AHS-2) enrollees who completed a comprehensive lifestyle and dietary questionnaire between 2002 and 2007. Every two years after enrolment, a short questionnaire on hospitalizations and selected disease outcomes including hip fractures was sent to these members. Respondents (n 33,208) to a baseline and a follow-up questionnaire. In a multivariable model, legumes intake of once daily or more reduced the risk of hip fracture by 64% (hazard ratio = 0·36, 95% CI 0·21, 0·61) compared with those with legumes intake of less than once weekly. Similarly, meat intake of four or more times weekly was associated with a 40% reduced risk of hip fracture (hazard ratio = 0·60, 95% CI 0·41, 0·87) compared with those whose meat intake was less than once weekly. Furthermore, consumption of meat analogues once daily or more was associated with a 49 % reduced risk of hip fracture (hazard ratio = 0·51, 95% CI 0·27, 0·98) compared with an intake of less than once weekly. Hip fracture incidence was inversely associated with legumes intake and, to a lesser extent, meat intake, after accounting for other food groups and important covariates. Similarly, a high intake of meat analogues was associated with a significantly reduced risk of hip fracture.

Legumes and meat analogues consumption are associated with hip fracture risk independently of meat intake among Caucasian men and women: the Adventist Health Study-2

PubMed Central

Lousuebsakul-Matthews, Vichuda; Thorpe, Donna L; Knutsen, Raymond; Beeson, W Larry; Fraser, Gary E; Knutsen, Synnove F

2014-01-01

Objective In contrast to non-vegetarians, vegetarians consume more legumes and meat analogues as sources of protein to substitute for meat intake. The present study aimed to assess the association between foods with high protein content (legumes, meat, meat analogues) by dietary pattern (vegetarians, non-vegetarians) and hip fracture incidence, adjusted for selected lifestyle factors. Design A prospective cohort of Adventist Health Study-2 (AHS-2) enrollees who completed a comprehensive lifestyle and dietary questionnaire between 2002 and 2007. Setting Every two years after enrolment, a short questionnaire on hospitalizations and selected disease outcomes including hip fractures was sent to these members. Subjects Respondents (n 33 208) to a baseline and a follow-up questionnaire. Results In a multivariable model, legumes intake of once daily or more reduced the risk of hip fracture by 64% (hazard ratio=0·36, 95% CI 0·21, 0·61) compared with those with legumes intake of less than once weekly. Similarly, meat intake of four or more times weekly was associated with a 40% reduced risk of hip fracture (hazard ratio=0·60, 95% CI 0·41, 0·87) compared with those whose meat intake was less than once weekly. Furthermore, consumption of meat analogues once daily or more was associated with a 49% reduced risk of hip fracture (hazard ratio=0·51, 95% CI 0·27, 0·98) compared with an intake of less than once weekly. Conclusions Hip fracture incidence was inversely associated with legumes intake and, to a lesser extent, meat intake, after accounting for other food groups and important covariates. Similarly, a high intake of meat analogues was associated with a significantly reduced risk of hip fracture. PMID:24103482

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron Clearing and Toxicity Profiles

PubMed Central

Bergeron, Raymond J.; Wiegand, Jan; Bharti, Neelam; McManis, James S.

2012-01-01

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. Iron clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron clearing properties. PMID:22889170

Comparison of a digital and an optical analogue hand-held refractometer for the measurement of canine urine specific gravity.

PubMed

Paris, J K; Bennett, A D; Dodkin, S J; Gunn-Moore, D A

2012-05-05

Urine specific gravity (USG) is used clinically as a measure of urine concentration, and is routinely assessed by refractometry. A comparison between optical analogue and digital refractometers for evaluation of canine urine has not been reported. The aim of this study was to compare a digital and an optical analogue hand-held refractometer for the measurement of canine USG, and to assess correlation with urine osmolality. Prospective study. Free-catch urine samples were collected from 285 hospitalised adult dogs, and paired USG readings were obtained with a digital and an optical analogue refractometer. In 50 dogs, urine osmolality was also measured using a freezing point depression osmometer. There was a small but statistically significant difference between the two refractometers (P<0.001), with the optical analogue refractometer reading higher than the digital refractometer (mean difference 0.0006, sd 0.0012). Paired refractometer measurements varied by <0.002 in 91.5 per cent of cases. The optical analogue and digital refractometer readings showed excellent correlation with osmolality (r=0.980 and r=0.977, respectively, P<0.001 in both cases). Despite statistical significance, the difference between the two refractometers is unlikely to be clinically significant. Both instruments provide an accurate assessment of USG in dogs.

Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis

NASA Astrophysics Data System (ADS)

Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

2012-08-01

Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

Arginine analogues incorporating carboxylate bioisosteric functions are micromolar inhibitors of human recombinant DDAH-1.

PubMed

Tommasi, Sara; Zanato, Chiara; Lewis, Benjamin C; Nair, Pramod C; Dall'Angelo, Sergio; Zanda, Matteo; Mangoni, Arduino A

2015-12-14

Dimethylarginine dimethylaminohydrolase (DDAH) is a key enzyme involved in the metabolism of asymmetric dimethylarginine (ADMA) and N-monomethyl arginine (NMMA), which are endogenous inhibitors of the nitric oxide synthase (NOS) family of enzymes. Two isoforms of DDAH have been identified in humans, DDAH-1 and DDAH-2. DDAH-1 inhibition represents a promising strategy to limit the overproduction of NO in pathological states without affecting the homeostatic role of this important messenger molecule. Here we describe the design and synthesis of 12 novel DDAH-1 inhibitors and report their derived kinetic parameters, IC50 and Ki. Arginine analogue 10a, characterized by an acylsulfonamide isosteric replacement of the carboxylate, showed a 13-fold greater inhibitory potential relative to the known DDAH-1 inhibitor, L-257. Compound 10a was utilized to study the putative binding interactions of human DDAH-1 inhibition using molecular dynamics simulations. The latter suggests that several stabilizing interactions occur in the DDAH-1 active-site, providing structural insights for the enhanced inhibitory potential demonstrated by in vitro inhibition studies.

Synthesis and biological activity of pyrrole analogues of combretastatin A-4.

PubMed

Jung, Eun-Kyung; Leung, Euphemia; Barker, David

2016-07-01

A series of pyrrole analogues of combretastatin (CA-4) were synthesized and tested for their anti-proliferative activity. The highly diastereoselective acyl-Claisen rearrangement was used to provide 2,3-syn disubstituted morpholine amides which were used as precursors for the various analogues. This synthesis allows for the preparation of 1,2- and 2,3-diaryl-1H-pyrroles which are both geometrically similar to CA-4. These pyrrolic analogues were tested for their anti-proliferative activity against two human cell lines, K562 and MDA-MB-231 with 2,3-diaryl-1H-pyrrole 35 exhibiting the most potent activity with IC50 value of 0.07μM against MDA-MB-231 cell line. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effect of pre-existing vulnerability factors on a laboratory analogue trauma experience.

PubMed

Laposa, Judith M; Alden, Lynn E

2008-12-01

This study examined how pre-existing emotional and personality vulnerability factors affect responses to an analogue trauma experience. Sixty-eight undergraduate participants viewed a distressing film and completed measures of trait anxiety, intelligence, depression, trait dissociation, as well as changes in state anxiety, then recorded intrusions over the following week. Results revealed that trait anxiety, depression, trait dissociation, change in anxiety, and post-state anxiety were associated with intrusion frequency. Post-state anxiety mediated the relationship between trait anxiety, depression and trait dissociation, and intrusions. Implications for PTSD theories and laboratory trauma analogue research examining specific elements of cognitive models of PTSD are discussed.

Synthesis and preliminary pharmacological evaluation of asymmetric chloroquine analogues.

PubMed

Witiak, D T; Grattan, D A; Heaslip, R J; Rahwan, R G

1981-06-01

Asymmetric chloroquine analogues (1-4) were prepared of known absolute configuration in order to assess stereochemical influences on selected biological activities. Since chloroquine has been shown to possess spasmolytic properties, analogues 1-4 were tested for similar pharmacological effects on smooth-muscle contraction. The (S)- and (R)-chlorochloroquine enantiomers (1 and 2, respectively) were more potent antispasmodics than the less lipophilic (S)- and (R)-hydroxychloroquines (3 and 4, respectively) when tested against KCl- or acetylcholine-induced contractions of the isolated mouse ileum. A membrane stabilizing mechanism of action for the chloroquine analogues is proposed since neither cellular toxicity nor calcium antagonism plays a role in the spasmolytic action of these compounds. Although compounds 1-4 also inhibited PGF2 alpha-induced contractions of the ileum, 1 was significantly more potent than 2; the latter in turn was equipotent to 3 and 4. It is tentatively proposed that 1 may possess stereoselective affinity for the PGF2 alpha receptor in the ileum. This observation may be further exploited to obtain more selective profiles of biological activity through molecular manipulation.

Do film soundtracks contain nonlinear analogues to influence emotion?

PubMed

Blumstein, Daniel T; Davitian, Richard; Kaye, Peter D

2010-12-23

A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses.

Do film soundtracks contain nonlinear analogues to influence emotion?

PubMed Central

Blumstein, Daniel T.; Davitian, Richard; Kaye, Peter D.

2010-01-01

A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses. PMID:20504815

Synthesis of biotinylated glycoconjugates and their use in a novel ELISA for direct comparison of HIV-1 Gp120 recognition of GalCer and related carbohydrate analogues.

PubMed

McReynolds, K D; Hadd, M J; Gervay-Hague, J

1999-01-01

As part of our program directed toward the design and synthesis of high-affinity ligands for the GalCer-binding site on the HIV cell surface glycoprotein, gp120, we required a reliable method for qualitatively assessing relative binding affinities for related analogues. Due to the hydrophilic nature of these synthetic conjugates, difficulties were encountered with typical ELISA methods, which rely upon hydrophobic interactions to anchor the ligand to a microtiter plate. Other types of assays were also problematic due to nonspecific binding of gp120. Therefore, we developed a general method for plating water-soluble ligands on microtiter plates using biotin/NeutrAvidin recognition for adhesion. A water-soluble GalCer analogue was prepared by conjugating psychosine to biotin using a novel tetraethylene glycol linker. In a similar manner, LacCer and GlcCer analogues were prepared and these conjugates were plated into microtiter wells containing NeutrAvidin. Unoccupied sites were blocked using biotin functionalized as a primary amide. Gp120 binding to galactosyl sphingosine, GalSph (19), GlcSph (22), and LacSph (23) conjugates was assessed through incubation with recombinant HRP-gp120. It was determined that LacSph has the strongest interaction with gp120. The binding affinities of GalSph and GlcSph were similar to each other and less strong than LacSph. These data contradict earlier studies where HPTLC showed that LacCer and GlcCer do not significantly bind gp120. They also contradict liposome-based assays that reported psychosine is not recognized by gp120. The extent of plating for each biotinylated molecule was quantified using HRP-biotin, allowing direct comparison of ligand plating efficiencies for the first time. Several other synthetic biotin conjugates were prepared and tested, demonstrating the feasibility of performing ELISA on water-soluble ligands.

Analogue Hawking radiation in a dc-SQUID array transmission line.

PubMed

Nation, P D; Blencowe, M P; Rimberg, A J; Buks, E

2009-08-21

We propose the use of a superconducting transmission line formed from an array of direct-current superconducting quantum interference devices for investigating analogue Hawking radiation. Biasing the array with a space-time varying flux modifies the propagation velocity of the transmission line, leading to an effective metric with a horizon. Being a fundamentally quantum mechanical device, this setup allows for investigations of quantum effects such as backreaction and analogue space-time fluctuations on the Hawking process.

Synthesis and SAR studies of marine natural products ma'edamines A, B and their analogues.

PubMed

Saha, Sanjay; Reddy, Ch Venkata Ramana; Xu, Shili; Sankar, Saranya; Neamati, Nouri; Patro, Balaram

2013-09-15

The synthesis of several analogues of ma'edamines A and B are reported. The synthesized compounds were tested on hormone receptor positive and HER2 positive breast cancer cell lines, by MTT assay. MED-114, 115, 117, 119, 120, 124, 128 and 131 were found to be equally active as Lapatinib on HER2 +ve cell line SKBR3. Copyright © 2013 Elsevier Ltd. All rights reserved.

NMR study on the stabilization and chiral discrimination of sulforaphane enantiomers and analogues by cyclodextrins.

PubMed

Recio, Rocío; Elhalem, Eleonora; Benito, Juan M; Fernández, Inmaculada; Khiar, Noureddine

2018-05-01

Sulforaphane (SFN), a phytochemical isolated from broccoli, is an important antitumoral compound with additional beneficial effect on other important diseases. However, the chemical instability of SFN has hampered its clinical use. In order to circumvent this problem, we report the first comparative study on the inclusion complexes of SFN and SFN homologues with different cyclodextrins by NMR spectroscopy. From this study it has been shown that α-CD is the most indicated cyclodextrin for the stabilization of SFN and SFN homologues, and that the highest affinity constant is that of the isothiocyanate obtained from the wasabi. Furthermore, the study of the inclusion complexes of α-CD and the non-natural SFN and analogues with S absolute configuration at sulfur shows for the first time that α-CD is able to discriminate between the two enantiomers, with the natural R enantiomers forming the inclusion complexes with higher affinity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Human Factor Studies on a Mars Analogue During Crew 100b International Lunar Exploration Working Group EuroMoonMars Crew: Proposed New Approaches for Future Human Space and Interplanetary Missions.

PubMed

Rai, Balwant; Kaur, Jasdeep

2012-11-01

Knowing the risks, costs, and complexities associated with human missions to Mars, analogue research can be a great (low-risk) tool for exploring the challenges associated with the preparation for living, operating, and undertaking research in interplanetary missions. Short-duration analogue studies, such as those being accomplished at the Mars Desert Research Station (MDRS), offer the chance to study mission operations and human factors in a simulated environment, and therefore contribute to exploration of the Moon and Mars in planned future missions. This article is based upon previously published articles, abstracts, and presentations by a series of independent authors, human factor studies performed on mars analogue station by Crew 100B. The MDRS Crew 100B performed studies over 15 days providing a unique insight into human factor issues in simulated short-duration Mars mission. In this study, 15 human factors were evaluated and analyzed by subjective and objective means, and from the summary of results it was concluded that optimum health of an individual and the crew as a whole is a necessity in order to encourage and maintain high performance and the satisfaction of project goals.

Human Factor Studies on a Mars Analogue During Crew 100b International Lunar Exploration Working Group EuroMoonMars Crew: Proposed New Approaches for Future Human Space and Interplanetary Missions

PubMed Central

Rai, Balwant; Kaur, Jasdeep

2012-01-01

Knowing the risks, costs, and complexities associated with human missions to Mars, analogue research can be a great (low-risk) tool for exploring the challenges associated with the preparation for living, operating, and undertaking research in interplanetary missions. Short-duration analogue studies, such as those being accomplished at the Mars Desert Research Station (MDRS), offer the chance to study mission operations and human factors in a simulated environment, and therefore contribute to exploration of the Moon and Mars in planned future missions. This article is based upon previously published articles, abstracts, and presentations by a series of independent authors, human factor studies performed on mars analogue station by Crew 100B. The MDRS Crew 100B performed studies over 15 days providing a unique insight into human factor issues in simulated short-duration Mars mission. In this study, 15 human factors were evaluated and analyzed by subjective and objective means, and from the summary of results it was concluded that optimum health of an individual and the crew as a whole is a necessity in order to encourage and maintain high performance and the satisfaction of project goals. PMID:23181225

Numerical simulation of an experimental analogue of a planetary magnetosphere

NASA Astrophysics Data System (ADS)

Liao, Andy Sha; Li, Shule; Hartigan, Patrick; Graham, Peter; Fiksel, Gennady; Frank, Adam; Foster, John; Kuranz, Carolyn

2015-12-01

Recent improvements to the Omega Laser Facility's magneto-inertial fusion electrical discharge system (MIFEDS) have made it possible to generate strong enough magnetic fields in the laboratory to begin to address the physics of magnetized astrophysical flows. Here, we adapt the MHD code AstroBEAR to create 2D numerical models of an experimental analogue of a planetary magnetosphere. We track the secular evolution of the magnetosphere analogue and we show that the magnetospheric components such as the magnetopause, magnetosheath, and bow shock, should all be observable in experimental optical band thermal bremsstrahlung emissivity maps, assuming equilibrium charge state distributions of the plasma. When the magnetosphere analogue nears the steady state, the mid-plane altitude of the magnetopause from the wire surface scales as the one-half power of the ratio of the magnetic pressure at the surface of the free wire to the ram pressure of an unobstructed wind; the mid-plane thickness of the magnetosheath is directly related to the radius of the magnetopause. This behavior conforms to Chapman and Ferraro's theory of planetary magnetospheres. Although the radial dependence of the magnetic field strength differs between the case of a current-carrying wire and a typical planetary object, the major morphological features that develop when a supersonic flow passes either system are identical. Hence, this experimental concept is an attractive one for studying the dynamics of planetary magnetospheres in a controlled environment.

Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus.

PubMed

Hogan, Andrew E; Gaoatswe, Gadintshware; Lynch, Lydia; Corrigan, Michelle A; Woods, Conor; O'Connell, Jean; O'Shea, Donal

2014-04-01

Glucagon-like peptide 1 (GLP-1) is a gut hormone used in the treatment of type 2 diabetes mellitus. There is emerging evidence that GLP-1 has anti-inflammatory activity in humans, with murine studies suggesting an effect on macrophage polarisation. We hypothesised that GLP-1 analogue therapy in individuals with type 2 diabetes mellitus would affect the inflammatory macrophage molecule soluble CD163 (sCD163) and adipocytokine profile. We studied ten obese type 2 diabetes mellitus patients starting GLP-1 analogue therapy at a hospital-based diabetes service. We investigated levels of sCD163, TNF-α, IL-1β, IL-6, adiponectin and leptin by ELISA, before and after 8 weeks of GLP-1 analogue therapy. GLP-1 analogue therapy reduced levels of the inflammatory macrophage activation molecule sCD163 (220 ng/ml vs 171 ng/ml, p < 0.001). This occurred independent of changes in body weight, fructosamine and HbA1c. GLP-1 analogue therapy was associated with a decrease in levels of the inflammatory cytokines TNF-α (264 vs 149 pg/ml, p < 0.05), IL-1β (2,919 vs 748 pg/ml, p < 0.05) and IL-6 (1,379 vs 461 pg/ml p < 0.05) and an increase in levels of the anti-inflammatory adipokine adiponectin (4,480 vs 6,290 pg/ml, p < 0.002). In individuals with type 2 diabetes mellitus, GLP-1 analogue therapy reduces the frequency of inflammatory macrophages. This effect is not dependent on the glycaemic or body weight effects of GLP-1.

Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria.

PubMed

Duveau, Damien Y; Arce, Pablo M; Schoenfeld, Robert A; Raghav, Nidhi; Cortopassi, Gino A; Hecht, Sidney M

2010-09-01

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2-4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6-8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6-8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. Copyright 2010 Elsevier Ltd. All rights reserved.

Therapeutic index of gramicidin S is strongly modulated by D-phenylalanine analogues at the beta-turn.

PubMed

Solanas, Concepción; de la Torre, Beatriz G; Fernández-Reyes, María; Santiveri, Clara M; Jiménez, M Angeles; Rivas, Luis; Jiménez, Ana I; Andreu, David; Cativiela, Carlos

2009-02-12

Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-D-Phe-Pro)2, with d-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all D-Phe substitutions are shown by NMR to preserve the overall beta-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating D-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the D-Tic aromatic ring and the Orn delta-amino group may help explain the improved antibiotic profile of this analogue.

Therapeutic index of gramicidin S is strongly modulated by d-phenylalanine analogues at the β-turn

PubMed Central

Solanas, Concepción; de la Torre, Beatriz G.; Fernández-Reyes, María; Santiveri, Clara M.; Jiménez, M. Ángeles; Rivas, Luis; Jiménez, Ana I.; Andreu, David; Cativiela, Carlos

2009-01-01

Analogues of the cationic antimicrobial peptide gramicidin S (GS), cyclo(Val-Orn-Leu-d-Phe-Pro)2, with d-Phe residues replaced by different (restricted mobility, mostly) surrogates have been synthesized and used in SAR studies against several pathogenic bacteria. While all d-Phe substitutions are shown by NMR to preserve the overall β-sheet conformation, they entail subtle structural alterations that lead to significant modifications in biological activity. In particular, the analogue incorporating d-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) shows a modest but significant increase in therapeutic index, mostly due to a sharp decrease in hemolytic effect. The fact that NMR data show a shortened distance between the d-Tic aromatic ring and the Orn δ-amino group may help explain the improved antibiotic profile of this analogue. PMID:19132829

Proline analogue of nitrosourea as a new cytotoxic prodrug.

PubMed

Stankiewicz-Kranc, Anna; Bielawska, Anna; Bielawski, Krzysztof; Skrzydlewska, Elzbieta

2009-11-01

Carmustine is frequently used as anticancer drug. High toxicity and low selectivity reduces the application of this drug. Though, there is a necessity to find new compounds characterized by similar therapeutic effects but a higher selectivity and safety. As a result, the proline analogue of nitrosourea, N-[N'-(2-bromophenyl)-N'-nitrosocarbamoyl]proline (AC), has been synthesized. The aim of this study was to compare the influence of carmustine and the proline analogue of nitrosourea on the antioxidant abilities of fibroblasts and leukemia cells, MOLT4. It was shown that carmustine as well as AC cause an increase in hydrogen peroxide concentration in normal and neoplastic cells. Incubation with both compounds led to a diminution of the activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and reductase. Changes in activity / level of antioxidant parameters were accompanied by augmentation of lipid and oxidative protein modifications. In conclusion, carmustine and AC cause changes in the antioxidative system of normal and MOLT4 cells and are a reason of oxidative stress formation.

Isolation and structural identification of a novel minoxidil analogue in an illegal dietary supplement: triaminodil.

PubMed

Lee, Ji Hyun; Park, Han Na; Park, Hyoung Joon; Kim, Nam Sook; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

2018-01-01

A new minoxidil analogue was detected in an illegal dietary supplement advertised as a hair-growth treatment. The analogue was identified using ultra-performance liquid chromatography (UPLC), high-resolution mass spectrometry (LC-HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The compound was structurally elucidated as a minoxidil analogue in which the piperidinyl group of minoxidil was replaced with a pyrrolidinyl group corresponding to a molecular formula of C 8 H 13 N 5 O. The new analogue has been named triaminodil. As this is the first report of the compound, there are no chemical, toxicology or pharmacological data available.

Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: synthesis and pharmacological evaluation.

PubMed

Ongarora, Dennis S B; Gut, Jiri; Rosenthal, Philip J; Masimirembwa, Collen M; Chibale, Kelly

2012-08-01

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC(50)s ranging from 7 to 22 nM. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effect of a synthetic indolicidin analogue on lipid peroxidation in thermal burns.

PubMed

Lazarenko, V A; Lyashev, Yu D; Shevchenko, N I

2014-08-01

Experimental simulation of burn was followed by accumulation of LPO products and suppression of antioxidant enzyme activity in the burn wound. Application of a synthetic analogue of indolicidin led to an increase in MDA and acylhydroperoxide concentrations in the burn wound on experimental day 1. Further application of the peptide in a dose of 100 mg/kg had no significant effect on the studied parameters, while the peptide in a dose of 500 mg/kg was followed by a decrease in the level of LPO products on days 10 and 14. Changes in antioxidant enzyme activities in rats treated with 500 mg/kg indolicidin analogue had a two-phase pattern: an increase on day 4 was followed by a decrease.

Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity

PubMed Central

Chianese, Giuseppina; Scala, Fernando; Calcinai, Barbara; Cerrano, Carlo; Dien, Henny A.; Kaiser, Marcel; Tasdemir, Deniz; Taglialatela-Scafati, Orazio

2013-01-01

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents. PMID:23989650

Design and synthesis of novel arctigenin analogues for the amelioration of metabolic disorders.

PubMed

Duan, Shudong; Huang, Suling; Gong, Jian; Shen, Yu; Zeng, Limin; Feng, Ying; Ren, Wenming; Leng, Ying; Hu, Youhong

2015-04-09

Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes.

PubMed

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte; Bräuner-Osborne, Hans

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.

Vacuum ultraviolet photoabsorption of prime ice analogues of Pluto and Charon

NASA Astrophysics Data System (ADS)

Pavithraa, S.; Lo, J.-I.; Rahul, K.; Raja Sekhar, B. N.; Cheng, B.-M.; Mason, N. J.; Sivaraman, B.

2018-02-01

Here we present the first Vacuum UltraViolet (VUV) photoabsorption spectra of ice analogues of Pluto and Charon ice mixtures. For Pluto the ice analogue is an icy mixture containing nitrogen (N2), carbon monoxide (CO), methane (CH4) and water (H2O) prepared with a 100:1:1:3 ratio, respectively. Photoabsorption of icy mixtures with and without H2O were recorded and no significant changes in the spectra due to presence of H2O were observed. For Charon a VUV photoabsorption spectra of an ice analogue containing ammonia (NH3) and H2O prepared with a 1:1 ratio was recorded, a spectrum of ammonium hydroxide (NH4OH) was also recorded. These spectra may help to interpret the P-Alice data from New Horizons.

Low-frequency analogue Hawking radiation: The Bogoliubov-de Gennes model

NASA Astrophysics Data System (ADS)

Coutant, Antonin; Weinfurtner, Silke

2018-01-01

We analytically study the low-frequency properties of the analogue Hawking effect in Bose-Einstein condensates. We show that in one-dimensional flows displaying an analogue horizon, the Hawking effect is dominant in the low-frequency regime. This happens despite nonvanishing grey-body factors, that is, the coupling of the Hawking mode and its partner to the mode propagating with the flow. To show this, we obtained analytical expressions for the scattering coefficients, in general flows and taking into account the full Bogoliubov dispersion relation. We discuss the obtained expressions for the grey-body factors. In particular, we show that they can be significantly decreased if the flow obeys a conformal coupling condition. We argue that in the presence of a small but non-zero temperature, reducing grey-body factors greatly facilitates the observation of entanglement, that is, establishing that the state of the Hawking mode and its partner is non-separable.

Collaborative Student Laboratory Exercise Using FT-IR Spectroscopy for the Kinetics Study of a Biotin Analogue

ERIC Educational Resources Information Center

Leong, Jhaque; Ackroyd, Nathan C.; Ho, Karen

2014-01-01

The synthesis of N-methoxycarbonyl-2-imidazolidone, an analogue of biotin, was conducted by organic chemistry students and confirmed using FT-IR and H NMR. Spectroscopy students used FT-IR to measure the rate of hydrolysis of the product and determined the rate constant for the reaction using the integrated rate law. From the magnitude of the rate…

Insulin biosimilars: the impact on rapid-acting analogue-based therapy.

PubMed

Franzè, S; Cilurzo, F; Minghetti, P

2015-04-01

The impending expiration of patent protection for recombinant insulins provides the opportunity to introduce cost-saving copies, named biosimilars, onto the market. Although there is broad experience in the production and characterisation of insulins, the development of copies is still a challenge. In this paper, the main features of insulins and the EU regulatory framework for their biosimilar products are reviewed. The main focus is on rapid-acting insulin analogues (Humalog(®); Novolog(®)/NovoRapid(®); Apidra(®)). Since they differ by one or two amino acids in chain B, production of one biosimilar for all three drug products is not feasible. However, from post-marketing-collected clinical data, rapid-acting insulin analogues seem to have similar therapeutic efficacy. It is reasonable to suppose that, for prescription to treatment-naïve patients, the cheaper biosimilar would be the preferred choice of physicians, either spontaneously or induced by health insurance. Therefore, its introduction will affect the market share of all the other rapid-acting insulin analogues.

Natural analogues of nuclear waste glass corrosion.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

1999-01-06

This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information availablemore » on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.« less

Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

PubMed Central

Palacios, Rosario; Santos, Jesús; Camino, Xavier; Arazo, Piedad; Torres Perea, Rafael; Echevarrfa, Santiago; Ribera, Esteban; Sánchez de la Rosa, Rainel; Moreno Guillen, Santiago

2005-01-01

Background: The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain. Objective: The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study. Methods: Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003. Results: A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART

Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues

NASA Astrophysics Data System (ADS)

Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

2014-03-01

A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

DOTA-derivatives of octreotide dicarba-analogues with high affinity for somatostatin sst2,5 receptors

NASA Astrophysics Data System (ADS)

Pratesi, Alessandro; Ginanneschi, Mauro; Lumini, Marco; Papini, Anna M.; Novellino, Ettore; Brancaccio, Diego; Carotenuto, Alfonso

2017-02-01

In vivo somatostatin receptor scintigraphy is a valuable method for the visualization of human endocrine tumours and their metastases. In fact, peptide ligands of somatostatin receptors (sst’s) conjugated with chelating agents are in clinical use. We have recently developed octreotide dicarba-analogues, which show interesting binding profiles at sst’s. In this context, it was mandatory to explore the possibility that our analogues could maintain their activity also upon conjugation with DOTA. In this paper, we report and discuss the synthesis, binding affinity and conformational preferences of three DOTA-conjugated dicarba-analogues of octreotide. Interestingly, two conjugated analogues exhibited nanomolar affinities on sst2 and sst5 somatostatin receptor subtypes.

Advancing Translational Space Research Through Biospecimen Sharing: Amplified Impact of Studies Utilizing Analogue Space Platforms

NASA Technical Reports Server (NTRS)

Staten, B.; Moyer, E.; Vizir, V.; Gompf, H.; Hoban-Higgins, T.; Lewis, L.; Ronca, A.; Fuller, C. A.

2016-01-01

Biospecimen Sharing Programs (BSPs) have been organized by NASA Ames Research Center since the 1960s with the goal of maximizing utilization and scientific return from rare, complex and costly spaceflight experiments. BSPs involve acquiring otherwise unused biological specimens from primary space research experiments for distribution to secondary experiments. Here we describe a collaboration leveraging Ames expertise in biospecimen sharing to magnify the scientific impact of research informing astronaut health funded by the NASA Human Research Program (HRP) Human Health Countermeasures (HHC) Element. The concept expands biospecimen sharing to one-off ground-based studies utilizing analogue space platforms (e.g., Hindlimb Unloading (HLU), Artificial Gravity) for rodent experiments, thereby significantly broadening the range of research opportunities with translational relevance for protecting human health in space and on Earth.

Nematic order-disorder state transition in a liquid crystal analogue formed by oriented and migrating amoeboid cells

NASA Astrophysics Data System (ADS)

Kemkemer, R.; Teichgräber, V.; Schrank-Kaufmann, S.; Kaufmann, D.; Gruler, H.

2000-10-01

In cell culture, liquid crystal analogues are formed by elongated, migrating, and interacting amoeboid cells. An apolar nematic liquid crystal analogue is formed by different cell types like human melanocytes (=pigment cells of the skin), human fibroblasts (=connective tissue cells), human osteoblasts (=bone cells), human adipocytes (=fat cells), etc. The nematic analogue is quite well described by i) a stochastic machine equation responsible for cell orientation and ii) a self-organized extracellular guiding signal, E_2, which is proportional to the orientational order parameter as well as to the cell density. The investigations were mainly made with melanocytes. The transition to an isotropic state analogue can be accomplished either by changing the strength of interaction (e.g. variation of the cell density) or by influencing the cellular machinery by an externally applied signal: i) An isotropic gaseous state analogue is observed at low cell density (ρ < 110melanocytes/mm^2) and a nematic liquid crystal state analogue at higher cell density. ii) The nematic state analogue disappears if the bipolar shaped melanocytes are forced to become a star-like shape (induced by colchicine or staurosporine). The analogy between nematic liquid crystal state analogue formed by elongated, migrating and interacting cells and the nematic liquid crystal phase formed by interacting elongated molecules is discussed.

Quantitative comparisons of analogue models of brittle wedge dynamics

NASA Astrophysics Data System (ADS)

Schreurs, Guido

2010-05-01

Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct implications for comparisons between structures in analogue models and natural field examples. All laboratories used the same frictional analogue materials (quartz and corundum sand) and prescribed model-building techniques (sieving and levelling). Although each laboratory used its own experimental apparatus, the same type of self-adhesive foil was used to cover the base and all the walls of the experimental apparatus in order to guarantee identical boundary conditions (i.e. identical shear stresses at the base and walls). Three experimental set-ups using only brittle frictional materials were examined. In each of the three set-ups the model was shortened by a vertical wall, which moved with respect to the fixed base and the three remaining sidewalls. The minimum width of the model (dimension parallel to mobile wall) was also prescribed. In the first experimental set-up, a quartz sand wedge with a surface slope of ˜20° was pushed by a mobile wall. All models conformed to the critical taper theory, maintained a stable surface slope and did not show internal deformation. In the next two experimental set-ups, a horizontal sand pack consisting of alternating quartz sand and corundum sand layers was shortened from one side by the mobile wall. In one of the set-ups a thin rigid sheet covered part of the model base and was attached to the mobile wall (i.e. a basal velocity discontinuity distant from the mobile wall). In the other set-up a basal rigid sheet was absent and the basal velocity discontinuity was located at the mobile wall. In both types of experiments

Dimeric [Mo₂S₁₂]²⁻ Cluster: A Molecular Analogue of MoS₂ Edges for Superior Hydrogen-Evolution Electrocatalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Zhongjie; Luo, Wenjia; Ma, Lu

2015-12-07

Proton reduction is one of the most fundamental and important reactions in nature. MoS2 edges have been identified as the active sites for hydrogen evolution reaction (HER) electrocatalysis. Designing molecular mimics of MoS2 edge sites is an attractive strategy to understand the underlying catalytic mechanism of different edge sites and improve their activities. Herein we report a dimeric molecular analogue [Mo₂S₁₂]²⁻, as the smallest unit possessing both the terminal and bridging disulfide ligands. Our electrochemical tests show that [Mo₂S₁₂]²⁻ is a superior heterogeneous HER catalyst under acidic conditions. Computations suggest that the bridging disulfide ligand of [Mo₂S₁₂]²⁻ exhibits a hydrogenmore » adsorption free energy near zero (-0.05eV). This work helps shed light on the rational design of HER catalysts and biomimetics of hydrogen-evolving enzymes.« less

Simulation of traumatic brain injury symptoms on the Personality Assessment Inventory: an analogue study.

PubMed

Keiski, Michelle A; Shore, Douglas L; Hamilton, Joanna M; Malec, James F

2015-04-01

The purpose of this study was to characterize the operating characteristics of the Personality Assessment Inventory (PAI) validity scales in distinguishing simulators feigning symptoms of traumatic brain injury (TBI) while completing the PAI (n = 84) from a clinical sample of patients with TBI who achieved adequate scores on performance validity tests (n = 112). The simulators were divided into two groups: (a) Specific Simulators feigning cognitive and somatic symptoms only or (b) Global Simulators feigning cognitive, somatic, and psychiatric symptoms. The PAI overreporting scales were indeed sensitive to the simulation of TBI symptoms in this analogue design. However, these scales were less sensitive to the feigning of somatic and cognitive TBI symptoms than the feigning of a broad range of cognitive, somatic, and emotional symptoms often associated with TBI. The relationships of TBI simulation to consistency and underreporting scales are also explored. © The Author(s) 2014.

Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin.

PubMed

Deck, Lorraine M; Hunsaker, Lucy A; Vander Jagt, Thomas A; Whalen, Lisa J; Royer, Robert E; Vander Jagt, David L

2018-01-01

Inflammation and oxidative stress are common in many chronic diseases. Targeting signaling pathways that contribute to these conditions may have therapeutic potential. The transcription factor Nrf2 is a major regulator of phase II detoxification and anti-oxidant genes as well as anti-inflammatory and neuroprotective genes. Nrf2 is widespread in the CNS and is recognized as an important regulator of brain inflammation. The natural product curcumin exhibits numerous biological activities including ability to induce the expression of Nrf2-dependent phase II and anti-oxidant enzymes. Curcumin has been examined in a number of clinical studies with limited success, mainly owing to limited bioavailability and rapid metabolism. Enone analogues of curcumin were examined with an Nrf2 reporter assay to identify Nrf2 activators. Analogues were separated into groups with a 7-carbon dienone spacer, as found in curcumin; a 5-carbon enone spacer with and without a ring; and a 3-carbon enone spacer. Activators of Nrf2 were found in all three groups, many of which were more active than curcumin. Dose-response studies demonstrated that a range of substituents on the aromatic rings of these enones influenced not only the sensitivity to activation, reflected in EC 50 values, but also the extent of activation, which suggests that multiple mechanisms are involved in the activation of Nrf2 by these analogues. Copyright © 2017. Published by Elsevier Masson SAS.

Anticancer and antiviral effects and inactivation of S-adenosyl-L-homocysteine hydrolase with 5'-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues.

PubMed

Wnuk, S F; Yuan, C S; Borchardt, R T; Balzarini, J; De Clercq, E; Robins, M J

1997-05-23

Selectively protected adenine nucleosides were converted into 5'-carboxaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohexylcarbodiimide/dichloroacetic acid) or with the Dess-Martin periodinane reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (alpha-fluoro thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Treatment of 5'-carboxaldehydes with hydroxylamine [or O-(methyl, ethyl, and benzyl)hydroxylamine] hydrochloride gave E/Z oximes. Treatment of purified oximes with aqueous trifluoroacetic acid and acetone effected trans-oximation to provide clean samples of 5'-carboxaldehydes. Adenosine (Ado)-5'-carboxaldehyde and its 4'-epimer are potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. They bind efficiently to the enzyme and undergo oxidation at C3' to give 3'-keto analogues with concomitant reduction of the NAD+ cofactor to give an inactive, tightly bound NADH-enzyme complex (type I cofactor-depletion inhibition). Potent type I inhibition was observed with 5'-carboxaldehydes that contain a ribo cis-2',3'-glycol. Their oxime derivatives are "proinhibitors" that undergo enzyme-catalyzed hydrolysis to release the inhibitors at the active site. The 2'-deoxy and 2'-epimeric (arabinosyl) analogues were much weaker inhibitors, and the 3'-deoxy compounds bind very weakly. Ado-5'-carboxaldehyde oxime had potent cytotoxicity in tumor cell lines and was toxic to normal human cells. Analogues had weaker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.

Hierarchically Superstructured Prussian Blue Analogues: Spontaneous Assembly Synthesis and Applications as Pseudocapacitive Materials

DOE PAGES

Yue, Yanfeng; Zhang, Zhiyong; Binder, Andrew J.; ...

2014-11-10

Hierarchically superstructured Prussian blue analogues (hexa- conventional hybrid graphene/MnO 2 nanostructured textiles. cyanoferrate, M = Ni II, Co II and Cu II) are synthesized through Because sodium or potassium ions are involved in energy stor- a spontaneous assembly technique. In sharp contrast to mac- age processes, more environmentally neutral electrolytes can roporous-only Prussian blue analogues, the hierarchically su- be utilized, making the superstructured porous Prussian blue perstructured porous Prussian blue materials are demonstrated analogues a great contender for applications as high-per- to possess a high capacitance, which is similar to those of the formance pseudocapacitors.

Activities of dl-α-Difluoromethylarginine and Polyamine Analogues against Cryptosporidium parvum Infection in a T-Cell Receptor Alpha-Deficient Mouse Model▿

PubMed Central

Yarlett, Nigel; Waters, W. Ray; Harp, James A.; Wannemuehler, Michael J.; Morada, Mary; Bellcastro, Josephine; Upton, Steve J.; Marton, Laurence J.; Frydman, Benjamin J.

2007-01-01

The in vivo effectiveness of a series of conformationally restricted polyamine analogues alone and selected members in combination with dl-α-difluoromethylarginine against Cryptosporidium parvum infection in a T-cell receptor alpha-deficient mouse model was tested. Polyamine analogues were selected from the extended bis(ethyl)-sym-homospermidine or bis(ethyl)-spermine backbone having cis or trans double bonds at the center of the molecule. The cis isomers were found to have significantly greater efficacy in both preventing and curing infection in a mouse model than the trans polyamine analogues when tested in a T-cell receptor alpha-deficient mouse model. When tested in combination with dl-α-difluoromethylarginine, the cis-restricted analogues were found to be more effective in preventing oocyst shedding. This study demonstrates the potential of polyamine analogues as anticryptosporidial agents and highlights the presence of multiple points in polyamine synthesis by this parasite that are susceptible to inhibition resulting in growth inhibition. PMID:17242149

Evidence of soft bound behaviour in analogue memristive devices for neuromorphic computing.

PubMed

Frascaroli, Jacopo; Brivio, Stefano; Covi, Erika; Spiga, Sabina

2018-05-08

The development of devices that can modulate their conductance under the application of electrical stimuli constitutes a fundamental step towards the realization of synaptic connectivity in neural networks. Optimization of synaptic functionality requires the understanding of the analogue conductance update under different programming conditions. Moreover, properties of physical devices such as bounded conductance values and state-dependent modulation should be considered as they affect storage capacity and performance of the network. This work provides a study of the conductance dynamics produced by identical pulses as a function of the programming parameters in an HfO 2 memristive device. The application of a phenomenological model that considers a soft approach to the conductance boundaries allows the identification of different operation regimes and to quantify conductance modulation in the analogue region. Device non-linear switching kinetics is recognized as the physical origin of the transition between different dynamics and motivates the crucial trade-off between degree of analog modulation and memory window. Different kinetics for the processes of conductance increase and decrease account for device programming asymmetry. The identification of programming trade-off together with an evaluation of device variations provide a guideline for the optimization of the analogue programming in view of hardware implementation of neural networks.

Field-programmable analogue arrays for the sensorless control of DC motors

NASA Astrophysics Data System (ADS)

Rivera, J.; Dueñas, I.; Ortega, S.; Del Valle, J. L.

2018-02-01

This work presents the analogue implementation of a sensorless controller for direct current motors based on the super-twisting (ST) sliding mode technique, by means of field programmable analogue arrays (FPAA). The novelty of this work is twofold, first is the use of the ST algorithm in a sensorless scheme for DC motors, and the implementation method of this type of sliding mode controllers in FPAAs. The ST algorithm reduces the chattering problem produced with the deliberate use of the sign function in classical sliding mode approaches. On the other hand, the advantages of the implementation method over a digital one are that the controller is not digitally approximated, the controller gains are not fine tuned and the implementation does not require the use of analogue-to-digital and digital-to-analogue converter circuits. In addition to this, the FPAA is a reconfigurable, lower cost and power consumption technology. Simulation and experimentation results were registered, where a more accurate transient response and lower power consumption were obtained by the proposed implementation method when compared to a digital implementation. Also, a more accurate performance by the DC motor is obtained with proposed sensorless ST technique when compared with a classical sliding mode approach.

Vacuum ultraviolet photoabsorption of prime ice analogues of Pluto and Charon.

PubMed

Pavithraa, S; Lo, J-I; Rahul, K; Raja Sekhar, B N; Cheng, B-M; Mason, N J; Sivaraman, B

2018-02-05

Here we present the first Vacuum UltraViolet (VUV) photoabsorption spectra of ice analogues of Pluto and Charon ice mixtures. For Pluto the ice analogue is an icy mixture containing nitrogen (N 2 ), carbon monoxide (CO), methane (CH 4 ) and water (H 2 O) prepared with a 100:1:1:3 ratio, respectively. Photoabsorption of icy mixtures with and without H 2 O were recorded and no significant changes in the spectra due to presence of H 2 O were observed. For Charon a VUV photoabsorption spectra of an ice analogue containing ammonia (NH 3 ) and H 2 O prepared with a 1:1 ratio was recorded, a spectrum of ammonium hydroxide (NH 4 OH) was also recorded. These spectra may help to interpret the P-Alice data from New Horizons. Copyright © 2017 Elsevier B.V. All rights reserved.

Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosis in vitro

PubMed Central

Guckian, M; Dransfield, I; Hay, P; Dalgleish, A G

2000-01-01

Thalidomide has significant immunomodulatory properties and has been used successfully in the treatment of oral ulcers and wasting in HIV patients. However, its use is limited by its poor bioavailability due to low solubility and short half life in solution, and teratogenic and neurotoxic side-effects. Recently, water-soluble analogues of thalidomide with significantly greater immunomodulatory activity and reduced side-effects have become available. We examined the effect of thalidomide and one analogue, CC-3052, on neutrophil apoptosis following culture for 20 h in vitro. Apoptosis was assessed by reduced CD16 expression and Annexin V binding using flow cytometry. Thalidomide or CC-3052 alone had no effect on neutrophil apoptosis when used at physiological levels. However, when used together with prostaglandin E2 (10−7 m), a potent adenylate cyclase activator, CC-3052 but not thalidomide (both 10−5 m) reduced apoptosis in neutrophils from normal and HIV+ donors. The reduced apoptosis could not be attributed to the ability of CC-3052 to reduce tumour necrosis factor-alpha (TNF-α) production, but may be due to its PDE4 inhibitor properties, as it increased [cAMP]i, and mimicked the effect of increasing [cAMP]i using dibutryl cAMP, a membrane-permeable analogue of cAMP. The results suggest a role for thalidomide analogue CC-3052 in reducing persistent activation of the TNF-α system in HIV without markedly impairing neutrophil viability. PMID:10971513

Effector analogues detect varied allosteric roles for conserved protein-effector interactions in pyruvate kinase isozymes†

PubMed Central

Alontaga, Aileen Y.; Fenton, Aron W.

2011-01-01

The binding site for allosteric inhibitor (amino acid) is highly conserved between human liver pyruvate kinase (hL-PYK) and the rabbit muscle isozyme (rM1-PYK). To detail similarities/differences in the allosteric function of these two homologs, we quantified the binding of 45 amino acid analogues to hL-PYK and their allosteric impact on affinity for the substrate, phosphoenolpyruvate (PEP). This complements a similar study previously completed for rM1-PYK. In hL-PYK, the minimum chemical requirements for effector binding are the same as those identified for rM1-PYK (i.e. the L-2-aminopropanaldehyde substructure of the effector is primarily responsible for binding). However different regions of the effector determine the magnitude of the allosteric response in hL-PYK vs. rM1-PYK. This finding is inconsistent with the idea that allosteric pathways are conserved between homologs of a protein family. PMID:21261284

Theoretical analysis of the electronic properties of the sex pheromone and its analogue derivatives in the female processionary moth Thaumetopoea pytiocampa.

PubMed

Chamorro, Ester R; Sequeira, Alfredo F; Zalazar, M Fernanda; Peruchena, Nélida M

2008-09-15

In the present work, the distribution of the electronic charge density of the natural sex pheromone, the (Z)-13-hexadecen-11-ynyl acetate, in the female processionary moth, Thaumetopoea pytiocampa, and its nine analogue derivatives was studied within the framework of the Density Functional Theory and the Atoms in Molecules (AIM) Theory at B3LYP/6-31G *//B3LYP/6-31++G * * level. Additionally, molecular electrostatic potential (MEP) maps of the previously mentioned compounds were computed and compared. Furthermore, the substitution of hydrogen atoms from the methyl group in the acetate group by electron withdrawing substituents (i.e., halogen atoms) as well as the replacement effect of hydrogen by electron donor substituents (+I effect) as methyl group, were explored. The key feature of the topological distribution of the charge density in analogue compounds, such as the variations of the topological properties encountered in the region formed by neighbouring atoms from the substitution site were presented and discussed. Using topological parameters, such as electronic charge density, Laplacian, kinetic energy density, and potential energy density evaluated at bond critical points (BCP), we provide here a detailed analysis of the nature of the chemical bonding of these molecules. In addition, the atomic properties (population, charge, energy, volume, and dipole moment) were determined on selected atoms. These properties were analyzed at the substitution site (with respect to the natural sex pheromone) and related to the biological activity and to the possible binding site with the pheromone binding protein, (PBP). Moreover, the Laplacian function of the electronic density was used to locate electrophilic regions susceptible to be attacked (by deficient electron atoms or donor hydrogen). Our results indicate that the change in the atomic properties, such as electronic population and atomic volume, are sensitive indicators of the loss of the biological activity in the

Synthetic Cannabis Analogues and Suicidal Behavior: Case Report.

PubMed

Oliveira, Pedro Miguel Dos Santos; Morais, Ana Sofia Félix; Madeira, Nuno Gonçalo Gomes Fernandes

Despite growing legal control, a wide range of synthetic cannabis analogues is currently used for recreational purposes, notwithstanding their well adverse outcomes, which appear to be more frequent and more serious than those associated with cannabis use. We present the case report of a patient with paranoid schizophrenia, who attempted suicide by serious bodily harm after a single use of "Shiva Ultra Strong," a compound of several synthetic cannabis analogues. A 32-year-old male patient with paranoid schizophrenia was brought to the emergency department presenting with a severe self-inflicted wound to the neck which lacerated the right jugular vein and ipsilateral airway, and narrowly missed the carotid bifurcation. On examination, the patient exhibited psychomotor agitation and anxiety. Laboratory tests, which included routine substance use screening, proved unremarkable. The patient was admitted to the ENT Department for surgical treatment, after which he was transferred to our Psychiatry Department, exhibiting consistent improvement with his usual antipsychotic regimen, to which he had good previous adherence. Later, after discharge, he admitted to having used a smartshop drug, so-called "Shiva Ultra Strong," shortly before the suicide attempt. Although current data on the suicide risk of synthetic cannabis analogues are limited, there is growing evidence of relevant psychiatric effects after their use. Patients with serious mental disorders could prove particularly vulnerable to these drugs, resulting in severe behavioral changes and self-harm.

Development of Ion Chemosensors Based on Porphyrin Analogues.

PubMed

Ding, Yubin; Zhu, Wei-Hong; Xie, Yongshu

2017-02-22

Sensing of metal ions and anions is of great importance because of their widespread distribution in environmental systems and biological processes. Colorimetric and fluorescent chemosensors based on organic molecular species have been demonstrated to be effective for the detection of various ions and possess the significant advantages of low cost, high sensitivity, and convenient implementation. Of the available classes of organic molecules, porphyrin analogues possess inherently many advantageous features, making them suitable for the design of ion chemosensors, with the targeted sensing behavior achieved and easily modulated based on their following characteristics: (1) NH moieties properly disposed for binding of anions through cooperative hydrogen-bonding interactions; (2) multiple pyrrolic N atoms or other heteroatoms for selectively chelating metal ions; (3) variability of macrocycle size and peripheral substitution for modulation of ion selectivity and sensitivity; and (4) tunable near-infrared emission and good biocompatibility. In this Review, design strategies, sensing mechanisms, and sensing performance of ion chemosensors based on porphyrin analogues are described by use of extensive examples. Ion chemosensors based on normal porphyrins and linear oligopyrroles are also briefly described. This Review provides valuable information for researchers of related areas and thus may inspire the development of more practical and effective approaches for designing high-performance ion chemosensors based on porphyrin analogues and other relevant compounds.

Analogue and numerical modelling in Volcanology: Development, evolution and future challenges

NASA Astrophysics Data System (ADS)

Kavanagh, Janine; Annen, Catherine

2015-04-01

Since the inception of volcanology as a science, analogue modelling has been an important methodology to study the formation and evolution of the volcanic system. With the development of computing capacities numerical modelling has become a widely used tool to explore magmatic process quantitatively and try to predict eruptive behaviour. Processes of interest include the development and establishment of the volcanic plumbing system, the propagation of magma to the surface to feed eruptions, the construction of a volcanic edifice and the dynamics of eruptive processes. An important ultimate aim is to characterise and measure the experimental volcanic and magmatic phenomena, to inform and improve eruption forecasting for hazard assessments. In nature, volcanic activity is often unpredictable and in an environment that is highly changeable and forbidding. Volcanic or magmatic activity cannot be repeated at will and has many (often unconstrained) variables. The processes of interest are frequently hidden from view, for example occurring beneath the Earth's surface or within a pyroclastic flow or plume. The challenges of working in volcanic terrains and gathering 'real' volcano data mean that analogue and numerical models have gained significant importance as a method to study the geometrics, kinematics, and dynamics of volcano growth and eruption. A huge variety of analogue materials have been used in volcanic modelling, often bringing out the more creative side of the scientific mind. As with all models, the choice of appropriate materials and boundary conditions are critical for assessing the relevance and usefulness of the experimental results. Numerical simulation has proved a useful tool to test the physical plausibility of conceptual models and presents the advantage of being applicable at different scales. It is limited however in its predictive power by the number of free parameters needed to describe geological systems. In this special symposium we will

Design and Synthesis of Novel Arctigenin Analogues for the Amelioration of Metabolic Disorders

PubMed Central

2015-01-01

Analogues of the natural product (−)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (−)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure–activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes. PMID:25941553

Sulphur Spring: Busy Intersection and Possible Martian Analogue

NASA Technical Reports Server (NTRS)

Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

2000-01-01

Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

Successful desensitization to Gonadotropin-releasing hormone analogue Triptorelin Acetate using a sustained-release depot preparation.

PubMed

Chan Ng, Pauline; Huang, Chiung-Hui; Rajakulendran, Mohana; Tan, Michelle Meiling; Wang, Ping Ping; Tay, Lei Qiu; Goh, Siok Ying; Shek, Lynette Pei-Chi; Tham, Elizabeth Huiwen

2018-05-29

Gonadotropin-releasing hormone (GnRH) analogues are commonly used in pediatric patients in the treatment of central precocious puberty 1 . GnRH analogues suppress the secretion of gonadotropins and sex hormones, preventing progression to advanced puberty and reduced final adult height secondary to accelerated fusion of growth plates. GnRH analogues are also used in adults for treatment of endometriosis 2 and prostatic cancer 3 . Hypersensitivity reactions to GnRH analogues are exceedingly rare 4-6 and to date, we are unaware of any desensitization protocols for GnRH hypersensitivity in the literature or used in clinical practice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Stereoselective synthesis of conformationally constrained omega-amino acid analogues from pyroglutamic acid.

PubMed

Bentz, Emilie L; Goswami, Rajesh; Moloney, Mark G; Westaway, Susan M

2005-08-07

Bicyclic lactams derived from pyroglutamic acid provide a useful scaffold for synthesis of conformationally restricted analogues of lysine, ornithine and glutamine, as well as an Ala-Ala dipeptide analogue. Amino alcohol and carboxylic acid derivatives are accessible from a common intermediate. In this strategy, the bicyclic lactam system not only controls, but also facilitates the determination of the stereochemistry of the synthetic intermediates.

Synthesis and acetylcholinesterase inhibitory activity of several pyrimidone analogues of huperzine A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozlkowski, A.P.; Campiani, G.; Saxena, A.

1995-12-31

Synthesis of four new pyrimidone analogues of the acetyicholinesterase (AChE) inhibitor huperzine A are reported together with the inhibitory potendes of these compounds for foetal bovine calf serum AChE; t3-lactone formation followed by a thermal cycloreversion reaction serves as the key step for introduction of the ethylidene appendage of analogue 12 in the stereochemically correct form.

Synthesis and biological evaluation of manzamine analogues.

PubMed

Winkler, Jeffrey D; Londregan, Allyn T; Ragains, Justin R; Hamann, Mark T

2006-07-20

[Structure: see text] The synthesis and biological evaluation of a series of analogues of manzamine A, representing partial structures of the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum and demonstrated attenuated antimalarial activity relative to that of manzamine A.

Adjuvant role of vitamin B analogue (sulbutiamine) with anti-infective treatment in infection associated asthenia.

PubMed

Shah, Siddharth N

2003-09-01

Asthenic symptoms such as weakness accompany illness. This study investigates whether the centrally acting cholinergic agent, vitamin B analogue (sulbutiamine), is effective and acceptable in relieving these symptoms in infectious disease when combined with specific anti-infective treatment. In a prospective uncontrolled, non-randomised, commercial, observational study, 1772 patients with an infectious disease and asthenic symptoms, drawn from the practice of 350 randomly selected physicians throughout India, received vitamin B analogue (sulbutiamine) in addition to specific anti-infective treatment for 15 days. The primary outcome variable was complete resolution of asthenic symptoms with treatment. The number (%, 95% confidence interval) of patients with complete resolution of all asthenic symptoms was 916 (51.7, 49.4-54). In the remaining patients, severe asthenia was reduced but persisted in 11 (0.6, 0-26); and moderate asthenia in 94 (5.3, 0-17.6). The response was greater in patients with acute infection and symptoms more related to cerebral function. Side effects occurred in 10 (0.6%), patients and well being improved significantly. Vitamin B analogue (sulbutiamine) may be a useful adjunct to specific anti-infective treatment.

A precision analogue integrator system for heavy current measurement in MFDC resistance spot welding