Anti-inflammatory sesquiterpene lactones from the flower of Vernonia cinerea.

PubMed

Youn, Ui Joung; Park, Eun-Jung; Kondratyuk, Tamara P; Simmons, Charles J; Borris, Robert P; Tanamatayarat, Patcharawan; Wongwiwatthananukit, Supakit; Toyama, Onoomar; Songsak, Thanapat; Pezzuto, John M; Chang, Leng Chee

2012-09-01

Bioassay-guided fractionation of the hexane extract from the flowers of Vernonia cinerea (Asteraceae) led to the isolation of a new sesquiterpene lactone, 8α-hydroxyhirsutinolide (2), and a new naturally occurring derivative, 8α-hydroxyl-1-O-methylhirsutinolide (3), along with seven known compounds (1 and 4-9). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison with the structure of compound 1, whose relative stereochemistry was determined by X-ray analysis. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor alpha (TNF-α)-induced NF-κB activity. Compounds 1, 2, 4, 5, and 9 inhibited TNF-α-induced NF-κB activity with IC(50) values of 3.1, 1.9, 0.6, 5.2, and 1.6 μM, respectively; compounds 4 and 6-9 exhibited significant NO inhibitory activity with IC(50) values of 2.0, 1.5, 1.2, 2.7, and 2.4 μM, respectively. Published by Elsevier Ltd.

Structure-Based Design and Synthesis of a Small Molecule that Exhibits Anti-inflammatory Activity by Inhibition of MyD88-mediated Signaling to Bacterial Toxin Exposure.

PubMed

Alam, Shahabuddin; Javor, Sacha; Degardin, Melissa; Ajami, Dariush; Rebek, Mitra; Kissner, Teri L; Waag, David M; Rebek, Julius; Saikh, Kamal U

2015-08-01

Both Gram-positive and Gram-negative pathogens or pathogen-derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88-mediated pro-inflammatory cellular immunity for host defense. However, dysregulated MyD88-mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB-loop structure of MyD88 was capable of inhibiting pro-inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non-polar cyclohexane linker which strongly inhibited the production of pro-inflammatory cytokines in human primary cells to SEB (IC50 1-50 μm) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10-200 μm). Consistent with cytokine inhibition, in a ligand-induced cell-based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS-induced MyD88-mediated NF-kB-dependent expression of reporter activity (IC50 10-30 μm). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro-inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin-induced inflated pro-inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic. © 2014 John Wiley & Sons A/S.

Radiation-induced disorder in compressed lanthanide zirconates.

PubMed

Park, Sulgiye; Tracy, Cameron L; Zhang, Fuxiang; Park, Changyong; Trautmann, Christina; Tkachev, Sergey N; Lang, Maik; Mao, Wendy L; Ewing, Rodney C

2018-02-28

The effects of swift heavy ion irradiation-induced disordering on the behavior of lanthanide zirconate compounds (Ln 2 Zr 2 O 7 where Ln = Sm, Er, or Nd) at high pressures are investigated. After irradiation with 2.2 GeV 197 Au ions, the initial ordered pyrochlore structure (Fd3[combining macron]m) transformed to a defect-fluorite structure (Fm3[combining macron]m) in Sm 2 Zr 2 O 7 and Nd 2 Zr 2 O 7 . For irradiated Er 2 Zr 2 O 7 , which has a defect-fluorite structure, ion irradiation induces local disordering by introducing Frenkel defects despite retention of the initial structure. When subjected to high pressures (>29 GPa) in the absence of irradiation, all of these compounds transform to a cotunnite-like (Pnma) phase, followed by sluggish amorphization with further compression. However, if these compounds are irradiated prior to compression, the high pressure cotunnite-like phase is not formed. Rather, they transform directly from their post-irradiation defect-fluorite structure to an amorphous structure upon compression (>25 GPa). Defects and disordering induced by swift heavy ion irradiation alter the transformation pathways by raising the energetic barriers for the transformation to the high pressure cotunnite-like phase, rendering it inaccessible. As a result, the high pressure stability field of the amorphous phase is expanded to lower pressures when irradiation is coupled with compression. The responses of materials in the lanthanide zirconate system to irradiation and compression, both individually and in tandem, are strongly influenced by the specific lanthanide composition, which governs the defect energetics at extreme conditions.

ent-Kaurane Diterpenoids with Neuroprotective Properties from Corn Silk ( Zea mays).

PubMed

Qi, Xiao-Li; Zhang, Ying-Ying; Zhao, Peng; Zhou, Le; Wang, Xiao-Bo; Huang, Xiao-Xiao; Lin, Bin; Song, Shao-Jiang

2018-05-25

Thirteen new ent-kaurane diterpenoids, stigmaydenes A-M (1-13), together with two known compounds (14, 15), were isolated from the crude extract of corn silk ( Zea mays). The structures of the compounds were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray diffraction. The absolute configurations of the compounds were also confirmed by comparison of experimental and calculated specific rotations. The compounds were evaluated for their neuroprotective effects against H 2 O 2 -induced SH-SY5Y cell injury, and compound 8 was active at 100 μM, as determined by flow cytometry (annexin V-FITC/PI staining) and Hoechst 33258 staining. The results suggested that compound 8 could protect neuronal cells from H 2 O 2 -induced injury by inhibiting apoptosis in SH-SY5Y cells.

Polyphenolic compounds with antioxidant potential and neuro-protective effect from Cimicifuga dahurica (Turcz.) Maxim.

PubMed

Qin, Rulan; Zhao, Ying; Zhao, Yudan; Zhou, Wanrong; Lv, Chongning; Lu, Jincai

2016-12-01

Three new phenolic compounds (1-3), along with five known compounds (4-8) were isolated from the rhizome of Cimicifuga dahurica (Turcz.) Maxim. Their structures were elucidated by spectroscopic methods including 1D-NMR, 2D-NMR and HR-MS techniques. DPPH method and protective effect on PC12 cells against H 2 O 2 -induced oxidative damage model were carried to evaluate the antioxidant capability of these compounds. Compound 5 showed significant antioxidant activity with IC 50 values 9.33μM in DPPH assay and compound 2 displayed marked neuro-protective effect with 87.65% cell viability at the concentration of 10μM. Additionally, the possible structure-activity relationships of these phenolic compounds were tentatively discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Isolation of furocoumarins from bergamot fruits as HL-60 differentiation-inducing compounds.

PubMed

Kawaii, S; Tomono, Y; Katase, E; Ogawa, K; Yano, M

1999-10-01

The HL-60 differentiation-inducing compounds in bergamot fruits were isolated with column chromatography and identified as bergamottin, bergapten, and citropten by (1)H and (13)C NMR. Their HL-60 differentiation-inducing activity was measured by examining nitro blue tetrazolium (NBT) reducing, nonspecific acid esterase (NSE), specific esterase (SE), and phagocytic activities, and bergamottin showed the strongest activity among the coumarins isolated from bergamot fruits. The structure-activity relationship obtained from HL-60 differentiation assay suggests that hydrophobicity of furocoumarins is correlated with their activity.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

PubMed Central

Kenyon, Emma J.; Kirkwood, Nerissa K.; Kitcher, Siân R.; O’Reilly, Molly; Cantillon, Daire M.; Goodyear, Richard J.; Secker, Abigail; Baxendale, Sarah; Bull, James C.; Waddell, Simon J.; Whitfield, Tanya T.; Ward, Simon E.; Kros, Corné J.; Richardson, Guy P.

2017-01-01

Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red–conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem. PMID:29263311

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death.

PubMed

Kenyon, Emma J; Kirkwood, Nerissa K; Kitcher, Siân R; O'Reilly, Molly; Derudas, Marco; Cantillon, Daire M; Goodyear, Richard J; Secker, Abigail; Baxendale, Sarah; Bull, James C; Waddell, Simon J; Whitfield, Tanya T; Ward, Simon E; Kros, Corné J; Richardson, Guy P

2017-12-21

Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red-conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem.

Mechanistic review of drug-induced steatohepatitis

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

Schumacher, Justin D., E-mail: Justin.d.schumacher@rutgers.edu; Guo, Grace L.

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structuremore » with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.« less

Design and Synthesis of Novel Phenylpiperazine Derivatives as Potential Anticonvulsant Agents.

PubMed

Habib, Monica M W; Abdelfattah, Mohamed A O; Abadi, Ashraf H

2015-12-01

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Structure-Activity Study with Aryl Acylamidases

PubMed Central

Villarreal, David T.; Turco, Ronald F.; Konopka, Allan

1994-01-01

We examined the relationship between chemical structure and biodegradability of acylanilide herbicides by using a set of model compounds. Four bacterial isolates (one gram-negative and three gram-positive) that grew on acetanilide were used. These soil isolates cleaved the amide bond of acetanilide via an aryl acylamidase reaction, producing aniline and the organic acid acetate. A series of acetanilide analogs with alkyl substitutions on the nitrogen atom or the aromatic ring were tested for their ability to induce aryl acylamidase activity and act as substrates for the enzyme. The substrate range, in general, was limited to those analogs not disubstituted in the ortho position of the benzene ring or which did not contain an alkyl group on the nitrogen atom. These same N-substituted compounds did not induce enzyme activity either, whereas the ortho-substituted compounds could in some cases. PMID:16349428

Germacrane sesquiterpenes isolated from the rhizome of Curcuma xanthorrhiza Roxb. inhibit UVB-induced upregulation of MMP-1, -2, and -3 expression in human keratinocytes.

PubMed

Park, Ji-Hae; Mohamed, Mohamed Antar Aziz; Jung, Ye-Jin; Shrestha, Sabina; Lee, Tae Hoon; Lee, Chang-Ho; Han, Daeseok; Kim, Jiyoung; Baek, Nam-In

2015-10-01

Four sesquiterpenes were isolated from the rhizome of Curcuma xanthorrhiza Roxb.: furanodiene (1), germacrone (2), furanodienone (3), and 13-hydroxygermacrone (4). Importantly, this was the first time compounds 1 and 4 were isolated from this plant. The chemical structures of these compounds were determined using 1D- and 2D-nuclear magnetic resonance, infrared spectroscopy, and electron ionization mass spectrometry analyses. Among the isolated compounds, compounds 2 and 4 inhibited UVB-induced upregulation of the mRNA and protein expression levels of MMP-1, MMP-2, and MMP-3 in human keratinocytes (HaCaT). Moreover, this upregulation occurred in a dose-dependent manner over the range of 1-10 μM for each compound.

A new phenol glycoside from Physalis angulata.

PubMed

Sun, Cheng-Peng; Nie, Xiu-Fang; Kang, Ning; Zhao, Feng; Chen, Li-Xia; Qiu, Feng

2017-05-01

A new phenol glycoside, physanguloside A (1), was isolated from Physalis angulata together with four known compounds. We report herein, for the first time, the presence of compounds 2-5 in the genus Physalis. The structures of all the compounds were established by NMR, IR, UV and HRESIMS spectroscopic analyses, and comparison with the literature data. All isolated compounds were assayed for inhibitory activity on nitric oxide production by LPS-induced in RAW 264.7 macrophages.

Identification of marine neuroactive molecules in behaviour-based screens in the larval zebrafish.

PubMed

Long, Si-Mei; Liang, Feng-Yin; Wu, Qi; Lu, Xi-Lin; Yao, Xiao-Li; Li, Shi-Chang; Li, Jing; Su, Huanxing; Pang, Ji-Yan; Pei, Zhong

2014-05-30

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1-36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37-42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.

Identification of Small Molecule Inhibitors of Clostridium perfringens ε-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen.

PubMed

Lewis, Michelle; Weaver, Charles David; McClain, Mark S

2010-07-01

The Clostridium perfringens epsilon toxin, a select agent, is responsible for a severe, often fatal enterotoxemia characterized by edema in the heart, lungs, kidney, and brain. The toxin is believed to be an oligomeric pore-forming toxin. Currently, there is no effective therapy for countering the cytotoxic activity of the toxin in exposed individuals. Using a robust cell-based high-throughput screening (HTS) assay, we screened a 151,616-compound library for the ability to inhibit ε-toxin-induced cytotoxicity. Survival of MDCK cells exposed to the toxin was assessed by addition of resazurin to detect metabolic activity in surviving cells. The hit rate for this screen was 0.6%. Following a secondary screen of each hit in triplicate and assays to eliminate false positives, we focused on three structurally-distinct compounds: an N-cycloalkylbenzamide, a furo[2,3-b]quinoline, and a 6H-anthra[1,9-cd]isoxazol. None of the three compounds appeared to inhibit toxin binding to cells or the ability of the toxin to form oligomeric complexes. Additional assays demonstrated that two of the inhibitory compounds inhibited ε-toxin-induced permeabilization of MDCK cells to propidium iodide. Furthermore, the two compounds exhibited inhibitory effects on cells pre-treated with toxin. Structural analogs of one of the inhibitors identified through the high-throughput screen were analyzed and provided initial structure-activity data. These compounds should serve as the basis for further structure-activity refinement that may lead to the development of effective anti-ε-toxin therapeutics.

Identification of Small Molecule Inhibitors of Clostridium perfringens ε-Toxin Cytotoxicity Using a Cell-Based High-Throughput Screen

PubMed Central

Lewis, Michelle; Weaver, Charles David; McClain, Mark S.

2010-01-01

The Clostridium perfringens epsilon toxin, a select agent, is responsible for a severe, often fatal enterotoxemia characterized by edema in the heart, lungs, kidney, and brain. The toxin is believed to be an oligomeric pore-forming toxin. Currently, there is no effective therapy for countering the cytotoxic activity of the toxin in exposed individuals. Using a robust cell-based high-throughput screening (HTS) assay, we screened a 151,616-compound library for the ability to inhibit ε-toxin-induced cytotoxicity. Survival of MDCK cells exposed to the toxin was assessed by addition of resazurin to detect metabolic activity in surviving cells. The hit rate for this screen was 0.6%. Following a secondary screen of each hit in triplicate and assays to eliminate false positives, we focused on three structurally-distinct compounds: an N-cycloalkylbenzamide, a furo[2,3-b]quinoline, and a 6H-anthra[1,9-cd]isoxazol. None of the three compounds appeared to inhibit toxin binding to cells or the ability of the toxin to form oligomeric complexes. Additional assays demonstrated that two of the inhibitory compounds inhibited ε-toxin-induced permeabilization of MDCK cells to propidium iodide. Furthermore, the two compounds exhibited inhibitory effects on cells pre-treated with toxin. Structural analogs of one of the inhibitors identified through the high-throughput screen were analyzed and provided initial structure-activity data. These compounds should serve as the basis for further structure-activity refinement that may lead to the development of effective anti-ε-toxin therapeutics. PMID:20721308

Potential hypoglycaemic activity phenolic glycosides from Moringa oleifera seeds.

PubMed

Wang, Fang; Zhong, Huan-Huan; Chen, Wei-Ke; Liu, Qing-Pu; Li, Cun-Yu; Zheng, Yun-Feng; Peng, Guo-Ping

2017-08-01

Moringa oleifera seed has remarkable curative effects on reducing blood pressure, blood sugar and enhancing human immunity. In this study, one novel phenolic glycoside (1) together with four known compounds 2-5 were isolated from the macroporous resin adsorption extract of M. oleifera seeds, and the compound 3 was reported for the first time from this plant. The structure of the new crystalline compound was determined on the basis of spectroscopic analyses including mass spectrometry, 1D and 2D NMR experiments. The hypoglycaemic activity of isolated compounds was investigated with HepG2 cell and STZ-induced mice. It was found that compound 1, 4 and 5 could promote the glucose consumption of insulin resistance cells and reduce blood glucose levels of STZ-induced mice. This study concludes that compound 1, 4 and 5 may be developed as new and safe hypoglycaemic drugs.

TOXIC EQUIVALENCY APPROACH FOR DIOXINS: AN EXAMPLE OF DOSE ADDITIVITY

EPA Science Inventory

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is often called the most toxic man-made compound. However, it is but the prototype for a family of structurally related compounds which have a common mechanism of action, induce a common spectrum of biological responses, and are...

Chemical structure of bismuth compounds determines their gastric ulcer healing efficacy and anti-Helicobacter pylori activity.

PubMed

Sandha, G S; LeBlanc, R; Van Zanten, S J; Sitland, T D; Agocs, L; Burford, N; Best, L; Mahoney, D; Hoffman, P; Leddin, D J

1998-12-01

The recognition of the role of Helicobacter pylori in the pathogenesis of peptic ulcer disease has led to renewed interest in bismuth pharmacology since bismuth compounds have both anti-Helicobacter pylori and ulcer healing properties. The precise chemical structure of current bismuth compounds is not known. This has hindered the development of new and potentially more efficacious formulations. We have created two new compounds, 2-chloro-1,3-dithia-2-bismolane (CDTB) and 1,2-[bis(1,3-dithia-2-bismolane)thio]ethane (BTBT), with known structure. In a rat model of gastric ulceration, BTBT was comparable to, and CDTB was significantly less effective than colloidal bismuth subcitrate in healing cryoprobe-induced ulcers. However, both BTBT and CDTB inhibited H. pylori growth in vitro at concentrations <1/10 that of colloidal bismuth subcitrate. The effects on ulcer healing are not mediated by suppression of acid secretion, pepsin inhibition, or prostaglandin production. Since all treated animals received the same amount of elemental bismuth, it appears that the efficacy of bismuth compounds varies with compound structure and is not simply dependent on the delivery of bismuth ion. Because the structure of the novel compounds is known, our understanding of the relationship of bismuth compound structure and to biologic activity will increase. In the future it may be possible to design other novel bismuth compounds with more potent anti-H. pylori and ulcer healing effects.

Supercritical fluid extraction and analysis of compounds from Clivia miniata for uterotonic activity.

PubMed

Sewram, V; Raynor, M W; Mulholland, D A; Raidoo, D M

2001-07-01

In this descriptive study, the superciritical fluid extract of the roots of Clivia miniata L. was tested for uterotonic activity using guinea pig uterine smooth muscle in vitro. Extraction was performed with water modified supercritical carbon dioxide at 400 atm and 80 degrees C. The uterine contractions induced by this extract were compared to those induced by the aqueous extract and found to be active at lower doses. The active compounds were isolated and the structures elucidated by spectroscopic and chromatographic techniques. Both linoleic acid and 5-hydroxymethyl-2-furancarboxaldehyde isolated from the extract were found to induce muscle contractions individually. The pharmacological mode of action of 5-hydroxymethyl-2-furancarboxaldehyde was assessed using two receptor agonists and antagonists. This compound was found to mediate its effect through cholinergic receptors.

The Pressure-Induced Structural Response of A2Hf2O7 (A=Y, Sm, Eu, Gd, Dy, Yb) Compounds from 0.1-50 GPa

NASA Astrophysics Data System (ADS)

Turner, K. M.; Rittman, D.; Heymach, R.; Turner, M.; Tracy, C.; Mao, W. L.; Ewing, R. C.

2016-12-01

A2B2O7 (A, B= cations) compounds have structures that make their properties conducive to many applications; for example they are a proposed waste-form for actinides generated in the nuclear fuel cycle. This interest in part is due to their structural responses to extreme environments of high P, T, or under intense irradiation. Depending on their cationic radius ratio, ra/rb, A2B2O7 compounds either crystallize as pyrochlore (ra/rb=1.46-1.7) or "defect fluorite" (ra/rb>1.46). The structure types are similar: they are derivatives of ideal fluorite with two cations and 1/8 missing anions. In pyrochlore, the cations and anion vacancy are ordered. In "defect fluorite"-structured oxides, the cations and anion vacancies are random. A2B2O7 compounds rarely amorphize in extreme environments. Rather, they disorder and undergo phase transitions; this resistance to amorphization contributes to the durability of this potential actinide waste-form. Under high-pressure, A2B2O7 compounds are known to disorder or form a cottunite-like phase. Their radius ratio affects their response to extreme environments; "defect fluorite" type compounds tend to disorder, and pyrochlore type compounds tend to form the cottunite-like phase. We have examined six A2Hf2O7 compounds (A=Y, Sm, Eu, Gd, Dy, Yb) in situ to 50 GPa. By keeping the B-site constant (Hf), we examined the effect of a changing radius ratio on the pressure-induced structural response of hafnates. We used symmetric DACs, ruby fluorescence, stainless steel gaskets, and methanol: ethanol (4:1 by volume) pressure medium. We characterized these materials with in situ Raman spectroscopy at Stanford University, and synchrotron X-Ray Diffraction (XRD) at APS 16 BM-D and ALS 12.2.2. The compounds were pyrochlore structured (Sm, Eu, Gd) and "defect-fluorite" structured (Y, Dy, Yb) hafnates . These compounds undergo a slow phase transition to a high-pressure cotunnite-like phase between 18-30 GPa. They undergo disordering of their cation and anionic sites as pressure is increased. The pressure of their phase transitions correlates directly with their radius ratio. Our results are comparable to many high-pressure studies of rare earth zirconates and titanates, but contrast from previous experiments performed on rare earth hafnates, specifically La2Hf2O7.

Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

NASA Astrophysics Data System (ADS)

Kaushik, Aman C.; Kumar, Sanjay; Wei, Dong Q.; Sahi, Shakti

2018-02-01

GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to ‘Class A’ of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

Anti-inflammatory activity effect of 2-substituted-1,4,5,6-tetrahydrocyclopenta[b]pyrrole on TPA-induced skin inflammation in mice.

PubMed

Xu, Xue-Tao; Mou, Xue-Qing; Xi, Qin-Mei; Liu, Wei-Ting; Liu, Wen-Feng; Sheng, Zhao-Jun; Zheng, Xi; Zhang, Kun; Du, Zhi-Yun; Zhao, Su-Qing; Wang, Shao-Hua

2016-11-01

2-Substituted-1,4,5,6-tetrahydrocyclopenta[b]pyrrole, a key structural moiety exiting in many bioactive molecules, has been shown to have excellent selective activity on COX-2. In the present study, the anti-inflammatory activity and the underlying molecular mechanism of 2-substituted-1,4,5,6-tetrahydrocyclopenta[b]pyrrole on skin inflammation were assessed by 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice. Most of the compounds showed anti-inflammatory activity on TPA-induced skin inflammation. The anti-inflammatory activity of compound 4 showed higher anti-inflammatory activity than celecoxib (3.2-fold). Compound 4 pretreatment resulted in markedly suppression of TPA-induced IL-1β, IL-6, TNF-α, and COX-2, respectively. Furthermore, the mechanical study indicated that the anti-inflammatory activity of compound 4 was associated with its ability to inhibit activation of factor kappa-κB (NF-κB) by blocking IκB kinase (IKK) activities. Accordingly, compound 4 could be used as a potential anti-inflammatory agent for skin inflammation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigating the antiproliferative activity of quinoline-5,8-diones and styrylquinolinecarboxylic acids on tumor cell lines.

PubMed

Podeszwa, B; Niedbala, H; Polanski, J; Musiol, R; Tabak, D; Finster, J; Serafin, K; Milczarek, M; Wietrzyk, J; Boryczka, S; Mol, W; Jampilek, J; Dohnal, J; Kalinowski, D S; Richardson, D R

2007-11-15

The structure-activity relationships of new quinoline based compounds were investigated. Quinoline-5,8-dione and styrylquinoline scaffolds were used for the design of potentially active compounds. The novel analogues had comparable antiproliferative activity to cisplatin when evaluated in a bioassay against the P388 leukemia cell line. However, these compounds appeared far less efficient against SK-N-MC neuroepithelioma cells. Analogues without the 5,8-dione structure but containing the 8-carboxylic acid group were also found to induce antiproliferative activity. Hydrophobicity as measured by HPLC did not correlate with antiproliferative activity.

Large positive magnetoresistance in intermetallic compound NdCo2Si2

NASA Astrophysics Data System (ADS)

Roy Chowdhury, R.; Dhara, S.; Das, I.; Bandyopadhyay, B.; Rawat, R.

2018-04-01

The magnetic, magneto-transport and magnetocaloric properties of antiferromagnetic intermetallic compound NdCo2Si2 (TN = 32K) have been studied. The compound yields a positive magnetoresistance (MR) of about ∼ 123 % at ∼ 5K in 8 T magnetic field. The MR value is significantly large vis - a - vis earlier reports of large MR in intermetallic compounds, and possibly associated with the changes in magnetic structure of the compound. The large MR value can be explained in terms of field induced pseudo-gaps on Fermi surface.

Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton.

PubMed

Naman, C Benjamin; Li, Jie; Moser, Arvin; Hendrycks, Jeffery M; Benatrehina, P Annécie; Chai, Heebyung; Yuan, Chunhua; Keller, William J; Kinghorn, A Douglas

2015-06-19

Melanodiol 4″-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These noncrystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed.

Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton

PubMed Central

Naman, C. Benjamin; Li, Jie; Moser, Arvin; Hendrycks, Jeffery M.; Benatrehina, P. Annécie; Chai, Heebyung; Yuan, Chunhua; Keller, William J.; Kinghorn, A. Douglas

2015-01-01

Melanodiol 4″-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These non-crystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed PMID:26030740

Six New Polyketide Decalin Compounds from Mangrove Endophytic Fungus Penicillium aurantiogriseum 328#

PubMed Central

Ma, Yanhong; Li, Jing; Huang, Meixiang; Liu, Lan; Wang, Jun; Lin, Yongcheng

2015-01-01

Six new compounds with polyketide decalin ring, peaurantiogriseols A–F (1–6), along with two known compounds, aspermytin A (7), 1-propanone,3-hydroxy-1-(1,2,4a,5,6,7,8,8a-octahydro-2,5-dihydroxy-1,2,6-trimethyl-1-naphthalenyl) (8), were isolated from the fermentation products of mangrove endophytic fungus Penicillium aurantiogriseum 328#. Their structures were elucidated based on their structure analysis. The absolute configurations of compounds 1 and 2 were determined by 1H NMR analysis of their Mosher esters; the absolute configurations of 3–6 were determined by using theoretical calculations of electronic circular dichroism (ECD). Compounds 1–8 showed low inhibitory activity against human aldose reductase, no activity of inducing neurite outgrowth, nor antimicrobial activity. PMID:26473887

Specific reaction of alpha,beta-unsaturated carbonyl compounds such as 6-shogaol with sulfhydryl groups in tubulin leading to microtubule damage.

PubMed

Ishiguro, Kazuhiro; Ando, Takafumi; Watanabe, Osamu; Goto, Hidemi

2008-10-15

6-Shogaol and 6-gingerol are ginger components with similar chemical structures. However, while 6-shogaol damages microtubules, 6-gingerol does not. We have investigated the molecular mechanism of 6-shogaol-induced microtubule damage and found that the action of 6-shogaol results from the structure of alpha,beta-unsaturated carbonyl compounds. alpha,beta-Unsaturated carbonyl compounds such as 6-shogaol react with sulfhydryl groups of cysteine residues in tubulin, and impair tubulin polymerization. The reaction with sulfhydryl groups depends on the chain length of alpha,beta-unsaturated carbonyl compounds. In addition, alpha,beta-unsaturated carbonyl compounds are more reactive with sulfhydryl groups in tubulin than in 2-mercaptoethanol, dithiothreitol, glutathione and papain, a cysteine protease.

Hepatoprotective triterpenoids and lignans from the stems of Schisandra pubescens.

PubMed

Wang, Guo-Wei; Deng, Li-Qing; Luo, You-Ping; Liao, Zhi-Hua; Chen, Min

2017-08-01

One new triterpenoid (1) and 13 known compounds (2-14) were isolated from Schisandra pubescens stems. The structure of the new compound was established on the basis of 1D/2D NMR and HRESIMS spectroscopic analyses. The isolated compounds were evaluated for their hepatoprotective activities against D-GalN-induced cell injury in QSG7701 cells. Compounds 1, 13 and 14 at 10 μM showed hepatoprotective activities, with survival rates of 60.5, 50.4 and 48.9%, respectively.

Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds.

PubMed

Macfarlane, D E; Manzel, L

1998-02-01

Phosphorothioate oligodeoxynucleotides containing CpG (CpG-ODN) activate immune responses. We report that quinacrine, chloroquine, and structurally related compounds completely inhibit the antiapoptotic effect of CpG-ODN on WEHI 231 murine B lymphoma cells and inhibit CpG-ODN-induced secretion of IL-6 by WEHI 231. They also inhibit IL-6 synthesis and thymidine uptake by human unfractionated PBMC induced by CpG-ODN. The compounds did not inhibit LPS-induced responses. Half-maximal inhibition required 10 nM quinacrine or 100 nM chloroquine. Inhibition was noncompetitive with respect to CpG-ODN. Quinine, quinidine, and primaquine were much less powerful. Quinacrine was effective even when added after the CpG-ODN. Near-toxic concentrations of ammonia plus bafilomycin A1 (used to inhibit vesicular acidification) did not reduce the efficacy of the quinacrine, but the effects of both quinacrine and chloroquine were enhanced by inhibition of the multidrug resistance efflux pump by verapamil. Agents that bind to DNA, including propidium iodide, Hoechst dye 33258, and coralyne chloride did not inhibit CpG-ODN effect, nor did 4-bromophenacyl bromide, an inhibitor of phospholipase A2. Examination of the structure-activity relationship of seventy 4-aminoquinoline and 9-aminoacridine analogues reveals that increased activity was conferred by bulky hydrophobic substituents on positions 2 and 6 of the quinoline nucleus. No correlation was found between published antimalarial activity and ability to block CpG-ODN-induced effects. These results are discussed in the light of the ability of quinacrine and chloroquine to induce remission of rheumatoid arthritis and lupus erythematosus.

Effects of natural and chemically synthesized furanones on quorum sensing in Chromobacterium violaceum

PubMed Central

Martinelli, Daniel; Grossmann, Gilles; Séquin, Urs; Brandl, Helmut; Bachofen, Reinhard

2004-01-01

Background Cell to cell signaling systems in Gram-negative bacteria rely on small diffusible molecules such as the N-acylhomoserine lactones (AHL). These compounds are involved in the production of antibiotics, exoenzymes, virulence factors and biofilm formation. They belong to the class of furanone derivatives which are frequently found in nature as pheromones, flavor compounds or secondary metabolites. To obtain more information on the relation between molecular structure and quorum sensing, we tested a variety of natural and chemically synthesized furanones for their ability to interfere with the quorum sensing mechanism using a quantitative bioassay with Chromobacterium violaceum CV026 for antagonistic and agonistic action. We were looking at the following questions: 1. Do these compounds affect growth? 2) Do these compounds activate the quorum sensing system of C. violaceum CV026? 3) Do these compounds inhibit violacein formation induced by the addition of the natural inducer N-hexanoylhomoserine lactone (HHL)? 4) Do these compounds enhance violacein formation in presence of HHL? Results The naturally produced N-acylhomoserine lactones showed a strong non-linear concentration dependent influence on violacein production in C. violaceum with a maximum at 3.7*10-8 M with HHL. Apart from the N-acylhomoserine lactones only one furanone (emoxyfurane) was found to simulate N-acylhomoserine lactone activity and induce violacein formation. The most effective substances acting negatively both on growth and quorum sensing were analogs and intermediates in synthesis of the butenolides from Streptomyces antibioticus. Conclusion As the regulation of many bacterial processes is governed by quorum sensing systems, the finding of natural and synthetic furanones acting as agonists or antagonists suggests an interesting tool to control and handle detrimental AHL induced effects. Some effects are due to general toxicity; others are explained by a competitive interaction for LuxR proteins. For further experiments it is important to be aware of the fact that quorum sensing active compounds have non-linear effects. Inducers can act as inhibitors and inhibitors might be able to activate or enhance the quorum sensing system depending on chemical structure and concentration levels. PMID:15233843

In vitro activity of synthetic tetrahydroindeno[2,1-c]quinolines on Leishmania mexicana.

PubMed

Hernández-Chinea, Concepción; Carbajo, Erika; Sojo, Felipe; Arvelo, Francisco; Kouznetsov, Vladimir V; Romero-Bohórquez, Arnold R; Romero, Pedro J

2015-12-01

New synthetic compounds based on tetrahydroindenoquinoline structure were evaluated for their in vitro antileishmanial activities. The seven compounds assayed have antiproliferative activities against promastigotes of Leishmania mexicana. Compound 1 and 3 were the most active (IC50 1.0 μg/ml) and showed high selectivity towards the parasite. These compounds were selected to evaluate their effect on promastigote morphology and mitochondrial transmembrane potential as well as on the amastigote capability to survive into macrophages J774 cell line. Whereas compound 1 affected the promastigote cell cycle, compound 3 induced morphological changes and the total collapse of the mitochondrial transmembrane potential, a hallmark of apoptosis. Both compounds also affected the amastigote form of the parasite, decreasing their survival rate in J774 macrophages. Due to the greatest selectivity index, the apparent effect as apoptotic inducer and its sustained inhibition on intracellular amastigote replication, compound 3 is the best candidate to be tested in vivo. This compound is worth considering for the development of new antileishmanial drugs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

PubMed

Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

2016-05-23

In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

S-52, a novel nootropic compound, protects against β-amyloid induced neuronal injury by attenuating mitochondrial dysfunction.

PubMed

Gao, Xin; Zheng, Chun Yan; Qin, Guo Wei; Tang, Xi Can; Zhang, Hai Yan

2012-10-01

Accumulating evidence suggests that β-amyloid (Aβ)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Aβ-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Aβ, S-52 was observed to attenuate the toxicity of Aβ to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Aβ-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy. Copyright © 2012 Wiley Periodicals, Inc.

Multifunctional Hybrid Compounds Derived from 2-(2,5-Dioxopyrrolidin-1-yl)-3-methoxypropanamides with Anticonvulsant and Antinociceptive Properties.

PubMed

Abram, Michał; Zagaja, Mirosław; Mogilski, Szczepan; Andres-Mach, Marta; Latacz, Gniewomir; Baś, Sebastian; Łuszczki, Jarogniew J; Kieć-Kononowicz, Katarzyna; Kamiński, Krzysztof

2017-10-26

The focused set of new pyrrolidine-2,5-diones as potential broad-spectrum hybrid anticonvulsants was described. These derivatives integrate on the common structural scaffold the chemical fragments of well-known antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. Such hybrids demonstrated effectiveness in two of the most widely used animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure models. Compound 33 showed the highest anticonvulsant activity in these models (ED 50 MES = 79.5 mg/kg, ED 50 6 Hz = 22.4 mg/kg). Compound 33 was also found to be effective in pentylenetetrazole-induced seizure model (ED 50 PTZ = 123.2 mg/kg). In addition, 33 demonstrated effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, and notably in oxaliplatin-induced neuropathic pain in mice. The pharmacological data of stereoisomers of compound 33 revealed greater anticonvulsant activity by R(+)-33 enantiomer in both MES and 6 Hz seizure models.

Weighted similarity-based clustering of chemical structures and bioactivity data in early drug discovery.

PubMed

Perualila-Tan, Nolen Joy; Shkedy, Ziv; Talloen, Willem; Göhlmann, Hinrich W H; Moerbeke, Marijke Van; Kasim, Adetayo

2016-08-01

The modern process of discovering candidate molecules in early drug discovery phase includes a wide range of approaches to extract vital information from the intersection of biology and chemistry. A typical strategy in compound selection involves compound clustering based on chemical similarity to obtain representative chemically diverse compounds (not incorporating potency information). In this paper, we propose an integrative clustering approach that makes use of both biological (compound efficacy) and chemical (structural features) data sources for the purpose of discovering a subset of compounds with aligned structural and biological properties. The datasets are integrated at the similarity level by assigning complementary weights to produce a weighted similarity matrix, serving as a generic input in any clustering algorithm. This new analysis work flow is semi-supervised method since, after the determination of clusters, a secondary analysis is performed wherein it finds differentially expressed genes associated to the derived integrated cluster(s) to further explain the compound-induced biological effects inside the cell. In this paper, datasets from two drug development oncology projects are used to illustrate the usefulness of the weighted similarity-based clustering approach to integrate multi-source high-dimensional information to aid drug discovery. Compounds that are structurally and biologically similar to the reference compounds are discovered using this proposed integrative approach.

Merging Structural Motifs of Functionalized Amino Acids and α-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-Gated Sodium Channels and in the Treatment of Neuropathic Pain

PubMed Central

2011-01-01

We recently reported that merging key structural pharmacophores of the anticonvulsant drugs lacosamide (a functionalized amino acid) with safinamide (an α-aminoamide) resulted in novel compounds with anticonvulsant activities superior to that of either drug alone. Here, we examined the effects of six such chimeric compounds on Na+-channel function in central nervous system catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that these compounds affected Na+ channel fast and slow inactivation processes. Detailed electrophysiological characterization of two of these chimeric compounds that contained either an oxymethylene ((R)-7) or a chemical bond ((R)-11) between the two aromatic rings showed comparable effects on slow inactivation, use-dependence of block, development of slow inactivation, and recovery of Na+ channels from inactivation. Both compounds were equally effective at inducing slow inactivation; (R)-7 shifted the fast inactivation curve in the hyperpolarizing direction greater than (R)-11, suggesting that in the presence of (R)-7 a larger fraction of the channels are in an inactivated state. None of the chimeric compounds affected veratridine- or KCl-induced glutamate release in neonatal cortical neurons. There was modest inhibition of KCl-induced calcium influx in cortical neurons. Finally, a single intraperitoneal administration of (R)-7, but not (R)-11, completely reversed mechanical hypersensitivity in a tibial-nerve injury model of neuropathic pain. The strong effects of (R)-7 on slow and fast inactivation of Na+ channels may contribute to its efficacy and provide a promising novel therapy for neuropathic pain, in addition to its antiepileptic potential. PMID:21765969

Pyridine-pyrimidine amides that prevent HGF-induced epithelial scattering by two distinct mechanisms.

PubMed

Siddiqui-Jain, Adam; Hoj, Jacob P; Hargiss, J Blade; Hoj, Taylor H; Payne, Carter J; Ritchie, Collin A; Herron, Steven R; Quinn, Colette; Schuler, Jeffrey T; Hansen, Marc D H

2017-09-01

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure-activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ferroelectric properties of oxalate and phenanthroline based 1-D single chain molecular magnet [{FeII(Δ)FeII(Λ)}0.5{CrII(Δ)CrII(Λ)}0.5(ox)2(phen)2

NASA Astrophysics Data System (ADS)

Bhatt, Pramod; Mukadam, M. D.; Mandal, B. P.; Yusuf, S. M.

2018-04-01

The one-dimensional (1-D) single chain molecular magnet [{FeII(Δ)FeII(Λ)}0.5{CrII(Δ)CrII(Λ)}0.5(ox)2(phen)2] is hydrothermally synthesized using oxalate (ox) and phenanthroline (phen) ligands with transition metal ions (Fe and Cr). The compound is characterized using x-ray diffraction, dc magnetization measurements and P-E ferroelectric loop measurements. The diffraction analysis using Rietveld refinement confirms a single phase formation of the compound in monoclinic structure with space group of P21. The compound crystallizes in 1-D chain like structure containing two different crystallographic sites of metal ions (Δ- and Λ-), which are bridged by the ox ligand and Phen ligand. These two metals site are different in bond length and bond angles results lattice distortions. The lattice distortion induces ferroelectric behavior in the compound which is discussed in terms of lattice distortion induced dipole moments.

Nitric oxide inhibitory daphnane diterpenoids as potential anti-neuroinflammatory agents for AD from the twigs of Trigonostemon thyrsoideus.

PubMed

Liu, Feng; Yang, Xueyuan; Ma, Jun; Yang, Yuling; Xie, Chunfeng; Tuerhong, Muhetaer; Jin, Da-Qing; Xu, Jing; Lee, Dongho; Ohizumi, Yasushi; Guo, Yuanqiang

2017-12-01

The extensive pathology studies revealed that Alzheimer's disease (AD) is closely related to neuroinflammation and anti-neuroinflammatory agents may be potentially useful for the treatment of AD. A continuous search for new nitric oxide (NO) inhibitory compounds as anti-neuroinflammatory agents for AD resulted in the isolation of four new (1-4) and eight known (5-12) daphnane diterpenoids from the twigs of Trigonostemon thyrsoideus. Their structures were elucidated on the basis of extensive nuclear magnetic resonance (NMR) spectroscopic data analysis and the time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. Compounds 1-4 represent new examples of daphnane diterpenoid orthoesters and 4 features a rare and complex macroring diterpenoid structure. The anti-neuroinflammatory effects were examined by inhibiting NO release in lipopolysaccharide (LPS)-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction of quinone reductase (QR) by withanolides isolated from Physalis pubescens L. (Solanaceae).

PubMed

Ji, Long; Yuan, Yonglei; Ma, Zhongjun; Chen, Zhe; Gan, Lishe; Ma, Xiaoqiong; Huang, Dongsheng

2013-09-01

In the present study, it was demonstrated that the dichloromethane extract of Physalis pubescens L. (DEPP) had weak potential quinone reductase (QR) inducing activity, but an UPLC-ESI-MS method with glutathione (GSH) as the substrate revealed that the DEPP had electrophiles (with an α,β-unsaturated ketone moiety). These electrophiles could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, four withanolides, including three new compounds physapubescin B (2), physapubescin C (3), physapubescin D (4), together with one known steroidal compound physapubescin (1) were isolated. Structures of these compounds were determined by spectroscopic analysis and that of physapubescin C (3) was confirmed by a combination of molecular modeling and quantum chemical DFT-GIAO calculations. Evaluation of the QR inducing activities of all withanolides indicated potent activities of compounds 1 and 2, which had a common α,β-unsaturated ketone moiety. Copyright © 2013 Elsevier Ltd. All rights reserved.

Structural and numerical chromosome aberration inducers in liver micronucleus test in rats with partial hepatectomy.

PubMed

Itoh, Satoru; Hattori, Chiharu; Nagata, Mayumi; Sanbuissho, Atsushi

2012-08-30

The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH. Copyright © 2012 Elsevier B.V. All rights reserved.

Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. I. Multimode effect on early membrane events.

PubMed

Rocher, Françoise; Dédaldéchamp, Fabienne; Saeedi, Saed; Fleurat-Lessard, Pierrette; Chollet, Jean-Francois; Roblin, Gabriel

2014-11-01

A study of the structure-activity relationship carried out on several benzoic acid-related phenolics indicates that this type of compounds hinders the osmocontractile reaction of pulvinar cells in the range of 0-100%. Tentatively, we tried to find a way that could explain this differential action. With this aim, the relationship between the inhibitory effect and important molecular physico-chemical parameters (namely lipophilicity and degree of dissociation) was drawn. In addition, the effect of a variety of these compounds was investigated on their capacity to modify the electrical transmembrane potential and induce modifications in proton fluxes. Finally, using plasma membrane vesicles purified from pulvinar tissues, we examined the effects of some selected compounds on the proton pump activity and catalytic activity of the plasma membrane H(+)-ATPase. Taken together, the results indicate that a modification of the molecular structure of phenolics may induce important variation in the activity of the compound on these early membrane events. Among the tested phenolics, salicylic acid (SA) and acetylsalicylic acid (ASA, aspirin) are of particuler note, as they showed atypical effects on the physiological processes studied. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Development of functional ectopic compound eyes in scarabaeid beetles by knockdown of orthodenticle.

PubMed

Zattara, Eduardo E; Macagno, Anna L M; Busey, Hannah A; Moczek, Armin P

2017-11-07

Complex traits like limbs, brains, or eyes form through coordinated integration of diverse cell fates across developmental space and time, yet understanding how complexity and integration emerge from uniform, undifferentiated precursor tissues remains limited. Here, we use ectopic eye formation as a paradigm to investigate the emergence and integration of novel complex structures following massive ontogenetic perturbation. We show that down-regulation via RNAi of a single head patterning gene- orthodenticle -induces ectopic structures externally resembling compound eyes at the middorsal adult head of both basal and derived scarabaeid beetle species (Onthophagini and Oniticellini). Scanning electron microscopy documents ommatidial organization of these induced structures, while immunohistochemistry reveals the presence of rudimentary ommatidial lenses, crystalline cones, and associated neural-like tissue within them. Further, RNA-sequencing experiments show that after orthodenticle down-regulation, the transcriptional signature of the middorsal head-the location of ectopic eye induction-converges onto that of regular compound eyes, including up-regulation of several retina-specific genes. Finally, a light-aversion behavioral assay to assess functionality reveals that ectopic compound eyes can rescue the ability to respond to visual stimuli when wild-type eyes are surgically removed. Combined, our results show that knockdown of a single gene is sufficient for the middorsal head to acquire the competence to ectopically generate a functional compound eye-like structure. These findings highlight the buffering capacity of developmental systems, allowing massive genetic perturbations to be channeled toward orderly and functional developmental outcomes, and render ectopic eye formation a widely accessible paradigm to study the evolution of complex systems. Published under the PNAS license.

Synthesis of some novel orcinol based coumarin triazole hybrids with capabilities to inhibit RANKL-induced osteoclastogenesis through NF-κB signaling pathway.

PubMed

Rama Krishna, Boddu; Thummuri, Dinesh; Naidu, V G M; Ramakrishna, Sistla; Venkata Mallavadhani, Uppuluri

2018-08-01

A total of twenty-two novel coumarin triazole hybrids (4a-4k and 6a-6k) were synthesized from orcinol in good to excellent yields of 70-94%. The structures of all the synthesized compounds were elucidated by spectroscopic techniques such as 1 H NMR, 13 C NMR, and HRMS. The anti-inflammatory potential of synthesized compounds was investigated against the proinflammatory cytokine, TNF-α on U937 cell line and compounds 4d, 4j, and 6j were found to exhibit promising anti-inflammatory activity. These three compounds were further screened against TNF-α on LPS-stimulated RAW 264.7 cells, which confirm their anti-inflammatory potential. Furthermore, the above said active compounds were tested for their inhibitory effect on RANKL-induced osteoclastogenesis in RAW 264.7 cells by using tartrate resistant acid phosphatase (TRAP) staining assay at 10 µM. Molecular mechanism studies demonstrated that compound 4d exhibited dose dependent inhibition of RANKL-induced osteoclastogenesis by suppression of the NF-kB pathway. Thus, compound 4d is a promising candidate for further optimization to develop as a potent anti-osteoporotic agent. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthesis, crystal structure, Hirshfeld surfaces analysis and anti-ischemic activity of cinnamide derivatives

NASA Astrophysics Data System (ADS)

Zhong, Jian-gang; Han, Jia-pei; Li, Xiao-feng; Xu, Yi; Zhong, Yan; Wu, Bin

2018-02-01

Two cinnamide derivatives, namely, (E)-1-(4-(bis(4-methylphenyl)- methyl)piperazin-1-yl)-3-(3,4-diethoxyphenyl)prop-2-en-1-one (5) and (E)-1-(4-(bis- (4-fluorophenyl)methyl)piperazin-1-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (6), have been synthesized and characterized by IR spectra, High resolution mass spectra, 1H NMR spectra, 13C NMR spectra. The compound 5 is a novel compound and has never been reported in the literature. Their crystal structures were studied by single-crystal X-ray diffraction. They all crystallize in the monoclinic system. The single-crystal X-ray revealed that compound 5 has infinite X-shaped 1-D polymeric chains structure and compound 6 has a layered 3-D structure by intermolecular interactions. Hirshfeld surface analysis demonstrated the presence of H⋯H, O⋯H, C⋯H, F⋯H, Csbnd H⋯π and π⋯π intermolecular interactions. In addition, the MTT assay results indicated that the compounds 5 and 6 display effective activities against neurotoxicity which is induced by glutamine in PC12 cells. The in vivo experiment indicated that the compound 6 has a good protective effect on cerebral infarction.

Neutron and X-ray Scattering Study of Structure and Dynamics of Condensed Matters

NASA Astrophysics Data System (ADS)

Fujii, Yasuhiko

In this article, I have reviewed a series of research on a various phase transitions such as (1) structural phase transitions of perovskite compounds driven by soft phonons, (2) pressure-induced molecular dissociation and metallization observed in solid halogens, and (3) the “Devil's Flower” type phase diagram observed in two compounds with frustrating interactions. Also commented is on the so-called “Small Science at Large Facility” typically symbolized by neutron and synchrotron radiation experiments like the present research.

Isolation and Structure Elucidation of Cembranoids from a Dongsha Atoll Soft Coral Sarcophyton stellatum.

PubMed

Ahmed, Atallah F; Chen, Yi-Wei; Huang, Chiung-Yao; Tseng, Yen-Ju; Lin, Chi-Chen; Dai, Chang-Feng; Wu, Yang-Chang; Sheu, Jyh-Horng

2018-06-14

Six new polyoxygenated cembrane-based diterpenoids, stellatumolides A⁻C ( 1 ⁻ 3 ), stellatumonins A and B ( 4 and 5 ), and stellatumonone ( 6 ), were isolated together with ten known related compounds ( 7 ⁻ 16 ) from the ethyl acetate (EtOAc) extract of soft coral Sarcophyton stellatum . The structures of the new compounds were established by extensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and data comparison with related structures. Compounds 8 and 14 were isolated from a natural source for the first time. The isolated metabolites were shown to be not cytotoxic against a limited panel of cancer cells. Compound 9 showed anti-inflammatory activity by reducing the expression of proinflammatory cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins in lipopolysaccharide (LPS)-stimulated mouse leukaemic monocyte macrophage (RAW 264.7) cells.

Synthesis of (S)-(+)-decursin and its analogues as potent inhibitors of melanin formation in B16 murine melanoma cells.

PubMed

Lee, Kyeong; Lee, Jee-Hyun; Boovanahalli, Shanthaveerappa K; Choi, Yongseok; Choo, Soo-Jin; Yoo, Ick-dong; Kim, Dong Hee; Yun, Mi Young; Lee, Gye Won; Song, Gyu-Yong

2010-12-01

We report the synthesis of a novel series of highly potent melanin inhibitors which were obtained through structural modification of an anticancer compound S-(+)-decursinol. The in vitro inhibitory potencies of the newly synthesized compounds were evaluated against α-MSH induced melanin production in B16 murine melanoma cells. Among the compounds evaluated, compounds 2, 3, 6b, 7a, 7b, 8a and 8b emerged as highly potent inhibitors of melanin production. Besides, these compounds demonstrated significantly low cytotoxicity. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Substituted piperazines as nootropic agents: 2- or 3-phenyl derivatives structurally related to the cognition-enhancer DM235.

PubMed

Guandalini, Luca; Martino, Maria Vittoria; Di Cesare Mannelli, Lorenzo; Bartolucci, Gianluca; Melani, Fabrizio; Malik, Ruchi; Dei, Silvia; Floriddia, Elisa; Manetti, Dina; Orlandi, Francesca; Teodori, Elisabetta; Ghelardini, Carla; Romanelli, Maria Novella

2015-04-15

A series of 2-phenyl- or 3-phenyl piperazines, structurally related to DM235 and DM232, two potent nootropic agents, have been prepared and tested in the mouse passive-avoidance test, to assess their ability to revert scopolamine-induced amnesia. Although the newly synthesized molecules were less potent than the parent compounds, some useful information has been obtained from structure-activity relationships. A small but significant enantioselectivity has been found for the most potent compound 5a. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pressure-induced superconductivity in the iron-based ladder material BaFe2S3.

PubMed

Takahashi, Hiroki; Sugimoto, Akira; Nambu, Yusuke; Yamauchi, Touru; Hirata, Yasuyuki; Kawakami, Takateru; Avdeev, Maxim; Matsubayashi, Kazuyuki; Du, Fei; Kawashima, Chizuru; Soeda, Hideto; Nakano, Satoshi; Uwatoko, Yoshiya; Ueda, Yutaka; Sato, Taku J; Ohgushi, Kenya

2015-10-01

All the iron-based superconductors identified so far share a square lattice composed of Fe atoms as a common feature, despite having different crystal structures. In copper-based materials, the superconducting phase emerges not only in square-lattice structures but also in ladder structures. Yet iron-based superconductors without a square-lattice motif have not been found, despite being actively sought out. Here, we report the discovery of pressure-induced superconductivity in the iron-based spin-ladder material BaFe2S3, a Mott insulator with striped-type magnetic ordering below ∼120 K. On the application of pressure this compound exhibits a metal-insulator transition at about 11 GPa, followed by the appearance of superconductivity below Tc = 14 K, right after the onset of the metallic phase. Our findings indicate that iron-based ladder compounds represent promising material platforms, in particular for studying the fundamentals of iron-based superconductivity.

Triosephosphate isomerase tyrosine nitration induced by heme-NaNO2 -H2 O2 or peroxynitrite: Effects of different natural phenolic compounds.

PubMed

Gao, Wanxia; Zhao, Jie; Li, Hailing; Gao, Zhonghong

2017-06-01

Peroxynitrite and heme peroxidases (or heme)-H 2 O 2 -NaNO 2 system are the two common ways to cause protein tyrosine nitration in vitro, but the effects of antioxidants on reducing these two pathways-induced protein nitration and oxidation are controversial. Both nitrating systems can dose-dependently induce triosephosphate isomerase (TIM) nitration, however, heme-H 2 O 2 -NaNO 2 was less destructive to protein secondary structures and led to more nitrated tyrosine residue than 3-morpholinosydnonimine hydrochloride (SIN-1, a peroxynitrite donor). Both of desferrioxamine and catechin could inhibit TIM nitration induced by heme-H 2 O 2 -NaNO 2 and SIN-1 and protein oxidation induced by SIN-1, but promoted heme-H 2 O 2 -NaNO 2 -induced protein oxidation. Moreover, the antagonism of natural phenolic compounds on SIN-1-induced tyrosine nitration was consistent with their radical scavenging ability, but no similar consensus was found in heme-H 2 O 2 -NaNO 2 -induced nitration. Our results indicated that peroxynitrite and heme-H 2 O 2 -NaNO 2 -induced protein nitration was different, and the later one could be a better model for anti-nitration compounds screening. © 2017 Wiley Periodicals, Inc.

Synthesis and analgesic activity of some side-chain modified anpirtoline derivatives.

PubMed

Rádl, S; Hezky, P; Proska, J; Hejnová, L; Krejcí, I

2000-05-01

New derivatives of anpirtoline and deazaanpirtoline modified in the side chain have been synthesized. The series includes compounds 3 with side-chains containing piperidine or pyrrolidine rings, compounds 4 containing 8-azabicyclo[3.2.1]octane moiety, and compounds 5 having piperazine ring in their side-chains. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Optimized structures (PM3-MOPAC, Alchemy 2000, Tripos Inc.) of the synthesized compounds 3-5 were compared with that of anpirtoline.

New Sesquiterpenoids and Anti-Platelet Aggregation Constituents from the Rhizomes of Curcuma zedoaria.

PubMed

Chen, Jih-Jung; Tsai, Tung-Han; Liao, Hsiang-Ruei; Chen, Li-Chai; Kuo, Yueh-Hsiung; Sung, Ping-Jyun; Chen, Chun-Lin; Wei, Chun-Sheng

2016-10-17

Two new sesquiterpenoids-13-hydroxycurzerenone ( 1 ) and 1-oxocurzerenone ( 2 )-have been isolated from the rhizomes of Curcuma zedoaria , together with 13 known compounds ( 3 - 15 ). The structures of two new compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, 13-hydroxycurzerenone ( 1 ), 1-oxocurzerenone ( 2 ), curzerenone ( 3 ), germacrone ( 4 ), curcolone ( 5 ), procurcumenol ( 6 ), ermanin ( 7 ), curcumin ( 8 ), and a mixture of stigmast-4-en-3,6-dione ( 12 ) and stigmasta-4,22-dien-3,6-dione ( 13 ) exhibited inhibition (with inhibition % in the range of 21.28%-67.58%) against collagen-induced platelet aggregation at 100 μM. Compounds 1 , 5 , 7 , 8 , and the mixture of 12 and 13 inhibited arachidonic acid (AA)-induced platelet aggregation at 100 μM with inhibition % in the range of 23.44%-95.36%.

Magnetic-field-induced effects in the electronic structure of itinerant d- and f-metal systems

NASA Astrophysics Data System (ADS)

Grechnev, G. E.

2009-08-01

A paramagnetic response of transition metals and itinerant d- and f-metal compounds in an external magnetic field is studied by employing ab initio full-potential LMTO method in the framework of the local spin density approximation. Within this method the anisotropy of the magnetic susceptibility in hexagonal close-packed transition metals is evaluated for the first time. This anisotropy is owing to the orbital Van Vleck-like paramagnetic susceptibility, which is revealed to be substantial in transition-metal systems due to hybridization effects in the electronic structure. It is demonstrated that compounds TiCo, Ni3Al, YCo2, CeCo2, YNi5, LaNi5, and CeNi5 are strong paramagnets close to the quantum critical point. For these systems the Stoner approximation underestimates the spin susceptibility, whereas the calculated field-induced spin moments provide a good description of the large paramagnetic susceptibilities and magnetovolume effects. It is revealed that an itinerant description of hybridized f electrons produces magnetic properties of the compounds CeCo2, CeNi5, UAl3, UGa3, USi3, and UGe3 in close agreement with experiment. In the uranium compounds UX3 the strong spin-orbit coupling together with hybridization effects give rise to peculiar magnetic states in which the field-induced spin moments are antiparallel to the external field, and the magnetic response is dominated by the orbital contribution.

Pressure induced structural phase transition in IB transition metal nitrides compounds

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

Soni, Shubhangi; Kaurav, Netram, E-mail: netramkaurav@yahoo.co.uk; Jain, A.

2015-06-24

Transition metal mononitrides are known as refractory compounds, and they have, relatively, high hardness, brittleness, melting point, and superconducting transition temperature, and they also have interesting optical, electronic, catalytic, and magnetic properties. Evolution of structural properties would be an important step towards realizing the potential technological scenario of this material of class. In the present study, an effective interionic interaction potential (EIOP) is developed to investigate the pressure induced phase transitions in IB transition metal nitrides TMN [TM = Cu, Ag, and Au] compounds. The long range Coulomb, van der Waals (vdW) interaction and the short-range repulsive interaction upto second-neighbormore » ions within the Hafemeister and Flygare approach with modified ionic charge are properly incorporated in the EIOP. The vdW coefficients are computed following the Slater-Kirkwood variational method, as both the ions are polarizable. The estimated value of the phase transition pressure (Pt) and the magnitude of the discontinuity in volume at the transition pressure are consistent as compared to the reported data.« less

Compound 49b Reduces Inflammatory Markers and Apoptosis after Ocular Blast Injury

DTIC Science & Technology

2013-09-01

retinal endothelial cells and in a diabetic retinopathy model [7, 10]. Compound 49b was based on the chemical structure of isoproterenol with chemical...Iraq and Afghanistan wars. N Engl J Med, 2011; 364: 2172-3. 7. Zhang Q, Guy K, Pagadala J, et al., Compound 49b Prevents Diabetes -Induced Apoptosis...is effective in reducing TNF and apoptotic 9 proteins in diabetic animals up to 6 months, when applied daily [7]. Isoproterenol was

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

PubMed Central

Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S.; Nallaganchu, Bhaskara Rao; Olson, Gary L.; Dicker, David T.; Allen, Joshua E.; El-Deiry, Wafik S.

2014-01-01

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers. PMID:25587031

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity.

PubMed

Wagner, Jessica; Kline, Christina Leah; Pottorf, Richard S; Nallaganchu, Bhaskara Rao; Olson, Gary L; Dicker, David T; Allen, Joshua E; El-Deiry, Wafik S

2014-12-30

We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.

Two structurally distinct inhibitors of glycogen synthase kinase 3 induced centromere positive micronuclei in human lymphoblastoid TK6 cells.

PubMed

Mishima, Masayuki; Tanaka, Kenji; Takeiri, Akira; Harada, Asako; Kubo, Chiyomi; Sone, Sachiko; Nishimura, Yoshikazu; Tachibana, Yukako; Okazaki, Makoto

2008-08-25

Glycogen synthase kinase 3 (GSK3) is an attractive novel pharmacological target. Inhibition of GSK3 is recently regarded as one of the viable approaches to therapy for Alzheimer's disease, cancer, diabetes mellitus, osteoporosis, and bipolar mood disorder. Here, we have investigated the aneugenic potential of two potent and highly specific inhibitors of GSK3 by using an in vitro micronucleus test with human lymphoblastoid TK6 cells. One inhibitor was a newly synthesized maleimide derivative and the other was a previously known aminopyrimidine derivative. Both compounds elicited statistically significant and concentration-dependent increases in micronucleated cells. One hundred micronuclei (MN) of each were analyzed using centromeric DNA staining with fluorescence in situ hybridization. Both the two structurally distinct compounds induced centromere-positive micronuclei (CMN). Calculated from the frequency of MN cells and the percentage of CMN, CMN cell incidence after treatment with the maleimide compound at 1.2 microM, 2.4 microM, and 4.8 microM was 11.6, 27.7, and 56.3 per 1000 cells, respectively; the negative control was 4.5. CMN cell incidence after the treatment with the aminopyrimidine compound at 1.8 microM, 3.6 microM, and 5.4 microM was 6.7, 9.8 and 17.2 per 1000 cells, respectively. Both compounds exhibited concentration-dependent increase in the number of mitotic cells. The frequency of CMN cells correlated well with mitotic cell incidence after treatment with either compound. Furthermore, both inhibitors induced abnormal mitotic cells with asymmetric mitotic spindles and lagging anaphase chromosomes. These results lend further support to the hypothesis that the inhibition of GSK3 activity affects microtubule function and exhibits an aneugenic mode of action.

EPR spectral investigation of radiation-induced radicals of gallic acid.

PubMed

Tuner, Hasan

2017-11-01

In the present work, spectroscopic features of the radiation-induced radicals of gallic acid compounds were investigated using electron paramagnetic resonance (EPR) spectroscopy. While un-irradiated samples presented no EPR signal, irradiated samples exhibited an EPR spectrum consisting of an intense resonance line at the center and weak lines on both sides. Detailed microwave saturation investigations were carried out to determine the origin of the experimental EPR lines. It is concluded that the two side lines of the triplet satellite originate from forbidden "spin-flip" transitions. The spectroscopic and structural features of the radiation-induced radicals were determined using EPR spectrum fittings. The experimental EPR spectra of the two gallic acid compounds were consistent with the calculated EPR spectroscopic features of the proposed radicals. It is concluded that the most probable radicals are the cyclohexadienyl-type, [Formula: see text] radicals for both compounds.

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

NASA Astrophysics Data System (ADS)

Gameiro, Isabel; Michalska, Patrycja; Tenti, Giammarco; Cores, Ángel; Buendia, Izaskun; Rojo, Ana I.; Georgakopoulos, Nikolaos D.; Hernández-Guijo, Jesús M.; Teresa Ramos, María; Wells, Geoffrey; López, Manuela G.; Cuadrado, Antonio; Menéndez, J. Carlos; León, Rafael

2017-03-01

The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.

Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

PubMed Central

Gameiro, Isabel; Michalska, Patrycja; Tenti, Giammarco; Cores, Ángel; Buendia, Izaskun; Rojo, Ana I.; Georgakopoulos, Nikolaos D.; Hernández-Guijo, Jesús M.; Teresa Ramos, María; Wells, Geoffrey; López, Manuela G.; Cuadrado, Antonio; Menéndez, J. Carlos; León, Rafael

2017-01-01

The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD. PMID:28361919

Water-Soluble Ruthenium (II) Chiral Heteroleptic Complexes with Amoebicidal in Vitro and in Vivo Activity.

PubMed

Toledano-Magaña, Yanis; García-Ramos, Juan C; Torres-Gutiérrez, Carolina; Vázquez-Gasser, Cristina; Esquivel-Sánchez, José M; Flores-Alamo, Marcos; Ortiz-Frade, Luis; Galindo-Murillo, Rodrigo; Nequiz, Mario; Gudiño-Zayas, Marco; Laclette, Juan P; Carrero, Julio C; Ruiz-Azuara, Lena

2017-02-09

Three water-soluble Ru(II) chiral heteroleptic coordination compounds [Ru(en)(pdto)]Cl 2 (1), [Ru(gly)(pdto)]Cl (2), and [Ru(acac)(pdto)]Cl (3), where pdto = 2,2'-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, have been synthezised and fully characterized. The crystal structures of compounds 1-3 are described. The IC 50 values for compounds 1-3 are within nanomolar range (14, 12, and 6 nM, respectively). The cytotoxicity for human peripheral blood lymphocytes is extremely low (>100 μM). Selectivity indexes for Ru(II) compounds are in the range 700-1300. Trophozoites exposed to Ru(II) compounds die through an apoptotic pathway triggered by ROS production. The orally administration to infected mice induces a total elimination of the parasite charge in mice faeces 1-2-fold faster than metronidazole. Besides, all compounds inhibit the trophozoite proliferation in amoebic liver abscess induced in hamster. All our results lead us to propose these compounds as promising candidates as antiparasitic agents.

Temperature dependent rapid annealing effect induces amorphous aggregation of human serum albumin.

PubMed

Ishtikhar, Mohd; Ali, Mohd Sajid; Atta, Ayman M; Al-Lohedan, Hammad; Badr, Gamal; Khan, Rizwan Hasan

2016-01-01

This study represents an analysis of the thermal aggregation of human serum albumin (HSA) induced by novel rosin modified compounds. The aggregation process causes conformational alterations in the secondary and tertiary structures of the proteins. The conversion of globular protein to amorphous aggregates was carried out by spectroscopic, calorimetric and microscopic techniques to investigate the factors that are responsible for the structural, conformational and morphological alteration in the protein. Our outcome results show that the aggregation of HSA was dependent on the hydrophobicity, charge and temperature, because the formation of amorphous aggregates occurs in the presence of a novel cationic rosin compound, quaternary amine of rosin diethylaminoethyl ester (QRMAE), at 40°C and pH 7.4 (but at 25°C on similar pH value, there was no evidence of aggregate formation). In addition, the parent compound of QRMAE, i.e., abietic acid, and other derivatives such as nonionic rosin compounds [(RMPEG-750) and (RMA-MPEG-750)] do not shows the aggregating property. This work provides precise and necessary information that aid in the understanding the effects of rosin derivative compounds on HSA. This study also restrains important information for athletes, health providers, pharmaceutical companies, industries, and soft drink-processing companies. Copyright © 2015 Elsevier B.V. All rights reserved.

Natural Diterpenoid Compound Elevates Expression of Bim Protein, Which Interacts with Antiapoptotic Protein Bcl-2, Converting It to Proapoptotic Bax-like Molecule*

PubMed Central

Zhao, Lixia; He, Feng; Liu, Haiyang; Zhu, Yushan; Tian, Weili; Gao, Ping; He, Hongping; Yue, Wen; Lei, Xiaobo; Ni, Biyun; Wang, Xiaohui; Jin, Haijing; Hao, Xiaojiang; Lin, Jialing; Chen, Quan

2012-01-01

Overwhelming evidence indicates that Bax and Bak are indispensable for mediating cytochrome c release from mitochondria during apoptosis. Here we report a Bax/Bak-independent mechanism of cytochrome c release and apoptosis. We identified a natural diterpenoid compound that induced apoptosis in bax/bak double knock-out murine embryonic fibroblasts and substantially reduced the tumor growth from these cells implanted in mice. Treatment with the compound significantly increased expression of Bim, which migrated to mitochondria, altering the conformation of and forming oligomers with resident Bcl-2 to induce cytochrome c release and caspase activation. Importantly, purified Bim and Bcl-2 proteins cooperated to permeabilize a model mitochondrial outer membrane; this was accompanied by oligomerization of these proteins and deep embedding of Bcl-2 in the membrane. Therefore, the diterpenoid compound induces a structural and functional conversion of Bcl-2 through Bim to permeabilize the mitochondrial outer membrane, thereby inducing apoptosis independently of Bax and Bak. Because Bcl-2 family proteins play important roles in cancer development and relapse, this novel cell death mechanism can be explored for developing more effective anticancer therapeutics. PMID:22065578

The R2R3MYB VvMYBPA1 from grape reprograms the phenylpropanoid pathway in tobacco flowers.

PubMed

Passeri, Valentina; Martens, Stefan; Carvalho, Elisabete; Bianchet, Chantal; Damiani, Francesco; Paolocci, Francesco

2017-08-01

This work shows that, in tobacco, the ectopic expression of VvMYBPA1 , a grape regulator of proanthocyanidin biosynthesis, up- or down-regulates different branches of the phenylproanoid pathway, in a structure-specific fashion. Proanthocyanidins are flavonoids of paramount importance for animal and human diet. Research interest increasingly tilts towards generating crops enriched with these health-promoting compounds. Flavonoids synthesis is regulated by the MBW transcriptional complex, made of R2R3MYB, bHLH and WD40 proteins, with the MYB components liable for channeling the complex towards specific branches of the pathway. Hence, using tobacco as a model, here, we tested if the ectopic expression of the proanthocyanidin regulator VvMYBPA1 from grape induces the biosynthesis of these compounds in not-naturally committed cells. Here, we show, via targeted transcriptomic and metabolic analyses of primary transgenic lines and their progeny, that VvMYBPA1 alters the phenylpropanoid pathway in tobacco floral organs, in a structure-specific fashion. We also report that a modest VvMYBPA1 expression is sufficient to induce the expression of both proanthocyanidin-specific and early genes of the phenylpropanoid pathway. Consequently, proanthocyanidins and chlorogenic acids are induced or de novo synthetised in floral limbs, tubes and stamens. Other phenylpropanoid branches are conversely induced or depleted according to the floral structure. Our study documents a novel and distinct function of VvMYBPA1 with respect to other MYBs regulating proanthocyanidins. Present findings may have major implications in designing strategies for enriching crops with health-promoting compounds.

Antiphase Fermi-surface modulations accompanying displacement excitation in a parent compound of iron-based superconductors

NASA Astrophysics Data System (ADS)

Okazaki, Kozo; Suzuki, Hakuto; Suzuki, Takeshi; Yamamoto, Takashi; Someya, Takashi; Ogawa, Yu; Okada, Masaru; Fujisawa, Masami; Kanai, Teruto; Ishii, Nobuhisa; Itatani, Jiro; Nakajima, Masamichi; Eisaki, Hiroshi; Fujimori, Atsushi; Shin, Shik

2018-03-01

We investigate the transient electronic structure of BaFe2As2 , a parent compound of iron-based superconductors, by time- and angle-resolved photoemission spectroscopy. In order to probe the entire Brillouin zone, we utilize extreme ultraviolet photons and observe photoemission intensity oscillation with the frequency of the A1 g phonon which is antiphase between the zone-centered hole Fermi surfaces (FSs) and zone-cornered electron FSs. We attribute the antiphase behavior to the warping in one of the zone-centered hole FSs accompanying the displacement of the pnictogen height and find that this displacement is the same direction as that induced by substitution of P for As, where superconductivity is induced by a structural modification without carrier doping in this system.

A saponin-detoxifying enzyme mediates suppression of plant defences

NASA Astrophysics Data System (ADS)

Bouarab, K.; Melton, R.; Peart, J.; Baulcombe, D.; Osbourn, A.

2002-08-01

Plant disease resistance can be conferred by constitutive features such as structural barriers or preformed antimicrobial secondary metabolites. Additional defence mechanisms are activated in response to pathogen attack and include localized cell death (the hypersensitive response). Pathogens use different strategies to counter constitutive and induced plant defences, including degradation of preformed antimicrobial compounds and the production of molecules that suppress induced plant defences. Here we present evidence for a two-component process in which a fungal pathogen subverts the preformed antimicrobial compounds of its host and uses them to interfere with induced defence responses. Antimicrobial saponins are first hydrolysed by a fungal saponin-detoxifying enzyme. The degradation product of this hydrolysis then suppresses induced defence responses by interfering with fundamental signal transduction processes leading to disease resistance.

Synthesis and biological evaluation of kresoxim-methyl analogues as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer cells.

PubMed

Lee, Sanghyuck; Kwon, Oh Seok; Lee, Chang-Soo; Won, Misun; Ban, Hyun Seung; Ra, Choon Sup

2017-07-01

We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC 50 values of 0.60-0.94µM. Under hypoxic condition, compounds 11b, 11c, and 11d increased the intracellular oxygen contents, thereby attenuating the hypoxia-induced accumulation of HIF-1α protein. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of matrine derivatives containing benzo-α-pyrone structure as potent anti-lung cancer agents

PubMed Central

Wu, Lichuan; Wang, Guizhen; Liu, Shuaibing; Wei, Jinrui; Zhang, Sen; Li, Ming; Zhou, Guangbiao; Wang, Lisheng

2016-01-01

Matrine, an active component of root extracts from Sophora flavescens Ait, is the main chemical ingredient of Fufang Kushen injection which was approved by Chinese FDA (CFDA) in 1995 as an anticancer drug to treat non-small cell lung cancer and liver cancer in combination with other anticancer drugs. Owning to its druggable potential, matrine is considered as an ideal lead compound for modification. We delineate herein the synthesis and anticancer effects of 17 matrine derivatives bearing benzo-α-pyrone structures. The results of cell viability assays indicated that most of the target compounds showed improved anticancer effects. Further studies showed that compound 5i could potently inhibit lung cancer cell proliferation in vitro and in vivo with no obvious side effects. Moreover, compound 5i could induce G1 cell cycle arrest and autophagy in lung cancer cells through up-regulating P27, down-regulating CDK4 and cyclinD1 and attenuating PI3K/Akt/mTOR pathway. Suppression of autophagy attenuated 5i induced proliferation inhibition. Collectively, our results infer that matrine derivative 5i bears therapeutic potentials for lung cancer. PMID:27786281

Effect of C6+ Ion Irradiation on structural and electrical properties of Yb and Eu doped Bi1.5 Zn0.92 Nb1.5 O6.92 pyrochlores

NASA Astrophysics Data System (ADS)

Yumak, Mehmet; Mergen, Ayhan; Qureshi, Anjum; Singh, N. L.

2015-03-01

Pyrochlore general formula of A2B2X7 where A and B are cations and X is an anion Pyrochlore compounds exhibit semiconductor, metallic or ionic conduction properties, depending on the doping, compositions/ substituting variety of cations and oxygen partial pressure. Ion beam irradiation can induce the structural disordering by mixing the cation and anion sublattices, therefore we aim to inevestigate effects of irradiation in pyrochlore compounds. In this study, Eu and Yb-doped Bi1.5Zn0.92Nb1.5O6.92 (Eu-BZN, Yb-BZN) Doping effect and single phase formation of Eu-BZN, Yb-BZN was characterized by X-ray diffraction technique (XRD). Radiation-induced effect of 85 MeV C6+ ions on Eu-BZN, Yb-BZN was studied by XRD, scanning electron microscopy (SEM) and temperature dependent dielectric measurements at different fluences. XRD results revealed that the ion beam-induced structural amorphization processes in Eu-BZN and Yb-BZN structures. Our results suggested that the ion beam irradiation induced the significant change in the temprature depndent dielectric properties of Eu-BZN and Yb-BZN pyrochlores due to the increased oxygen vacancies as a result of cation and anion disordering. Department of Metallurgical and Materials Eng., Marmara University, Istanbul-81040, Turkey.

HPLC-Based Activity Profiling for GABAA Receptor Modulators in Searsia pyroides Using a Larval Zebrafish Locomotor Assay.

PubMed

Moradi-Afrapoli, Fahimeh; van der Merwe, Hannes; De Mieri, Maria; Wilhelm, Anke; Stadler, Marco; Zietsman, Pieter C; Hering, Steffen; Swart, Kenneth; Hamburger, Matthias

2017-10-01

A dichloromethane extract from leaves of Searsia pyroides potentiated gamma aminobutyric acid-induced chloride currents by 171.8 ± 54% when tested at 100 µg/mL in Xenopus oocytes transiently expressing gamma aminobutyric acid type A receptors composed of α 1 β 2 γ 2 s subunits. In zebrafish larvae, the extract significantly lowered pentylenetetrazol-provoked locomotion when tested at 4 µg/mL. Active compounds of the extract were tracked with the aid of HPLC-based activity profiling utilizing a previously validated zebrafish larval locomotor activity assay. From two active HPLC fractions, compounds 1  -  3 were isolated. Structurally related compounds 4  -  6 were purified from a later eluting inactive HPLC fraction. With the aid of 1 H and 13 C NMR and high-resolution mass spectrometry, compounds 1  -  6 were identified as analogues of anacardic acid. Compounds 1  -  3 led to a concentration-dependent decrease of pentylenetetrazol-provoked locomotion in the zebrafish larvae model, while 4  -  6 were inactive. Compounds 1  -  3 enhanced gamma aminobutyric acid-induced chloride currents in Xenopus oocytes in a concentration-dependent manner, while 4  -  6 only showed marginal enhancements of gamma aminobutyric acid-induced chloride currents. Compounds 2, 3 , and 5 have not been reported previously. Georg Thieme Verlag KG Stuttgart · New York.

Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities.

PubMed

Deshpande, Shreenivas Ramachandrarao; Pai, Karkala Vasantakumar

2012-04-01

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg\\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.

Magnetically-induced ferroelectricity in the (ND4)2[FeCl5(D2O)] molecular compound

PubMed Central

Alberto Rodríguez-Velamazán, José; Fabelo, Óscar; Millán, Ángel; Campo, Javier; Johnson, Roger D.; Chapon, Laurent

2015-01-01

The number of magnetoelectric multiferroic materials reported to date is scarce, as magnetic structures that break inversion symmetry and induce an improper ferroelectric polarization typically arise through subtle competition between different magnetic interactions. The (NH4)2[FeCl5(H2O)] compound is a rare case where such improper ferroelectricity has been observed in a molecular material. We have used single crystal and powder neutron diffraction to obtain detailed solutions for the crystal and magnetic structures of (NH4)2[FeCl5(H2O)], from which we determined the mechanism of multiferroicity. From the crystal structure analysis, we observed an order-disorder phase transition related to the ordering of the ammonium counterion. We have determined the magnetic structure below TN, at 2 K and zero magnetic field, which corresponds to a cycloidal spin arrangement with magnetic moments contained in the ac-plane, propagating parallel to the c-axis. The observed ferroelectricity can be explained, from the obtained magnetic structure, via the inverse Dzyaloshinskii-Moriya mechanism. PMID:26417890

Radiation-induced amorphization resistance and radiation tolerance in structurally related oxides.

PubMed

Sickafus, Kurt E; Grimes, Robin W; Valdez, James A; Cleave, Antony; Tang, Ming; Ishimaru, Manabu; Corish, Siobhan M; Stanek, Christopher R; Uberuaga, Blas P

2007-03-01

Ceramics destined for use in hostile environments such as nuclear reactors or waste immobilization must be highly durable and especially resistant to radiation damage effects. In particular, they must not be prone to amorphization or swelling. Few ceramics meet these criteria and much work has been devoted in recent years to identifying radiation-tolerant ceramics and the characteristics that promote radiation tolerance. Here, we examine trends in radiation damage behaviour for families of compounds related by crystal structure. Specifically, we consider oxides with structures related to the fluorite crystal structure. We demonstrate that improved amorphization resistance characteristics are to be found in compounds that have a natural tendency to accommodate lattice disorder.

Interplay between crystal and magnetic structures in YFe{sub 2}(H{sub α}D{sub 1−α}){sub 4.2} compounds studied by neutron diffraction

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

Paul-Boncour, V., E-mail: paulbon@icmpe.cnrs.fr; Guillot, M.; Isnard, O.

We report a detailed magnetic structure investigation of YFe{sub 2}(H{sub α}D{sub 1−α}){sub 4.2} (α=0, 0.64, 1) compounds presenting a strong (H,D) isotope effect by neutron diffraction and Mössbauer spectroscopy analysis. They crystallize in the same monoclinic structure (Pc space group) with 8 inequivalent Fe sites having different H(D) environment. At low temperature, the compounds are ferromagnetic (FM) and show an easy magnetization axis perpendicular to the b axis and only slightly tilted away from the c axis. Upon heating, they display a first order transition from a ferromagnetic towards an antiferromagnetic (AFM) structure at T{sub M0} which is sensitive tomore » the H/D isotope nature. The AFM cell is described by doubling the crystal cell along the monoclinic b axis. It presents an unusual coexistence of non magnetic Fe layer sandwiched by two thicker ferromagnetic Fe layers which are antiparallel to each other. This FM-AFM transition is driven by the loss of ordered moment on one Fe site (Fe7) through an itinerant electron metamagnetic (IEM) behaviour. The key role of the Fe7 position is assigned to both its hydrogen rich atomic environment and its geometric position. Above T{sub M0} a field induced metamagnetic transition is observed from the AFM towards the FM structure accompanied by a cell volume increase. Both thermal and magnetic field dependence of the magnetic structure are found strongly related to the anisotropic cell distortion induced by (H,D) order in interstitial sites. - Graphical abstract: Representation of the FM-AFM magnetic structures of YFe{sub 2}D{sub 4.2} deuteride. - Highlights: • YFe{sub 2}(H,D){sub 4.2} compounds undergoes a isotope sensitive FM-AFM transition at T{sub M0}. • The FM structure is formed of Fe moments perpendicular to the monoclinic b axis. • AFM structure is formed by antiparallel Fe layers separated by non-magnetic Fe layer. • One Fe site among eight loses its moment at T{sub M0} due to larger Fe–H bonding. • Magnetic properties are driven by the monoclinic distortion induced by D order.« less

Pressure induced structural phase transition in metal nitrides: An effective interionic potential calculations

NASA Astrophysics Data System (ADS)

Soni, Shubhangi; Choudhary, K. K.; Kaurav, Netram

2018-05-01

Structural and elastic properties of transition metal nitrides, XN (X = Co, Fe and Cu), are investigated through an effective inter-ionic potential method. The B3(ZnS) type ambient crystal structure of these compounds undergoes to B1(NaCl) type structure with pressure. Structural phase transition pressure in CoN, FeN and CuN was 35, 55 and 35 GPa, respectively, predicated by computing Gibbs' free energy (G) as a function of pressure and has good agreement with available theoretical results. The elastic properties were also estimated as a function of pressure. It is found that the elastic constants increased linearly with increasing pressure due to stronger hybridization, bonding and covalent properties of constituent elements of a compound.

Cytotoxic and apoptosis-inducing activity of C21 steroids from the roots of Cynanchum atratum.

PubMed

Zhang, Jian; Ma, Lin; Wu, Zheng-Feng; Yu, Shu-Le; Wang, Lei; Ye, Wen-Cai; Zhang, Qing-Wen; Yin, Zhi-Qi

2017-06-01

Two new (1-2) and two known C 21 steroids (3-4) were isolated from the roots of Cynanchum atratum. Their structures were elucidated by detailed 1D and 2D spectroscopic. The MTT assay showed that compounds 1-4 displayed obvious cytotoxic activities against HepG2 cells with IC 50 values ranging from 10.19μM to 76.12μM. Compounds 1-3 also exhibited cytotoxic effects in A549 cells with IC 50 values of 30.87-95.39μM. Compound 3 showed the antiproliferative activity via G0/G1 cell cycle arrest and proapoptosis in HepG2 cells by Flowcytometry analysis. Western blotting analysis revealed that compound 3 could induce HepG2 cell apoptosis via the mitochondrial pathway by downregulating Bcl-2 expression, upregulating Bax protein expression, and activating caspase-9 and caspase-3. Copyright © 2017 Elsevier Inc. All rights reserved.

Pressure induced phase transition and elastic properties of cerium mono-nitride (CeN)

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

Yaduvanshi, Namrata, E-mail: namrata-yaduvanshi@yahoo.com; Singh, Sadhna

2016-05-23

In the present paper, we have investigated the high-pressure structural phase transition and elastic properties of cerium mono-nitride. We studied theoretically the structural properties of this compound (CeN) by using the improved interaction potential model (IIPM) approach. This compound exhibits first order crystallographic phase transition from NaCl (B{sub 1}) to tetragonal (BCT) phase at 37 GPa. The phase transition pressures and associated volume collapse obtained from present potential model (IIPM) show a good agreement with available theoretical data.

Organotin compounds cause structure-dependent induction of progesterone in human choriocarcinoma Jar cells.

PubMed

Hiromori, Youhei; Yui, Hiroki; Nishikawa, Jun-ichi; Nagase, Hisamitsu; Nakanishi, Tsuyoshi

2016-01-01

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are typical environmental contaminants and suspected endocrine-disrupting chemicals because they cause masculinization in female mollusks. In addition, previous studies have suggested that the endocrine disruption by organotin compounds leads to activation of peroxisome proliferator-activated receptor (PPAR)γ and retinoid X receptor (RXR). However, whether organotin compounds cause crucial toxicities in human development and reproduction is unclear. We here investigated the structure-dependent effect of 12 tin compounds on mRNA transcription of 3β-hydroxysteroid dehydrogenase type I (3β-HSD I) and progesterone production in human choriocarcinoma Jar cells. TBT, TPT, dibutyltin, monophenyltin, tripropyltin, and tricyclohexyltin enhanced progesterone production in a dose-dependent fashion. Although tetraalkyltin compounds such as tetrabutyltin increased progesterone production, the concentrations necessary for activation were 30-100 times greater than those for trialkyltins. All tested active organotins increased 3β-HSD I mRNA transcription. We further investigated the correlation between the agonistic activity of organotin compounds on PPARγ and their ability to promote progesterone production. Except for DBTCl2, the active organotins significantly induced the transactivation function of PPARγ. In addition, PPARγ knockdown significantly suppressed the induction of mRNA transcription of 3β-HSD I by all active organotins except DBTCl2. These results suggest that some organotin compounds promote progesterone biosynthesis in vitro by inducing 3β-HSD I mRNA transcription via the PPARγ signaling pathway. The placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might cause local changes in progesterone concentration in pregnant women. Copyright © 2014 Elsevier Ltd. All rights reserved.

Local epigenetic reprograming induced by G-quadruplex ligands

PubMed Central

Recolin, Bénédicte; Campbell, Beth C.; Maiter, Ahmed; Sale, Julian E.; Balasubramanian, Shankar

2017-01-01

DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here we demonstrate that impeding replication by small molecule-mediated stabilisation of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterisation of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps, first loss of H3K4me3 and subsequently DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming. PMID:29064488

Local epigenetic reprogramming induced by G-quadruplex ligands

NASA Astrophysics Data System (ADS)

Guilbaud, Guillaume; Murat, Pierre; Recolin, Bénédicte; Campbell, Beth C.; Maiter, Ahmed; Sale, Julian E.; Balasubramanian, Shankar

2017-11-01

DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here, we demonstrate that impeding replication by small-molecule-mediated stabilization of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterization of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps: the loss of H3K4me3 and then subsequent DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming.

Structure-Based Design of Potent Bcl-2/Bcl-xL Inhibitors with Strong in Vivo Antitumor Activity

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

Zhou, Haibin; Aguilar, Angelo; Chen, Jianfang

Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 {angstrom} resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K{sub i} values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC{sub 50} values in multiple small-cell lung cancer cellmore » lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.« less

Pressure evolution of electrical transport in the 3D topological insulator (Bi,Sb) 2 (Se,Te) 3

DOE PAGES

Jeffries, J. R.; Butch, N. P.; Vohra, Y. K.; ...

2015-03-18

The group V-VI compounds|like Bi 2Se 3, Sb 2Te 3, or Bi 2Te 3|have been widely studied in recent years for their bulk topological properties. The high-Z members of this series form with the same crystal structure, and are therefore amenable to isostructural substitution studies. It is possible to tune the Bi-Sb and Te-Se ratios such that the material exhibits insulating behavior, thus providing an excellent platform for understanding how a topological insulator evolves with applied pressure. We report our observations of the pressure-dependent electrical transport and crystal structure of a pseudobinary (Bi,Sb) 2(Te,Se) 3 compound. Similar to some ofmore » its sister compounds, the (Bi,Sb) 2(Te,Se) 3 pseudobinary compound undergoes multiple, pressure-induced phase transformations that result in metallization, the onset of a close-packed crystal structure, and the development of distinct superconducting phases.« less

A new compound, withangulatin A, promotes type II DNA topoisomerase-mediated DNA damage.

PubMed

Juang, J K; Huang, H W; Chen, C M; Liu, H J

1989-03-31

Withangulatin A, a new compound with a known chemical structure and from the antitumor Chinese herb Physalis angulata L, was found to act on topoisomerase II to induce topoisomerase II-mediated DNA damage in vitro. It has two effective dosage ranges of approximate 0.5 and 20 microM, with about one-third the activity of 20 microM VM-26.

Photochemically Induced Transformations of Transition Complexes.

DTIC Science & Technology

1993-05-17

simple Iron dinuclear species, the DPPM and DPPE phosphine bridged compounds undergo photolysis in CHCI3 to yield products containing formyl substitued...possible reaction pathway for the synthesis of these two monomers as byproducts In the ruthenium phosphine dimer preparation Is suggested. Full structural...DPPM dimer is also described. In contrast to the behavior of the simple iron dinuclear species, the DPPM and DPPE phosphine bridged compounds undergo

Two new compounds from the aerial parts of Bergenia himalaica Boriss and their anti-hyperglycemic effect in streptozotocin-nicotinamide induced diabetic rats.

PubMed

Siddiqui, Bina S; Hasan, Mashooda; Mairaj, Farah; Mehmood, Iffat; Hafizur, Rahman Md; Hameed, Abdul; Khan Shinwari, Zabta

2014-03-28

Bergenia himalaica Boriss is mainly distributed in the temperate Himalayas between altitudes of 900 and 3000m ranging from the southeastern regions in central Asia and northern regions in South Asia. The plant has a long history of its use in traditional medicine for the treatment of various diseases such as diabetes, urinary complaints, kidney stones, hemorrhagic diseases and epilepsy. The aim of this study is to isolate pure compounds from Bergenia himalaica Boriss, elucidate their structures and determine their blood glucose lowering activity to obtain additional scientific evidence for its usage in traditional medicine for the management of diabetes. The crude methanolic extract from the aerial parts of Bergenia himalaica Boriss was separated into EtOAc and water sub-extracts and the EtOAc sub-extract was further divided into petroleum ether soluble and insoluble fractions. The pet-ether insoluble fraction was subjected to fractionation through column chromatography followed by prep. TLC. The blood glucose lowering activity of the 2 new compounds was evaluated in streptozotocin-nicotinamide induced diabetic rats. Additionally, glucose-stimulated insulin secretion was measured on isolated mice islets. Two new compounds bergenicin and bergelin were isolated and their structures determined on the basis of spectral analysis. Significant decrease of blood glucose was observed at 1-h (1.0mg/kg) and 2-h (0.5mg/kg), after bergenicin administration to the diabetic rats and at 2-h (1.0mg/kg) and 3-h (0.5mg/kg), after bergelin administration. Bergenicin, but not bergelin, enhanced glucose-stimulated insulin secretion in isolated pancreatic islets. In the present studies two new compounds, bergenicin and bergelin were isolated from Bergenia himalaica Boriss and their structures were elucidated. Both the compounds showed anti-hyperglycemic effects in streptozotocin-nicotinamide induced diabetic rats. Bergenicin showed insulinotropic effect; suggesting that the anti-hyperglycemic effect is mostly due to enhancement of insulin secretion from pancreatic β-cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A new triterpene from callus of Pterocarpus santalinus.

PubMed

Krishnaveni, K S; Srinivasa Rao, J V

2000-02-01

A new pentacyclic triterpene was isolated from the callus induced from the stem cuttings of Pterocarpus santalinus. Based on spectral methods, the structure of the new compound was elucidated as 3-ketooleanane (1).

Superconductivity in strong spin orbital coupling compound Sb 2Se 3

DOE PAGES

Kong, P. P.; Sun, F.; Xing, L. Y.; ...

2014-10-20

Recently, A 2B 3 type strong spin orbital coupling compounds such as Bi 2Te 3, Bi 2Se 3 and Sb 2Te 3 were theoretically predicated to be topological insulators and demonstrated through experimental efforts. The counterpart compound Sb 2Se 3 on the other hand was found to be topological trivial, but theoretical studies indicated that the pressure might induce Sb 2Se 3 into a topological nontrivial state. We report on the discovery of superconductivity in Sb 2Se 3 single crystal induced via pressure. Our experiments indicated that Sb 2Se 3 became superconductive at high pressures above 10 GPa proceeded bymore » a pressure induced insulator to metal like transition at ~3 GPa which should be related to the topological quantum transition. The superconducting transition temperature (T C) increased to around 8.0 K with pressure up to 40 GPa while it keeps ambient structure. As a result, high pressure Raman revealed that new modes appeared around 10 GPa and 20 GPa, respectively, which correspond to occurrence of superconductivity and to the change of T C slop as the function of high pressure in conjunction with the evolutions of structural parameters at high pressures.« less

Predatory Mite Attraction to Herbivore-induced Plant Odors is not a Consequence of Attraction to Individual Herbivore-induced Plant Volatiles

PubMed Central

De Bruijn, Paulien J. A.; Sabelis, Maurice W.

2008-01-01

Predatory mites locate herbivorous mites, their prey, by the aid of herbivore-induced plant volatiles (HIPV). These HIPV differ with plant and/or herbivore species, and it is not well understood how predators cope with this variation. We hypothesized that predators are attracted to specific compounds in HIPV, and that they can identify these compounds in odor mixtures not previously experienced. To test this, we assessed the olfactory response of Phytoseiulus persimilis, a predatory mite that preys on the highly polyphagous herbivore Tetranychus urticae. The responses of the predatory mite to a dilution series of each of 30 structurally different compounds were tested. They mites responded to most of these compounds, but usually in an aversive way. Individual HIPV were no more attractive (or less repellent) than out-group compounds, i.e., volatiles not induced in plants fed upon by spider-mites. Only three samples were significantly attractive to the mites: octan-1-ol, not involved in indirect defense, and cis-3-hexen-1-ol and methyl salicylate, which are both induced by herbivory, but not specific for the herbivore that infests the plant. Attraction to individual compounds was low compared to the full HIPV blend from Lima bean. These results indicate that individual HIPV have no a priori meaning to the mites. Hence, there is no reason why they could profit from an ability to identify individual compounds in odor mixtures. Subsequent experiments confirmed that naive predatory mites do not prefer tomato HIPV, which included the attractive compound methyl salicylate, over the odor of an uninfested bean. However, upon associating each of these odors with food over a period of 15 min, both are preferred. The memory to this association wanes within 24 hr. We conclude that P. persimilis possesses a limited ability to identify individual spider mite-induced plant volatiles in odor mixtures. We suggest that predatory mites instead learn to respond to prey-associated mixtures of volatiles and, thus, to odor blends as a whole. PMID:18521678

Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities.

PubMed

Chao, Shi-Wei; Chen, Liang-Chieh; Yu, Chia-Chun; Liu, Chang-Yi; Lin, Tony Eight; Guh, Jih-Hwa; Wang, Chen-Yu; Chen, Chun-Yung; Hsu, Kai-Cheng; Huang, Wei-Jan

2018-01-01

Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC 50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pressure-Induced Structural Phase Transition in CeNi: X-ray and Neutron Scattering Studies and First-Principles Calculations

DOE PAGES

Mirmelstein, A.; Podlesnyak, Andrey A.; dos Santos, Antonio M.; ...

2015-08-03

The pressure-induced structural phase transition in the intermediate-valence compound CeNi has been investigated by x-ray and neutron powder diffraction techniques. It is shown that the structure of the pressure-induced CeNi phase (phases) can be described in terms of the Pnma space group. Equations of state for CeNi on both sides of the phase transition are derived and an approximate P-T phase diagram is suggested for P<8 GPa and T<300 K. The observed Cmcm→Pnma structural transition is then analyzed using density functional theory calculations, which successfully reproduce the ground state volume, the phase transition pressure, and the volume collapse associated withmore » the phase transition.« less

Cytotoxic constituents from the mangrove endophytic Pestalotiopsis sp. induce G0/G1 cell cycle arrest and apoptosis in human cancer cells.

PubMed

Zhou, Jing; Li, Gang; Deng, Qin; Zheng, Dongyao; Yang, Xiaobo; Xu, Jing

2017-10-31

Chemical examination of Chinese mangrove Rhizophora mucronata endophytic Pestalotiopsis sp., yielded  11 known metabolites with various structure types, including demethylincisterol A 3 (1), dankasterone B (2), (22E, 24R)-ergosta-7,9(11), 22-triene-3β, 5α, 6α-triol (3), ergosta-5,7,22-trien-3-ol (4), 5, 8-epidioxy-5, 8-ergosta-6, 22E-dien-3-ol (5), stigmastan-3-one (6), stigmast-4-en-3-one (7), stigmast-4-en-6 -ol-3-one (8), flufuran (9), (2-cis, 4-trans)-abscisic acid (10), similanpyrone B (11). Their structures were unambiguously elucidated on the basis of extensive NMR spectroscopic and mass spectrometric analyses. Compounds 1, 4, 6-9 showed significant in vitro cytotoxicity against the human cancer cell lines Hela, A549 and HepG, of which compound 1 was the most potential with IC 50 values reaching nM degree ranging from 0.17 to 14.16 nM. Flow cytometric investigation demonstrated that compound 1 mainly inhibited cell cycle at G 0 /G 1 phase in a dose-dependent manner with a significant induction of apoptosis on the three tested cell lines. The involvement of the mitochondria in compound 1 induced apoptosis was investigated using MMP. We suggested that R. mucronata endophytic Pestalotiopsis sp. contained a potential anticancer compound demethylincisterol A 3 .

High pressure and temperature induced structural and elastic properties of lutetium chalcogenides

NASA Astrophysics Data System (ADS)

Shriya, S.; Kinge, R.; Khenata, R.; Varshney, Dinesh

2018-04-01

The high-pressure structural phase transition and pressure as well temperature induced elastic properties of rock salt to CsCl structures in semiconducting LuX (X = S, Se, and Te) chalcogenides compound have been performed using effective interionic interaction potential with emphasis on charge transfer interactions and covalent contribution. Estimated values of phase transition pressure and the volume discontinuity in pressure-volume phase diagram indicate the structural phase transition from ZnS to NaCl structure. From the investigations of elastic constants the pressure (temperature) dependent volume collapse/expansion, melting temperature TM, Hardness (HV), and young modulus (E) the LuX lattice infers mechanical stiffening, and thermal softening.

Fragmentation pathways of O-alkyl methylphosphonothionocyanidates in the gas phase: toward unambiguous structural characterization of chemicals in the Chemical Weapons Convention framework.

PubMed

Saeidian, Hamid; Babri, Mehran; Ashrafi, Davood; Sarabadani, Mansour; Naseri, Mohammad Taghi

2013-08-01

The electron-impact (EI) mass spectra of a series of O-alkyl methylphosphonothionocyanidates were studied for Chemical Weapons Convention (CWC) purposes. General EI fragmentation pathways were constructed and discussed, and collision-induced dissociation studies of the major EI ions were performed to confirm proposed fragment structures by analyzing fragment ions of deuterated analogs and by use of density functional theory (DFT) calculations. Thiono-thiolo rearrangement, McLafferty-type rearrangement, and a previously unknown intramolecular electrophilic aromatic substitution reaction were observed and confirmed. The study also focused on differentiation of isomeric compounds. Retention indices for all compounds, and an electrophilicity index for several compounds, are reported and interpreted.

Synthesis and Neuroprotective Action of Xyloketal Derivatives in Parkinson’s Disease Models

PubMed Central

Li, Shichang; Shen, Cunzhou; Guo, Wenyuan; Zhang, Xuefei; Liu, Shixin; Liang, Fengyin; Xu, Zhongliang; Pei, Zhong; Song, Huacan; Qiu, Liqin; Lin, Yongcheng; Pang, Jiyan

2013-01-01

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1–39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD. PMID:24351912

Selenitetriglicerydes affect CYP1A1 and QR activity by involvement of reactive oxygen species and Nrf2 transcription factor.

PubMed

Suchocki, Piotr; Misiewicz-Krzemińska, Irena; Skupińska, Katarzyna; Niedźwiecka, Katarzyna; Lubelska, Katarzyna; Fijałek, Zbigniew; Kasprzycka-Guttman, Teresa

2010-01-01

Selenitetriglycerides are a group of compounds that contain selenium (Se) (IV). In this paper, we present the results of examinations of three structurally-related selenitetriglicerydes that contain various Se concentrations: 2%, 5% and 7% Selol. The present study concentrates on the effect of Selol on phase 1 and 2 enzyme activity and the implications of free radicals and the nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in the activity of this compound. The cytotoxic and cytostatic activities of the three kinds of Selol were evaluated; however, the cytotoxic effect was observed only for 7% Selol. Our results show that 2% Selol acts as a monofunctional inducer of phase 2 enzyme activity, and the induction is mediated by the Nrf2 transcription factor. Selol 7% acts in an opposite manner and induces phase 1 with simultaneous inhibition of phase 2 enzyme activity. The differential effect can be associated with the increase in Se content, leading to a change in the structure of the compound.

Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives.

PubMed

Huang, Ai-Ling; Zhang, Yi-Long; Ding, Hai-Wen; Li, Bo; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

2018-05-28

Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1β (IL-1β), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1β and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl 4 -induced acute liver injury mouse models. Copyright © 2018 Elsevier B.V. All rights reserved.

Gas Chromatography-Tandem Mass Spectrometry of Lignin Pyrolyzates with Dopant-Assisted Atmospheric Pressure Chemical Ionization and Molecular Structure Search with CSI:FingerID

NASA Astrophysics Data System (ADS)

Larson, Evan A.; Hutchinson, Carolyn P.; Lee, Young Jin

2018-06-01

Dopant-assisted atmospheric pressure chemical ionization (dAPCI) is a soft ionization method rarely used for gas chromatography-mass spectrometry (GC-MS). The current study combines GC-dAPCI with tandem mass spectrometry (MS/MS) for analysis of a complex mixture such as lignin pyrolysis analysis. To identify the structures of volatile lignin pyrolysis products, collision-induced dissociation (CID) MS/MS using a quadrupole time-of-flight mass spectrometer (QTOFMS) and pseudo MS/MS through in-source collision-induced dissociation (ISCID) using a single stage TOFMS are utilized. To overcome the lack of MS/MS database, Compound Structure Identification (CSI):FingerID is used to interpret CID spectra and predict best matched structures from PubChem library. With this approach, a total of 59 compounds were positively identified in comparison to only 22 in NIST database search of GC-EI-MS dataset. This study demonstrates the effectiveness of GC-dAPCI-MS/MS to overcome the limitations of traditional GC-EI-MS analysis when EI-MS database is not sufficient. [Figure not available: see fulltext.

Structures and mechanisms of antitumor agents: xestoquinones uncouple cellular respiration and disrupt HIF signaling in human breast tumor cells.

PubMed

Du, Lin; Mahdi, Fakhri; Datta, Sandipan; Jekabsons, Mika B; Zhou, Yu-Dong; Nagle, Dale G

2012-09-28

The organic extract of a marine sponge, Petrosia alfiani, selectively inhibited iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in a human breast tumor T47D cell-based reporter assay. Bioassay-guided fractionation yielded seven xestoquinones (1-7) including three new compounds: 14-hydroxymethylxestoquinone (1), 15-hydroxymethylxestoquinone (2), and 14,15-dihydroxestoquinone (3). Compounds 1-7 were evaluated for their effects on HIF-1 signaling, mitochondrial respiration, and tumor cell proliferation/viability. The known metabolites adociaquinones A (5) and B (6), which possess a 3,4-dihydro-2H-1,4-thiazine-1,1-dioxide moiety, potently and selectively inhibited iron chelator-induced HIF-1 activation in T47D cells, each with an IC(50) value of 0.2 μM. Mechanistic studies revealed that adociaquinones promote oxygen consumption without affecting mitochondrial membrane potential. Compound 1 both enhances respiration and decreases mitochondrial membrane potential, suggesting that it acts as a protonophore that uncouples mitochondrial respiration.

Identification of Compounds That Prolong Type I Interferon Signaling as Potential Vaccine Adjuvants.

PubMed

Shukla, Nikunj M; Arimoto, Kei-Ichiro; Yao, Shiyin; Fan, Jun-Bao; Zhang, Yue; Sato-Kaneko, Fumi; Lao, Fitzgerald S; Hosoya, Tadashi; Messer, Karen; Pu, Minya; Cottam, Howard B; Carson, Dennis A; Hayashi, Tomoko; Zhang, Dong-Er; Corr, Maripat

2018-05-01

Vaccines are reliant on adjuvants to enhance the immune stimulus, and type I interferons (IFNs) have been shown to be beneficial in augmenting this response. We were interested in identifying compounds that would sustain activation of an endogenous type I IFN response as a co-adjuvant. We began with generation of a human monocytic THP-1 cell line with an IFN-stimulated response element (ISRE)-β-lactamase reporter construct for high-throughput screening. Pilot studies were performed to optimize the parameters and conditions for this cell-based Förster resonance energy transfer (FRET) reporter assay for sustaining an IFN-α-induced ISRE activation signal. These conditions were confirmed in an initial pilot screen, followed by the main screen for evaluating prolongation of an IFN-α-induced ISRE activation signal at 16 h. Hit compounds were identified using a structure enrichment strategy based on chemoinformatic clustering and a naïve "Top X" approach. A select list of confirmed hits was then evaluated for toxicity and the ability to sustain IFN activity by gene and protein expression. Finally, for proof of concept, a panel of compounds was used to immunize mice as co-adjuvant with a model antigen and an IFN-inducing Toll-like receptor 4 agonist, lipopolysaccharide, as an adjuvant. Selected compounds significantly augmented antigen-specific immunoglobulin responses.

Changes in the structural composition and reactivity of Acer rubrum leaf litter tannins exposed to warming and altered precipitation: climatic stress-induced tannins are more reactive.

PubMed

Tharayil, Nishanth; Suseela, Vidya; Triebwasser, Daniella J; Preston, Caroline M; Gerard, Patrick D; Dukes, Jeffrey S

2011-07-01

• Climate change could increase the frequency with which plants experience abiotic stresses, leading to changes in their metabolic pathways. These stresses may induce the production of compounds that are structurally and biologically different from constitutive compounds. • We studied how warming and altered precipitation affected the composition, structure, and biological reactivity of leaf litter tannins in Acer rubrum at the Boston-Area Climate Experiment, in Massachusetts, USA. • Warmer and drier climatic conditions led to higher concentrations of protective compounds, including flavonoids and cutin. The abundance and structure of leaf tannins also responded consistently to climatic treatments. Drought and warming in combination doubled the concentration of total tannins, which reached 30% of leaf-litter DW. This treatment also produced condensed tannins with lower polymerization and a greater proportion of procyanidin units, which in turn reduced sequestration of tannins by litter fiber. Furthermore, because of the structural flexibility of these tannins, litter from this treatment exhibited five times more enzyme (β-glucosidase) complexation capacity on a per-weight basis. Warmer and wetter conditions decreased the amount of foliar condensed tannins. • Our finding that warming and drought result in the production of highly reactive tannins is novel, and highly relevant to climate change research as these tannins, by immobilizing microbial enzymes, could slow litter decomposition and thus carbon and nutrient cycling in a warmer, drier world. © 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.

[Changes of structures of anterior chamber angle in rabbit chronic high intraocular pressure model].

PubMed

Lei, Xun-wen; Wei, Ping; Li, Xiao-lin; Yang, Kan; Lei, Jian-zhen

2009-10-01

To observe the anterior chamber angle changes occurred in compound Carbomer-induced chronic high intraocular pressure (IOP) model in rabbit eyes. It was an experimental study. Thirty two rabbits were randomly divided into eight groups. Compound Carbomer (0.3%, 0.3 ml) was injected into the left anterior chamber. A group of rabbits were randomly killed after 1, 2, 3, 4, 6, 8, 10 and 12 weeks. The anterior chamber of the rabbit eye specimens was observed. IOP increased slowly following the application of the drug, high IOP lasted for 3 months. The drug-induced changes of anterior chamber angle consisted of early inflammatory response and late fibrous changes. Inflammatory response occurred in early stage and reduced or disappeared after 3 weeks. Fibrous degeneration and adhesion obstruction occurred in the anterior chamber angle after 4 weeks. Under the electron microscope, the trabecular was expanded and deformed, with hyperplasia of collagen and elastic fibers. Endothelial cells were separated from the trabecular, and showed the morphology of lymphocytes, with the function similar to the macrophages. Phagocytized Carbomer particles were transported through the vacuoles of Schlemm's canal endothelial cells. Large vacuoles gradually reduced. Excessive Carbomer particles were accumulated in the endothelial cells and obstructed the Schlemm's canal. This induced the fibrous proliferation and the destruction of anterior chamber angle structures. The obstruction of aqueous humor outflow induced by compound Carbomer in rabbit high IOP model is caused mainly by the changes in trabecular endothelial cells.

Antinociceptive Grayanoids from the Roots of Rhododendron molle.

PubMed

Li, Yong; Liu, Yun-Bao; Zhang, Jian-Jun; Liu, Yang; Ma, Shuang-Gang; Qu, Jing; Lv, Hai-Ning; Yu, Shi-Shan

2015-12-24

Nine new grayanoids (1-9), together with 11 known compounds, were isolated from the roots of Rhododendron molle. The structures of the new compounds (1-9) were determined on the basis of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR data. Compounds 4, 6, 12, and 14-20 showed significant antinociceptive activities in an acetic acid-induced writhing test. In particular, 14 and 15 were found to be more potent than morphine for both acute and inflammatory pain models and 100-fold more potent than gabapentin in a diabetic neuropathic pain model.

Identification and hit-to-lead optimization of a novel class of CB1 antagonists.

PubMed

Letourneau, Jeffrey J; Jokiel, Patrick; Olson, John; Riviello, Christopher M; Ho, Koc-Kan; McAleer, Lihong; Yang, Jingchun; Swanson, Robert N; Baker, James; Cowley, Phillip; Edwards, Darren; Ward, Nick; Ohlmeyer, Michael H J; Webb, Maria L

2010-09-15

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components.

PubMed

Rath, Emma M; Duff, Anthony P; Håkansson, Anders P; Vacher, Catherine S; Liu, Guo Jun; Knott, Robert B; Church, William Bret

2015-01-01

The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Synthesis and Antidepressant Activity Profile of Some Novel Benzothiazole Derivatives.

PubMed

Demir Özkay, Ümide; Kaya, Ceren; Acar Çevik, Ulviye; Can, Özgür Devrim

2017-09-07

Within the scope of our new antidepressant drug development efforts, in this study, we synthesized eight novel benzothiazole derivatives 3a - 3h . The chemical structures of the synthesized compounds were elucidated by spectroscopic methods. Test compounds were administered orally at a dose of 40 mg/kg to mice 24, 5 and 1 h before performing tail suspension, modified forced swimming, and activity cage tests. The obtained results showed that compounds 3c , 3d , 3f - 3h reduced the immobility time of mice as assessed in the tail suspension test. Moreover, in the modified forced swimming tests, the same compounds significantly decreased the immobility, but increased the swimming frequencies of mice, without any alteration in the climbing frequencies. These results, similar to the results induced by the reference drug fluoxetine (20 mg/kg, po), indicated the antidepressant-like activities of the compounds 3c , 3d , 3f - 3h . Owing to the fact that test compounds did not induce any significant alteration in the total number of spontaneous locomotor activities, the antidepressant-like effects of these derivatives seemed to be specific. In order to predict ADME parameters of the synthesized compounds 3a - 3h , some physicochemical parameters were calculated. The ADME prediction study revealed that all synthesized compounds may possess good pharmacokinetic profiles.

Thermal degradation products formed from carotenoids during a heat-induced degradation process of paprika oleoresins (Capsicum annuum L.).

PubMed

Pérez-Gálvez, Antonio; Rios, José J; Mínguez-Mosquera, María Isabel

2005-06-15

The high-temperature treatment of paprika oleoresins (Capsicum annuum L.) modified the carotenoid profile, yielding several degradation products, which were analyzed by HPLC-APCI-MS. From the initial MS data, compounds were grouped in two sets. Set 1 grouped compounds with m/z 495, and set 2 included compounds with m/z 479, in both cases for the protonated molecular mass. Two compounds of the first set were tentatively identified as 9,10,11,12,13,14,19,20-octanor-capsorubin (compound II) and 9,10,11,12,13,14,19,20-octanor-5,6-epoxide-capsanthin (compound IV), after isolation by semipreparative HPLC and analysis by EI-MS. Compounds VII, VIII, and IX from set 2 were assigned as 9,10,11,12,13,14,19,20-octanor-capsanthin and isomers, respectively. As these compounds were the major products formed in the thermal process, it was possible to apply derivatization techniques (hydrogenation and silylation) to analyze them by EI-MS, before and after chemical derivatization. Taking into account structures of the degradation products, the cyclization of polyolefins could be considered as the general reaction pathway in thermally induced reactions, yielding in the present study xylene as byproduct and the corresponding nor-carotenoids.

Anti-ulcer agents: chemical aspect of solving the problem

NASA Astrophysics Data System (ADS)

Rogoza, L. N.; Salakhutdinov, N. F.

2015-01-01

The data on chemical structures and specific activities of compounds functioning as histamine H2-receptor antagonists, H+/K+-ATPase inhibitors at the exchange sites of hydrogen ions (proton pump inhibitors) and potassium ions (K+-competitive acid blockers) published from 1990 to 2013 are surveyed. The antisecretory agents with studied cytoprotective activity or with additional therapeutic properties compensating for disorders of internal defence mechanisms are presented. A separate section is devoted to the drugs that prevent or mitigate the NSAID-induced intestinal damage. All of the considered structures are classified according to the type of biological mechanism of action. Some aspects of the structure-activity relationships for such compounds are considered. The bibliography includes 83 references.

Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions

PubMed Central

Verma, Vandana; Larsen, Bjarne Due; Coombs, Wanda; Lin, Xianming; Sarrou, Eliana; Taffet, Steven M.; Delmar, Mario

2010-01-01

Background Gap junctions are potential targets for pharmacological intervention. We have previously developed a series of peptide sequences that prevent closure of Cx43 channels, bind to cardiac Cx43 and prevent acidification-induced uncoupling of cardiac gap junctions. Objective We aimed to identify and validate the minimum core active structure in peptides containing an RR-N/Q-Y motif. Based on that information, we sought to generate a peptidomimetic molecule that acts on the chemical regulation of Cx43 channels. Methods Experiments were based on a combination of biochemical, spectroscopic and electrophysiological techniques, as well as molecular modeling of active pharmacophores with Cx43 activity. Results Molecular modeling analysis indicated that the functional elements of the side chains in the motif RRXY form a triangular structure. Experimental data revealed that compounds containing such a structure bind to Cx43 and prevent Cx43 chemical gating. These results provided us with the first platform for drug design targeted to the carboxyl terminal of Cx43. Using that platform, we designed and validated a peptidomimetic compound (ZP2519; molecular weight 619 Da) that prevented octanol-induced uncoupling of Cx43 channels, and pH gating of cardiac gap junctions. Conclusion Structure-based drug design can be applied to the development of pharmacophores that act directly on Cx43. Small molecules containing these pharmacophores can serve as tools to determine the role of gap junction regulation in the control of cardiac rhythm. Future studies will determine whether these compounds can function as pharmacological agents for the treatment of a selected subset of cardiac arrhythmias. PMID:20601149

Two new phenolic constituents from the root bark of Morus alba L. and their cardioprotective activity.

PubMed

Cao, Yan-Gang; Zheng, Xiao-Ke; Yang, Fang-Fang; Li, Fang; Qi, Man; Zhang, Yan-Li; Zhao, Xuan; Kuang, Hai-Xue; Feng, Wei-Sheng

2018-02-01

A new biphenyl-furocoumarin, named morescoumarin A (1), and a new prenylated flavanone, named morflavanone A (2) were isolated from the root bark of Morus alba L., together with four known compounds (3-6). Their structures were determined by extensive spectroscopic analyses and comparison with literature data. The cardioprotective effects of these compounds against doxorubicin-induced cell death were evaluated by MTT method.

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis.

PubMed

Bleich, Rachel; Watrous, Jeramie D; Dorrestein, Pieter C; Bowers, Albert A; Shank, Elizabeth A

2015-03-10

Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called "secondary" metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin's antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects--acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes.

Effects of high salt stress on secondary metabolite production in the marine-derived fungus Spicaria elegans.

PubMed

Wang, Yi; Lu, Zhenyu; Sun, Kunlai; Zhu, Weiming

2011-01-01

To obtain structurally novel and bioactive natural compounds from marine-derived microorganisms, the effect of high salt stress on secondary metabolite production in the marine-derived fungal strain, Spicaria elegans KLA-03, was investigated. The organism, which was isolated from marine sediment, produced different secondary metabolites when cultured in 3% and 10% saline conditions. Four characteristic metabolites, only produced in the 10% salinity culture, were isolated, and their structures were identified as (2E,2'Z)-3,3'-(6,6'-dihydroxybiphenyl-3,3'-diyl)diacrylic acid (1), aspulvinone E (2), aspochalasin E (3) and trichodermamide B (6), according to their 1D and 2D NMR spectra. Compound 1 is a new compound. High salt stress may therefore be a promising means to induce the production of new and chlorinated compounds in halotolerant fungi. Compound 1 showed moderate antibacterial activity against Pseudomonas aeruginosa and Escherichia coli with minimum inhibitory concentration (MIC) values of 0.038 and 0.767 mM, respectively.

Phytochemical analysis of the triterpenoids with cytotoxicity and QR inducing properties from the total tea seed saponin of Camellia sinensis.

PubMed

Li, Ning; Ma, Zhong-Jun; Chu, Yang; Wang, Ying; Li, Xian

2013-01-01

The tea seed triterpene saponin (TS) from Camellia sinensis was found to exhibit better antitumor activity in vivo in S180 implanted ICR mice and QR inducing activity for hepa lclc7 cells respectively compared with the total tea seed saponin (TTS), hydrolysate of the TTS and tea seed flavonoid glycosides (TF). By bioassay-guided isolation, the TS fraction was separated and seven major components were purified and identified as theasaponin E1 (1), theasaponin E2 (2), theasaponin C1 (3), assamsaponin C (4), theasaponin H1 (5), theasaponin A9 (6), and theasaponin A8 (7), among which compounds 4 and 5 were isolated from this genus for the first time. The antitumor bioassay of the isolated compounds showed that compounds 1, 2 and 3 exhibited potential activities against the human tumor cell lines K562 and HL60. Furthermore, compound 1 (the major constituent with a mass content of over 1%) showed significant QR inducing activity with an IR value of 4.2 at 4μg/ml. So it can be concluded that tea seed especially the compound 1 (theasaponin E1) could be used as an antitumor agent and a chemoprevention agent of cancer. The preliminary structure-activity relationship in the anti-tumor activity and QR inducing activity of tea saponins was discussed briefly. Copyright © 2012 Elsevier B.V. All rights reserved.

Antisite occupation induced single anionic redox chemistry and structural stabilization of layered sodium chromium sulfide

DOE PAGES

Shadike, Zulipiya; Zhou, Yong -Ning; Chen, Lan -Li; ...

2017-08-30

The intercalation compounds with various electrochemically active or inactive elements in the layered structure have been the subject of increasing interest due to their high capacities, good reversibility, simple structures and ease of synthesis. However, their reversible intercalation/deintercalation redox chemistries in all previous compounds involve a single cationic redox reaction or a cumulative cationic and anionic redox reaction. Here we report an anionic redox only chemistry and structural stabilization of layered sodium chromium sulfide. It is discovered that sulfur in sodium chromium sulfide is electrochemical active undergoing oxidation/reduction of sulfur rather than chromium. Significantly, sodium ions can successfully move outmore » and into without changing its lattice parameter c, which is explained in terms of the occurrence of chromium/sodium vacancy antisite during desodiation and sodiation processes. Here, our present work not only enriches the electrochemistry of layered intercalation compounds, but also extends the scope of investigation on high-capacity electrodes.« less

Antisite occupation induced single anionic redox chemistry and structural stabilization of layered sodium chromium sulfide

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

Shadike, Zulipiya; Zhou, Yong -Ning; Chen, Lan -Li

The intercalation compounds with various electrochemically active or inactive elements in the layered structure have been the subject of increasing interest due to their high capacities, good reversibility, simple structures and ease of synthesis. However, their reversible intercalation/deintercalation redox chemistries in all previous compounds involve a single cationic redox reaction or a cumulative cationic and anionic redox reaction. Here we report an anionic redox only chemistry and structural stabilization of layered sodium chromium sulfide. It is discovered that sulfur in sodium chromium sulfide is electrochemical active undergoing oxidation/reduction of sulfur rather than chromium. Significantly, sodium ions can successfully move outmore » and into without changing its lattice parameter c, which is explained in terms of the occurrence of chromium/sodium vacancy antisite during desodiation and sodiation processes. Here, our present work not only enriches the electrochemistry of layered intercalation compounds, but also extends the scope of investigation on high-capacity electrodes.« less

Effect of divalent Ba cation substitution with Sr on coupled ‘multiglass’ state in the magnetoelectric multiferroic compound Ba3NbFe3Si2O14

PubMed Central

Rathore, Satyapal Singh; Vitta, Satish

2015-01-01

(Ba/Sr)3NbFe3Si2O14 is a magneto-electric multiferroic with an incommensurate antiferromagnetic spiral magnetic structure which induces electric polarization at 26 K. Structural studies show that both the compounds have similar crystal structure down to 6 K. They exhibit a transition, TN at 26 K and 25 K respectively, as indicated by heat capacity and magnetization, into an antiferromagnetic state. Although Ba and Sr are isovalent, they exhibit very different static and dynamic magnetic behaviors. The Ba-compound exhibits a glassy behavior with critical slowing dynamics with a freezing temperature of ~35 K and a critical exponent of 3.9, a value close to the 3-D Ising model above TN, in addition to the invariant transition into an antiferromagnetic state. The Sr-compound however does not exhibit any dispersive behavior except for the invariant transition at TN. The dielectric constant reflects magnetic behavior of the two compounds: the Ba-compound has two distinct dispersive peaks while the Sr-compound has a single dispersive peak. Thus the compounds exhibit coupled ‘multiglass’ behavior. The difference in magnetic properties between the two compounds is found to be due to modifications to super exchange path angle and length as well as anti-site defects which stabilize either ferromagnetic or antiferromagnetic interactions. PMID:25988657

An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1.

PubMed

Dinkova-Kostova, Albena T; Talalay, Paul; Sharkey, John; Zhang, Ying; Holtzclaw, W David; Wang, Xiu Jun; David, Emilie; Schiavoni, Katherine H; Finlayson, Stewart; Mierke, Dale F; Honda, Tadashi

2010-10-29

The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

Monoterpene bisindole alkaloids, from the African medicinal plant Tabernaemontana elegans, induce apoptosis in HCT116 human colon carcinoma cells.

PubMed

Mansoor, Tayyab A; Borralho, Pedro M; Dewanjee, Saikat; Mulhovo, Silva; Rodrigues, Cecília M P; Ferreira, Maria-José U

2013-09-16

Tabernaemontana elegans is a medicinal plant used in African traditional medicine to treat several ailments including cancer. The aims of the present study were to identify anti-cancer compounds, namely apoptosis inducers, from Tabernaemontana elegans, and hence to validate its usage in traditional medicine. Six alkaloids, including four monomeric indole (1-3, and 6) and two bisindole (4 and 5) alkaloids, were isolated from the methanolic extract of Tabernaemontana elegans roots. The structures of these compounds were characterized by 1D and 2D NMR spectroscopic and mass spectrometric data. Compounds 1-6 along with compound 7, previously isolated from the leaves of the same species, were evaluated for in vitro cytotoxicity against HCT116 human colon carcinoma cells by the MTS metabolism assay. The cytotoxicity of the most promising compounds was corroborated by Guava-ViaCount flow cytometry assays. Selected compounds were next studied for apoptosis induction activity in HCT116 cells, by evaluation of nuclear morphology following Hoechst staining, and by caspase-3 like activity assays. Among the tested compounds (1-7), the bisindole alkaloids tabernaelegantine C (4) and tabernaelegantinine B (5) were found to be cytotoxic to HCT116 cells at 20 µM, with compound 5 being more cytotoxic than the positive control 5-Fluorouracil (5-FU), at a similar dose. In fact, even at 0.5 µM, compound 5 was more potent than 5-FU. Compounds 4 and 5 induced characteristic patterns of apoptosis in HCT116 cancer cells including, cell shrinkage, condensation, fragmentation of the nucleus, blebbing of the plasma membrane and chromatin condensation. Further, general caspase-3-like activity was increased in cells exposed to compounds 4 and 5, corroborating the nuclear morphology evaluation assays. Bisindole alkaloids tabernaelegantine C (4) and tabernaelegantinine B (5) were characterized as potent apoptosis inducers in HCT116 human colon carcinoma cells and as possible lead/scaffolds for the development of anti-cancer drugs. This study substantiates the usage of Tabernaemontana elegans in traditional medicine to treat cancer. © 2013 Elsevier Ireland Ltd. All rights reserved.

Photochemical isomerizations of thiosemicarbazide, a matrix isolation study.

PubMed

Rostkowska, Hanna; Lapinski, Leszek; Kozankiewicz, Boleslaw; Nowak, Maciej J

2012-10-11

Two thione conformers of monomeric thiosemicarbazide were trapped from the gas phase into a low-temperature Ar matrix. A phototransformation converting the less stable form of the compound into the most stable conformer was induced by irradiation with near-IR (λ = 1462 nm) or UV (λ > 320 nm) light. This photoeffect allowed separation of the IR spectra of the observed thione forms. The structures of both observed isomers were identified by comparison of the separated experimental IR spectra with the spectra theoretically predicted for two most stable forms of the compound. The population ratio of the two conformers in an Ar matrix, prior to any irradiation, was estimated to be equal ≈2:1. Irradiation of matrix-isolated thiosemicarbazide with shorter-wavelength UV (λ > 270 nm) light induced a phototautomeric reaction generating thiol forms of the compound.

Imbricatolic acid from Juniperus communis L. prevents cell cycle progression in CaLu-6 cells.

PubMed

De Marino, Simona; Cattaneo, Fabio; Festa, Carmen; Zollo, Franco; Iaccio, Annalisa; Ammendola, Rosario; Incollingo, Filomena; Iorizzi, Maria

2011-11-01

Imbricatolic acid was isolated from the methanolic extract of the fresh ripe berries of Juniperus communis (Cupressaceae) together with sixteen known compounds and a new dihydrobenzofuran lignan glycoside named juniperoside A. Their structures were determined by spectroscopic methods and by comparison with the spectral data reported in literature. Imbricatolic acid was evaluated for its ability to prevent cell cycle progression in p53-null CaLu-6 cells. This compound induces the upregulation of cyclin-dependent kinase inhibitors and their accumulation in the G1 phase of the cell cycle, as well as the degradation of cyclins A, D1, and E1. Furthermore, no significant imbricatolic acid-induced apoptosis was observed. Therefore, this plant-derived compound may play a role in the control of cell cycle. © Georg Thieme Verlag KG Stuttgart · New York.

Novel depsides as potential anti-inflammatory agents with potent inhibitory activity against Escherichia coli-induced interleukin-8 production.

PubMed

Lv, Peng-Cheng; Xiong, Jing; Chen, Jin; Wang, Kai-Rui; Mao, Wen-Jun; Zhu, Hai-Liang

2010-08-01

Sixteen novel depsides were synthesized for the first time. Their chemical structures were clearly determined by (1)H NMR, ESI mass spectra, and elemental analyses. All the compounds were assayed for antibacterial activities against three Gram-positive bacterial strains (Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, and Streptococcus faecalis ATCC 9790) and three Gram-negative bacterial strains (Escherichia coli ATCC 35218, Pseudomonas aeruginosa ATCC 13525, and Enterobacter cloacae ATCC 13047) by the MTT method. Compound 2-(2-methoxy-2-oxoethyl)phenyl 5-bromonicotinate (5) exhibited significant antibacterial activities against E. coli ATCC 35218 with an MIC of 0.78 microg/mL, which was superior to the positive control kanamycin B. In addition, compound 5 showed potent inhibitory activity against E. coli-induced interleukin-8 production.

A new ferulic acid ester from Rhodiola wallichiana var. cholaensis (Crassulaceae).

PubMed

Song, Yaling; Zhou, Jianming; Wang, Xuejing; Xie, Xue; Zhao, Yiwu; Ni, Fuyong; Huang, Wenzhe; Wang, Zhenzhong; Xiao, Wei

2018-01-01

A new ferulic acid ester, 6-feruloyloxyhexanoic acid (1), was isolated along with 10 known ones (2-11), from the concentrated water extract of Rhodiola wallichiana var. cholaensis. Their chemical structures were elucidated on the basis of extensive spectroscopic methods including Two-dimensional nuclear magnetic resonance (2D NMR) experiments. Compound 3 was isolated from this plant for the first time. The protective effects against H 2 O 2 -induced myocardial cell injury in cultured H9c2 cells were also evaluated. Compounds 1, 5 and 7-11 provided significant protective effects on H 2 O 2 -induced H9c2 cells injury at the concentration of 25 μg/mL. And the protective effects of compound 1 was also investigated by the oxygen-glucose deprivation/reperfusion (OGD/R) tests.

Neurosteroid-like Inhibitors of N-Methyl-d-aspartate Receptor: Substituted 2-Sulfates and 2-Hemisuccinates of Perhydrophenanthrene.

PubMed

Slavikova, Barbora; Chodounska, Hana; Nekardova, Michaela; Vyklicky, Vojtech; Ladislav, Marek; Hubalkova, Pavla; Krausova, Barbora; Vyklicky, Ladislav; Kudova, Eva

2016-05-26

N-Methyl-d-aspartate receptors (NMDARs) display a critical role in various diseases of the central nervous system. The activity of NMDARs can be modulated by neurosteroids. Herein, we report a structure-activity relationship study for perhydrophenanthrene analogues possessing a framework that mimics the steroidal ring system. This study comprises the design, synthesis, and assessment of the biological activity of a library of perhydrophenanthrene 2-sulfates and 2-hemisuccinates (1-10). Their ability to modulate NMDAR-induced currents was tested on recombinant GluN1/GluN2B receptors. Our results demonstrate that such structural optimization leads to compounds that are inhibitors of NMDARs. Notably, compound 9 (IC50 = 15.6 μM) was assessed as a more potent inhibitor of NMDAR-induced currents than the known endogenous neurosteroid, pregnanolone sulfate (IC50 = 24.6 μM).

Cytotoxic prenylated flavones from the stem and root bark of Daphne giraldii.

PubMed

Sun, Qian; Wang, Di; Li, Fei-Fei; Yao, Guo-Dong; Li, Xue; Li, Ling-Zhi; Huang, Xiao-Xiao; Song, Shao-Jiang

2016-08-15

Three new prenylated flavones (1-3), along with three known analogues (4-6), were isolated from the stem and root bark of Daphne giraldii. Their structures were determined by comprehensive NMR and HRESIMS spectroscopic data analyses. The absolute configurations of compounds 2 and 3 were assigned by optical rotation comparison, CD and [Rh2(OCOCF3)4]-induced CD spectral methods. The in vitro cytotoxicity experiments carried out involving five cancer cell lines (U251, A549, HepG2, MCF-7 and Bcap37) showed that 2 markedly inhibited the proliferation of all tested cells with IC50 values ranging from 4.26 to 20.82μM. The preliminary structure-activity relationships of these flavones are discussed. In addition, compound 2 was found to effectively induce apoptosis in HepG2 cells according to a flow cytometry analysis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway

PubMed Central

Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A.; Johnson, Jeffrey A.

2013-01-01

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to activate cytoprotective genes which may be useful in the treatment of neurodegenerative disease. In order to better understand the structure activity relationship of phenolic diterpenes from Salvia officinalis L., we isolated carnosic acid, carnosol, epirosmanol, rosmanol, 12-methoxy-carnosic acid, sageone, and carnosaldehyde using polyamide column, centrifugal partition chromatography, and semi-preparative high performance liquid chromatography. Isolated compounds were screened in-vitro for their ability to active the Nrf2 and general cellular toxicity using mouse primary cortical cultures. All compounds except 12-methoxy-carnosic acid were able to activate the antioxidant response element. Furthermore both carnosol and carnoasldehyde were able to induce Nrf2-dependent gene expression as well as protect mouse primary cortical neuronal cultures from H2O2 induced cell death. PMID:23507152

Band structure modification of the thermoelectric Heusler-phase TiFe2Sn via Mn substitution.

PubMed

Zou, Tianhua; Jia, Tiantian; Xie, Wenjie; Zhang, Yongsheng; Widenmeyer, Marc; Xiao, Xingxing; Weidenkaff, Anke

2017-07-19

Doping (or substitution)-induced modification of the electronic structure to increase the electronic density of states (eDOS) near the Fermi level is considered as an effective strategy to enhance the Seebeck coefficient, and may consequently boost the thermoelectric performance. Through density-functional theory calculations of Mn-substituted TiFe 2-x Mn x Sn compounds, we demonstrate that the d-states of the substituted Mn atoms induce a strong resonant level near the Fermi energy. Our experimental results are in good agreement with the calculations. They show that Mn substitution results in a large increase of the Seebeck coefficient, arising from an enhanced eDOS in Heusler compounds. The results prove that a proper substitution position and element selection can increase the eDOS, leading to a higher Seebeck coefficient and thermoelectric performance of ecofriendly materials.

Antioxidant and quinone reductase-inducing constituents of black chokeberry (Aronia melanocarpa) fruits.

PubMed

Li, Jie; Deng, Ye; Yuan, Chunhua; Pan, Li; Chai, Heebyung; Keller, William J; Kinghorn, A Douglas

2012-11-21

Using in vitro hydroxyl radical-scavenging and quinone reductase-inducing assays, bioactivity-guided fractionation of an ethyl acetate-soluble extract of the fruits of the botanical dietary supplement, black chokeberry (Aronia melanocarpa), led to the isolation of 27 compounds, including a new depside, ethyl 2-[(3,4-dihydroxybenzoyloxy)-4,6-dihydroxyphenyl] acetate (1), along with 26 known compounds (2-27). The structures of the isolated compounds were identified by analysis of their physical and spectroscopic data ([α](D), NMR, IR, UV, and MS). Altogether, 17 compounds (1-4, 9, 15-17, and 19-27) showed significant antioxidant activity in the hydroxyl radical-scavenging assay, with hyperin (24, ED(50) = 0.17 μM) being the most potent. The new compound (1, ED(50) = 0.44 μM) also exhibited potent antioxidant activity in this assay. Three constituents of black chokeberry fruits doubled quinone reductase activity at concentrations <20 μM, namely, protocatechuic acid [9, concentration required to double quinone reductase activity (CD) = 4.3 μM], neochlorogenic acid methyl ester (22, CD = 6.7 μM), and quercetin (23, CD = 3.1 μM).

Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer's disease.

PubMed

Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

2016-02-25

Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer's disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu(2+)-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

Fragmentation analysis of α-induced reactions using clusterization approach

NASA Astrophysics Data System (ADS)

Kaur, Amandeep; Sharma, Manoj K.

2018-01-01

The dynamics of α-induced reactions are worked out over an incident beam energy Eα ∼ 10- 15 MeV using targets of different masses. The decay patterns of odd mass compound systems 117Sb*, 145Pm* and 191Ir* formed in α +113In, α +141Pr and α +187Re reactions are investigated in view of n-evaporation data. The methodology of collective clusterization is applied by optimizing the neck-length parameter ΔR and the DCM calculated cross-sections find nice agreement with the experimental data. The resulting compound systems with ACN = 117- 191 cover a wide range of compound nucleus mass, and hence give an opportunity to explore various aspects related to the dynamics involved. Moreover the neutron-proton asymmetry dependence is explored in terms of the Bulk constant (α) (in the liquid drop binding energy expression) and radius term Ri and its consequent influence on the fragmentation structure of these compound systems is investigated.

New Butyrolactone Type Lignans from Arctii Fructus and Their Anti-inflammatory Activities.

PubMed

Yang, Ya-Nan; Huang, Xiao-Ying; Feng, Zi-Ming; Jiang, Jian-Shuang; Zhang, Pei-Cheng

2015-09-16

Arctiidilactone (1), a novel rare butyrolactone lignan with a 6-carboxyl-2-pyrone moiety, and 11 new butyrolactone lignans (2-12) were isolated from the fruits of Arctium lappa L., together with 5 known compounds (13-17). Their structures were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, ORD, and HRESIMS) and comparison to literature data. The absolute configurations of compounds 1-12 were determined by a combination of rotating-frame nuclear Overhauser effect spectroscopy (ROESY), circular dichroism (CD) spectroscopy, and Rh2(OCOCF3)4-induced CD spectroscopy. All of the compounds were tested for their anti-inflammatory properties in terms of suppressing the production of NO in lipopolysaccharide-induced BV2 cells. Compounds 1, 6, 8, and 10 exhibited stronger anti-inflammatory effects than the positive control curcumin, particularly 1, which exhibited 75.51, 70.72, and 61.17% inhibition at 10, 1, and 0.1 μM, respectively.

Oxidative stress protection by newly synthesized nitrogen compounds with pharmacological potential.

PubMed

Silva, João P; Areias, Filipe M; Proença, Fernanda M; Coutinho, Olga P

2006-02-09

In this study we used new nitrogen compounds obtained by organic synthesis whose structure predicted an antioxidant potential and then an eventual development as molecules of pharmacological interest in diseases involving oxidative stress. The compounds, identified as FMA4, FMA5, FMA7 and FMA8 differ in the presence of hydroxyl groups located in the C-3 and/or C-4 position of a phenolic unit, which is possibly responsible for their free radicals' buffering capacity. Data from the DPPH discoloration method confirm the high antiradical efficiency of the compounds. The results obtained with cellular models (L929 and PC12) show that they are not toxic and really protect from membrane lipid peroxidation induced by the ascorbate-iron oxidant pair. The level of protection correlates with the drug's lipophilic profile and is sometimes superior to trolox and equivalent to that observed for alpha-tocopherol. The compounds FMA4 and FMA7 present also a high protection from cell death evaluated in the presence of a staurosporine apoptotic stimulus. That protection results in a significant reduction of caspase-3 activity induced by staurosporine which by its turn seems to result from a protection observed in the membrane receptor pathway (caspase-8) together with a protection observed in the mitochondrial pathway (caspase-9). Taken together the results obtained with the new compounds, with linear chains, open up perspectives for their use as therapeutical agents, namely as antioxidants and protectors of apoptotic pathways. On the other hand the slight pro-oxidant profile obtained with the cyclic structures suggests a different therapeutic potential that is under current investigation.

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine.

PubMed

Manral, Apra; Meena, Poonam; Saini, Vikas; Siraj, Fouzia; Shalini, Shruti; Tiwari, Manisha

2016-10-01

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ1-42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

Design, synthesis, and structure-activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury.

PubMed

Xiao, Siyang; Zhang, Wenxin; Chen, Hongjin; Fang, Bo; Qiu, Yinda; Chen, Xianxin; Chen, Lingfeng; Shu, Sheng; Zhang, Yali; Zhao, Yunjie; Liu, Zhiguo; Liang, Guang

2018-01-01

The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f , was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.

Responses of polar organic compounds to different ionic environments in aqueous media are interrelated.

PubMed

Ferreira, L A; Chervenak, A; Placko, S; Kestranek, A; Madeira, P P; Zaslavsky, B Y

2014-11-14

Solubilities of 17 polar organic compounds in aqueous solutions of Na2SO4, NaCl, NaClO4, and NaSCN at the salt concentrations of up to 1.0-2.0 M were determined and the Setschenow constant, ksalt, values were estimated. It was found that NaClO4 may display both salting-in and salting-out effects depending on the particular compound structure. The Setschenow constant values for all the polar compounds examined in different salt solutions are found to be interrelated. Similar relationships were observed for partition coefficients of nonionic organic compounds in aqueous polyethylene glycol-sodium sulfate two-phase systems in the presence of different salt additives reported previously [Ferreira et al., J. Chromatogr. A, 2011, 1218, 5031], and for the effects of different salts on optical rotation of amino acids reported by Rossi et al. [J. Phys. Chem. B, 2007, 111, 10510]. In order to explain the observed relationships it is suggested that all the effects observed originate as responses of the compounds to the presence of a given ionic environment and its interaction with the compounds by forming direct or solvent-separated ionic pairs. The response is compound-specific and its strength is determined by the compound structure and the type (and concentration) of ions inducing the response.

1-methylmalate from camu-camu (Myrciaria dubia) suppressed D-galactosamine-induced liver injury in rats.

PubMed

Akachi, Toshiyuki; Shiina, Yasuyuki; Kawaguchi, Takumi; Kawagishi, Hirokazu; Morita, Tatsuya; Sugiyama, Kimio

2010-01-01

To evaluate the protective effects of fruit juices against D-galactosamine (GalN)-induced liver injury, lyophilized fruit juices (total 12 kinds) were fed to rats for 7 d, and then we evoked liver injury by injecting GalN. The juice of camu-camu (Myrciaria dubia) significantly suppressed GalN-induced liver injury when the magnitude of liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, although some other juices (acerola, dragon fruit, shekwasha, and star fruit) also tended to have suppressive effects. An active compound was isolated from camu-camu juice by solvent fractionation and silica gel column chromatography. The structure was determined to be 1-methylmalate. On the other hand, malate, 1,4-dimethylmalate, citrate, and tartrate had no significant effect on GalN-induced liver injury. It is suggested that 1-methylmalate might be a rather specific compound among organic acids and their derivatives in fruit juices in suppressing GalN-induced liver injury.

New 2-arylbenzofuran metabolite from cell cultures of Morus alba.

PubMed

Zhang, De-Wu; Tao, Xiao-Yu; Yu, Li-Yan; Dai, Jun-Gui

2015-01-01

A new 2-arylbenzofuran compound, 5-dehydroxy-moracin U (1), along with 10 known compounds (2-11), were isolated from cell cultures of Morus alba. Their structures were elucidated on the basis of extensive spectroscopic analyses. The anti-inflammatory activity assay of 1-8 showed that 2 and 8 exhibited significant inhibitory effect on LPS-induced NO production with the values of 76.4% and 98.7% at 10(- 5) M, respectively.

Vitexins, nature-derived lignan compounds, induce apoptosis and suppress tumor growth

PubMed Central

Zhou, YingJun; Liu, Yiliang Ellie; Cao, JianGuo; Zeng, GuangYao; Shen, Cui; Li, YanLan; Zhou, MeiChen; Chen, Yiding; Pu, Weiping; Potters, Louis; Shi, Eric Y.

2009-01-01

Purpose Lignans such as secoisolariciresinol diglucoside (SDG) in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators (SERM) and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo. Experimental Design We purified several Vitexin lignan compounds. Cytotoxic and antitumor effects were analyzed in cancer cells and in tumor xenograft models. In vivo metabolism of Vitexins was determined in rat. Results Contrasts to the classical lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound VB1 have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in PARP protein, up-regulation of Bax, and down-regulation of Bcl-2. This induction of apoptosis seems to be mediated by activation of caspases because inhibition of caspases activity significantly reduced induced apoptosis. We demonstrated a broad antitumor activity of EVn-50 on seven tumor xenograft models including breast, prostate, liver, and cervical cancers. Consistent with in vitro data, EVn-50 treatment induced apoptosis, down-regulated of Bcl-2, and up-regulated Bax in tumor xenografts. Conclusion Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classical lignans. Vitexin induced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases. PMID:19671865

Chrysotoxine, a novel bibenzyl compound selectively antagonizes MPP⁺, but not rotenone, neurotoxicity in dopaminergic SH-SY5Y cells.

PubMed

Song, Ju-Xian; Shaw, Pang-Chui; Wong, Ngok-Shun; Sze, Cho-Wing; Yao, Xin-Sheng; Tang, Chi-Wai; Tong, Yao; Zhang, Yan-Bo

2012-07-11

Chrysotoxine is a naturally occurring bibenzyl compound found in medicinal Dendrobium species. We previously reported that chrysotoxine structure-specifically suppressed 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death. Whether chrysotoxine and other structurally similar bibenzyl compounds could also inhibit the neurotoxicity of 1-methyl-4-phenyl pyridinium (MPP(+)) and rotenone has not been investigated. We showed herein that chrysotoxine inhibited MPP(+), but not rotenone, induced dopaminergic cell death in SH-SY5Y cells. The overproduction of reactive oxygen species (ROS), mitochondrial dysfunction as indexed by the decrease in membrane potential, increase in calcium concentration and NF-κB activation triggered by MPP(+) were blocked by chrysotoxine pretreatment. The imbalance between the pro-apoptotic signals (Bax, caspase-3, ERK and p38 MAPK) and the pro-survival signals (Akt/PI3K/GSK-3β) induced by MPP(+) was partially or totally rectified by chrysotoxine. The results indicated that ROS inhibition, mitochondria protection, NF-κB modulation and regulation of multiple signals determining cell survival and cell death were involved in the protective effects of chrysotoxine against MPP(+) toxicity in SH-SY5Y cells. Given the different toxic profiles of 6-OHDA and MPP(+) as compared to rotenone, our results also indicated that DAT inhibition may partially account for the neuroprotective effects of chrysotoxine. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.

PubMed

Gharibi Loron, Ali; Sardari, Soroush; Narenjkar, Jamshid; Sayyah, Mohammad

2017-01-01

Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures

PubMed Central

Loron, Ali Gharibi; Sardari, Soroush; Narenjkar, Jamshid; Sayyah, Mohammad

2017-01-01

Background: Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Methods: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Results: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Conclusion: Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA. PMID:27592363

[Effects of Aptamer-siRNA Nucleic Acid Compound on Growth and Apoptosis in Myeloid Leukemia Cell Line K562].

PubMed

Ping, Juan; Shen, Zhi-Hui; Wang, Bao-Quan; Zhao, Na; Li, Rui; Li, Mian; Pang, Xiao-Bin; Chen, Chuan-Bo

2015-04-01

To explore the effects of aptamer-siRNA nucleic acid compound on growth and apoptosis in myeloid leukemia cell line K562. the changes of cellular morphology and structure were observed by using fluorescence microscope, laser confocal microscope, JEM-4000EX transmission electron microscopy; MTT assay were performed to evaluate the sensibility of K562 cells to aptamer-siRNA compound, the apoptosis was detected by DNA gel electro-phoresis. The remarkably changes of morphology and structure of K562 cells treated with 200 µmol/L aptamer-siRNA were observed under fluorescence microscopy and electromicroscopy. As compared with control, the aptamer-siRNA compound showed more inhibitory effect on K562 cells and there was significant difference (P<0.05). The MTT assay showed that the IC50 value of aptamer-siRNA compound for K562 cells was 150 µmol/L. According to agarose gel electrophoresis observation, when the aptamer-siRNA compound showed effect on K562 cells, the typical DNA lader could be observed. The aptamer-siRNA compound can significantly induce K562 cell apoptosis, and provide reference for gene therapy of patients with chronic myelocytic lenkemia.

Theoretical analysis of the structural phase transformation in the ZnO under high pressure

NASA Astrophysics Data System (ADS)

Verma, Saligram; Jain, Arvind; Nagarch, R. K.; Shah, S.; Kaurav, Netram

2018-05-01

We report a phenomenological model based calculation of pressure-induced structural phase transition and elastic properties of ZnO compound. Gibb's free energy is obtained as a function of pressure by applying an effective inter ionic interaction potential, which includes the long range Coulomb, van der Waals (vdW) interaction and the short-range repulsive interaction upto second-neighbor ions within the Hafemeister and Flygare approach. From the present study, we predict a structural phase transition from ZnS structure (B3) to NaCl structure (B1) at 8.5 GPa. The estimated value of the phase transition pressure (Pt) and the magnitude of the discontinuity in volume at the transition pressure are consistent as compared to the reported data. The variations of elastic constants with pressure follow a systematic trend identical to that observed in others compounds of ZnS type structure family.

Defence syndromes in lodgepole - whitebark pine ecosystems relate to degree of historical exposure to mountain pine beetles.

PubMed

Raffa, Kenneth F; Mason, Charles J; Bonello, Pierluigi; Cook, Stephen; Erbilgin, Nadir; Keefover-Ring, Ken; Klutsch, Jennifer G; Villari, Caterina; Townsend, Philip A

2017-09-01

Warming climate is allowing tree-killing bark beetles to expand their ranges and access naïve and semi-naïve conifers. Conifers respond to attack using complex mixtures of chemical defences that can impede beetle success, but beetles exploit some compounds for host location and communication. Outcomes of changing relationships will depend on concentrations and compositions of multiple host compounds, which are largely unknown. We analysed constitutive and induced chemistries of Dendroctonus ponderosae's primary historical host, Pinus contorta, and Pinus albicaulis, a high-elevation species whose encounters with this beetle are transitioning from intermittent to continuous. We quantified multiple classes of terpenes, phenolics, carbohydrates and minerals. Pinus contorta had higher constitutive allocation to, and generally stronger inducibility of, compounds that resist these beetle-fungal complexes. Pinus albicaulis contained higher proportions of specific monoterpenes that enhance pheromone communication, and lower induction of pheromone inhibitors. Induced P. contorta increased insecticidal and fungicidal compounds simultaneously, whereas P. albicaulis responses against these agents were inverse. Induced terpene accumulation was accompanied by decreased non-structural carbohydrates, primarily sugars, in P. contorta, but not P. albicaulis, which contained primarily starches. These results show some host species with continuous exposure to bark beetles have more thoroughly integrated defence syndromes than less-continuously exposed host species. © 2017 John Wiley & Sons Ltd.

Structural diversities induced by cation sizes in a series of fluorogermanophosphates: A2[GeF2(HPO4)2] (A = Na, K, Rb, NH4, and Cs).

PubMed

Chen, Zhang-Gai; Huang, Xia; Zhuang, Rong-Chuan; Zhang, Yu; Liu, Xin; Shi, Tao; Wang, Shuai-Hua; Wu, Shao-Fan; Mi, Jin-Xiao; Huang, Ya-Xi

2017-09-12

Germanophosphates, in comparison with other metal phosphates, have been less studied but potentially exhibit more diverse structural chemistry with wide applications. Herein we applied a hydro-/solvo-fluorothermal route to make use of both the "tailor effect" of fluoride for the formation of low dimensional anionic clusters and the presence of alkali cations of different sizes to align the anionic clusters to control the overall crystal symmetries of germanophosphates. The synergetic effects of fluoride and alkali cations led to structural changes from chain-like structures to layered structures in a series of five novel fluorogermanophosphates: A 2 [GeF 2 (HPO 4 ) 2 ] (A = Na, K, Rb, NH 4 , and Cs, denoted as Na, K, Rb, NH4, and Cs). Although these fluorogermanophosphates have stoichiometrically equivalent formulas, they feature different anionic clusters, diverse structural dimensionalities, and contrasting crystal symmetries. Chain-like structures were observed for the compounds with the smaller sized alkali ions (Na + , K + , and Rb + ), whereas layered structures were found for those containing the larger sized cations ((NH 4 ) + and Cs + ). Specifically, monoclinic space groups were observed for the Na, K, Rb, and NH4 compounds, whereas a tetragonal space group P4/mbm was found for the Cs compound. These compounds provide new insights into the effects of cation sizes on the anionic clusters built from GeO 4 F 2 octahedra and HPO 4 tetrahedra as well as their influences on the overall structural symmetries in germanophosphates. Further characterization including IR spectroscopy and thermal analyses for all five compounds is also presented.

Electrophysiological investigation of the effect of structurally different bispyridinium non-oxime compounds on human α7-nicotinic acetylcholine receptor activity-An in vitro structure-activity analysis.

PubMed

Scheffel, Corinna; Niessen, Karin V; Rappenglück, Sebastian; Wanner, Klaus T; Thiermann, Horst; Worek, Franz; Seeger, Thomas

2018-09-01

Organophosphorus compounds, including nerve agents and pesticides, exert their toxicity through irreversible inhibition of acetylcholinesterase (AChE) resulting in an accumulation of acetylcholine and functional impairment of muscarinic and nicotinic acetylcholine receptors. Current therapy comprises oximes to reactivate AChE and atropine to antagonize effects induced by muscarinic acetylcholine receptors. Nicotinic malfunction leading to depression of the central and peripheral respiratory system is not directly treated calling for alternative therapeutic interventions. In the present study, we investigated the electrophysiological properties of the human nAChR subtype α7 (hα7-nAChR) and the functional effect of the 4-tert-butyl bispyridinium (BP) compound MB327 and of a series of novel substituted bispyridinium compounds on the receptors by an automated patch clamp technique. Activation of hα7-nAChRs was induced by nicotine and acetylcholine demonstrating rapid cationic influx up to 100μM. Agonist-induced currents decayed within a few milliseconds revealing fast desensitization of the receptors. Application of higher agonist concentrations led to a decline of current amplitudes which seemed to be due to increasing receptor desensitization. When 100μM of agonist was coapplied with low concentrations of the well characterized α7-specific positive allosteric modulator PNU-120596 (1μM-10μM), the maximum response and duration of nAChR activation were markedly augmented indicating an elongated mean open-time of receptors and prevention of receptor desensitization. However, co-application of increasing PNU-120596 concentrations (>10μM) with agonist induced a decline of potentiated current responses. Although less pronounced than PNU-120596, six of the twenty tested substituted BP compounds, in particular those with a substituent at 3-position and 4-position at the pyridinium moieties, were found to potentiate current responses of hα7-nAChRs, most pronounced MB327.This effect was clearly depended on the presence of the agonist indicating a positive allosteric mechanism of these compounds. Besides potentiation at low concentrations, these compounds seem to interact at different binding sites on hα7-nAChRs since enhancement decreased at high concentrations. The residual fourteen BP compounds, possessing either an isopropyl-group or more than one group at the pyridinium moiety, antagonized nicotinic currents exhibiting IC 50 of low up to high micromolar concentrations (∼1μM-300μM). Copyright © 2017 Elsevier B.V. All rights reserved.

Structural Transformation Detection Contributes to Screening of Behaviorally Active Compounds: Dynamic Binding Process Analysis of DhelOBP21 from Dastarcus helophoroides.

PubMed

Yang, Rui-Nan; Li, Dong-Zhen; Yu, Guangqiang; Yi, Shan-Cheng; Zhang, Yinan; Kong, De-Xin; Wang, Man-Qun

2017-12-01

In light of reverse chemical ecology, the fluorescence competitive binding assays of functional odorant binding proteins (OBPs) is a recent advanced approach for screening behaviorally active compounds of insects. Previous research on Dastareus helophoroides identified a minus-C OBP, DhelOBP21, which preferably binds to several ligands. In this study, only (+)-β-pinene proved attractive to unmated adult beetles. To obtain a more in-depth explanation of the lack of behavioral activity of other ligands we selected compounds with high (camphor) and low (β-caryophyllene) binding affinities. The structural transformation of OBPs was investigated using well-established approaches for studying binding processes, such as fluorescent quenching assays, circular dichroism, and molecular dynamics. The dynamic binding process revealed that the flexibility of DhelOBP21 seems conducive to binding specific ligands, as opposed to broad substrate binding. The compound (+)-β-pinene and DhelOBP21 formed a stable complex through a secondary structural transformation of DhelOBP21, in which its amino-terminus transformed from random coil to an α-helix to cover the binding pocket. On the other hand, camphor could not efficiently induce a stable structural transformation, and its high binding affinities were due to strong hydrogen-bonding, compromising the structure of the protein. The other compound, β-caryophyllene, only collided with DhelOBP21 and could not be positioned in the binding pocket. Studying structural transformation of these proteins through examining the dynamic binding process rather than using approaches that just measure binding affinities such as fluorescence competitive binding assays can provide a more efficient and reliable approach for screening behaviorally active compounds.

Organophosphate ester flame retardant-induced acute intoxications in dogs.

PubMed

Lehner, Andreas F; Samsing, Francisca; Rumbeiha, Wilson K

2010-12-01

Flame retardants have wide industrial applications and are incorporated into articles found in automobiles and home environments, including seat cushions. These compounds differ widely chemically and in their toxic potential. We report here two cases involving dogs following ingestion of car seat cushions impregnated with organophosphate ester fire retardants. Two case reports are presented. Two adult American Pit Bull dogs were presented at an emergency clinic with acute signs of central nervous system excitation including seizures. The most severely affected dog died 15 min after presentation, while the less affected dog fully recovered following treatment. In the second case, both a German Shepherd and a Rottweiler were found dead in the morning after they were left in a car overnight. A comprehensive toxicological analysis of samples from both cases revealed the presence of significant amounts (>2 ppm) of tris(2-chloroethyl)phosphate (TCEP) in stomach contents. This compound is a known inducer of epileptic seizures. Some other structurally related organophosphate ester compounds were found, and their role in the acute intoxications reported here is not known and remains to be determined. This is the first report linking acute deaths in dogs to the ingestion of car seat cushions found to contain large amounts of TCEP, an organophosphate ester compound. It is highly likely that this compound caused death through its known seizure-inducing activity.

Epigenetic modifiers alter the secondary metabolite composition of a plant endophytic fungus, Pestalotiopsis crassiuscula obtained from the leaves of Fragaria chiloensis.

PubMed

Yang, Xiao-Long; Huang, Le; Ruan, Xiao-Li

2014-01-01

The addition of the DNA methyltransferase inhibitor 500 μM 5-azacytidine to the culture medium of a plant endophytic fungus, Pestalotiopsis crassiuscula, obtained from the leaves of Fragaria chiloensis, dramatically altered the profiles of its metabolites and resulted in the isolation of one new coumarin (1), along with six known compounds (2-7). HPLC profiles revealed that only compounds 3, 4, and 7 belonged to the new induced secondary metabolites. The structures of all isolated compounds were elucidated on the basis of extensive analysis of NMR spectra.

(-)-Xanthienopyran, a new inhibitor of superoxide anion generation by activated neutrophils, and further constituents of the seeds of Xanthium strumarium.

PubMed

Lee, Chia-Lin; Huang, Po-Ching; Hsieh, Pei-Wen; Hwang, Tsong-Long; Hou, Yu-Yi; Chang, Fang-Rong; Wu, Yang-Chang

2008-08-01

The dried seeds of XANTHIUM STRUMARIUM (Asteraceae) are used after thorough stir-frying as an ingredient in traditional Chinese medicines for relieving allergy. Two new compounds, xanthialdehyde ( 2) and (-)-xanthienopyran ( 7), as well as 26 known compounds were isolated in the present study. The structures of the isolates were elucidated by spectroscopic methods. Among them, compound 7 exhibited significant selective inhibition of superoxide anion generation by human neutrophils induced by formyl- L-methionyl- L-leucyl- L-phenylalanine, with an IC50 value of 1.72 microg/mL.

New sesquiterpene lactones from Ambrosia cumanensis Kunth.

PubMed

Jimenez-Usuga, Nora Del Socorro; Malafronte, Nicola; Cotugno, Roberta; De Leo, Marinella; Osorio, Edison; De Tommasi, Nunziatina

2016-09-01

Eleven sesquiterpene lactones, including three new natural products (1-3), were isolated from the n-butanolic extract of Ambrosia cumanensis Kunth. aerial parts. The structure of all isolated compounds was elucidated by 1D- and 2D-NMR, and MS analyses. All compounds were tested for their antiproliferative activity on HeLa, Jurkat, and U937 cell lines. Compound 3, 2,3-dehydropsilostachyn C, showed cytotoxic activity with different potency in all cell lines. By means of flow cytometric studies, compound 3 was demonstrated to induce in Jurkat cells a G2/M cell cycle block, while in U937 elicited both cytostatic and cytotoxic responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Pressure-Induced Structural Evolution and Band Gap Shifts of Organometal Halide Perovskite-Based Methylammonium Lead Chloride.

PubMed

Wang, Lingrui; Wang, Kai; Xiao, Guanjun; Zeng, Qiaoshi; Zou, Bo

2016-12-15

Organometal halide perovskites are promising materials for optoelectronic devices. Further development of these devices requires a deep understanding of their fundamental structure-property relationships. The effect of pressure on the structural evolution and band gap shifts of methylammonium lead chloride (MAPbCl 3 ) was investigated systematically. Synchrotron X-ray diffraction and Raman experiments provided structural information on the shrinkage, tilting distortion, and amorphization of the primitive cubic unit cell. In situ high pressure optical absorption and photoluminescence spectra manifested that the band gap of MAPbCl 3 could be fine-tuned to the ultraviolet region by pressure. The optical changes are correlated with pressure-induced structural evolution of MAPbCl 3 , as evidenced by band gap shifts. Comparisons between Pb-hybrid perovskites and inorganic octahedra provided insights on the effects of halogens on pressure-induced transition sequences of these compounds. Our results improve the understanding of the structural and optical properties of organometal halide perovskites.

Stress-induced nematicity in EuFe 2 As 2 studied by Raman spectroscopy

DOE PAGES

Zhang, W. -L.; Sefat, Athena S.; Ding, H.; ...

2016-07-18

Here, we use polarized Raman scattering to study the structural phase transition in EuFe 2 As 2 , the parent compound of the 122-ferropnictide superconductors. The in-plane lattice anisotropy is characterized by measurements of the side surface with different strains induced by different preparation methods. We also show that while a fine surface polishing leaves the samples free of residual internal strain, in which case the onset of the C 4 symmetry breaking is observed at the nominal structural phase transition temperature T S , cutting the side surface induces a permanent fourfold rotational symmetry breaking spanning tens ofmore » degrees above T S .« less

Identification of small molecule compounds that inhibit the HIF-1 signaling pathway

PubMed Central

2009-01-01

Background Hypoxia-inducible factor-1 (HIF-1) is the major hypoxia-regulated transcription factor that regulates cellular responses to low oxygen environments. HIF-1 is composed of two subunits: hypoxia-inducible HIF-1α and constitutively-expressed HIF-1β. During hypoxic conditions, HIF-1α heterodimerizes with HIF-1β and translocates to the nucleus where the HIF-1 complex binds to the hypoxia-response element (HRE) and activates expression of target genes implicated in cell growth and survival. HIF-1α protein expression is elevated in many solid tumors, including those of the cervix and brain, where cells that are the greatest distance from blood vessels, and therefore the most hypoxic, express the highest levels of HIF-1α. Therapeutic blockade of the HIF-1 signaling pathway in cancer cells therefore provides an attractive strategy for development of anticancer drugs. To identify small molecule inhibitors of the HIF-1 pathway, we have developed a cell-based reporter gene assay and screened a large compound library by using a quantitative high-throughput screening (qHTS) approach. Results The assay is based upon a β-lactamase reporter under the control of a HRE. We have screened approximate 73,000 compounds by qHTS, with each compound tested over a range of seven to fifteen concentrations. After qHTS we have rapidly identified three novel structural series of HIF-1 pathway Inhibitors. Selected compounds in these series were also confirmed as inhibitors in a HRE β-lactamase reporter gene assay induced by low oxygen and in a VEGF secretion assay. Three of the four selected compounds tested showed significant inhibition of hypoxia-induced HIF-1α accumulation by western blot analysis. Conclusion The use of β-lactamase reporter gene assays, in combination with qHTS, enabled the rapid identification and prioritization of inhibitors specific to the hypoxia induced signaling pathway. PMID:20003191

Magnetic field-induced changes of lattice parameters and thermal expansion behavior of the CoMnSi compound

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

Kou, R. H.; Gao, J.; Wang, G.

2016-02-01

The crystal structure of the CoMnSi compound during zero-field cooling and field cooling from room temperature down to 200 K was studied using the synchrotron radiation X-ray diffraction technique. The results show that the lattice parameters and thermal expansion behavior of the sample are changed by the applied magnetic fields. The lattice contracts along the a axis, but expands along the b and c axes. Due to enlarged and anisotropic changes under a magnetic field of 6 T, the lattice shows an invar-like behavior along all three axes. Critical interatomic distances and bond angles also show large changes under themore » influence of such a high magnetic field. These magnetic field-induced changes of the lattice are discussed with respect to their contributions to the large magnetocaloric effect of the CoMnSi compound.« less

Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation.

PubMed

Li, Yan-Ping; Ning, Fang-Xian; Yang, Meng-Bi; Li, Yong-Cheng; Nie, Min-Hua; Ou, Tian-Miao; Tan, Jia-Heng; Huang, Shi-Liang; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

2011-05-01

A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Target identification by image analysis.

PubMed

Fetz, V; Prochnow, H; Brönstrup, M; Sasse, F

2016-05-04

Covering: 1997 to the end of 2015Each biologically active compound induces phenotypic changes in target cells that are characteristic for its mode of action. These phenotypic alterations can be directly observed under the microscope or made visible by labelling structural elements or selected proteins of the cells with dyes. A comparison of the cellular phenotype induced by a compound of interest with the phenotypes of reference compounds with known cellular targets allows predicting its mode of action. While this approach has been successfully applied to the characterization of natural products based on a visual inspection of images, recent studies used automated microscopy and analysis software to increase speed and to reduce subjective interpretation. In this review, we give a general outline of the workflow for manual and automated image analysis, and we highlight natural products whose bacterial and eucaryotic targets could be identified through such approaches.

Hepatoprotective activity of twelve novel 7'-hydroxy lignan glucosides from Arctii Fructus.

PubMed

Yang, Ya-Nan; Huang, Xiao-Ying; Feng, Zi-Ming; Jiang, Jian-Shuang; Zhang, Pei-Cheng

2014-09-17

Twelve novel 7'-hydroxy lignan glucosides (1-12), including two benzofuran-type neolignans, two 8-O-4' neolignans, two dibenzylbutyrolactone lignans, and six tetrahydrofuranoid lignans, together with six known lignan glucosides (13-18), were isolated from the fruit of Arctium lappa L. (Asteraceae), commonly known as Arctii Fructus. Their structures were elucidated using spectroscopy (1D and 2D NMR, MS, IR, ORD, and UV) and on the basis of chemical evidence. The absolute configurations of compounds 1-12 were confirmed using rotating frame nuclear overhauser effect spectroscopy (ROESY), the circular dichroic (CD) exciton chirality method, and Rh2(OCOCF3)4-induced CD spectrum analysis. All of the isolated compounds were tested for hepatoprotective effects against D-galactosamine-induced cytotoxicity in HL-7702 hepatic cells. Compounds 1, 2, 7-12, and 17 showed significantly stronger hepatoprotective activity than the positive control bicyclol at a concentration of 1 × 10(-5) M.

Cyanobacteria as a Source for Novel Anti-Leukemic Compounds.

PubMed

Humisto, Anu; Herfindal, Lars; Jokela, Jouni; Karkman, Antti; Bjørnstad, Ronja; Choudhury, Romi R; Sivonen, Kaarina

2016-01-01

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

New antimuscarinic agents for improved treatment of poisoning by cholinesterase inhibitors. Annual progress report No. 1, 1 November 1982-31 October 1983

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

Stubbins, J.F.

The object of this project is to find a more effective antimuscarinic agent than atropine for use as an antidote for poisoning by organophosphate cholinesterase inhibitors. To start this search, 22 structurally-diverse antimuscarinic agents have been selected for initial testing. These compounds are to be evaluated for peripheral and central antimuscarinic activity in a variety of in vitro and in vivo tests in addition to determining their effectiveness as antidotes (in combination with an oxime reactivator) for poisoning by soman. Fifteen of the compounds have now been evaluated for ability to block acetylcholine-induced contractions in guinea pig intestinal smooth musclemore » compared to atropine. Ability to displace radiolabeled quinuclidinyl benzilate from muscarinic receptors of mouse brain homogenate has been determined for atropine, scopolamine and 19 of the compounds. Several of these compounds have a relatively stronger affinity for brain than for intestinal muscarinic receptors. Atropine, scopolamine and 12 of the compounds have also been examined as inhibitors of tremors induced by oxotremorine in mice. Two of the compounds are much more potent than atropine. None of the compounds have been tested as yet as antidotes for soman poisoning. Samples of the test compounds are being sent to the Medical Research Institute of Chemical Defense for evaluation of this property.« less

A Receptor on Acid.

PubMed

Chen, Qiuyan; Tesmer, John J G

2017-01-26

Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT 2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds. Copyright © 2017 Elsevier Inc. All rights reserved.

Web server to identify similarity of amino acid motifs to compounds (SAAMCO).

PubMed

Casey, Fergal P; Davey, Norman E; Baran, Ivan; Varekova, Radka Svobodova; Shields, Denis C

2008-07-01

Protein-protein interactions are fundamental in mediating biological processes including metabolism, cell growth, and signaling. To be able to selectively inhibit or induce protein activity or complex formation is a key feature in controlling disease. For those situations in which protein-protein interactions derive substantial affinity from short linear peptide sequences, or motifs, we can develop search algorithms for peptidomimetic compounds that resemble the short peptide's structure but are not compromised by poor pharmacological properties. SAAMCO is a Web service ( http://bioware.ucd.ie/ approximately saamco) that facilitates the screening of motifs with known structures against bioactive compound databases. It is built on an algorithm that defines compound similarity based on the presence of appropriate amino acid side chain fragments and a favorable Root Mean Squared Deviation (RMSD) between compound and motif structure. The methodology is efficient as the available compound databases are preprocessed and fast regular expression searches filter potential matches before time-intensive 3D superposition is performed. The required input information is minimal, and the compound databases have been selected to maximize the availability of information on biological activity. "Hits" are accompanied with a visualization window and links to source database entries. Motif matching can be defined on partial or full similarity which will increase or reduce respectively the number of potential mimetic compounds. The Web server provides the functionality for rapid screening of known or putative interaction motifs against prepared compound libraries using a novel search algorithm. The tabulated results can be analyzed by linking to appropriate databases and by visualization.

The activation of fibroblast growth factors by heparin: synthesis, structure, and biological activity of heparin-like oligosaccharides.

PubMed

de Paz, J L; Angulo, J; Lassaletta, J M; Nieto, P M; Redondo-Horcajo, M; Lozano, R M; Giménez-Gallego, G; Martín-Lomas, M

2001-09-03

An effective strategy has been designed for the synthesis of oligosaccharides of different sizes structurally related to the regular region of heparin; this is illustrated by the preparation of hexasaccharide 1 and octasaccharide 2. This synthetic strategy provides the oligosaccharide sequence containing a D-glucosamine unit at the nonreducing end that is not available either by enzymatic or chemical degradation of heparin. It may permit, after slight modifications, the preparation of oligosaccharide fragments with different charge distribution as well. NMR spectroscopy and molecular dynamics simulations have shown that the overall structure of 1 in solution is a stable right-hand helix with four residues per turn. Hexasaccharide 1 and, most likely, octasaccharide 2 are, therefore, chemically well-defined structural models of naturally occurring heparin-like oligosaccharides for use in binding and biological activity studies. Both compounds 1 and 2 induce the mitogenic activity of acid fibroblast growth factor (FGF1), with the half-maximum activating concentration of 2 being equivalent to that of heparin. Sedimentation equilibrium analysis with compound 2 suggests that heparin-induced FGF1 dimerization is not an absolute requirement for biological activity.

Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

PubMed Central

Orfi, Z.; Waczek, F.; Baska, F.; Szabadkai, I.; Torka, R.; Hartmann, J.; Orfi, L.; Ullrich, A.

2017-01-01

According to clinical data, some tyrosine kinase inhibitors (TKIs) possess antidiabetic effects. Several proposed mechanisms were assigned to them, however their mode of action is not clear. Our hypothesis was that they directly stimulate insulin release in beta cells. In our screening approach we demonstrated that some commercially available TKIs and many novel synthesized analogues were able to induce insulin secretion in RIN-5AH beta cells. Our aim was to find efficient, more selective and less toxic compounds. Out of several hits, we chose members from a compound family with quinoline core structure for further investigation. Here we present the studies done with these novel compounds and reveal structure activity relationships and mechanism of action. One of the most potent compounds (compound 9) lost its affinity to kinases, but efficiently increased calcium influx. In the presence of calcium channel inhibitors, the insulinotropic effect was attenuated or completely abrogated. While the quinoline TKI, bosutinib substantially inhibited tyrosine phosphorylation, compound 9 had no such effect. Molecular docking studies further supported our data. We confirmed that some TKIs possess antidiabetic effects, moreover, we present a novel compound family developed from the TKI, bosutinib and optimized for the modulation of insulin secretion. PMID:28272433

Structure and stability of solid Xe(H 2) n

DOE PAGES

Somayazulu, Maddury; Dera, Przemyslaw; Smith, Jesse; ...

2015-03-10

Mixtures of xenon and molecular hydrogen form a series of hexagonal, van der Waals compounds at high pressures and at 300 K. Synchrotron, x-ray, single crystal diffraction studies reveal that below 7.5 GPa, Xe(H 2) 8 crystallizes in a P3¯m1 structure that displays pressure-induced occupancy changes of two pairs of xenon atoms located on the 2c and 2d sites (while the third pair on yet another 2c site remains fully occupied). The occupancy becomes 1 at the P3¯m1 to R3 transition and all the xenon atoms occupy the 3d sites in the high-pressure structure. These pressure-induced changes in occupancy coincidemore » with volume changes that maintain the average Xe:H 2 stoichiometry fixed at 1:8. Furthermore, the synchrotron x-ray diffraction and Raman measurements show that this unique hydrogen-bearing compound that can be synthesized at 4.2 GPa and 300 K, quenched at low temperatures to atmospheric pressure, and retained up to 90 K on subsequent warming.« less

Anion-induced structural transformation of a sulfate-incorporated 2D Cd(II)–organic framework

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

Lee, Li-Wei; Institute of Materials Science and Engineering, National Central University, Taoyuan 320, Taiwan; Luo, Tzuoo-Tsair

2016-07-15

A Cd(II)–organic framework {[Cd_2(tpim)_4(SO_4)(H_2O)_2]·(SO_4)·21H_2O}{sub n} (1) was synthesized by reacting CdSO{sub 4}·8/3H{sub 2}O and 2,4,5-tri(4-pyridyl)imidazole (tpim) under hydrothermal conditions. A structural analysis showed that compound 1 adopts a layered structure in which the [Cd(tpim){sub 2}]{sub n} chains are linked by sulfate anions. These 2D layers are further packed into a 3D supramolecular framework via π–π interactions. The structure contains two types of SO{sub 4}{sup 2−} anions, i.e., bridging SO{sub 4}{sup 2−} and free SO{sub 4}{sup 2−} anions, the latter of which are included in the large channels of the framework. Compound 1 exhibits interesting anion exchange behavior. In the presencemore » of SCN{sup −} anions, both the bridging and free SO{sub 4}{sup 2−} anions in 1 were completely exchanged by SCN{sup −} ligands to form a 1D species [Cd(tpim){sub 2}(SCN){sub 2}] (1A), in which the SCN{sup –} moieties function as a monodentate ligand. On the other hand, when compound 1 was ion exchanged with N{sub 3}{sup −} anions in aqueous solution, the bridging SO{sub 4}{sup 2−} moieties remained intact, and only the free guest SO{sub 4}{sup 2−} were replaced by N{sub 3}{sup −} anions. The gas adsorption behavior of the activated compound 1 was also investigated. - Highlights: • An interesting anion-induced structural transformation of a sulfate-incorporated 2D Cd(II)–organic framework is reported. • The sulfate-incorporated 2D layer compound exhibits very different anion exchange behavior with respect to SCN{sup −} and N{sub 3}{sup −}. • Both the bridging and free SO{sub 4}{sup 2−} anions in the 2D structure were completely exchanged by SCN{sup −} ligands, resulting in the formation of a 1D species. However, in the case of N{sub 3}{sup −} anions, only the free guest SO{sub 4}{sup 2−} in the structure was replaced.« less

Mechanistic Insights into the Specificity of Human Cytosolic Sulfotransferase 2A1 (hSULT2A1) for Hydroxylated Polychlorinated Biphenyls Through the Use of Fluoro-tagged Probes

PubMed Central

Ekuase, E.J.; van ’t Erve, T.J.; Rahaman, A.; Robertson, L.W.; Duffel, M.W.; Luthe, G.

2015-01-01

Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity. PMID:26165989

New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship

PubMed Central

Okoro, Uchechukwu Chris; Ahmad, Hilal

2017-01-01

Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib. PMID:28922386

Induction of trap formation in nematode-trapping fungi by bacteria-released ammonia.

PubMed

Su, H N; Xu, Y Y; Wang, X; Zhang, K Q; Li, G H

2016-04-01

A total of 11 bacterial strains were assayed for bacteria-induced trap formation in the nematode-trapping fungus Arthrobotrys oligospora YMF1·01883 with two-compartmented Petri dish. These strains were identified on the basis of their 16S rRNA gene sequences. Volatile organic compounds (VOCs) of eight isolates were extracted using solid-phase micro-extraction (SPME) and their structures were identified based on gas chromatography-mass spectrometry (GC-MS). At the same time, all isolates were used for quantitative measurement of ammonia by the indophenol blue method. The effects of pure commercial compounds on inducement of trap formation in A. oligospora were tested. Taken together, results demonstrated that the predominant bacterial volatile compound inducing trap formation was ammonia. Meanwhile, ammonia also played a role in other nematode-trapping fungi, including Arthrobotrys guizhouensis YMF1·00014, producing adhesive nets; Dactylellina phymatopaga YMF1·01474, producing adhesive knobs; Dactylellina cionopaga YMF1·01472, producing adhesive columns and Drechslerella brochopaga YMF1·01829, producing constricting rings. © 2016 The Society for Applied Microbiology.

Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway.

PubMed

Zhang, Cheng-Chen; Cao, Chen-Yu; Kubo, Miwa; Harada, Kenichi; Yan, Xi-Tao; Fukuyama, Yoshiyasu; Gao, Jin-Ming

2017-07-30

Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound ( 6 ) and one new natural product ( 2 ) together with five known compounds ( 1 , 3 - 5 , 7 ) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester ( 1 ) and a cyathane diterpenoid, erincine A ( 3 ), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3 -promoted NGF-induced neurite outgrowth in PC12 cells.

Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway

PubMed Central

Cao, Chen-Yu; Kubo, Miwa; Harada, Kenichi; Yan, Xi-Tao; Fukuyama, Yoshiyasu; Gao, Jin-Ming

2017-01-01

Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound (6) and one new natural product (2) together with five known compounds (1,3–5,7) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester (1) and a cyathane diterpenoid, erincine A (3), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3-promoted NGF-induced neurite outgrowth in PC12 cells. PMID:28758954

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis

PubMed Central

Bleich, Rachel; Watrous, Jeramie D.; Dorrestein, Pieter C.; Bowers, Albert A.; Shank, Elizabeth A.

2015-01-01

Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called “secondary” metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin’s antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects—acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes. PMID:25713360

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

Njema, H.; Debbichi, M., E-mail: mourad_fsm@yahoo.fr; Boughzala, K.

Highlights: • The structural and electronic properties of apatites with the general formula Ca{sub 10−x}La{sub x}(PO{sub 4}){sub 6−x}(SiO{sub 4}){sub x}F{sub 2} (0 ≤ x ≤ 6) have been investigated by means of the density functional theory. • The calculated enthalpy of formation of the compounds increased with the substitution degree. • The decrease in stability is probably due to the disorder induced in the Ca/LaO{sub 6}F polyhedron, following the substitution. - Abstract: The apatite-type compounds Ca{sub 10−x}La{sub x}(PO{sub 4}){sub 6−x}(SiO{sub 4}){sub x}F{sub 2} with 0 ≤ x ≤ 6 were prepared using a high temperature solid state reaction and weremore » characterized by X-ray diffraction. The crystal structure, chemical bonding, electronic structure and formation energy of all relaxed structures were analyzed by density functional theory (DFT). The calculated results show that the predicted geometry can well reproduce the structural parameters. The incorporation of La{sup 3+} into the fluorapatite (FA) structure induced especially at the level of the S(2) sites a certain disorder which is responsible for the weakening in the stability with x. Excellent agreement were obtained between the calculated and experimental results. Moreover, the band structure indicates that despite the reduction of the band gap with x content all materials remain insulating.« less

Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships.

PubMed

Prashantha Kumar, B R; Baig, Nasir R; Sudhir, Sai; Kar, Koyal; Kiranmai, M; Pankaj, M; Joghee, Nanjan M

2012-12-01

We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats. The liver samples of rats that received the most active compounds, 23 and 24, in the in vivo studies, were subjected to histopathological examination to assess their short term hepatotoxicity. The investigations on the in vitro glucose uptake, in vivo triglyceride and glucose lowering activity are described here along with the quantitative structure-activity relationships. Copyright © 2012 Elsevier Inc. All rights reserved.

Sesquiterpenes from the essential oil of Curcuma wenyujin and their inhibitory effects on nitric oxide production.

PubMed

Xia, Guiyang; Zhou, Li; Ma, Jianghao; Wang, Ying; Ding, Liqin; Zhao, Feng; Chen, Lixia; Qiu, Feng

2015-06-01

Three new sesquiterpenes including a new elemane-type sesquiterpene, 5βH-elem-1,3,7,8-tetraen-8,12-olide (1), and two new carabrane-type sesquiterpenes, 7α,11-epoxy-6α-methoxy-carabrane-4,8-dione (2) and 8,11-epidioxy-8-hydroxy-4-oxo-6-carabren (3), together with eight known sesquiterpenes (4-11) were isolated from Curcuma wenyujin Y. H. Chen et C. Ling. Their structures were elucidated based on extensive spectroscopic analyses. A possible biogenetic scheme for the related compounds was postulated. All of the isolated compounds were tested for inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages. Meanwhile, preliminary structure-activity relationships for these compounds are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Pressure-decoupled magnetic and structural transitions of the parent compound of iron-based 122 superconductors BaFe2As2

PubMed Central

Wu, J. J.; Lin, Jung-Fu; Wang, X. C.; Liu, Q. Q.; Zhu, J. L.; Xiao, Y. M.; Chow, P.; Jin, Changqing

2013-01-01

The recent discovery of iron ferropnictide superconductors has received intensive concern in connection with magnetically involved superconductors. Prominent features of ferropnictide superconductors are becoming apparent: the parent compounds exhibit an antiferromagnetic ordered spin density wave (SDW) state, the magnetic-phase transition is always accompanied by a crystal structural transition, and superconductivity can be induced by suppressing the SDW phase via either chemical doping or applied external pressure to the parent state. These features generated considerable interest in the interplay between magnetism and structure in chemically doped samples, showing crystal structure transitions always precede or coincide with magnetic transition. Pressure-tuned transition, on the other hand, would be more straightforward to superconducting mechanism studies because there are no disorder effects caused by chemical doping; however, remarkably little is known about the interplay in the parent compounds under controlled pressure due to the experimental challenge of in situ measuring both of magnetic and crystal structure evolution at high pressure and low temperatures. Here we show from combined synchrotron Mössbauer and X-ray diffraction at high pressures that the magnetic ordering surprisingly precedes the structural transition at high pressures in the parent compound BaFe2As2, in sharp contrast to the chemical-doping case. The results can be well understood in terms of the spin fluctuations in the emerging nematic phase before the long-range magnetic order that sheds light on understanding how the parent compound evolves from a SDW state to a superconducting phase, a key scientific inquiry of iron-based superconductors. PMID:24101468

Dinuclear RuII(bipy)2 Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation.

PubMed

Lenis-Rojas, Oscar A; Roma-Rodrigues, Catarina; Fernandes, Alexandra R; Marques, Fernanda; Pérez-Fernández, David; Guerra-Varela, Jorge; Sánchez, Laura; Vázquez-García, Digna; López-Torres, Margarita; Fernández, Alberto; Fernández, Jesús J

2017-06-19

Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy) 2 } 2 (μ-L)][CF 3 SO 3 ] 4 (L = bptz, 1a) and [{Ru(bipy) 2 } 2 (μ-L)][CF 3 SO 3 ] 2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy) 2 Cl 2 . The complexes were characterized by elemental analysis, mass spectrometry, 1 H and 31 P{ 1 H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 μM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC 50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells.

Influence of the anti-inflammatory compound flosulide on granulocyte function.

PubMed

Zimmerli, W; Sansano, S; Wiesenberg-Böttcher, I

1991-10-24

Polymorphonuclear leukocytes (PMN) are involved in inflammatory reactions. It is thought that oxygen-derived free radicals released from activated PMN may participate in tissue damage during inflammation. We have shown that flosulide (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ), a novel highly potent anti-inflammatory compound, inhibits superoxide production induced by N-formyl-Met-Leu-Phe (FMLP), C5a and PMA without impairing bacterial killing or chemotaxis. Flosulide (10(-5)-10(-7) M) was more potent in inhibiting the FMLP-induced respiratory burst of PMN than the structurally related compound nimesulide. FMLP-induced superoxide generation was also inhibited by two human flosulide metabolites. A good correlation between this in vitro effect and in vivo anti-inflammatory potency in rat adjuvant arthritis was found for flosulide and its metabolites. Indomethacin, piroxicam and ibuprofen did not inhibit the respiratory burst at 10(-5) M. FMLP receptor number was decreased by 36% in the presence of 10(-5) M flosulide. However, a 250-fold molar excess of flosulide could not displace labeled FMLP from the receptor. Inhibition of degranulation of primary and secondary granules was a common effect of all anti-inflammatory compounds tested. At a concentration of 10(-5) M, all drugs inhibited degranulation to about the same degree, independent of their in vivo anti-inflammatory activity.

Identification of Novel Small Molecule Activators of Nuclear Factor-κB With Neuroprotective Action Via High-Throughput Screening

PubMed Central

Manuvakhova, Marina S.; Johnson, Guyla G.; White, Misti C.; Ananthan, Subramaniam; Sosa, Melinda; Maddox, Clinton; McKellip, Sara; Rasmussen, Lynn; Wennerberg, Krister; Hobrath, Judith V.; White, E. Lucile; Maddry, Joseph A.; Grimaldi, Maurizio

2012-01-01

Neuronal noncytokine-dependent p50/p65 nuclear factor-κB (the primary NF-κB complex in the brain) activation has been shown to exert neuroprotective actions. Thus neuronal activation of NF-κB could represent a viable neuroprotective target. We have developed a cell-based assay able to detect NF-κB expression enhancement, and through its use we have identified small molecules able to up-regulate NF-κB expression and hence trigger its activation in neurons. We have successfully screened approximately 300,000 compounds and identified 1,647 active compounds. Cluster analysis of the structures within the hit population yielded 14 enriched chemical scaffolds. One high-potency and chemically attractive representative of each of these 14 scaffolds and four singleton structures were selected for follow-up. The experiments described here highlighted that seven compounds caused noncanonical long-lasting NF-κB activation in primary astrocytes. Molecular NF-κB docking experiments indicate that compounds could be modulating NF-κB-induced NF-κB expression via enhancement of NF-κB binding to its own promoter. Prototype compounds increased p65 expression in neurons and caused its nuclear translocation without affecting the inhibitor of NF-κB (I-κB). One of the prototypical compounds caused a large reduction of glutamate-induced neuronal death. In conclusion, we have provided evidence that we can use small molecules to activate p65 NF-κB expression in neurons in a cytokine receptor-independent manner, which results in both long-lasting p65 NF-κB translocation/activation and decreased glutamate neurotoxicity. PMID:21046675

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

Longenecker, Kenton L.; Stamper, Geoffrey F.; Hajduk, Philip J.

In a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small-molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X-ray crystallography, which reveal the multidomain structure of a MurF-inhibitor complex in a compact conformation that differsmore » dramatically from related structures. The lead molecule is bound in the substrate-binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure-based design to explore the suitability of MurF as a pharmaceutical target.« less

Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors.

PubMed

Wang, Beilei; Deng, Yuanxin; Chen, Yongfei; Yu, Kailin; Wang, Aoli; Liang, Qianmao; Wang, Wei; Chen, Cheng; Wu, Hong; Hu, Chen; Miao, Weili; Hur, Wooyoung; Wang, Wenchao; Hu, Zhenquan; Weisberg, Ellen L; Wang, Jinhua; Ren, Tao; Wang, Yinsheng; Gray, Nathanael S; Liu, Qingsong; Liu, Jing

2017-09-08

Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (k inact /K i ) of 0.01 μM -1 s -1 . Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC 50  < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacological tool for studying BTK-related pathologies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam.

PubMed

Reyes, Adelfo; Huerta, Leticia; Alfaro, Marisol; Navarrete, Andrés

2010-11-01

Three 2,3-dihydro-1H-isoindol-1-ones structurally related with piracetam (=2-oxopyrrolidine-1-acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)-2, (R,R)-3, and (R,S)-3 were obtained in good yields in only two steps starting from methyl DL-phthaloylalanine. Compound (RS)-2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)-3 and (R,S)-3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)-3 showed lower efficacy than (R,R)-3. Only (R,R)-3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor-coordination effect in mice. These synthesized 2,3-dihydro-1H-isoindol-1-one derivatives constitute a new kind of nootropic compounds.

Size-induced chemical and magnetic ordering in individual Fe-Au nanoparticles.

PubMed

Mukherjee, Pinaki; Manchanda, Priyanka; Kumar, Pankaj; Zhou, Lin; Kramer, Matthew J; Kashyap, Arti; Skomski, Ralph; Sellmyer, David; Shield, Jeffrey E

2014-08-26

Formation of chemically ordered compounds of Fe and Au is inhibited in bulk materials due to their limited mutual solubility. However, here we report the formation of chemically ordered L12-type Fe3Au and FeAu3 compounds in Fe-Au sub-10 nm nanoparticles, suggesting that they are equilibrium structures in size-constrained systems. The stability of these L12-ordered Fe3Au and FeAu3 compounds along with a previously discovered L10-ordered FeAu has been explained by a size-dependent equilibrium thermodynamic model. Furthermore, the spin ordering of these three compounds has been computed using ab initio first-principle calculations. All ordered compounds exhibit a substantial magnetization at room temperature. The Fe3Au had a high saturation magnetization of about 143.6 emu/g with a ferromagnetic spin structure. The FeAu3 nanoparticles displayed a low saturation magnetization of about 11 emu/g. This suggests a antiferromagnetic spin structure, with the net magnetization arising from uncompensated surface spins. First-principle calculations using the Vienna ab initio simulation package (VASP) indicate that ferromagnetic ordering is energetically most stable in Fe3Au, while antiferromagnetic order is predicted in FeAu and FeAu3, consistent with the experimental results.

Photophysics of covalently functionalized single wall carbon nanotubes with verteporfin

NASA Astrophysics Data System (ADS)

Staicu, Angela; Smarandache, Adriana; Pascu, Alexandru; Pascu, Mihail Lucian

2017-09-01

Covalently functionalized single wall carbon nanotubes (SWCNT) with the photosensitizer verteporfin (VP) were synthesized and studied. Photophysical properties of the obtained compounds like optical absorption, laser-induced fluorescence and generated singlet oxygen were investigated. In order to highlight the features of the conjugated compound, its photophysical characteristics were compared with those of the mixtures of the initial components. The optical absorption data evidenced a compound that combines features of the primary SWCNTs and VP. This is the also the case of the laser induced fluorescence of the synthesized product. Moreover, fluorescence quantum yield (Φf) of the compound (Φf = 2.4%) is smaller than for the mixture of SWCNT and VP in (Φf = 3.2%). The behavior is expected, because linked VP (carrying the fluorescent moiety) transfers easier a part of its excitation energy to the SWCNT in the covalent structure. Relative to the quantum yield of singlet oxygen generation (ΦΔ) by Methylene Blue, it was found that the ΦΔ for the conjugated VP-SWCNT is 51% while for the mixture ΦΔ is 23%. The results indicate covalently functionalized single walled carbon nanotubes with verteporfin as potential compounds of interest in targeted drug delivery and photodynamic therapy.

TRPA1-dependent reversible opening of tight junction by natural compounds with an α,β-unsaturated moiety and capsaicin.

PubMed

Kanda, Yusuke; Yamasaki, Youhei; Sasaki-Yamaguchi, Yoshie; Ida-Koga, Noriko; Kamisuki, Shinji; Sugawara, Fumio; Nagumo, Yoko; Usui, Takeo

2018-02-02

The delivery of hydrophilic macromolecules runs into difficulties such as penetration of the cell membrane lipid bilayer. Our prior experiment demonstrated that capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. Herein, we screened paracellular permeability enhancers other than capsaicin. As TJ opening by capsaicin is associated with Ca 2+ influx, we first screened the compounds that induce Ca 2+ influx in layered MDCK II cells, and then we determined the compounds' abilities to open TJs. Our results identified several natural compounds with α,β-unsaturated moiety. A structure-activity relationship (SAR) analysis and the results of pretreatment with reducing reagent DTT suggested the importance of α,β-unsaturated moiety. We also examined the underlying mechanisms, and our findings suggest that the actin reorganization seen in capsaicin treatment is important for the reversibility of TJ opening. Furthermore, our analyses revealed that TRPA1 is involved in the Ca 2+ influx and TJ permeability increase not only by an α,β-unsaturated compound but also by capsaicin. Our results indicate that the α,β-unsaturated moiety can be a potent pharmacophore for TJ opening.

Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents.

PubMed

Kamal, Ahmed; Reddy, T Srinivasa; Vishnuvardhan, M V P S; Nimbarte, Vijaykumar D; Subba Rao, A V; Srinivasulu, Vunnam; Shankaraiah, Nagula

2015-08-01

A new series of 2-aryl 1,2,4-oxadiazolo-benzimidazole conjugates have been synthesized and evaluated for their antiproliferative activity in the sixty cancer cell line panel of the National Cancer Institute (NCI). Compounds 5l (NSC: 761109/1) and 5x (NSC: 761814/1) exhibited remarkable cytotoxic activity against most of the cancer cell lines in the one dose assay and were further screened at five dose concentrations (0.01, 0.1, 1, 10 and 100 μM) which showed GI50 values in the range of 0.79-28.2 μM. Flow cytometric data of these compounds showed increased cells in G2/M phase, which is suggestive of G2/M cell cycle arrest. Further, compounds 5l and 5x showed inhibition of tubulin polymerization and disruption of the formation of microtubules. These compounds induce apoptosis by DNA fragmentation and chromatin condensation as well as by mitochondrial membrane depolarization. In addition, structure activity relationship studies within the series are also discussed. Molecular docking studies of compounds 5l and 5x into the colchicine-binding site of the tubulin, revealed the possible mode of interaction by these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

hERGCentral: a large database to store, retrieve, and analyze compound-human Ether-à-go-go related gene channel interactions to facilitate cardiotoxicity assessment in drug development.

PubMed

Du, Fang; Yu, Haibo; Zou, Beiyan; Babcock, Joseph; Long, Shunyou; Li, Min

2011-12-01

The unintended and often promiscous inhibition of the cardiac human Ether-à-go-go related gene (hERG) potassium channel is a common cause for either delay or removal of therapeutic compounds from development and withdrawal of marketed drugs. The clinical manifestion is prolongation of the duration between QRS complex and T-wave measured by surface electrocardiogram (ECG)-hence Long QT Syndrome. There are several useful online resources documenting hERG inhibition by known drugs and bioactives. However, their utilities remain somewhat limited because they are biased toward well-studied compounds and their number of data points tends to be much smaller than many commercial compound libraries. The hERGCentral ( www.hergcentral.org ) is mainly based on experimental data obtained from a primary screen by electrophysiology against more than 300,000 structurally diverse compounds. The system is aimed to display and combine three resources: primary electrophysiological data, literature, as well as online reports and chemical library collections. Currently, hERGCentral has annotated datasets of more than 300,000 compounds including structures and chemophysiological properties of compounds, raw traces, and biophysical properties. The system enables a variety of query formats, including searches for hERG effects according to either chemical structure or properties, and alternatively according to the specific biophysical properties of current changes caused by a compound. Therefore, the hERGCentral, as a unique and evolving resource, will facilitate investigation of chemically induced hERG inhibition and therefore drug development. © MARY ANN LIEBERT, INC.

hERGCentral: A Large Database to Store, Retrieve, and Analyze Compound-Human Ether-à-go-go Related Gene Channel Interactions to Facilitate Cardiotoxicity Assessment in Drug Development

PubMed Central

Du, Fang; Yu, Haibo; Zou, Beiyan; Babcock, Joseph; Long, Shunyou

2011-01-01

Abstract The unintended and often promiscous inhibition of the cardiac human Ether-à-go-go related gene (hERG) potassium channel is a common cause for either delay or removal of therapeutic compounds from development and withdrawal of marketed drugs. The clinical manifestion is prolongation of the duration between QRS complex and T-wave measured by surface electrocardiogram (ECG)—hence Long QT Syndrome. There are several useful online resources documenting hERG inhibition by known drugs and bioactives. However, their utilities remain somewhat limited because they are biased toward well-studied compounds and their number of data points tends to be much smaller than many commercial compound libraries. The hERGCentral (www.hergcentral.org) is mainly based on experimental data obtained from a primary screen by electrophysiology against more than 300,000 structurally diverse compounds. The system is aimed to display and combine three resources: primary electrophysiological data, literature, as well as online reports and chemical library collections. Currently, hERGCentral has annotated datasets of more than 300,000 compounds including structures and chemophysiological properties of compounds, raw traces, and biophysical properties. The system enables a variety of query formats, including searches for hERG effects according to either chemical structure or properties, and alternatively according to the specific biophysical properties of current changes caused by a compound. Therefore, the hERGCentral, as a unique and evolving resource, will facilitate investigation of chemically induced hERG inhibition and therefore drug development. PMID:22149888

Identification and Metabolite Profiling of Chemical Activators of Lipid Accumulation in Green Algae1[OPEN

PubMed Central

2017-01-01

Microalgae are proposed as feedstock organisms useful for producing biofuels and coproducts. However, several limitations must be overcome before algae-based production is economically feasible. Among these is the ability to induce lipid accumulation and storage without affecting biomass yield. To overcome this barrier, a chemical genetics approach was employed in which 43,783 compounds were screened against Chlamydomonas reinhardtii, and 243 compounds were identified that increase triacylglyceride (TAG) accumulation without terminating growth. Identified compounds were classified by structural similarity, and 15 were selected for secondary analyses addressing impacts on growth fitness, photosynthetic pigments, and total cellular protein and starch concentrations. TAG accumulation was verified using gas chromatography-mass spectrometry quantification of total fatty acids, and targeted TAG and galactolipid measurements were performed using liquid chromatography-multiple reaction monitoring/mass spectrometry. These results demonstrated that TAG accumulation does not necessarily proceed at the expense of galactolipid. Untargeted metabolite profiling provided important insights into pathway shifts due to five different compound treatments and verified the anabolic state of the cells with regard to the oxidative pentose phosphate pathway, Calvin cycle, tricarboxylic acid cycle, and amino acid biosynthetic pathways. Metabolite patterns were distinct from nitrogen starvation and other abiotic stresses commonly used to induce oil accumulation in algae. The efficacy of these compounds also was demonstrated in three other algal species. These lipid-inducing compounds offer a valuable set of tools for delving into the biochemical mechanisms of lipid accumulation in algae and a direct means to improve algal oil content independent of the severe growth limitations associated with nutrient deprivation. PMID:28652262

Neuroprotective effect of prenylated arylbenzofuran and flavonoids from morus alba fruits on glutamate-induced oxidative injury in HT22 hippocampal cells.

PubMed

Seo, Kyeong-Hwa; Lee, Dae-Young; Jeong, Rak-Hun; Lee, Dong-Sung; Kim, Young-Eon; Hong, Eock-Kee; Kim, Youn-Chul; Baek, Nam-In

2015-04-01

A prenylated arylbenzofuran and six flavonoids were isolated from the fruits of Morus alba L. through silica gel, octadecyl silica gel, and Diaion HP-20 column chromatography. Based on the nuclear magnetic resonance, mass spectrometry, and infrared spectroscopic data, the chemical structures of the compounds were determined to be artoindonesianin O (1), isobavachalcone (2), morachalcone A (3), quercetin (4), astragalin (5), isoquercetin (6), and rutin (7). The isolated compounds were evaluated for protection of HT22-immortalized hippocampal cells against glutamate-induced oxidative stress. Compounds 1 and 3 exhibited protective effects with EC(50) values of 19.7±1.2 and 35.5±2.1 μM, respectively. The major compounds 1-3 and 7 were quantified using liquid chromatography/mass spectrometry analysis and were determined to be 1.88±2.1, 1.90±1.8, 0.78±1.5, and 37.29±2.2 mg/kg, respectively, in the ethanol extract of M. alba L. fruits.

Sesquiterpenes from Neurolaena lobata and their antiproliferative and anti-inflammatory activities.

PubMed

Lajter, Ildikó; Vasas, Andrea; Béni, Zoltán; Forgo, Peter; Binder, Markus; Bochkov, Valery; Zupkó, István; Krupitza, Georg; Frisch, Richard; Kopp, Brigitte; Hohmann, Judit

2014-03-28

Five new sesquiterpenes, neurolobatin A (1), neurolobatin B (2), 5β-hydroxy-8β-isovaleroyloxy-9α-hydroxycalyculatolide (3), 3-epi-desacetylisovaleroylheliangine (4), and 3β-acetoxy-8β-isovaleroyloxyreynosin (5), were isolated from the aerial parts of Neurolaena lobata. The structures were established by means of a combined spectroscopic data analysis, including ESIMS, APCI-MS, and 1D- and 2D-NMR techniques. Neurolobatin A (1) and B (2) are unusual isomeric seco-germacranolide sesquiterpenes with a bicyclic acetal moiety, compounds 3 and 4 are unsaturated epoxy-germacranolide esters, and compound 5 is the first eudesmanolide isolated from the genus Neurolaena. The isolated compounds (1-5) were shown to have noteworthy antiproliferative activities against human tumor cell lines (A2780, A431, HeLa, and MCF7). The anti-inflammatory effects of 1-5, evaluated in vitro using LPS- and TNF-α-induced IL-8 expression inhibitory assays, revealed that all these compounds strongly down-regulated the LPS-induced production of IL-8 protein, with neurolobatin B (2) and 3-epi-desacetylisovaleroylheliangine (4) being the most effective.

Sesquiterpenes from Neurolaena lobata and Their Antiproliferative and Anti-inflammatory Activities

PubMed Central

2014-01-01

Five new sesquiterpenes, neurolobatin A (1), neurolobatin B (2), 5β-hydroxy-8β-isovaleroyloxy-9α-hydroxycalyculatolide (3), 3-epi-desacetylisovaleroylheliangine (4), and 3β-acetoxy-8β-isovaleroyloxyreynosin (5), were isolated from the aerial parts of Neurolaena lobata. The structures were established by means of a combined spectroscopic data analysis, including ESIMS, APCI-MS, and 1D- and 2D-NMR techniques. Neurolobatin A (1) and B (2) are unusual isomeric seco-germacranolide sesquiterpenes with a bicyclic acetal moiety, compounds 3 and 4 are unsaturated epoxy-germacranolide esters, and compound 5 is the first eudesmanolide isolated from the genus Neurolaena. The isolated compounds (1–5) were shown to have noteworthy antiproliferative activities against human tumor cell lines (A2780, A431, HeLa, and MCF7). The anti-inflammatory effects of 1–5, evaluated in vitro using LPS- and TNF-α-induced IL-8 expression inhibitory assays, revealed that all these compounds strongly down-regulated the LPS-induced production of IL-8 protein, with neurolobatin B (2) and 3-epi-desacetylisovaleroylheliangine (4) being the most effective. PMID:24476550

Xanthofulvin, a novel semaphorin inhibitor produced by a strain of Penicillium.

PubMed

Kumagai, Kazuo; Hosotani, Nobuo; Kikuchi, Kaoru; Kimura, Toru; Saji, Ikutaro

2003-07-01

A new semaphorin inhibitor xanthofulvin was isolated from the cultured broth of a fungus Penicillium sp. SPF-3059 along with a known compound vinaxanthone by solvent extraction and bioassay-guided fractionation. The tautomeric structure of xanthofulvin was determined by spectroscopic analyses. The two compounds exhibited significant semaphorin inhibitory activity with IC50 values of 0.09 and 0.1 microg/ml, respectively, in semaphorin3A-induced growth cone collapse assay using cultured chick dorsal root ganglia neurons.

Capgermacrenes A and B, Bioactive Secondary Metabolites from a Bornean Soft Coral, Capnella sp.

PubMed Central

Phan, Chin-Soon; Ng, Shean-Yeaw; Kim, Eun-A; Jeon, You-Jin; Palaniveloo, Kishneth; Santhanaraju Vairappan, Charles

2015-01-01

Two new bicyclogermacrenes, capgermacrenes A (1) and B (2), were isolated with two known compounds, palustrol (3) and litseagermacrane (4), from a population of Bornean soft coral Capnella sp. The structures of these metabolites were elucidated based on spectroscopic data. Compound 1 was found to inhibit the accumulation of the LPS-induced pro-inflammatory IL-1β and NO production by down-regulating the expression of iNOS protein in RAW 264.7 macrophages. PMID:25996100

Effects of hydroxylated benzaldehyde derivatives on radiation-induced reactions involving various organic radicals

NASA Astrophysics Data System (ADS)

Ksendzova, G. A.; Samovich, S. N.; Sorokin, V. L.; Shadyro, O. I.

2018-05-01

In the present paper, the effects of hydroxylated benzaldehyde derivatives and gossypol - the known natural occurring compound - on formation of decomposition products resulting from radiolysis of ethanol and hexane in deaerated and oxygenated solutions were studied. The obtained data enabled the authors to make conclusions about the effects produced by the structure of the compounds under study on their reactivity towards oxygen- and carbon-centered radicals. It has been found that 2,3-dihydroxybenzaldehyde, 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde and 4,6-di-tert-butyl-3-(1,3-dioxane-2-yl)-1,2-dihydroxybenzene are not inferior in efficiency to butylated hydroxytoluene - the industrial antioxidant - as regards suppression of the radiation-induced oxidation processes occurring in hexane. The derivatives of hydroxylated benzaldehydes were shown to have a significant influence on radiation-induced reactions involving α-hydroxyalkyl radicals.

A Full Dynamic Compound Inverse Method for output-only element-level system identification and input estimation from earthquake response signals

NASA Astrophysics Data System (ADS)

Pioldi, Fabio; Rizzi, Egidio

2016-08-01

This paper proposes a new output-only element-level system identification and input estimation technique, towards the simultaneous identification of modal parameters, input excitation time history and structural features at the element-level by adopting earthquake-induced structural response signals. The method, named Full Dynamic Compound Inverse Method (FDCIM), releases strong assumptions of earlier element-level techniques, by working with a two-stage iterative algorithm. Jointly, a Statistical Average technique, a modification process and a parameter projection strategy are adopted at each stage to achieve stronger convergence for the identified estimates. The proposed method works in a deterministic way and is completely developed in State-Space form. Further, it does not require continuous- to discrete-time transformations and does not depend on initialization conditions. Synthetic earthquake-induced response signals from different shear-type buildings are generated to validate the implemented procedure, also with noise-corrupted cases. The achieved results provide a necessary condition to demonstrate the effectiveness of the proposed identification method.

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

Huang, Shi-Wei; Wu, Chun-Ying; Wang, Yen-Ting

Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53more » status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.« less

Structural Basis for Activation of Fatty Acid-binding Protein 4

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

Gillilan,R.; Ayers, S.; Noy, N.

2007-01-01

Fatty acid-binding protein 4 (FABP4) delivers ligands from the cytosol to the nuclear receptor PPAR{gamma} in the nucleus, thereby enhancing the transcriptional activity of the receptor. Notably, FABP4 binds multiple ligands with a similar affinity but its nuclear translocation is activated only by specific compounds. To gain insight into the structural features that underlie the ligand-specificity in activation of the nuclear import of FABP4, we solved the crystal structures of the protein complexed with two compounds that induce its nuclear translocation, and compared these to the apo-protein and to FABP4 structures bound to non-activating ligands. Examination of these structures indicatesmore » that activation coincides with closure of a portal loop phenylalanine side-chain, contraction of the binding pocket, a subtle shift in a helical domain containing the nuclear localization signal of the protein, and a resultant change in oligomeric state that exposes the nuclear localization signal to the solution. Comparisons of backbone displacements induced by activating ligands with a measure of mobility derived from translation, libration, screw (TLS) refinement, and with a composite of slowest normal modes of the apo state suggest that the helical motion associated with the activation of the protein is part of the repertoire of the equilibrium motions of the apo-protein, i.e. that ligand binding does not induce the activated configuration but serves to stabilize it. Nuclear import of FABP4 can thus be understood in terms of the pre-existing equilibrium hypothesis of ligand binding.« less

Ising versus XY anisotropy in frustrated R(2)Ti(2)O(7) compounds as "Seen" by Polarized Neutrons.

PubMed

Cao, H; Gukasov, A; Mirebeau, I; Bonville, P; Decorse, C; Dhalenne, G

2009-07-31

We studied the field induced magnetic order in R(2)Ti(2)O(7) pyrochlore compounds with either uniaxial (R=Ho, Tb) or planar (R=Er, Yb) anisotropy, by polarized neutron diffraction. The determination of the local susceptibility tensor {chi(parallel to),chi(perpendicular)} provides a universal description of the field induced structures in the paramagnetic phase (2-270 K), whatever the field value (1-7 T) and direction. Comparison of the thermal variations of chi(parallel to) and chi(perpendicular) with calculations using the rare earth crystal field shows that exchange and dipolar interactions must be taken into account. We determine the molecular field tensor in each case and show that it can be strongly anisotropic.

Host lignin composition affects haustorium induction in the parasitic plants Phtheirospermum japonicum and Striga hermonthica.

PubMed

Cui, Songkui; Wada, Syogo; Tobimatsu, Yuki; Takeda, Yuri; Saucet, Simon B; Takano, Toshiyuki; Umezawa, Toshiaki; Shirasu, Ken; Yoshida, Satoko

2018-04-01

Parasitic plants in the family Orobanchaceae are destructive weeds of agriculture worldwide. The haustorium, an essential parasitic organ used by these plants to penetrate host tissues, is induced by host-derived phenolic compounds called haustorium-inducing factors (HIFs). The origin of HIFs remains unknown, although the structures of lignin monomers resemble that of HIFs. Lignin is a natural phenylpropanoid polymer, commonly found in secondary cell walls of vascular plants. We therefore investigated the possibility that HIFs are derived from host lignin. Various lignin-related phenolics, quinones and lignin polymers, together with nonhost and host plants that have different lignin compositions, were tested for their haustorium-inducing activity in two Orobanchaceae species, a facultative parasite, Phtheirospermum japonicum, and an obligate parasite, Striga hermonthica. Lignin-related compounds induced haustoria in P. japonicum and S. hermonthica with different specificities. High concentrations of lignin polymers induced haustorium formation. Treatment with laccase, a lignin degradation enzyme, promoted haustorium formation at low concentrations. The distinct lignin compositions of the host and nonhost plants affected haustorium induction, correlating with the response of the different parasitic plants to specific types of lignin-related compounds. Our study provides valuable insights into the important roles of lignin biosynthesis and degradation in the production of HIFs. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Aroma barrier properties of sodium caseinate-based films.

PubMed

Fabra, Maria José; Hambleton, Alicia; Talens, Pau; Debeaufort, Fréderic; Chiralt, Amparo; Voilley, Andrée

2008-05-01

The mass transport of six different aroma compounds (ethyl acetate, ethyl butyrate, ethyl hexanoate, 2-hexanone, 1-hexanol, and cis-3-hexenol) through sodium caseinate-based films with different oleic acid (OA)/beeswax (BW) ratio has been studied. OA is less efficient than BW in reducing aroma permeability, which can be attributed to its greater polarity. Control film (without lipid) and films prepared with 0:100 OA/BW ratio show the lowest permeability. OA involves a decrease in aroma barrier properties of the sodium caseinate-based films due to its plasticization ability. Preferential sorption and diffusion occurs through OA instead of caseinate matrix and/or BW. The efficiency of sodium caseinate-based films to retain or limit aroma compound transfers depend on the affinity of the volatile compound to the films, which relates physicochemical interaction between volatile compound and film. Specific interactions (aroma compound-hydrocolloid and aroma compound-lipid) induce structural changes during mass transfer.

A novel regulatory system in plants involving medium-chain fatty acids.

PubMed

Hunzicker, Gretel Mara

2009-12-01

Polyethylene glycol sorbitan monoacylates (Tween) are detergents of widespread use in plant sciences. However, little is known about the plant response to these compounds. Interestingly, the structure of Tweens' detergents (especially from Tween 20) resembles the lipid A structure from gram-negative bacteria polysaccharides (a backbone with short saturated fatty acids). Thus, different assays (microarray, GC-MS, RT-PCR, Northern blots, alkalinization and mutant analyses) were conducted in order to elucidate physiological changes in the plant response to Tween 20 detergent. Tween 20 causes a rapid and complex change in transcript abundance which bears all characteristics of a pathogenesis-associated molecular pattern (PAMP)/elicitor-induced defense response, and they do so at concentrations which cause no detectable deleterious effects on plant cellular integrity. In the present work, it is shown that the PAMP/elicitor-induced defense responses are caused by medium-chain fatty acids which are efficiently released from the Tween backbone by the plant, notably lauric acid (12:0) and methyl lauric acid. These compounds induce the production of ethylene, medium alkalinization and gene activation in a jasmonate-independent manner. Medium-chain fatty acids are thus novel elicitors/regulators of plant pathogen defense as they have being proved in animals.

Isocoumarin derivatives from the endophytic fungus, Pestalotiopsis sp.

PubMed

Song, Ren-Yu; Wang, Xiao-Bing; Yin, Guo-Ping; Liu, Rui-Huan; Kong, Ling-Yi; Yang, Ming-Hua

2017-10-01

Five new isocoumarin derivatives, pestalactone A-C (1-3) and pestapyrone D-E (4-5), together with two known compounds (6-7) were isolated from the solid cultures of the endophytic fungus Pestalotiopsis sp. obtained from Photinia frasery. Their structures were mainly determined by extensive spectroscopic analysis, Mo 2 (OCOCH 3 ) 4 -induced electronic circular dichroism (ECD), and ECD calculation. Compounds 1 and 2 were rare isocoumarin derivatives and derived from distinctive polyketide pathways. Compound 3 exhibited potent antifungal activity against Candida glabrata (ATCC 90030) with an MIC 50 value of 3.49±0.21μg/mL. Copyright © 2017. Published by Elsevier B.V.

A new cerebroside from the fruiting bodies of Hericium erinaceus and its applicability to cancer treatment.

PubMed

Lee, Seoung Rak; Jung, Kiwon; Noh, Hyung Jun; Park, Yong Joo; Lee, Hye Lim; Lee, Kang Ro; Kang, Ki Sung; Kim, Ki Hyun

2015-12-15

A new cerebroside, cerebroside E (1) was isolated from the fruiting bodies of Hericium erinaceus (Hericiaceae). The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR, HR-MS, and chemical reactions. Compound 1 was evaluated for its applicability to medicinal use in several human diseases using cell-based assays. As a result, compound 1 attenuated cisplatin-induced nephrotoxicity in LLC-PK1 cells and exhibited a significant inhibitory effect on angiogenesis in HUVECs. These results collectively reflect the beneficial effects of compound 1 in cancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Lessons learned in induced fit docking and metadynamics in the Drug Design Data Resource Grand Challenge 2

NASA Astrophysics Data System (ADS)

Baumgartner, Matthew P.; Evans, David A.

2018-01-01

Two of the major ongoing challenges in computational drug discovery are predicting the binding pose and affinity of a compound to a protein. The Drug Design Data Resource Grand Challenge 2 was developed to address these problems and to drive development of new methods. The challenge provided the 2D structures of compounds for which the organizers help blinded data in the form of 35 X-ray crystal structures and 102 binding affinity measurements and challenged participants to predict the binding pose and affinity of the compounds. We tested a number of pose prediction methods as part of the challenge; we found that docking methods that incorporate protein flexibility (Induced Fit Docking) outperformed methods that treated the protein as rigid. We also found that using binding pose metadynamics, a molecular dynamics based method, to score docked poses provided the best predictions of our methods with an average RMSD of 2.01 Å. We tested both structure-based (e.g. docking) and ligand-based methods (e.g. QSAR) in the affinity prediction portion of the competition. We found that our structure-based methods based on docking with Smina (Spearman ρ = 0.614), performed slightly better than our ligand-based methods (ρ = 0.543), and had equivalent performance with the other top methods in the competition. Despite the overall good performance of our methods in comparison to other participants in the challenge, there exists significant room for improvement especially in cases such as these where protein flexibility plays such a large role.

Investigation of gamma-ray induced polymer formation of the carboranes. Annual progress report, November 1, 1972--September 30, 1973

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

Klingen, T.J.

1973-10-01

Research is reported on the radiation chemistry of o-carborane STA 1, 2- dicarba-closo-dodecaborane (11)! and its l-alkyl and 1-alkenyl derivatives. The principal purpose of the research is to establish optirmum conditions for radiation-induced polymerization of such compounds. Properties and structures of polymeric products, identities and yields of minor products, and reaction mechanisms are being determined. (auth)

Structural characterization of human heme oxygenase-1 in complex with azole-based inhibitors.

PubMed

Rahman, Mona N; Vlahakis, Jason Z; Roman, Gheorghe; Vukomanovic, Dragic; Szarek, Walter A; Nakatsu, Kanji; Jia, Zongchao

2010-03-01

The development of inhibitors specific for heme oxygenases (HO) aims to provide powerful tools in understanding the HO system. Based on the lead structure (2S, 4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[((4-aminophenyl)thio)methyl]-1,3-dioxolane (azalanstat, QC-1) we have synthesized structural modifications to develop novel and selective HO inhibitors. The structural study of human HO-1 (hHO-1) in complex with a select group of the inhibitors was initiated using X-ray crystallographic techniques. Comparison of the structures of four such compounds each in complex with hHO-1 revealed a common binding mode, despite having different structural fragments. The compounds bind to the distal side of heme through an azole "anchor" which coordinates with the heme iron. An expansion of the distal pocket, mainly due to distal helix flexibility, allows accommodation of the compounds without displacing heme or the critical Asp140 residue. Rather, binding displaces a catalytically critical water molecule and disrupts an ordered hydrogen-bond network involving Asp140. The presence of a triazole "anchor" may provide further stability via a hydrogen bond with the protein. A hydrophobic pocket acts to stabilize the region occupied by the phenyl or adamantanyl moieties of these compounds. Further, a secondary hydrophobic pocket is formed via "induced fit" to accommodate bulky substituents at the 4-position of the dioxolane ring. Copyright 2009 Elsevier Inc. All rights reserved.

Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin.

PubMed

Liu, Feng-Cheng; Lu, Jeng-Wei; Chien, Chiao-Yun; Huang, Hsu-Shan; Lee, Chia-Chung; Lien, Shiu-Bii; Lin, Leou-Chyr; Chen, Liv Weichien; Ho, Yi-Jung; Shen, Min-Chung; Ho, Ling-Jun; Lai, Jenn-Haung

2018-05-14

In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2 H -benzo[ e ][1,3]oxazine-2,4(3 H )-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)⁻nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.

Assessment of ligand binding at a site relevant to SOD1 oxidation and aggregation.

PubMed

Manjula, Ramu; Wright, Gareth S A; Strange, Richard W; Padmanabhan, Balasundaram

2018-05-01

Cu/Zn superoxide dismutase-1 (SOD1) mutations are causative for a subset of amyotrophic lateral sclerosis (ALS) cases. These mutations lead to structural instability, aggregation and ultimately motor neuron death. We have determined crystal structures of SOD1 in complex with a naphthalene-catechol-linked compound which binds with low micro-molar affinity to a site important for oxidative damage-induced aggregation. SOD1 Trp32 oxidation is indeed significantly inhibited by ligand binding. Our work shows how compound linking can be applied successfully to ligand interactions on the SOD1 surface to generate relatively good binding strength. The ligand, positioned in a region important for SOD1 fibrillation, offers the possibility that it, or a similar compound, could prevent the abnormal self-association that drives SOD1 toxicity in ALS. © 2018 Federation of European Biochemical Societies.

A new approach to construct a fused 2-ylidene chromene ring: highly regioselective synthesis of novel chromeno quinoxalines.

PubMed

Kumar, K Shiva; Rambabu, D; Prasad, Bagineni; Mujahid, Mohammad; Krishna, G Rama; Rao, M V Basaveswara; Reddy, C Malla; Vanaja, G R; Kalle, Arunasree M; Pal, Manojit

2012-06-28

Regioselective construction of a fused 2-ylidene chromene ring was achieved for the first time by using AlCl(3)-induced C-C bond formation followed by Pd/C-Cu mediate coupling-cyclization strategy. A number of chromeno[4,3-b]quinoxaline derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound e.g. 6-(2,2-dimethylpropylidene)-4-methyl-6H-chromeno[4,3-b]quinoxalin-3-ol confirmed the presence of an exocyclic C-C double bond with Z-geometry. The crystal structure analysis and hydrogen bonding patterns of the same compound along with its structure elaboration via propargylation followed by Sonogashira coupling of the resulting terminal alkyne is presented. A probable mechanism for the formation of 2-ylidene chromene ring is discussed. Some of the compounds synthesized showed anticancer properties when tested in vitro.

Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species.

PubMed

Fourches, Denis; Barnes, Julie C; Day, Nicola C; Bradley, Paul; Reed, Jane Z; Tropsha, Alexander

2010-01-01

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automated text mining with limited manual curation, opening up new opportunities for generating and modeling chemical toxicology data.

Four new sesquiterpenes from the rhizomes of Curcuma phaeocaulis and their iNOS inhibitory activities.

PubMed

Ma, Jiang-Hao; Wang, Ying; Liu, Yue; Gao, Su-Yu; Ding, Li-Qin; Zhao, Feng; Chen, Li-Xia; Qiu, Feng

2015-05-01

Three new guaiane-type sesquiterpenes named phaeocaulisins K-M (1-3), and one germacrane-type sesquiterpenoid with new ring system of 1,5- and 1,8-ether groups named phagermadiol (4), were isolated from rhizomes of Curcuma phaeocaulis. Their structures were established based on extensive spectroscopic analysis. Compound 1, the first example of norsesquiterpene with tropone backbone, and compound 3 with a novel 1,2-dioxolane sesquiterpene alcohol were isolated from the genus Curcuma. All of the isolated compounds were tested for inhibitory activity against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compound 3 inhibited NO production with IC50 value of 6.05 ± 0.43 μM. The plausible biosynthetic pathway for compounds 3 and 4 in C. phaeocaulis was also discussed.

Survey and analysis of crystal polymorphism in organic structures

PubMed Central

Kaur, Ramanpreet

2018-01-01

With the intention of producing the most comprehensive treatment of the prevalence of crystal polymorphism among structurally characterized materials, all polymorphic compounds flagged as such within the Cambridge Structural Database (CSD) are analysed and a list of crystallographically characterized organic polymorphic compounds is assembled. Classifying these structures into subclasses of anhydrates, salts, hydrates, non-hydrated solvates and cocrystals reveals that there are significant variations in polymorphism prevalence as a function of crystal type, a fact which has not previously been recognized in the literature. It is also shown that, as a percentage, polymorphic entries are decreasing temporally within the CSD, with the notable exception of cocrystals, which continue to rise at a rate that is a constant fraction of the overall entries. Some phenomena identified that require additional scrutiny include the relative prevalence of temperature-induced phase transitions among organic salts and the paucity of polymorphism in crystals with three or more chemical components. PMID:29765601

Influence of intense THz radiation on spin state of photoswitchable compound Cu(hfac)2L(Pr).

PubMed

Veber, Sergey L; Fedin, Matvey V; Maryunina, Ksenia Yu; Boldyrev, Kirill N; Sheglov, Mikhail A; Kubarev, Vitaly V; Shevchenko, Oleg A; Vinokurov, Nikolay A; Kulipanov, Gennady N; Sagdeev, Renad Z; Ovcharenko, Victor I; Bagryanskaya, Elena G

2013-02-21

The family of magnetoactive compounds Cu(hfac)(2)L(R) exhibits thermo- and photoswitching phenomena promising for various applications. Photoswitching of the Cu(hfac)(2)L(Pr) compound can be observed at temperatures below 20 K and is accompanied by transition to metastable structural state. Reverse conversion to stable structure could not be induced by light of near-IR-vis-UV regions up to date. The far-IR spectra of metastable and stable structural states are different and show characteristic absorption lines in the range of 170-240 cm(-1). These frequencies are accessible by NovoFEL - high-power THz free-electron laser user facility in Novosibirsk. We investigate selective influence of THz radiation on relaxation processes from metastable to stable structural state, which can be monitored by electron paramagnetic resonance (EPR). For this purpose, the experimental station based on X-band EPR spectrometer has been constructed by the THz beamline of NovoFEL and equipped with multimodal THz waveguide allowing to fed radiation directly into the EPR resonator. It has been found that irradiation of studied compound with high-power THz light causes significant but nondestructive increase of its temperature. Apart from this effect, no resonant influence of THz irradiation on relaxation processes has been observed. The experimental results have been rationalized taking into account vibrational relaxation times of the studied compound. Further experiments based on pulse heating by THz radiation have been proposed.

A macrocyclic ellagitannin trimer, oenotherin T(1), from Oenothera species.

PubMed

Taniguchi, Shoko; Imayoshi, Yoko; Yabu-uchi, Ryoko; Ito, Hideyuki; Hatano, Tsutomu; Yoshida, Takashi

2002-01-01

Oenotherin T(1) was isolated from leaves of Oenothera tetraptera as a major ellagitannin. Its structure, that of a macrocyclic trimer with a new acyl group, an isodehydrovaloneoyl group, was established. This compound was also produced by callus tissues induced from O. laciniata leaves.

Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides ▿

PubMed Central

Warshakoon, Hemamali J.; Burns, Mark R.; David, Sunil A.

2009-01-01

We have recently confirmed that lipoteichoic acid (LTA), a major constituent of the gram-positive bacterial surface, is the endotoxin of gram-positive bacteria that induces proinflammatory molecules in a Toll-like receptor 2 (TLR2)-dependent manner. LTA is an anionic amphipath whose physicochemical properties are similar to those of lipopolysaccharide (LPS), which is found on the outer leaflet of the outer membranes of gram-negative organisms. Hypothesizing that compounds that sequester LPS could also bind to and inhibit LTA-induced cellular activation, we screened congeneric series of polyamine sulfonamides which we had previously shown effectively neutralized LPS both in vitro and in animal models of endotoxemia. We observed that these compounds do bind to and neutralize LTA, as reflected by the inhibition of TLR2-mediated NF-κB induction in reporter gene assays. Structure-activity studies showed a clear dependence of the acyl chain length on activity against LTA in compounds with spermine and homospermine scaffolds. We then sought to examine possible correlations between the neutralizing potency toward LTA and antimicrobial activity in Staphylococcus aureus. A linear relationship between LTA sequestration activity and antimicrobial activity for compounds with a spermine backbone was observed, while all compounds with a homospermine backbone were equally active against S. aureus, regardless of their neutralizing potency toward LTA. These results suggest that the number of protonatable charges is a key determinant of the activity toward the membranes of gram-positive bacteria. The development of resistance to membrane-active antibiotics has been relatively slower than that to conventional antibiotics, and it is possible that compounds such as the acylpolyamines may be useful clinically, provided that they have an acceptable safety profile and margin of safety. A more detailed understanding of the mechanisms of interactions of these compounds with LPS and LTA, as well as the gram-negative and -positive bacterial cell surfaces, will be instructive and should allow the rational design of analogues which combine antisepsis and antibacterial properties. PMID:18955537

Low toxic and high soluble camptothecin derivative 2–47 effectively induces apoptosis of tumor cells in vitro

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

Zhou, Yao; Zhao, Hong-Ye; Jiang, Du

The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2–47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2–47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC{sub 50}) of 2- to 3-fold lower than HCPT asmore » a control. In particular, 2–47 inhibited the proliferation of Jurkat cells with an IC{sub 50} of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2–47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2–47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2–47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2–47 solutes in CHCl{sub 3} 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2–47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro. - Highlights: • Compound 2–47 showed a wide inhibitory effect on the tested tumor cell lines with an IC{sub 50} of 3 times lower than that of HCPT in general. • Compound 2–47 inhibited the proliferation of the human leukemia cell Jurkat at an IC{sub 50} of as low as 40 nM. • As compared to HCPT, compound 2–47 showed much reduced cytotoxicity on normal human cells. • As compared to others, compound 2–47 showed a hundreds-fold higher solubility in non-polar organic solution.« less

Synthesis and Characterization of Novel Nonlinear Optical Materials

NASA Astrophysics Data System (ADS)

Liang, Cheryl Shuang

1992-01-01

Nonlinear optic materials are becoming increasingly important because of their many technological applications, such as second harmonic generation (SHG), optical switching, and waveguides for optical transmission. Currently, there is a demand for crystals transparent in the UV region, which would make the third and higher harmonic generations feasible. Compounds with the general stoichiometry ABCO _4 structural systems have shown to be promising candidates for frequency doubling into the UV region. The stuffed tridymite structure in which these ABCO_4 compounds crystallize is very tolerant to substitution, and over two hundred compounds have been synthesized up to date. While the presently available theories of optical nonlinearity have been applied to many inorganic solids, the threatened structure theory applied for ferroelectric properties can also be used to describe the structure/property relationship in the ABCO_4 structural family. Compounds synthesized for this study, ALiPO_4 (A = Sr, Ba, Pb) have shown that the SHG of these materials can be maximized by bringing each system close to its structural phase transition or by inducing stress in the pure phase structure. Studies have shown that the dielectric coefficients of KNbO_3 increase by more than tenfold with tantalum doping. This prompted the investigation of a mixed niobium/tantalum containing channelled tetrahedra/octahedra open framework, K_{2/3}Li _{1/3}Nb_ {rm 2-x}Ta_{ rm x}PO_8. These compounds are capable of ion exchange, where other cations are used to replace potassium. The cation-framework interaction mimics the guest-host relationship characteristic of many traditional zeolitic materials. This interaction also enables us to determine the role of the cation in framework polarizability, which can be measured by SHG intensities. Through ion exchange, many isostructural compounds can be made at low temperatures. A family of layered rubidium niobium/tantalum oxide compounds have been synthesized in an extension of the investigation of the above host-guest interaction. X -ray diffraction data have shown successful incorporation of n-butyl ammonium chloride followed by exchange of an organic salt which has very large SHG intensity, N-methylstilbazolium chloride, into the layers.

Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents.

PubMed

Kleczkowska, Patrycja; Hermans, Emmanuel; Kosson, Piotr; Kowalczyk, Agnieszka; Lesniak, Anna; Pawlik, Karolina; Bojnik, Engin; Benyhe, Sandor; Nowicka, Barbara; Bujalska-Zadrozny, Magdalena; Misicka, Aleksandra; Lipkowski, Andrzej W

2016-10-01

Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile(9)]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile(9)]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-inflammatory, antiproliferative, and cytoprotective activity of NO chimera nitrates of use in cancer chemoprevention.

PubMed

Hagos, Ghenet K; Abdul-Hay, Samer O; Sohn, Johann; Edirisinghe, Praneeth D; Chandrasena, R Esala P; Wang, Zhiqiang; Li, Qian; Thatcher, Gregory R J

2008-11-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094), a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess 1) antiproliferative and 2) anti-inflammatory actions and 3) the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these three biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro, and GT-094 was seen to induce phase 2 enzymes via the antioxidant responsive element. In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal, and combinations of nitrates with acetylsalicylic acid were inactive.

Electron-irradiation-induced crystallization at metallic amorphous/silicon oxide interfaces caused by electronic excitation

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

Nagase, Takeshi, E-mail: t-nagase@uhvem.osaka-u.ac.jp; Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, 2-1, Yamada-Oka, Suita, Osaka 565-0871; Yamashita, Ryo

2016-04-28

Irradiation-induced crystallization of an amorphous phase was stimulated at a Pd-Si amorphous/silicon oxide (a(Pd-Si)/SiO{sub x}) interface at 298 K by electron irradiation at acceleration voltages ranging between 25 kV and 200 kV. Under irradiation, a Pd-Si amorphous phase was initially formed at the crystalline face-centered cubic palladium/silicon oxide (Pd/SiO{sub x}) interface, followed by the formation of a Pd{sub 2}Si intermetallic compound through irradiation-induced crystallization. The irradiation-induced crystallization can be considered to be stimulated not by defect introduction through the electron knock-on effects and electron-beam heating, but by the electronic excitation mechanism. The observed irradiation-induced structural change at the a(Pd-Si)/SiO{sub x} and Pd/SiO{sub x}more » interfaces indicates multiple structural modifications at the metal/silicon oxide interfaces through electronic excitation induced by the electron-beam processes.« less

Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation.

PubMed

Chang, Yi; Hsu, Wen-Hsien; Yang, Wen-Bin; Jayakumar, Thanasekaran; Lee, Tzu-Yin; Sheu, Joen-Rong; Lu, Wan-Jung; Li, Jiun-Yi

2017-11-01

Antiplatelet agents have considerable benefits in the treatment of thromboembolic diseases; however, these agents still have substantial limitations due to their severe side-effects. In this study, the antiplatelet activity of three newly synthesized saccharide based benzimidazole derivatives, M3BIM, Malto-BIM and Melibio-BIM, in collagen and thrombin-stimulated human platelets in vitro was examined. Among the compounds tested, only compound M3BIM exerted concentration (20-60 µM)-dependent inhibitory effects against collagen (1 µg/ml) and thrombin (0.01 U/ml)-induced washed human platelet aggregation. Moreover, at a concentration of 60 µM, M3BIM distinctly abolished collagen-induced adenosine triphosphate (ATP) release and intracellular Ca2+ mobilization. Additionally, this compound attenuated the collagen-induced phosphorylation of p47, a marker of the activation of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK). However, Malto-BIM and Melibio-BIM were not effective in this regard. Moreover, the toxic effects of these compounds were evaluated using zebrafish embryo toxicity (ZET) assay, and the results revealed that all three compounds had no comparative cytotoxicity within the range of 25-200 µM. Overall, the results of this study provide evidence for the inhibitory effects of M3BIM on collagen-induced platelet aggregation in vitro compared to other imidazole derivatives. The presence of 1-imidazolyl moiety at one end with a longer chain length (three sugar moieties) may be mainly responsible for the observed effects of M3BIM. These results suggest that compound M3BIM may be used as a potential candidate for the treatment of aberrant platelet activation-related diseases as it inhibits the activation of p47 and p38 MAPK, and reduces ATP release and Ca2+ mobilization.

High frequency resonant waveguide grating imager for assessing drug-induced cardiotoxicity

NASA Astrophysics Data System (ADS)

Ferrie, Ann M.; Wu, Qi; Deichmann, Oberon D.; Fang, Ye

2014-05-01

We report a high-frequency resonant waveguide grating imager for assessing compound-induced cardiotoxicity. The imager sweeps the wavelength range from 823 nm to 838 nm every 3 s to identify and monitor compound-induced shifts in resonance wavelength and then switch to the intensity-imaging mode to detect the beating rhythm and proarrhythmic effects of compounds on induced pluripotent stem cell-derived cardiomyocytes. This opens possibility to study cardiovascular biology and compound-induced cardiotoxicity.

Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors

NASA Astrophysics Data System (ADS)

Kalid, Ori; Toledo Warshaviak, Dora; Shechter, Sharon; Sherman, Woody; Shacham, Sharon

2012-11-01

We present the Consensus Induced Fit Docking (cIFD) approach for adapting a protein binding site to accommodate multiple diverse ligands for virtual screening. This novel approach results in a single binding site structure that can bind diverse chemotypes and is thus highly useful for efficient structure-based virtual screening. We first describe the cIFD method and its validation on three targets that were previously shown to be challenging for docking programs (COX-2, estrogen receptor, and HIV reverse transcriptase). We then demonstrate the application of cIFD to the challenging discovery of irreversible Crm1 inhibitors. We report the identification of 33 novel Crm1 inhibitors, which resulted from the testing of 402 purchased compounds selected from a screening set containing 261,680 compounds. This corresponds to a hit rate of 8.2 %. The novel Crm1 inhibitors reveal diverse chemical structures, validating the utility of the cIFD method in a real-world drug discovery project. This approach offers a pragmatic way to implicitly account for protein flexibility without the additional computational costs of ensemble docking or including full protein flexibility during virtual screening.

Flavonoids and biphenylneolignans with anti-inflammatory activity from the stems of Millettia griffithii.

PubMed

Tang, Huan; Pei, He-Ying; Wang, Tai-Jin; Chen, Kai; Wu, Bo; Yang, Qiu-Nan; Zhang, Qiang; Yang, Jian-Hong; Wang, Xiao-Yan; Tang, Ming-Hai; Peng, Ai-Hua; Ye, Hao-Yu; Chen, Li-Juan

2016-09-15

Five new flavonoids, griffinones A-E (1-5), a new biphenylneolignan, griffilignan A (6) and ten known compounds were isolated from the n-hexane and EtOAc extracts of Millettia griffithii. The structures of the new compounds were determined by 1D and 2D NMR, and by HRMS. The anti-inflammatory activity of the isolated compounds was evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells. Among the isolated compounds, compounds 1, 2 and 14 showed significant anti-inflammatory activity with IC50 values of 20.4, 2.1 and 35.7μM, respectively and no obvious toxicities were observed at 100μM. Western blot and PCR assay further showed that inhibition of nitric oxide production by compound 2 was associated with suppression of iNOS expression. Modeling studies suggested that the amino group, phenyl ring as well as the isopentenyl tails of compound 2 could help bind to iNOs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of cytotoxicity of new trans-palladium(II) complex in human cells in vitro.

PubMed

Kontek, Renata; Matławska-Wasowska, Ksenia; Kalinowska-Lis, Urszula; Kontek, Bogdan; Ochocki, Justyn

2011-01-01

Studies of cytotoxicity allow to elucidate the mechanisms by which chemical compounds influence cells and tissues. On the basis of the structural analogy between platinum(II) and palladium(II) complexes, a variety of studies on palladium(II) compounds as potential anticancer drugs have been carried out (1, 2). The cytotoxicity was evaluated by MTT assay. Abilities of trans-palladium(II) complex containing diethyl (pyridin-2-ylmethyl)phosphates as non-leaving ligands (trans-[PdCl2(2-pmOpe 2)]) to induce apoptosis and necrosis in normal lymphocytes, A549 cells and HT29 cell lines were performed by use of fluorochrome staining. The obtained results revealed, that the new trans-palladium(II) complex was more cytotoxic against A549 and HT29 tumor cells than on the normal lymphocytes in vitro. The novel complex induces apoptosis in all tested cells, but in lymphocytes to a lesser degree. The compound tested also induced significant amounts of necrotic cells, which exceeded the level of apoptotic cell fractions. The results demonstrate that the trans-Pd(II) complex showed substantial cytotoxic activity against A549 and HT29 tumor cells and indicate that the new trans-palladium(II) complex effectively inhibited cancer cells growth.

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction.

PubMed

Virych, P A; Shelyuk, O V; Kabanova, T A; Khalimova, E I; Martynyuk, V S; Pavlovsky, V I; Andronati, S A

2017-01-01

Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.

PubMed

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Caciagli, Valerio; Catrambone, Fernando; D'Andrea, Piero; Felicetti, Patrizia; Gensini, Martina; Marastoni, Elena; Nannicini, Rossano; Paris, Marielle; Terracciano, Rosa; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2007-02-08

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Induction of quinone reductase (QR) by withanolides isolated from Physalis angulata L. var. villosa Bonati (Solanaceae).

PubMed

Ding, Hui; Hu, Zhijuan; Yu, Liyan; Ma, Zhongjun; Ma, Xiaoqiong; Chen, Zhe; Wang, Dan; Zhao, Xiaofeng

2014-08-01

In the present study, the EtOAc extract of the persistent calyx of Physalis angulata L. var. villosa Bonati (PA) was tested for its potential quinone reductase (QR) inducing activity with glutathione (GSH) as the substrate using an UPLC-ESI-MS method. The result revealed that the PA had electrophiles that could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, three new withanolides, compounds 3, 6 and 7, together with four known withanolides, compounds 1, 2, 4 and 5 were isolated from PA extract. Their structures were determined by spectroscopic techniques, including (1)H-, (13)C NMR (DEPT), and 2D-NMR (HMBC, HMQC, (1)H, (1)H-COSY, NOESY) experiments, as well as by HR-MS. All the seven compounds were tested for their QR induction activities towards mouse hepa 1c1c7 cells. Copyright © 2014 Elsevier Inc. All rights reserved.

APOPTOSIS OF CEREBELLAR GRANULE CELLS INDUCED BY ORGANOTIN COMPOUNDS FOUND IN DRINKING WATER: INVOLVEMENT OF MAP KINASES.

EPA Science Inventory

Mono- and dialkyl organotins have been found in drinking water in homes and businesses served by PVC pipes. Because the structurally related trialkyl organotins (eg. trimethyltin, tributyltin) are well known neurotoxicants, there is concern over the potential for the mono- and di...

Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury

PubMed Central

Zhang, Yali; Wu, Jianzhang; Ying, Shilong; Chen, Gaozhi; Wu, Beibei; Xu, Tingting; Liu, Zhiguo; Liu, Xing; Huang, Lehao; Shan, Xiaoou; Dai, Yuanrong; Liang, Guang

2016-01-01

Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co-receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases. In this study, we designed and synthesized 31 chalcone derivatives that contain the moiety of (E)-4-phenylbut-3-en-2-one, which we consider the core structure of current MD2 inhibitors. We first evaluated the anti-inflammatory activities of these compounds in MPMs. For the most active compound 20, we confirmed that it is a specific MD2 inhibitor through a series of biochemical experiments and elucidated that it binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg90 and Tyr102 residues. Compound 20 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-κB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with compound 20 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives we identified is a potential candidate for treating acute inflammatory diseases. PMID:27118147

Isolation, characterization and antihyperlipidemic activity of secoisolariciresinol diglucoside in poloxamer-407-induced experimental hyperlipidemia.

PubMed

Zanwar, Anand A; Hegde, Mahabaleshwar V; Rojatkar, Supada R; Sonawane, Kiran B; Rajamohanan, P R; Bodhankar, Subhash L

2014-09-01

Linum usitatissimum L. (Linaceae), commonly known as flaxseed, is a good source of dietary fiber and lignans. Earlier we reported cardioprotective, antihyperlipidemic, and in vitro antioxidant activity of flax lignan concentrate (FLC) obtained from flaxseed. To isolate secoisolariciresinol diglucoside (SDG) from FLC and to evaluate the antihyperlipidemic activity of SDG in poloxamer-407 (P-407)-induced hyperlipidaemic mice. FLC was subjected to column chromatography and further subjected to preparative HPTLC to isolate SDG. The chemical structure of the isolated compound was elucidated by UV, IR, (1)H NMR, (13)C NMR, DEPT, COSY, HSQC, HMBC, ROESY, MS, and specific optical rotation was recorded. Further, we have investigated the antihyperlipidaemic effect of SDG (20 mg/kg) in P-407-induced hyperlipidaemic rats. Hyperlipidaemia was induced by intraperitoneal administration of P-407 (30% w/v). Serum lipid parameters such as total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) levels were measured. The structure and stereochemistry of the isolated compound were confirmed on the basis of 1D and 2D spectral data and characterized as SDG. Finally, isolated pure SDG was screened using a P-407-induced mice model for its antihyperlipidemic action using serum lipid parameters. The isolated SDG (20 mg/kg) significantly reduced serum cholesterol, triglyceride (p < 0.001), very low-density lipoprotein (p < 0.05), and non-significantly increased HDL-C. Finally, it was concluded unequivocally that SDG showed antihyperlipidaemic effects in P-407-induced hyperlipidaemic mice. Isolated pure SDG confirms that SDG is beneficial in the prevention of experimental hyperlipidemia in laboratory animals.

Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters.

PubMed

Fayad, Walid; Fryknäs, Mårten; Brnjic, Slavica; Olofsson, Maria Hägg; Larsson, Rolf; Linder, Stig

2009-10-02

Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

Structures and Activities of Tiahuramides A-C, Cyclic Depsipeptides from a Tahitian Collection of the Marine Cyanobacterium Lyngbya majuscula.

PubMed

Levert, Annabel; Alvariño, Rebeca; Bornancin, Louis; Abou Mansour, Eliane; Burja, Adam M; Genevière, Anne-Marie; Bonnard, Isabelle; Alonso, Eva; Botana, Luis; Banaigs, Bernard

2018-05-24

The structures of three new cyclic depsipeptides, tiahuramides A (1), B (2), and C (3), from a French Polynesian collection of the marine cyanobacterium Lyngbya majuscula are described. The planar structures of these compounds were established by a combination of mass spectrometry and 1D and 2D NMR experiments. Absolute configurations of natural and nonproteinogenic amino acids were determined through a combination of acid hydrolysis, derivitization with Marfey's reagent, and HPLC. The absolute configuration of hydroxy acids was confirmed by Mosher's method. The antibacterial activities of tiahuramides against three marine bacteria were evaluated. Compound 3 was the most active compound of the series, with an MIC of 6.7 μM on one of the three tested bacteria. The three peptides inhibit the first cell division of sea urchin fertilized eggs with IC 50 values in the range from 3.9 to 11 μM. Tiahuramide B (2), the most potent compound, causes cellular alteration characteristics of apoptotic cells, blebbing, DNA condensation, and fragmentation, already at the first egg cleavage. The cytotoxic activity of compounds 1-3 was tested in SH-SY5Y human neuroblastoma cells. Compounds 2 and 3 showed an IC 50 of 14 and 6.0 μM, respectively, whereas compound 1 displayed no toxicity in this cell line at 100 μM. To determine the type of cell death induced by tiahuramide C (3), SH-SY5Y cells were costained with annexin V-FITC and propidium iodide and analyzed by flow cytometry. The double staining indicated that the cytotoxicity of compound 3 in this cell line is produced by necrosis.

Corallocins A-C, Nerve Growth and Brain-Derived Neurotrophic Factor Inducing Metabolites from the Mushroom Hericium coralloides.

PubMed

Wittstein, Kathrin; Rascher, Monique; Rupcic, Zeljka; Löwen, Eduard; Winter, Barbara; Köster, Reinhard W; Stadler, Marc

2016-09-23

Three new natural products, corallocins A-C (1-3), along with two known compounds were isolated from the mushroom Hericium coralloides. Their benzofuranone and isoindolinone structures were elucidated by spectral methods. All corallocins induced nerve growth factor and/or brain-derived neurotrophic factor expression in human 1321N1 astrocytes. Furthermore, corallocin B showed antiproliferative activity against HUVEC and human cancer cell lines MCF-7 and KB-3-1.

Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt/mTOR-independent pathway.

PubMed

Zhao, Xiaofang; Luo, Guosong; Cheng, Ying; Yu, Wenjing; Chen, Run; Xiao, Bin; Xiang, Yuancai; Feng, Chunhong; Fu, Wenguang; Duan, Chunyan; Yao, Fuli; Xia, Xianming; Tao, Qinghua; Wei, Mei; Dai, Rongyang

2018-07-01

Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to exert antitumor activities in some types of cells. Whether compound C can exert antitumor effects in human cholangiocarcinoma (CCA) remains unknown. Here, we demonstrated that compound C is a potent inducer of cell death and autophagy in human CCA cells. Autophagy inhibitors increased the cytotoxicity of compound C towards human CCA cells, as confirmed by increased LDH release, and PARP cleavage. It is notable that compound C treatment increased phosphorylated Akt, sustained high levels of phosphorylated p70S6K, and decreased mTOR regulated p-ULK1 (ser757). Based on the data that blocking PI3K/Akt or mTOR had no apparent influence on autophagic response, we suggest that compound C induces autophagy independent of Akt/mTOR signaling in human CCA cells. Further study demonstrated that compound C inhibited the phosphorylation of JNK and its target c-Jun. Blocking JNK by SP600125 or siRNA suppressed autophagy induction upon compound C treatment. Moreover, compound C induced p38 MAPK activation, and its inhibition promoted autophagy induction via JNK activation. In addition, compound C induced p53 expression, and its inhibition attenuated compound C-induced autophagic response. Thus, compound C triggers autophagy, at least in part, via the JNK and p53 pathways in human CCA cells. In conclusion, suppresses autophagy could increase compound C sensitivity in human CCA. © 2018 Wiley Periodicals, Inc.

New Labdane-Type Diterpenoids and Anti-Inflammatory Constituents from Hedychium coronarium

PubMed Central

Chen, Jih-Jung; Ting, Chia-Wei; Wu, Yi-Chin; Hwang, Tsong-Long; Cheng, Ming-Jen; Sung, Ping-Jyun; Wang, Tai-Chi; Chen, Jinn-Fen

2013-01-01

Four new labdane-type diterpenoids: hedychicoronarin (1), peroxycoronarin D (2), 7β-hydroxycalcaratarin A (3), and (E)-7β-hydroxy-6-oxo-labda-8(17),12-diene-15,16-dial (4), have been isolated from the rhizomes of Hedychium coronarium, together with 13 known compounds (5–17). The structures of these new compounds were determined through spectroscopic and MS analyses. Compounds 3, 5, 6, and 10 exhibited inhibition (IC50 values ≤4.52 μg/mL) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 3–6, 10, and 11 inhibited fMLP/CB-induced elastase release with IC50 values ≤6.17 μg/mL. PMID:23799360

Identification and Metabolite Profiling of Chemical Activators of Lipid Accumulation in Green Algae.

PubMed

Wase, Nishikant; Tu, Boqiang; Allen, James W; Black, Paul N; DiRusso, Concetta C

2017-08-01

Microalgae are proposed as feedstock organisms useful for producing biofuels and coproducts. However, several limitations must be overcome before algae-based production is economically feasible. Among these is the ability to induce lipid accumulation and storage without affecting biomass yield. To overcome this barrier, a chemical genetics approach was employed in which 43,783 compounds were screened against Chlamydomonas reinhardtii , and 243 compounds were identified that increase triacylglyceride (TAG) accumulation without terminating growth. Identified compounds were classified by structural similarity, and 15 were selected for secondary analyses addressing impacts on growth fitness, photosynthetic pigments, and total cellular protein and starch concentrations. TAG accumulation was verified using gas chromatography-mass spectrometry quantification of total fatty acids, and targeted TAG and galactolipid measurements were performed using liquid chromatography-multiple reaction monitoring/mass spectrometry. These results demonstrated that TAG accumulation does not necessarily proceed at the expense of galactolipid. Untargeted metabolite profiling provided important insights into pathway shifts due to five different compound treatments and verified the anabolic state of the cells with regard to the oxidative pentose phosphate pathway, Calvin cycle, tricarboxylic acid cycle, and amino acid biosynthetic pathways. Metabolite patterns were distinct from nitrogen starvation and other abiotic stresses commonly used to induce oil accumulation in algae. The efficacy of these compounds also was demonstrated in three other algal species. These lipid-inducing compounds offer a valuable set of tools for delving into the biochemical mechanisms of lipid accumulation in algae and a direct means to improve algal oil content independent of the severe growth limitations associated with nutrient deprivation. © 2017 American Society of Plant Biologists. All Rights Reserved.

Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis.

PubMed

Amawi, Haneen; Hussein, Noor A; Ashby, Charles R; Alnafisah, Rawan; Sanglard, Leticia M; Manivannan, Elangovan; Karthikeyan, Chandrabose; Trivedi, Piyush; Eisenmann, Kathryn M; Robey, Robert W; Tiwari, Amit K

2018-01-01

The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a-15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro , 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.

Computational and in vitro insights on snake venom phospholipase A2 inhibitor of phytocompound ikshusterol3-O-glucoside of Clematis gouriana Roxb. ex DC.

PubMed

Muthusamy, Karthikeyan; Chinnasamy, Sathishkumar; Nagarajan, Subbiah; Sivaraman, Thirunavukkarasu

2017-12-14

Ikshusterol3-O-glucoside was isolated from Clematis gouriana Roxb. ex DC. root. A structure of the isolated compound was determined on the basis of various spectroscopic interpretations (UV, NMR, FTIR, and GC-MS-EI). This structure was submitted in the PubChem compound database (SID 249494133). SID 249494133 was carried out by density functional theory calculation to observe the chemical stability and electrostatic potential of this compound. The absorption, distribution, metabolism, and excretion property of this compound was predicted to evaluate the drug likeness and toxicity. In addition, molecular docking, quantum polarized ligand docking, prime MMGBSA calculation, and induced fit docking were performed to predict the binding status of SID 249494133 with the active site of phospholipase A 2 (PLA 2 ) (PDB ID: 1A3D). The stability of the compound in the active site of PLA 2 was carried out using molecular dynamics simulation. Further, the anti-venom activity of the compound was assessed using the PLA 2 assay against Naja naja (Indian cobra) crude venom. The results strongly show that Ikshusterol3-O-glucoside has a potent snake-venom neutralizing capacity and it might be a potential molecule for the therapeutic treatment for snakebites.

Anti-inflammatory, anti-bacterial activity and structure-activity relationships of substitutions on 4-thiazolidinone derivatives - Part-1.

PubMed

Naeem, Muhammad; Chadhury, Muhammad Nawaz; Amjad, Rana; Rehaman, Salma; Khan, Kahlida

2012-10-01

Environmentally benign and economically feasible procedures have been adopted for the synthesis of novel biologically potential 4-thiazolidinone derivatives. Purpose built microwave oven and ionic liquids (PTCs) showed wrack improvements in yield, time and cost. The yield of 1st series (01-08) obtained in the ranged from 82.4-94.2% and for 2nd series (09-16) obtained 80.6-92.8%. The compounds (01-16) were applied for anti-inflammatory activity at concentrations of 0.5 and 01 mg/kg in carrageenan induced acute and formalin induced chronic inflammatory procedures in mice and better results were obtained at 0.5 mg/kg dose. Some of the compounds 03, 04, 07, 12, 13 showed remarkable anti-inflammatory activity in both procedures as compared to the standard reference drug 2-(2,6-dichloranilino) phenyl acetic acid (diclofenac). Particularly compound 12 and 13 may be used as a non-steroidal anti-inflammatory drug (NSAID) to reduce inflammation. The compounds (01-16) were screened for their antimicrobial activity (in-vivo) and found that the compounds 12, 13 and 14 exhibited comparable or higher antibacterial activity then ciprofloxacin (standard) against E. coli, S. enteritidis, P. aeruginosa, S. aureus and B. subtilis. The compounds of series-2 showed significant activity as compared with ciprofloxacin. These compounds could be lead to the selection and use as efficient antimicrobial agents, especially for the treatment of multi-drug resistant infections.

Analgesic principle from Curcuma amada.

PubMed

Faiz Hossain, Chowdhury; Al-Amin, Mohammad; Rahman, Kazi Md Mahabubur; Sarker, Aurin; Alam, Md Mahamudul; Chowdhury, Mahmudul Hasan; Khan, Shamsun Nahar; Sultana, Gazi Nurun Nahar

2015-04-02

The rhizome of Curcuma amada has been used as a folk medicine for the treatment of rheumatic disorders in the northern part of Bangladesh and has also used for the treatment of inflammation and fever in the Ayurvedic and Unani systems of medicine. Aim of the study was to investigate the analgesic principle of the MeOH extract of the rhizome of Curcuma amada by an in vivo bioassay guided chromatographic separation and purification, and the structure elucidation of the purified compound by spectroscopic methods. Dried powder of Curcuma amada rhizomes was extracted with MeOH. The analgesic activity of the crude extract and its chromatographic fractions as well as the purified compound itself was evaluated by the acetic acid induced writhing method and the formalin induced licking test in Swiss albino mice. The MeOH extract was separated by chromatographic methods and the pure active compound was purified by crystallization in hexanes. The structure of the pure compound was then elucidated by spectroscopic methods. The MeOH extract of Curcuma amada exhibited 41.63% and 45.53% inhibitions in the acetic acid induced writhing method at doses of 200mg/kg and 400mg/kg, respectively. It also exerted 20.43% and 28.50% inhibitions in early phase at doses of 200mg/kg and 400mg/kg, respectively, and 30.41% and 42.95% inhibitions in late phase at doses of 200mg/kg and 400mg/kg, respectively in the formalin induced licking test. Vacuum Liquid Chromatography (VLC) of crude extract yielded five fractions and Fr. 1 was found to have the most potent analgesic activity with inhibitions of 36.96% in the acetic acid induced writhing method and 47.51% (early phase), 39.50% (late phase) in the formalin induced licking test at a dose of 200mg/kg. Column chromatography of Fr. 1 on silica gel generated seven fractions (SF. 1-SF. 7). SF. 2 showed the most potent activity with inhibition of 49.81% in the acetic acid induced writhing method at a dose of 100mg/kg. Crystallization of SF. 2 yielded (1) (zederone, 520mg). It showed statistically significant inhibitions of 38.91% and 52.14% in the acetic acid induced writhing method at doses of 20mg/kg and 40mg/kg, respectively. Moreover, it also showed statistically significant inhibitions of 27.79% and 29.93% (early phase) and of 38.24% and 46.08% (late phase) in the formalin induced licking test at doses of 20mg/kg and 40mg/kg, respectively. Isolation and characterization of zederone (1) as analgesic principle of Curcuma amada corroborate its use in Ayurvedic, Unani and folk medicines for the treatment of rheumatic disorders and also contributing to its pharmacological validation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Isolation, characterization and hypolipidemic activity of ferulic acid in high-fat-diet-induced hyperlipidemia in laboratory rats

PubMed Central

Jain, Pankaj G.; Surana, Sanjay J.

2016-01-01

Prosopis cineraria (L.) Druce (Leguminosae) (syn. Prosopis spicigera L.) has antidiabetic and antioxidant potential. Earlier we reported its hypolipidemic activity obtained from ethanol extract (ET-PCF). Object of this work was to isolate ferulic acid (FA) from ET-PCF and evaluate hypolipidemic activity against high-fat diet (HFD)-induced hyperlipidemic laboratory rats. ET-PCF was subjected to flash column chromatography to isolate FA. The chemical structure of the isolated compound was elucidated by UV, IR, 1H NMR,13C NMR and LC-MS. Further, the antihyperlipidemic effect of FA (10, 20 and 40 mg/kg, p.o.) in HFD-induced hyperlipidemic rats was investigated. Hyperlipidemia was induced in male Sprague-Dawley rats by feeding with HFD for 60 days. Lipid parameters such as total cholesterol (TC), Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) levels were measured in serum and hepatic tissue. Hepatic oxido-nitrosative stress (SOD, GSH, MDA and NO) were also determined. Histological evaluation of liver tissue was carried out. The structure of the isolated compound was characterized based on spectral data and confirmed as FA. HFD induced an alteration in serum, and hepatic lipid profile (triglyceride, cholesterol, HDL, and LDL) was significantly restored (p < 0.001) by administration of FA (20 and 40 mg/kg, p.o.). The elevated level of oxido-nitrosative stress in liver was significantly reduced (p < 0.001) by FA (20 and 40 mg/kg, p.o.). Histological aberration induced in the liver after HFD ingestion were restored by FA administration. Ferulic acid isolated from ET-PCF showed hypolipidemic effects in HFD-induced hyperlipidemic rats via modulation of elevated oxido-nitrosative stress. PMID:28096790

Metabolites with Gram-negative bacteria quorum sensing inhibitory activity from the marine animal endogenic fungus Penicillium sp. SCS-KFD08.

PubMed

Kong, Fan Dong; Zhou, Li Man; Ma, Qing Yun; Huang, Sheng Zhuo; Wang, Pei; Dai, Hao Fu; Zhao, You Xing

2017-01-01

Three new compounds named penicitor A, aculene E and penicitor B, as well as four known compounds, were isolated from the fermentation broth of Penicillium sp. SCS-KFD08 associated with a marine animal Sipunculus nudus from the Haikou bay of China. Their planar structures and absolute configurations were unambiguously elucidated by spectroscopic data, Mosher's method, CD spectrum analysis along with quantum ECD calculation. Among them, compounds 2-7 showed quorum sensing inhibitory activity against Chromobacterium violaceum CV026, and could significantly reduce violacein production in N-hexanoyl-l-homoserine lactone (C6-HSL) induced C. violaceum CV026 cultures at sub-inhibitory concentrations.

Pressure induced structural transitions in CuSbS 2 and CuSbSe 2 thermoelectric compounds

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

Baker, Jason; Kumar, Ravhi S.; Sneed, Daniel

Here, we investigate the structural behavior of CuSbS 2 and CuSbSe 2 thermoelectric materials under high pressure conditions up to 80 GPa using angle dispersive X-ray diffraction in a diamond anvil cell (DAC). We also perform high pressure Raman spectroscopy measurements up to 16 GPa. We observed a pressure-induced structural transformation from the ambient orthorhombic structure with space group Pnma to a triclinic type structure with space group P1 beginning around 8 GPa in both samples and completing at 13 GPa and 10 GPa in CuSbS 2 and CuSbSe 2, respectively. High pressure Raman experiments complement the transitions observed bymore » high pressure X-ray diffraction (HPXRD). Finally, the transitions were found to be reversible on releasing the pressure to ambient in the DAC. The bulk modulus and compressibility of these materials are further discussed.« less

Pressure induced structural transitions in CuSbS 2 and CuSbSe 2 thermoelectric compounds

DOE PAGES

Baker, Jason; Kumar, Ravhi S.; Sneed, Daniel; ...

2015-04-27

Here, we investigate the structural behavior of CuSbS 2 and CuSbSe 2 thermoelectric materials under high pressure conditions up to 80 GPa using angle dispersive X-ray diffraction in a diamond anvil cell (DAC). We also perform high pressure Raman spectroscopy measurements up to 16 GPa. We observed a pressure-induced structural transformation from the ambient orthorhombic structure with space group Pnma to a triclinic type structure with space group P1 beginning around 8 GPa in both samples and completing at 13 GPa and 10 GPa in CuSbS 2 and CuSbSe 2, respectively. High pressure Raman experiments complement the transitions observed bymore » high pressure X-ray diffraction (HPXRD). Finally, the transitions were found to be reversible on releasing the pressure to ambient in the DAC. The bulk modulus and compressibility of these materials are further discussed.« less

Neuroprotective Properties of Compounds Extracted from Dianthus superbus L. against Glutamate-induced Cell Death in HT22 Cells

PubMed Central

Yun, Bo-Ra; Yang, Hye Jin; Weon, Jin Bae; Lee, Jiwoo; Eom, Min Rye; Ma, Choong Je

2016-01-01

Background: Dianthus superbus L. has been used in Chinese herbal medicine as a diuretic and anti-inflammatory agent. Objective: In this study, we isolated ten bioactive compounds from D. superbus and evaluated their neuroprotective activity against glutamate-induced cell death in the hippocampal neuronal HT22 cells. Materials and Methods: New compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O (2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10), were isolated by bioactivity-guided separation. Structures of the isolated compounds were identified on the basis of 1H nuclear magnetic resonance (NMR), 13C NMR, and two-dimensional NMR spectra, while their neuroprotective properties were evaluated by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: D. superbus extract had a neuroprotective effect and isolated 10 compounds. Among the compounds, compounds 5 and 6 effectively protected HT22 cells against glutamate toxicity. Conclusion: In conclusion, the extract of D. superbus and compounds isolated from it exhibited neuroprotective properties, suggesting therapeutic potential for applications in neurotoxic diseases. SUMMARY D. superbus extract significantly protected on glutamate-induced cell death in HT22 cellsNew compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O(2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10) were isolated from D. superbus extract4-hydroxy-benzeneacetic acid and 4-methoxybenzeneacetic acid showed significant protective activity against glutamate-induced toxicity in HT22 cells. Abbreviations used: CNS: Central nervous system, ROS: Reactive oxygen species, CHCl3: Chloroform, EtOAc: Ethyl acetate, BuOH: Butanol, HPLC: High performance liquid chromatography, TLC: Thin layer chromatography, MPLC: Middle performance liquid chromatography, MeOH: Methanol, OD: Optical density, COSY: Correlation spectroscopy, HMQC: Heteronuclear multiple-quantum correlation, HMBC: Heteronuclear multiple-bond correlation, HR-MS: High-resolution molecular spectroscopy, MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. PMID:27076746

Neuroprotective Properties of Compounds Extracted from Dianthus superbus L. against Glutamate-induced Cell Death in HT22 Cells.

PubMed

Yun, Bo-Ra; Yang, Hye Jin; Weon, Jin Bae; Lee, Jiwoo; Eom, Min Rye; Ma, Choong Je

2016-01-01

Dianthus superbus L. has been used in Chinese herbal medicine as a diuretic and anti-inflammatory agent. In this study, we isolated ten bioactive compounds from D. superbus and evaluated their neuroprotective activity against glutamate-induced cell death in the hippocampal neuronal HT22 cells. New compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O (2'',6''-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10), were isolated by bioactivity-guided separation. Structures of the isolated compounds were identified on the basis of (1)H nuclear magnetic resonance (NMR), (13)C NMR, and two-dimensional NMR spectra, while their neuroprotective properties were evaluated by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. D. superbus extract had a neuroprotective effect and isolated 10 compounds. Among the compounds, compounds 5 and 6 effectively protected HT22 cells against glutamate toxicity. In conclusion, the extract of D. superbus and compounds isolated from it exhibited neuroprotective properties, suggesting therapeutic potential for applications in neurotoxic diseases. D. superbus extract significantly protected on glutamate-induced cell death in HT22 cellsNew compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O(2'',6''-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10) were isolated from D. superbus extract4-hydroxy-benzeneacetic acid and 4-methoxybenzeneacetic acid showed significant protective activity against glutamate-induced toxicity in HT22 cells. Abbreviations used: CNS: Central nervous system, ROS: Reactive oxygen species, CHCl3: Chloroform, EtOAc: Ethyl acetate, BuOH: Butanol, HPLC: High performance liquid chromatography, TLC: Thin layer chromatography, MPLC: Middle performance liquid chromatography, MeOH: Methanol, OD: Optical density, COSY: Correlation spectroscopy, HMQC: Heteronuclear multiple-quantum correlation, HMBC: Heteronuclear multiple-bond correlation, HR-MS: High-resolution molecular spectroscopy, MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

Defect propagation in one-, two-, and three-dimensional compounds doped by magnetic atoms

DOE PAGES

Furrer, A.; Podlesnyak, A.; Krämer, K. W.; ...

2014-10-29

Inelastic neutron scattering experiments were performed to study manganese(II) dimer excitations in the diluted one-, two-, and three-dimensional compounds CsMn xMg 1-xBr 3, K 2Mn xZn 1-xF 4, and KMn xZn 1-xF 3 (x≤0.10), respectively. The transitions from the ground-state singlet to the excited triplet, split into a doublet and a singlet due to the single-ion anisotropy, exhibit remarkable fine structures. These unusual features are attributed to local structural inhomogeneities induced by the dopant Mn atoms which act like lattice defects. Statistical models support the theoretically predicted decay of atomic displacements according to 1/r 2, 1/r, and constant (for three-,more » two-, and one-dimensional compounds, respectively) where r denotes the distance of the displaced atoms from the defect. In conclusion, the observed fine structures allow a direct determination of the local exchange interactions J, and the local intradimer distances R can be derived through the linear law dJ/dR.« less

Design of high breakdown voltage vertical GaN p-n diodes with high-K/low-K compound dielectric structure for power electronics applications

NASA Astrophysics Data System (ADS)

Du, Jiangfeng; Li, Zhenchao; Liu, Dong; Bai, Zhiyuan; Liu, Yang; Yu, Qi

2017-11-01

In this work, a vertical GaN p-n diode with a high-K/low-K compound dielectric structure (GaN CD-VGD) is proposed and designed to achieve a record high breakdown voltage (BV) with a low specific on-resistance (Ron,sp). By introducing compound dielectric structure, the electric field near the p-n junction interface is suppressed due to the effects of high-K passivation layer, and a new electric field peak is induced into the n-type drift region, because of a discontinuity of electrical field at the interface of high-K and low-K layer. Therefore the distribution of electric field in GaN p-n diode becomes more uniform and an enhancement of breakdown voltage can be achieved. Numerical simulations demonstrate that GaN CD-VGD with a BV of 10650 V and a Ron,sp of 14.3 mΩ cm2, resulting in a record high figure-of-merit of 8 GW/cm2.

Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors

PubMed Central

Zhong, Bo; Chennamaneni, Snigdha; Lama, Rati; Yi, Xin; Geldenhuys, Werner J.; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

2013-01-01

Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development. PMID:23767669

Bioactive Steroids with Methyl Ester Group in the Side Chain from a Reef Soft Coral Sinularia brassica Cultured in a Tank.

PubMed

Huang, Chiung-Yao; Su, Jui-Hsin; Liaw, Chih-Chuang; Sung, Ping-Jyun; Chiang, Pei-Lun; Hwang, Tsong-Long; Dai, Chang-Feng; Sheu, Jyh-Horng

2017-09-01

A c ontinuing chemical investigation of the ethyl acetate (EtOAc) extract of a reef soft coral Sinularia brassica , which was cultured in a tank, afforded four new steroids with methyl ester groups, sinubrasones A-D (1-4) for the first time. In particular, 1 possesses a β-D-xylopyranose. The structures of the new compounds were elucidated on the basis of spectroscopic analyses. The cytotoxicities of compounds 1-4 against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of these new compounds 1-4 were also evaluated by measuring their ability to suppress superoxide anion generation and elastase release in N -formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced human neutrophils. Compounds 2 and 3 were shown to exhibit significant cytotoxicity, and compounds 3 and 4 were also found to display attracting anti-inflammatory activities.

Particulate reduction in ternary-compound film growth via pulsed laser deposition from segmented binary-targets

NASA Astrophysics Data System (ADS)

Grant-Jacob, James A.; Prentice, Jake J.; Beecher, Stephen J.; Shepherd, David P.; Eason, Robert W.; Mackenzie, Jacob I.

2018-03-01

We present the hetero-epitaxial growth of high-quality crystalline Y3Ga5O12 onto a 〈100〉-oriented YAG substrate via pulsed laser deposition, using mixed ternary-compound and segmented binary-compound targets. We observe that a Y3Ga5O12 film fabricated using a segmented target (Y2O3/Ga2O3) contained ∼100 times fewer scattering points than a film grown using a mixed Y3Ga5O12 target. We show that following ablation, the surface of the mixed compound (ternary) target had laser-induced cone structures, whereas the surface of single compound (binary) targets did not. It is concluded that the different ablation dynamics of the oxide constituents in the respective targets plays a significant role in the origin of the scattering points in the resultant films.

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

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

Zeng, Mei; Lu, Jia; Li, Lianbo

Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency,more » and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.« less

The amphiphilic alkyl ester derivatives of l-ascorbic acid induce reorganization of phospholipid vesicles.

PubMed

Giudice, Francesca; Ambroggio, Ernesto E; Mottola, Milagro; Fanani, Maria Laura

2016-09-01

l-ascorbic acid alkyl esters (ASCn) are lipophilic forms of vitamin C, which maintain some of its antioxidant power. Those properties make this drug family attractive to be used in pharmacological preparations protecting other redox-sensible drugs or designed to reduce possible toxic oxidative processes. In this work, we tested the ability of l-ascorbic acid alkyl esters (ASCn) to modulate the structure, permeability, and rheological properties of phospholipid bilayers. The ASCn studied here (ASC16, ASC14, and ASC12) alter the structural integrity as well as the rheological properties of phospholipid membranes without showing any evident detergent activity. ASC14 appeared as the most efficient drug in destabilize the membrane structure of nano- and micro-size phospholipid liposomes inducing vesicle content leakage and shape elongation on giant unilamellar vesicles. It also was the most potent enhancer of membrane microviscosity and surface water structuring. Only ASC16 induced the formation of drug-enriched condensed domains after its incorporation into the lipid bilayer, while ASC12 appeared as the less membrane-disturbing compound, likely because of its poor, and more superficial, partition into the membrane. We also found that incorporation of ASCn into the lipid bilayers enhanced the reduction of membrane components, compared with soluble vitamin C. Our study shows that ASCn compounds, which vary in the length of the acyl chain, show different effects on phospholipid vesicles used as biomembrane models. Those variances may account for subtly differences in the effectiveness on their pharmacological applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure and dynamics in low-dimensional guest host solids

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

Fischer, J.

1991-04-01

This progress report presents results from work during the period of June 1, 1990 through May 31st, 1991. Topics discussed include instrumentation, publications, and personnel. Work areas discussed include: pressure-induced transitions in Li- and Ag-TiS{sub 2}, hyper-dense superconducting GIC's, temperature-dependent x-ray structure of (CH){sub x} and (CH){sub 2{sup x}}:analogies to rotator phases in short-chain alkanes, trans-(CH){sub x} at high'' pressure, broken symmetries'' in polymer intercalation channel lattices, high-resolution study of conductivity and cell potential vs. concentration in K-doped (CH){sub x}, new'' doped (CH){sub x} phases: ternary compounds and amorphous'' intercalation compounds, and vibrational density states from inelastic neutron scattering. (JF).

Picrotoxane sesquiterpenoids from the stems of Dendrobium nobile and their absolute configurations and angiogenesis effect.

PubMed

Meng, Chun-Wang; He, Yu-Lin; Peng, Cheng; Ding, Xing-Jie; Guo, Li; Xiong, Liang

2017-09-01

Five picrotoxane sesquiterpenoids belonging to the unusual dendrobine-type (1 and 4) and the picrotoxinin-type (2, 3, and 5) were isolated from the stems of Dendrobium nobile Lindl. Their structures were established by spectroscopic analyses and physical properties. Compound 1 was a new dendrobine analogue. Although the planar structure of 2 and 3 had been reported, their absolute configurations were first determined by single-crystal X-ray diffraction and circular dichroism. Compound 2 exhibited angiogenesis effect against sunitinib-induced damage on intersegmental blood vessels in Tg (flk1: EGFP) and Tg (fli1: nEGFP) transgenic zebrafish at concentrations of 3.13, 6.25, 12.50, and 25.00μM. Copyright © 2017. Published by Elsevier B.V.

Absence of pressure-induced amorphization in LiKSO4.

PubMed

Machon, D; Pinheiro, C B; Bouvier, P; Dmitriev, V P; Crichton, W A

2010-08-11

Angle-resolved synchrotron radiation diffraction was used to investigate lithium potassium sulfate (LiKSO(4)) crystals under high pressure. We confirm that the title compound undergoes three phase transitions, α →β, β → γ and γ →δ, observed at around 0.8 GPa, 4.0 GPa and 7.0 GPa, respectively. Two competitive structures are proposed for the β-phase after powder diffraction data Rietveld refinements: an orthorhombic (space group Cmc 2(1)) or a monoclinic (space group Cc) structure. These structures correspond to the models of the low temperature phases. The γ-phase is indexed by a monoclinic structure. Finally, the δ-phase is found to be highly disordered. No evidence of any pressure-induced amorphous phase was observed up to 24 GPa, even under imposed highly non-hydrostatic conditions, contrary to previous propositions.

Ravynic acid, an antibiotic polyeneyne tetramic acid from Penicillium sp. elucidated through synthesis.

PubMed

Myrtle, J D; Beekman, A M; Barrow, R A

2016-09-21

A new antibiotic natural product, ravynic acid, has been isolated from a Penicillium sp. of fungus, collected from Ravensbourne National Park. The 3-acylpolyenyne tetramic acid structure was definitively elucidated via synthesis. Highlights of the synthetic method include the heat induced formation of the 3-acylphosphorane tetramic acid and a selective Wittig cross-coupling to efficiently prepare the natural compounds carbon skeleton. The natural compound was shown to inhibit the growth of Staphylococcus aureus down to concentrations of 2.5 µg mL(-1).

(M)- and (P)-bicelaphanol A, dimeric trinorditerpenes with promising neuroprotective activity from Celastrus orbiculatus.

PubMed

Wang, Luo-Yi; Wu, Jian; Yang, Zhuo; Wang, Xu-Jie; Fu, Yan; Liu, Shuang-Zhu; Wang, Hong-Min; Zhu, Wei-Liang; Zhang, Hai-Yan; Zhao, Wei-Min

2013-04-26

(M)-Bicelaphanol A (1) and (P)-bicelaphanol A (2), two unprecedented dimeric trinorditerpenes existing as atropisomers, together with their monomer celaphanol A (3), were isolated from the root bark of Celastrus orbiculatus. The structures and absolute configurations of 1 and 2 were determined by spectroscopic and single-crystal X-ray diffraction analyses. Compound 1 exhibited a significant in vitro neuroprotective effect against a hydrogen peroxide-induced cell viability decrease in PC12 cells at 1 μM, while compounds 2 and 3 showed such effects at 10 μM.

Krempfielins Q and R, Two New Eunicellin-Based Diterpenoids from the Soft Coral Cladiella krempfi

PubMed Central

Tai, Chi-Jen; Chokkalingam, Uvarani; Cheng, Yang; Shih, Shou-Ping; Lu, Mei-Chin; Su, Jui-Hsin; Hwang, Tsong-Long; Sheu, Jyh-Horng

2014-01-01

Two new eunicellin-based diterpenoids, krempfielins Q and R (1 and 2), and one known compound cladieunicellin K (3) have been isolated from a Formosan soft coral Cladiella krempfi. The structures of these two new metabolites were elucidated by extensive spectroscopic analysis. Anti-inflammatory activity of new metabolites to inhibit the superoxide anion generation and elastase release in N-formyl-methionyl-leucyl phenylalanine/cytochalasin B (FMLP/CB)-induced human neutrophil cells and cytotoxicity of both new compounds toward five cancer cell lines were reported. PMID:25437917

Krempfielins Q and R, two new eunicellin-based diterpenoids from the soft coral Cladiella krempfi.

PubMed

Tai, Chi-Jen; Chokkalingam, Uvarani; Cheng, Yang; Shih, Shou-Ping; Lu, Mei-Chin; Su, Jui-Hsin; Hwang, Tsong-Long; Sheu, Jyh-Horng

2014-11-27

Two new eunicellin-based diterpenoids, krempfielins Q and R (1 and 2), and one known compound cladieunicellin K (3) have been isolated from a Formosan soft coral Cladiella krempfi. The structures of these two new metabolites were elucidated by extensive spectroscopic analysis. Anti-inflammatory activity of new metabolites to inhibit the superoxide anion generation and elastase release in N-formyl-methionyl-leucyl phenylalanine/cytochalasin B (FMLP/CB)-induced human neutrophil cells and cytotoxicity of both new compounds toward five cancer cell lines were reported.

Utilization of a quantitative mammalian cell mutation system, CHO/HGPRT, in experimental mutagenesis and genetic toxicology

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

Hsie, A. W.; Couch, D. B.; O'Neill, J. P.

1977-01-01

Development of the CHO/HGPRT system is described and a host-mediated CHO/HGPRT assay is discussed. The following topics are discussed: evidence for the genetic origin of mutation induction in the CHO/HGPRT system; dose-response relationship for EMS-mediated mutation induction and cell lethality; apparent dosimetry of EMS-induced mutagenesis; structure-activity relationship of alkylating agents and ICR compounds; mutagenicity and cytotoxicity of congeners of two classes of nitrosi compounds; and preliminary validation of the CHO/HGPRT assay in predicting chemical carcinogenicity. (HLW)

International Conference on Phonon Physics, 31 August-3 September 1981. Bloomington, Indiana,

DTIC Science & Technology

1981-12-01

sics.Dept., Bloomington, IN 565, Japan. 47405, U.S.A. IWASA, I.- Dept. of Physics, Univ. of Tokyo, 7-3-1 Bongo , Bunkyo- ku, 113 Tokyo, Japan...electron phonon interaction in IV compounds (4). In IV compounds with NaCl structure the phonons mostly affected by the coupling to the RE ion are those...photo-Induced bend edge shift which io on the order of 0.1 *Y towardI the red.* None of the phoson parameters discussed In this paper were affected by

Tuning reactivity of diphenylpropynone derivatives with metal-associated amyloid-β species via structural modifications.

PubMed

Liu, Yuzhong; Kochi, Akiko; Pithadia, Amit S; Lee, Sanghyun; Nam, Younwoo; Beck, Michael W; He, Xiaoming; Lee, Dongkuk; Lim, Mi Hee

2013-07-15

A diphenylpropynone derivative, DPP2, has been recently demonstrated to target metal-associated amyloid-β (metal-Aβ) species implicated in Alzheimer's disease (AD). DPP2 was shown to interact with metal-Aβ species and subsequently control Aβ aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Aβ species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (C1/C2, P1/P2, and PA1/PA2) as structurally modified DPP2 analogues. A similar metal binding site to that of DPP2 was contained in these compounds while their structures were varied to afford different interactions and reactivities with metal ions, Aβ species, and metal-Aβ species. Distinct reactivities of our chemical family toward in vitro Aβ aggregation in the absence and presence of metal ions were observed. Among our chemical series, the compound (C2) with a relatively rigid backbone and a dimethylamino group was observed to noticeably regulate both metal-free and metal-mediated Aβ aggregation to different extents. Using our compounds, cell viability was significantly improved, compared to that with DPP2. Lastly, modifications on the DPP framework maintained the structural properties for potential blood-brain barrier (BBB) permeability. Overall, our studies demonstrated that structural variations adjacent to the metal binding site of DPP2 could govern different metal binding properties, interactions with Aβ and metal-Aβ species, reactivity toward metal-free and metal-induced Aβ aggregation, and cytotoxicity of the compounds, establishing a structure-reactivity-cytotoxicity relationship. This information could help gain insight into structural optimization for developing nontoxic chemical reagents toward targeting metal-Aβ species and modulating their reactivity in biological systems.

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

Eldridge, Sandy R.; Covey, Joseph; Morris, Joel

NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100 mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule withmore » a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100 mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia. - Highlights: • NSC-743380 induced biliary hyperplasia in rats. • Toxicity of NSC-743380 appears to be related to its anticancer activity. • The model provides an opportunity to explore biomarkers of biliary hyperplasia.« less

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 1. Synthesis and SAR of alpha,alpha-dimethylglycine sulfonamides.

PubMed

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Berettoni, Marco; Calvani, Federico; Catrambone, Fernando; Felicetti, Patrizia; Gensini, Martina; Terracciano, Rosa; Altamura, Maria; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2006-06-15

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.

LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.

PubMed

Alexandre-Moreira, Magna S; Takiya, Christina M; de Arruda, Luciana B; Pascarelli, Bernardo; Gomes, Raquel N; Castro Faria Neto, Hugo C; Lima, Lídia M; Barreiro, Eliezer J

2005-03-01

As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.

Regulation of the Feruloyl Esterase (faeA) Gene from Aspergillus niger

PubMed Central

de Vries, Ronald P.; Visser, Jaap

1999-01-01

Feruloyl esterases can remove aromatic residues (e.g., ferulic acid) from plant cell wall polysaccharides (xylan, pectin) and are essential for complete degradation of these polysaccharides. Expression of the feruloyl esterase-encoding gene (faeA) from Aspergillus niger depends on d-xylose (expression is mediated by XlnR, the xylanolytic transcriptional activator) and on a second system that responds to aromatic compounds with a defined ring structure, such as ferulic acid and vanillic acid. Several compounds were tested, and all of the inducing compounds contained a benzene ring which had a methoxy group at C-3 and a hydroxy group at C-4 but was not substituted at C-5. Various aliphatic groups occurred at C-1. faeA expression in the presence of xylose or ferulic acid was repressed by glucose. faeA expression in the presence of ferulic acid and xylose was greater than faeA expression in the presence of either compound alone. The various inducing systems allow A. niger to produce feruloyl esterase not only during growth on xylan but also during growth on other ferulic acid-containing cell wall polysaccharides, such as pectin. PMID:10584009

Toxicity, mutagenicity and transport in Saccharomyces cerevisiae of three popular DNA intercalating fluorescent dyes.

PubMed

Sayas, Enric; García-López, Federico; Serrano, Ramón

2015-09-01

We have compared the toxicity, mutagenicity and transport in Saccharomyces cerevisiae of three DNA-intercalating fluorescent dyes widely used to stain DNA in gels. Safety data about ethidium bromide (EtBr) are contradictory, and two compounds of undisclosed structure (Redsafe and Gelred) have been proposed as safe alternatives. Our results indicate that all three compounds inhibit yeast growth, with Gelred being the most inhibitory and also the only one causing cell death. EtBr and Gelred, but not Redsafe, induce massive formation of petite (non-respiratory) mutants, but only EtBr induces massive loss of mitochondrial DNA. All three compounds increase reversion of a chromosomal point mutation (lys2-801(amber) ), with Gelred being the most mutagenic and Redsafe the least. These dyes are all cationic and are probably taken by cells through non-selective cation channels. We could measure the glucose-energized transport of EtBr and Gelred inside the cells, while uptake of Redsafe was below our detection limit. We conclude that although all three compounds are toxic and mutagenic in the yeast system, Redsafe is the safest for yeast, probably because of very limited uptake by these cells. Copyright © 2015 John Wiley & Sons, Ltd.

The influence of projectile ion induced chemistry on surface pattern formation

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

Karmakar, Prasanta, E-mail: prasantak@vecc.gov.in; Satpati, Biswarup

We report the critical role of projectile induced chemical inhomogeneity on surface nanostructure formation. Experimental inconsistency is common for low energy ion beam induced nanostructure formation in the presence of uncontrolled and complex contamination. To explore the precise role of contamination on such structure formation during low energy ion bombardment, a simple and clean experimental study is performed by selecting mono-element semiconductors as the target and chemically inert or reactive ion beams as the projectile as well as the source of controlled contamination. It is shown by Atomic Force Microscopy, Cross-sectional Transmission Electron Microscopy, and Electron Energy Loss Spectroscopy measurementsmore » that bombardment of nitrogen-like reactive ions on Silicon and Germanium surfaces forms a chemical compound at impact zones. Continuous bombardment of the same ions generates surface instability due to unequal sputtering and non-uniform re-arrangement of the elemental atom and compound. This instability leads to ripple formation during ion bombardment. For Argon-like chemically inert ion bombardment, the chemical inhomogeneity induced boost is absent; as a result, no ripples are observed in the same ion energy and fluence.« less

Limonin Methoxylation Influences Induction of Glutathione S-Transferase and Quinone Reductase

PubMed Central

PEREZ, JOSE LUIS; JAYAPRAKASHA, G. K.; VALDIVIA, VIOLETA; MUNOZ, DIANA; DANDEKAR, DEEPAK V.; AHMAD, HASSAN; PATIL, BHIMANAGOUDA S.

2009-01-01

Previous studies have indicated the chemoprevention potential of citrus limonoids due to the induction of phase II detoxifying enzymes. In the present study, three citrus limonoids were purified and identified from sour orange seeds as limonin, limonin glucoside (LG), deacetylnomilinic acid glucoside (DNAG). In addition, limonin was modified to defuran limonin and limonin 7-methoxime. The structures of these compounds were confirmed by NMR studies. These five compounds were used to investigate the influence of Phase II enzymes in female A/J mice. Our results indicated that the highest induction of Glutathione S-Transferase (GST) activity against 1-chloro-2, 4-dinitrobenzene (CDNB) by DNAG (67%) in lung homogenates followed by limonin-7-methoxime (32%) in treated liver homogenates. Interestingly, the limonin-7-methoxime showed the highest GST activity (270%) in liver against 4-nitroquinoline 1-oxide (4NQO), while the same compound in stomach induced GST by 51% compared to the control. DNAG treated group induced 55% in stomach homogenates. Another Phase II enzyme, quinone reductase (QR), was significantly induced by limonin-7-methoxime by 65 and 32% in liver and lung homogenates, respectively. Defuran limonin, induced QR in lung homogenates by 45%. Our results indicated that modification of the limonin have differential induction of phase II enzymes. These findings are indicative of a possible mechanism for the prevention of cancer by aiding in detoxification of xenobiotics. PMID:19480426

Density functional theory molecular modeling, chemical synthesis, and antimicrobial behaviour of selected benzimidazole derivatives

NASA Astrophysics Data System (ADS)

Marinescu, Maria; Tudorache, Diana Gabriela; Marton, George Iuliu; Zalaru, Christina-Marie; Popa, Marcela; Chifiriuc, Mariana-Carmen; Stavarache, Cristina-Elena; Constantinescu, Catalin

2017-02-01

Eco-friendly, one-pot, solvent-free synthesis of biologically active 2-substituted benzimidazoles is presented and discussed herein. Novel N-Mannich bases are synthesized from benzimidazoles, secondary amines and formaldehyde, and their structures are confirmed by 1H nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), and elemental analysis. All benzimidazole derivatives are evaluated by qualitative and quantitative methods against 9 bacterial strains. The largest microbicide and anti-biofilm effect is observed for the 2-(1-hydroxyethyl)-compounds. Density functional theory (DFT) modeling of the molecular structure and frontier molecular orbitals, i.e. highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO/LUMO), is accomplished by using the GAMESS 2012 software. Antimicrobial activity is correlated with the electronic parameters (chemical hardness, electronic chemical potential, global electrophilicity index), Mullikan atomic charges and geometric parameters of the benzimidazole compounds. The planarity of the compound, symmetry of the molecule, and the presence of a nucleophilic group, are advantages for a high antimicrobial activity. Finally, we briefly show that further accurate processing of such compounds into thin films and hybrid structures, e.g. by laser ablation matrix-assisted pulsed laser evaporation and/or laser-induced forward transfer, may indeed provide simple and environmental friendly, state-of-the-art solutions for antimicrobial coatings.

Identification of Transthyretin Fibril Formation Inhibitors Using Structure-Based Virtual Screening.

PubMed

Ortore, Gabriella; Martinelli, Adriano

2017-08-22

Transthyretin (TTR) is the primary carrier for thyroxine (T 4 ) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild-type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti-Pseudomonas aeruginosa compound, 1,2,3,4-tetrahydro-1,3,5-triazine derivative, exerts its action by primarily targeting MreB.

PubMed

Yamachika, Shinichiro; Sugihara, Chika; Tsuji, Hayato; Muramatsu, Yasunori; Kamai, Yasuki; Yamashita, Makoto

2012-01-01

In order to find new anti-Pseudomonas agents, we carried out whole-cell based P. aeruginosa growth assay, and identified 1,2,3,4-tetrahydro-1,3,5-triazine (Compound A). This compound showed anti-Pseudomonas activity against wild as well as pumpless strain equally at a same concentration. Also, this compound was structurally very similar to A22, which is known to inhibit the bacterial actin-like protein MreB. By the analysis of resistant strains, the primary target of this compound in P. aeruginosa was definitely confirmed to be MreB. In addition, these compounds showed a bacteriostatic effect, and induced the morphology changes in P. aeruginosa from rod shape to sphere shape, which leads to be clinically favorable in terms of susceptibility to phagocytosis and release of endotoxin. These results display that Compound A is a very attractive compound which shows anti-P. aeruginosa activity based on inhibition of MreB without being affected by efflux pumps, and could provide a new step toward development of new promising anti-Pseudomonas agents, MreB inhibitors.

Potentiation of Tumor Necrosis Factor-α-induced Tumor Cell Apoptosis by a Small Molecule Inhibitor for Anti-apoptotic Protein hPEBP4

PubMed Central

Qiu, Jianming; Xiao, Jianfeng; Han, Chaofeng; Li, Nan; Shen, Xu; Jiang, Hualiang; Cao, Xuetao

2010-01-01

hPEBP4 (human phosphatidylethanolamine-binding protein 4) has been identified to be able to potentiate the resistance of breast, prostate, and ovarian cancers, with the preferential expression of hPEBP4, to tumor necrosis factor-α (TNF-α) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, suggesting that inhibitors targeting the anti-apoptotic protein hPEBP4 may be useful to increase the sensitivity of hPEBP4-expressing cancer cells to TNF-α or TRAIL-induced apoptosis. By structure-based virtual screening and following surface plasmon resonance-based binding assay, seven small compounds were found to potently bind with hPEBP4. The hit compounds were further functionally screened for their ability to inhibit cancer cell growth, and one small compound, IOI-42, was identified to be able to promote TNF-α-mediated growth inhibition of MCF-7 breast cancer cells. IOI-42 could potentiate TNF-α-induced apoptosis of MCF-7 cells by inhibiting hPEBP4 and could suppress anchorage-independent cell growth of MCF-7 cells. We further demonstrated that IOI-42 could reduce the endogenous association of hPEBP4 with Raf-1/MEK1 and enhance the activation of ERK1/2 and JNK while inhibiting Akt activation. Furthermore, IOI-42 also promoted TRAIL-induced cell apoptosis of prostate cancer cells. Taken together, our data suggest that IOI-42, as the first chemical inhibitor of anti-apoptotic protein hPEBP4, may serve as a potential anti-tumor drug by sensitizing tumor cells to apoptotic inducers. PMID:20177075

Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data

PubMed Central

Muehlbacher, Markus; Tripal, Philipp; Roas, Florian; Kornhuber, Johannes

2012-01-01

Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 μm and 5.0 μm). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood–brain barrier, and compounds that violate Lipinski’s rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID:22945602

Small-molecule inducers of Aβ-42 peptide production share a common mechanism of action.

PubMed

Bettayeb, Karima; Oumata, Nassima; Zhang, Yuanyuan; Luo, Wenjie; Bustos, Victor; Galons, Hervé; Greengard, Paul; Meijer, Laurent; Flajolet, Marc

2012-12-01

The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin-4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 μM. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of γ-secretase components and could, therefore, modify γ-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other "AD accelerator" compounds. In summary, treatment with three Aβ42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.

Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers.

PubMed

Llanos, Gabriel G; Araujo, Liliana M; Jiménez, Ignacio A; Moujir, Laila M; Rodríguez, Jaime; Jiménez, Carlos; Bazzocchi, Isabel L

2017-11-10

Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds (2-64), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC 50 values ranging 0.3-4.8 μM) than the lead (IC 50 values ranging 1.3-10.1 μM) either in lag or log growth phases. SAR analysis revealed that acylation enhances cytotoxicity, suggesting the hydrophobic moiety contributes to the activity, presumably by increasing affinity and/or cell membrane permeability. Further investigation clearly indicated that compounds 3, 11, 12, and 18 induce apoptosis evidenced by chromatin condensation, phosphatidylserine externalization, and caspase-3 activation effects on HeLa cells. The potent capacity to induce apoptosis with concomitant cell loss in G2/M highlights the potential of 27-benzyl analogue (18) as an apoptotic inducer drug candidate. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells.

PubMed

Ordóñez, Paola E; Sharma, Krishan K; Bystrom, Laura M; Alas, Maria A; Enriquez, Raul G; Malagón, Omar; Jones, Darin E; Guzman, Monica L; Compadre, Cesar M

2016-04-22

The sesquiterpene lactones dehydroleucodine (1) and leucodine (2) were isolated from Gynoxys verrucosa, a species used in traditional medicine in southern Ecuador. The activity of these compounds was determined against eight acute myeloid leukemia (AML) cell lines and compared with their activity against normal peripheral blood mononuclear cells. Compound 1 showed cytotoxic activity against the tested cell lines, with LD50 values between 5.0 and 18.9 μM. Compound 2 was inactive against all of the tested cell lines, demonstrating that the exocyclic methylene in the lactone ring is required for cytotoxic activity. Importantly, compound 1 induced less toxicity to normal blood cells than to AML cell lines and was active against human AML cell samples from five patients, with an average LD50 of 9.4 μM. Mechanistic assays suggest that compound 1 has a similar mechanism of action to parthenolide (3). Although these compounds have significant structural differences, their lipophilic surface signatures show striking similarities.

Antitussive, expectorant, and anti-inflammatory activities of four caffeoylquinic acids isolated from Tussilago farfara.

PubMed

Wu, Qi-Zhen; Zhao, Dong-Xia; Xiang, Juan; Zhang, Mian; Zhang, Chao-Feng; Xu, Xiang-Hong

2016-07-01

The flower bud of Tussilago farfara L. (Compositae) (FTF) is one of the traditional Chinese medicinal herbs used to treat cough, phlegm, bronchitic, and asthmatic conditions. The objective of this study is to isolate four caffeoylquinic acids from the ethyl acetate extract (EtE) of FTF and to evaluate their antitussive, expectorant, and anti-inflammatory activities. The structures of compounds 1-4 isolated from EtE were determined by spectral analysis. Mice were orally treated with these compounds and their mixture (in a ratio of 5:28:41:26 as in EtE) at doses of 10 and 20 mg/kg once daily for 3 d. The antitussive and expectorant activities were evaluated separately with the ammonia liquor-induced model and the phenol red secretion model. The anti-inflammation activity was evaluated using leukocyte count in the bronchoalveolar lavage fluid after ammonia liquor-induced acute airway inflammation. The four compounds were identified as chlorogenic acid (1), 3,5-dicaffeoylquinic acid (2), 3,4-dicaffeoylquinic acid (3), and 4,5-dicaffeoylquinic acid (4). All compounds, especially compound 4 (58.0% inhibition in cough frequency), showed a significant antitussive effect. However, the mixture was the most effective to inhibit the cough frequency by 61.7%. All compounds also showed a significant expectorant effect, while compound 2 was the most potent to enhance the phenol red secretion by 35.7%. All compounds significantly alleviated inflammation, but compound 4 showed the strongest effect to inhibit the leukocytosis by 49.7%. The caffeoylquinic acids and their mixture, exhibiting significant antitussive, expectorant, and anti-inflammatory effects, could be considered as the main effective ingredients of FTF, and they may act in a collective and synergistic way.

Bioactive Constituents from an Endophytic Fungus, Penicillium polonicum NFW9, Associated with Taxus fauna.

PubMed

Fatima, Nighat; Sripisut, Tawanun; Youn, Ui J; Ahmed, Safia; Ul-Haq, Ihsan; Munoz-Acuna, Ulyana; Simmons, Charles J; Qazi, Muneer A; Jadoon, Muniba; Tan, Ghee T; de Blanco, Esperanza J C; Chang, Leng C

2017-01-01

Endophytic fungi are being recognized as vital and untapped sources of a variety of structurally novel and unique bioactive secondary metabolites in the field of natural products drug discovery. Herein, this study reports the isolation and characterization of secondary metabolites from an endophytic fungus Penicillium polonicum (NFW9) associated with Taxus fuana. The extracts of the endophytic fungus cultured on potato dextrose agar were purified using several chromatographic techniques. Biological evaluation was performed based on their abilities to inhibit tumor necrosis factor-alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) and cytotoxicity assays. Bioactivity-directed fractionation of the ethyl acetate extract of a fermentation culture of an endophytic fungus, Penicillium polonicum led to the isolation of a dimeric anthraquinone, (R)- 1,1',3,3',5,5'-hexahydroxy-7,7'-dimethyl[2,2'-bianthracene]-9,9',10,10'-tetraone (1), a steroidal furanoid (-)-wortmannolone (2), along with three other compounds (3-4). Moreover, this is the first report on the isolation of compound 1 from an endophytic fungus. All purified metabolites were characterized by NMR and MS data analyses. The stereo structure of compound 1 was determined by the measurement of specific optical rotation and CD spectrum. The relative stereochemistry of 2 was confirmed by single-crystal X-ray diffraction. Compounds 2-3 showed inhibitory activities in the TNF-α-induced NF-κB assay with IC50 values in the range of 0.47-2.11 µM. Compounds 1, 4 and 5 showed moderate inhibition against NF-κB and cancer cell lines. The endophytic fungus Penicillium polonicum of Taxus fuana is capable of producing biologically active natural compounds. Our results provide a scientific rationale for further chemical investigations into endophyte-producing natural products, drug discovery and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

PubMed

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

Phenolics and compartmentalization in the sapwood of broad-leaved trees

Treesearch

Kevin T. Smith

1997-01-01

Tree survival depends on the chemistry of phenolic compounds, a broad class of chemicals characterized by a hydroxylated benzene ring. In trees, phenolics occur frequently as polymers, acids, or glycosylated esters and perform diverse functions. For example, lignin, a phenylpropane heteropolymer, provides structural strength to wood. The induced production of phenols...

Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142

PubMed Central

Shin, Hee Jae; Pil, Gam Bang; Heo, Soo-Jin; Lee, Hyi-Seung; Lee, Jong Seok; Lee, Yeon-Ju; Lee, Jihoon; Won, Ho Shik

2016-01-01

Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1–5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID:26761016

Pressure induced phase transitions in ceramic compounds containing tetragonal zirconia

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

Sparks, R.G.; Pfeiffer, G.; Paesler, M.A.

Stabilized tetragonal zirconia compounds exhibit a transformation toughening process in which stress applied to the material induces a crystallographic phase transition. The phase transition is accompanied by a volume expansion in the stressed region thereby dissipating stress and increasing the fracture strength of the material. The hydrostatic component of the stress required to induce the phase transition can be investigated by the use of a high pressure technique in combination with Micro-Raman spectroscopy. The intensity of Raman lines characteristic for the crystallographic phases can be used to calculate the amount of material that has undergone the transition as a functionmore » of pressure. It was found that pressures on the order of 2-5 kBar were sufficient to produce an almost complete transition from the original tetragonal to the less dense monoclinic phase; while a further increase in pressure caused a gradual reversal of the transition back to the original tetragonal structure.« less

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale).

PubMed

Lohning, Anna E; Marx, Wolfgang; Isenring, Liz

2016-11-01

Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale). These compounds have demonstrated in vitro to exert 5-HT 3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT 3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT 3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. These were assessed concurrently with the top-scoring poses of the docked ligands and included key active gingerols, shogaols and dehydroshogaols as well as competitive antagonists (e.g. setron class of pharmacologically active drugs), serotonin and its structural analogues, curcumin and capsaicin, non-competitive antagonists and decoys. Unexpectedly, we found that the ginger compounds and their structural analogs generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues. We have identified new residues important for binding the ginger compounds. Overall, the results suggest that the ginger compounds and their structural analogues possess a high binding affinity to both sites. Notwithstanding the limitations of such theoretical analyses, these results suggest that the ginger compounds could act both competitively or non-competitively as has been shown for palonosetron and other modulators of CYS loop receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Two New Stilbenoids from the Aerial Parts of Arundina graminifolia (Orchidaceae).

PubMed

Auberon, Florence; Olatunji, Opeyemi Joshua; Krisa, Stéphanie; Antheaume, Cyril; Herbette, Gaëtan; Bonté, Frédéric; Mérillon, Jean-Michel; Lobstein, Annelise

2016-10-27

Two new phenanthrene derivatives, a phenanthrenequinone named arundiquinone ( 1 ) and a 9,10-dihydrophenanthrene named arundigramin ( 2 ) together with a known lignin dimer ( 3 ) and seven known stilbenoids ( 4 - 10 ) were isolated from the aerial parts of the Asian orchid Arundina graminifolia . The structures of the isolated compounds were elucidated by spectroscopic methods, including extensive 1D, 2D NMR (heteronuclear single quantum coherence (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC), and HR-ESI-MS techniques, as well as comparison with respective literature reports. The cytoprotective activity of the isolated compounds were evaluated for their ability to reduce beta amyloid induced toxicity on undifferentiated PC12 cells. Compound 8 showed moderate cytoprotective activity at 0.5 µmol/L (71% of cell viability) while the other compounds showed no significant activity at the highest concentration tested.

Chirality Emergence in Thin Solid Films of Amino Acids by Polarized Light from Synchrotron Radiation and Free Electron Laser

PubMed Central

Takahashi, Jun-ichi; Shinojima, Hiroyuki; Seyama, Michiko; Ueno, Yuko; Kaneko, Takeo; Kobayashi, Kensei; Mita, Hajime; Adachi, Mashahiro; Hosaka, Masahito; Katoh, Masahiro

2009-01-01

One of the most attractive hypothesis for the origin of homochirality in terrestrial bioorganic compounds is that a kind of “chiral impulse” as an asymmetric excitation source induced asymmetric reactions on the surfaces of such materials such as meteorites or interstellar dusts prior to the existence of terrestrial life (Cosmic Scenario). To experimentally introduce chiral structure into racemic films of amino acids (alanine, phenylalanine, isovaline, etc.), we irradiated them with linearly polarized light (LPL) from synchrotron radiation and circularly polarized light (CPL) from a free electron laser. After the irradiation, we evaluated optical anisotropy by measuring the circular dichroism (CD) spectra and verified that new Cotton peaks appeared at almost the same peak position as those of the corresponding non-racemic amino acid films. With LPL irradiation, two-dimensional anisotropic structure expressed as linear dichroism and/or linear birefringence was introduced into the racemic films. With CPL irradiation, the signs of the Cotton peaks exhibit symmetrical structure corresponding to the direction of CPL rotation. This indicates that some kinds of chiral structure were introduced into the racemic film. The CD spectra after CPL irradiation suggest the chiral structure should be derived from not only preferential photolysis but also from photolysis-induced molecular structural change. These results suggest that circularly polarized light sources in space could be associated with the origin of terrestrial homochirality; that is, they would be effective asymmetric exciting sources introducing chiral structures into bio-organic molecules or complex organic compounds. PMID:19742124

Homochiral zinc(II) coordination compounds based on in-situ-generated chiral amino acid-tetrazole ligands: circular dichroism, excitation light-induced tunable photoluminescence, and energetic performance.

PubMed

Wang, Shuai-Hua; Zheng, Fa-Kun; Zhang, Ming-Jian; Liu, Zhi-Fa; Chen, Jun; Xiao, Yu; Wu, A-Qing; Guo, Guo-Cong; Huang, Jin-Shun

2013-09-03

We employed two pairs of new in-situ-generated chiral amino acid-tetrazole ligands in constructing homochiral Zn(II) coordination compounds: [Zn(tzet)]n (1a for (S)-tzet and 1b for (R)-tzet, H2tzet = N-[2-(1H-tetrazol-5-yl)ethyl]tryptophan) and [Zn(tzep)(H2O)2]·H2O (2a for (S)-tzep and 2b for (R)-tzep, H2tzep = N-[2-(1H-tetrazol-5-yl)ethyl]proline), which were hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction. Structural analysis reveals that 1 features a 2D homochiral framework generated by both tetrazolate and carboxylate bridges in tzet(2-) ligands. The isolated structure of 2 is stabilized by extensive hydrogen bonds, which leads to formation of a supramolecular 2D architecture. The absolute configuration induced at the nitrogen atoms of 1 and 2 is strictly related to the neighboring chiral carbon atoms by hydrogen-bond interactions. To further investigate their chirality, the combined experimental and theoretical analyses of circular dichroism spectra reveal the absolute configurations and nature of the Cotton effects. Solid-state excitation and emission spectra for 1 and 2 at room temperature were investigated with relevant density of states calculation, and tunable photoluminescence emission of 1 under different excitation wavelengths was discussed. As nitrogen-rich tetrazolate compounds, 1 and 2 possess higher enthalpies of combustion and may serve as a new family of promising energetic materials.

Molecular Structure-Based Large-Scale Prediction of Chemical-Induced Gene Expression Changes.

PubMed

Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Wallqvist, Anders

2017-09-25

The quantitative structure-activity relationship (QSAR) approach has been used to model a wide range of chemical-induced biological responses. However, it had not been utilized to model chemical-induced genomewide gene expression changes until very recently, owing to the complexity of training and evaluating a very large number of models. To address this issue, we examined the performance of a variable nearest neighbor (v-NN) method that uses information on near neighbors conforming to the principle that similar structures have similar activities. Using a data set of gene expression signatures of 13 150 compounds derived from cell-based measurements in the NIH Library of Integrated Network-based Cellular Signatures program, we were able to make predictions for 62% of the compounds in a 10-fold cross validation test, with a correlation coefficient of 0.61 between the predicted and experimentally derived signatures-a reproducibility rivaling that of high-throughput gene expression measurements. To evaluate the utility of the predicted gene expression signatures, we compared the predicted and experimentally derived signatures in their ability to identify drugs known to cause specific liver, kidney, and heart injuries. Overall, the predicted and experimentally derived signatures had similar receiver operating characteristics, whose areas under the curve ranged from 0.71 to 0.77 and 0.70 to 0.73, respectively, across the three organ injury models. However, detailed analyses of enrichment curves indicate that signatures predicted from multiple near neighbors outperformed those derived from experiments, suggesting that averaging information from near neighbors may help improve the signal from gene expression measurements. Our results demonstrate that the v-NN method can serve as a practical approach for modeling large-scale, genomewide, chemical-induced, gene expression changes.

Hyperfine interactions in titanates: Study of orbital ordering and local magnetic properties

NASA Astrophysics Data System (ADS)

Agzamova, P. A.; Leskova, Yu. V.; Nikiforov, A. E.

2013-05-01

Hyperfine magnetic fields induced on the nuclei of nonmagnetic ions 139La and 89Y in LaTiO3 and YTiO3, respectively, have been microscopically calculated. The dependence of the hyperfine fields on the orbital and magnetic structures of the compounds under study has been analyzed. The comparative analysis of the calculated and known experimental data confirms the existence of the static orbital structure in lanthanum and yttrium titanates.

Model of cohesive properties and structural phase transitions in non-metallic solids

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

Majewski, J.A.; Vogl, P.

1986-01-01

We have developed a simple, yet microscopic and universal model for cohesive properties of solids. This model explains the physical mechanisms determining the chemical and predicts semiquantitatively static and dynamic cohesive properties. It predicts a substantial softening of the long-wavelength transverse optical phonons across the pressure induced phase transition from the zincblenda to rocksalt structure in II-VI compounds. The origin of this softening is shown to be closely related to ferroelectricity.

Helium induced fine structure in the electronic spectra of anthracene derivatives doped into superfluid helium nanodroplets

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

Pentlehner, D.; Slenczka, A., E-mail: alkwin.slenczka@chemie.uni-regensburg.de

2015-01-07

Electronic spectra of organic molecules doped into superfluid helium nanodroplets show characteristic features induced by the helium environment. Besides a solvent induced shift of the electronic transition frequency, in many cases, a spectral fine structure can be resolved for electronic and vibronic transitions which goes beyond the expected feature of a zero phonon line accompanied by a phonon wing as known from matrix isolation spectroscopy. The spectral shape of the zero phonon line and the helium induced phonon wing depends strongly on the dopant species. Phonon wings, for example, are reported ranging from single or multiple sharp transitions to broadmore » (Δν > 100 cm{sup −1}) diffuse signals. Despite the large number of example spectra in the literature, a quantitative understanding of the helium induced fine structure of the zero phonon line and the phonon wing is missing. Our approach is a systematic investigation of related molecular compounds, which may help to shed light on this key feature of microsolvation in superfluid helium droplets. This paper is part of a comparative study of the helium induced fine structure observed in electronic spectra of anthracene derivatives with particular emphasis on a spectrally sharp multiplet splitting at the electronic origin. In addition to previously discussed species, 9-cyanoanthracene and 9-chloroanthracene will be presented in this study for the first time.« less

3D chiral and 2D achiral cobalt(ii) compounds constructed from a 4-(benzimidazole-1-yl)benzoic ligand exhibiting field-induced single-ion-magnet-type slow magnetic relaxation.

PubMed

Wang, Yu-Ling; Chen, Lin; Liu, Cai-Ming; Du, Zi-Yi; Chen, Li-Li; Liu, Qing-Yan

2016-05-04

Organizing magnetically isolated 3d transition metal ions, which behave as single-ion magnet (SIM) units, in a coordination network is a promising approach to design novel single-molecule magnets (SMMs). Herein 3D chiral and 2D achiral cobalt(ii) coordination compounds based on single metal nodes with a 4-(benzimidazole-1-yl)benzoic acid (Hbmzbc) ligand, namely, [Co(bmzbc)2(1,2-etdio)]n () (1,2-etdio = 1,2-ethanediol) and [Co(bmzbc)2(Hbmzbc)]n (), have been synthesized and structurally characterized. The 3D chiral structure with 2-fold interpenetrating qtz topological nets consisting of totally achiral components was obtained via spontaneous resolution, while the achiral structure is a 2D (4,4) net. In both structures, individual cobalt(ii) ions are spatially well separated by the long organic ligands in the well-defined networks. Magnetic measurements on and showed field-induced slow magnetic relaxation resulting from single-ion anisotropy of the individual Co(ii) ions. Analysis of the dynamic ac susceptibilities with the Arrhenius law afforded an anisotropy energy barrier of 16.8(3) and 31.3(2) K under a 2 kOe static magnetic field for and , respectively. The distinct coordination environments of the Co(ii) ions in and lead to the different anisotropic energy barriers.

Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

PubMed Central

Fayad, Walid; Fryknäs, Mårten; Brnjic, Slavica; Olofsson, Maria Hägg; Larsson, Rolf; Linder, Stig

2009-01-01

Background Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. Method and Findings A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. Conclusions The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids. PMID:19798419

Structure-Antiplatelet Activity Relationships of Novel Ruthenium (II) Complexes: Investigation of Its Molecular Targets.

PubMed

Hsia, Chih-Hsuan; Jayakumar, Thanasekaran; Sheu, Joen-Rong; Tsao, Shin-Yi; Velusamy, Marappan; Hsia, Chih-Wei; Chou, Duen-Suey; Chang, Chao-Chien; Chung, Chi-Li; Khamrang, Themmila; Lin, Kao-Chang

2018-02-22

The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1-5 μM) dependent inhibitory effect on platelet aggregation induced by collagen (1 μg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 μM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca 2+ ]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases.

Poly(acrylic acid) to induce competitive crystallization of a theophylline/oxalic acid cocrystal and a theophylline polymorph

NASA Astrophysics Data System (ADS)

Jang, Jisun; Kim, Il Won

2016-01-01

Polymeric additives to induce competitive crystallization of pharmaceutical compounds were explored. A cocrystal of theophylline and oxalic acid was used as a model system, and poly(acrylic acid), poly(caprolactone), and poly(ethylene glycol) were the additives. The cocrystal formation was selectively hindered with addition of poly(acrylic acid). First the size of the cocrystals were reduced, and eventually the cocrystallization was inhibited to generate neat theophylline crystals. The theophylline crystals were of a distinctively different crystal structure from known polymorphs, based on powder X-ray diffraction. They were also obtained in nanoscale size, when millimeter-scale crystals formed without poly(acrylic acid). Polymeric additives that could form specific interactions with crystallizing compounds seem to be useful tools for the phase and size control of pharmaceutical crystals.

Study of the UV Light Conversion of Feruloyl Amides from Portulaca oleracea and Their Inhibitory Effect on IL-6-Induced STAT3 Activation.

PubMed

Hwang, Joo Tae; Kim, Yesol; Jang, Hyun-Jae; Oh, Hyun-Mee; Lim, Chi-Hwan; Lee, Seung Woong; Rho, Mun-Chual

2016-06-30

Two new feruloyl amides, N-cis-hibiscusamide (5) and (7'S)-N-cis-feruloylnormetanephrine (9), and eight known feruloyl amides were isolated from Portulaca oleracea L. and the geometric conversion of the ten isolated feruloyl amides by UV light was verified. The structures of the feruloyl amides were determined based on spectroscopic data and comparison with literature data. The NMR data revealed that the structures of the isolated compounds showed cis/trans-isomerization under normal laboratory light conditions. Therefore, cis and trans-isomers of feruloyl amides were evaluated for their convertibility and stability by UV light of a wavelength of 254 nm. After 96 h of UV light exposure, 23.2%-35.0% of the cis and trans-isomers were converted to trans-isomers. Long-term stability tests did not show any significant changes. Among all compounds and conversion mixtures collected, compound 6 exhibited the strongest inhibition of IL-6-induced STAT3 activation in Hep3B cells, with an IC50 value of 0.2 μM. This study is the first verification of the conversion rates and an equilibrium ratio of feruloyl amides. These results indicate that this natural material might provide useful information for the treatment of various diseases involving IL-6 and STAT3.

HPLC-Based Activity Profiling: Discovery of Piperine as a Positive GABAA Receptor Modulator Targeting a Benzodiazepine-Independent Binding Site

PubMed Central

Zaugg, Janine; Baburin, Igor; Strommer, Barbara; Kim, Hyun-Jung; Hering, Steffen; Hamburger, Matthias

2011-01-01

A plant extract library was screened for GABAA receptor activity making use of a two-microelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 μg/mL] potentiated GABA-induced chloride currents through GABAA receptors (composed of α1, β2, and γ2S subunits) by 169.1 ± 2.4%. With the aid of an HPLC-based activity profiling approach, piperine (5) was identified as the main active compound, together with 12 structurally related less active or inactive piperamides (1–4, 6–13). Identification was achieved by on-line high-resolution mass spectrometry and off-line microprobe 1D and 2D NMR spectroscopy, using only milligram amounts of extract. Compound 5 induced a maximum potentiation of the chloride currents by 301.9 ± 26.5% with an EC50 of 52.4 ± 9.4 μM. A comparison of the modulatory activity of 5 and other naturally occurring piperamides enabled insights into structural features critical for GABAA receptor modulation. The stimulation of chloride currents through GABAA receptors by compound 5 was not antagonized by flumazenil (10 μM). These data show that piperine (5) represents a new scaffold of positive allosteric GABAA receptor modulators targeting a benzodiazepine-independent binding site. PMID:20085307

Effect of salicylic acid and structurally related compounds in the accumulation of phytoalexins in cotyledons of common bean (Phaseolus vulgaris L.) cultivars.

PubMed

Durango, Diego; Pulgarin, Natalia; Echeverri, Fernando; Escobar, Gustavo; Quiñones, Winston

2013-09-02

In the present work, isoflavonoid phytoalexin production in response to the application of salicylic acid in cotyledons of four common bean (Phaseolus vulgaris) cultivars (SA) was evaluated. The time-course and dose-response profiles of the induction process were established by quantifying the isoflavonoids by HPLC. Cotyledons of anthracnose-resistant cultivars induced by SA produced substantially higher phytoalexin contents as compared to the susceptible ones. In addition, maximum levels of phytoalexins (50-100 fold increases) were reached between 96 and 144 h, and when a concentration of SA from 3.62 to 14.50 mM was used. The observations also indicate that there was a relatively good correlation between the phytoalexin contents and the inhibitory effect against C. lindemuthianum; the higher antifungal activity was observed during the first 48 hours for extracts from cotyledons treated with SA at 1.45 and 3.62 mM, and between 96 and 144 h after induction. Finally, compounds structurally related to SA (dihydro-quinazolinones and some imines) showed a strong elicitor effect. Moreover, induced extracts from cotyledons treated with these potential elicitors, besides the properly elicitors, displayed a weak to moderated antifungal activity. These compounds may be considered good candidates for developing of new phytoprotectants. Furthermore, phytoalexin-eliciting substances may contribute for selecting disease resistant cultivars.

Spectroscopy reveals that ethyl esters interact with proteins in wine.

PubMed

Di Gaspero, Mattia; Ruzza, Paolo; Hussain, Rohanah; Vincenzi, Simone; Biondi, Barbara; Gazzola, Diana; Siligardi, Giuliano; Curioni, Andrea

2017-02-15

Impairment of wine aroma after vinification is frequently associated to bentonite treatments and this can be the result of protein removal, as recently demonstrated for ethyl esters. To evaluate the existence of an interaction between wine proteins and ethyl esters, the effects induced by these fermentative aroma compounds on the secondary structure and stability of VVTL1, a Thaumatin-like protein purified from wine, was analyzed by Synchrotron Radiation Circular Dichroism (SRCD) spectroscopy. The secondary structure of wine VVTL1 was not strongly affected by the presence of selected ethyl esters. In contrast, VVTL1 stability was slightly increased by the addition of ethyl-octanoate, -decanoate and -dodecanoate, but decreased by ethyl-hexanoate. This indicates the existence of an interaction between VVTL1 and at least some aroma compounds produced during fermentation. The data suggest that proteins removal from wine by bentonite can result in indirect removal of at least some aroma compounds associated with them. Copyright © 2016 Elsevier Ltd. All rights reserved.

Isolation and Total Synthesis of Stolonines A–C, Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

PubMed Central

Tran, Trong D.; Pham, Ngoc B.; Ekins, Merrick; Hooper, John N. A.; Quinn, Ronald J.

2015-01-01

Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A–C (1–3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A–C (1–3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells. PMID:26204949

Phonon Instability and Broken Long-Ranged p Bond in Ge-Sb-Te Phase-Change Materials from First Principles

NASA Astrophysics Data System (ADS)

Song, Young-Sun; Kim, Jeongwoo; Jhi, Seung-Hoon

2018-05-01

Ge-Sb-Te (GST) compounds exhibit substantial electrical and optical contrast between the amorphous and crystalline phases. Despite extensive studies of GST compounds, the underlying mechanism for fast transitions between the amorphous and crystalline phases is yet to be revealed. In this paper, we study the properties of phonons and a long-ranged p -orbital network of hexagonal GST compounds using first-principles calculations. By investigating volume-dependent phonon dispersions, we observe the structural instability at elevated temperature due to the spontaneous softening of a specific in-plane vibrational mode (Eu ). We find that the atomic distortion by the Eu mode is associated with weakening of delocalized p bonding inducing large structural and electrical changes. We also discuss how to manipulate the Eu mode to control the device performance. Our finding helps deepen the understanding of the phase-change mechanism and improve the device performance, especially the switching power and operating temperature.

Psychedelics Promote Structural and Functional Neural Plasticity.

PubMed

Ly, Calvin; Greb, Alexandra C; Cameron, Lindsay P; Wong, Jonathan M; Barragan, Eden V; Wilson, Paige C; Burbach, Kyle F; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R; Duim, Whitney C; Dennis, Megan Y; McAllister, A Kimberley; Ori-McKenney, Kassandra M; Gray, John A; Olson, David E

2018-06-12

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Insights on the origin of the Tb5Ge4 magnetocaloric effect

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

Belo, J. H.; Barbosa, M. B.; Pires, A. L.

2017-05-01

In this report the magnetic, atomic structures and spin-lattice coupling have been thoroughly studied through high magnetic field magnetometry, Synchrotron X-ray diffraction under applied magnetic field and magnetostriction measurements in the Tb5Ge4 compounds. A field induced phase transition from an antiferromagnetic towards a ferromagnetic ordering was confirmed but with absence of structural transformation. This absence has been confirmed experimentally through synchrotron x-ray diffraction under applied field (up to 30 T). Moreover, this absence was explained via a thermodynamic free energy model: first principles calculations determined a large energy gap (ΔE=0.65 eV) between the two possible structures, O(I) and O(II). Frommore » magnetic and structural properties, a H-T phase diagram has been proposed for Tb5Ge4. Finally it was observed a large magnetostriction (up to 600 ppm) induced by ΔH=7 T.« less

NO inhibitory constituents as potential anti-neuroinflammatory agents for AD from Blumea balsamifera.

PubMed

Ma, Jun; Ren, Quanhui; Dong, Bangjian; Shi, Zhaoyu; Zhang, Jie; Jin, Da-Qing; Xu, Jing; Ohizumi, Yasushi; Lee, Dongho; Guo, Yuanqiang

2018-02-01

Our continuous search for new nitric oxide (NO) inhibitory substances as anti-neuroinflammatory agents for AD resulted in the isolation of one new labdane diterpenoid and three new guaiane sesquiterpenoids, as well as ten known compounds from Blumea balsamifera. Their structures were elucidated by NMR spectroscopic data analysis and the time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The anti-neuroinflammatory effects were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis, analgesic activity, and binding properties of some epibatidine analogs with a tropine skeleton.

PubMed

Rádl, S; Hafner, W; Budesínsky, M; Hejnová, L; Krejcí, I

2000-06-01

A series of epibatidine analogs and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety is described. Also some of their simplified analogs bearing a 3-piperidine moiety are reported. Their receptor binding profiles (5-HT1A, 5-HT1B, M1, M2, neuronal nicotinic receptor) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Some of the compounds, especially those containing an 8-azabicyclo[3.2.1]oct-2-ene moiety possess high afinity for the nicotinic cholinergic receptor. The most analgesically active compounds are also highly toxic. Optimized structures (PM3-MOPAC, Alchemy 2000, Tripos Inc.) of compounds 1-9 were compared with that of epibatidine.

Eunicellin-based diterpenoids from the Formosan soft coral Klyxum molle with inhibitory activity on superoxide generation and elastase release by neutrophils.

PubMed

Lin, Ming-Chang; Chen, Bo-Wei; Huang, Chiung-Yao; Dai, Chang-Feng; Hwang, Tsong-Long; Sheu, Jyh-Horng

2013-09-27

Eleven new eunicellin-based diterpenoids possessing a cladiellane skeleton with a C-2, C-9 ether bridge, klymollins I-S (1-11), have been isolated from the EtOAc extract of the soft coral Klyxum molle from Taiwan waters. The structures of compounds 1-11 were elucidated by extensive spectroscopic analysis, including 2D NMR spectroscopy (COSY, HSQC, HMBC, and NOESY). Compound 5 exhibited cytotoxicity toward several cancer cell lines. Compound 5 is the first eunicellin-based metabolite bearing a phenyl group and displays significant inhibition of both superoxide anion generation and elastase release in N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced human neutrophils.

High-pressure NaCl-phase of tetrahedral compounds

NASA Astrophysics Data System (ADS)

Soma, T.; -Matsuo Kagaya, H.

1984-04-01

The phase transition of tetrahedral compounds such as GaP, InP, ZnS, ZnSe, ZnTe and CdTe under pressure is investigated from the electronic theory of solids by using our recently presented binding force, which includes mainly covalent interactions in the pseudopotential formalism and partially ionic interactions. The partially ionic forces give the important contributions to the high-pressure phase and stabilize the NaCl-type structure for the high-pressure phase of these compounds, although not reported for GaP experimentally. Then, the numerical results such as the transition pressure, the volume-discontinuity, the transition heat with respect to the pressure-induced phase transition from the zinc-blende-to the NaCl-type lattice are obtained theoretically.

Magneto-structural correlation in Co0.8Cu0.2Cr2O4 cubic spinel

NASA Astrophysics Data System (ADS)

Kumar, Ram; Rayaprol, S.; Siruguri, V.; Xiao, Y.; Ji, W.; Pal, D.

2018-05-01

Neutron and X-ray diffraction, magnetic susceptibility, and specific heat measurements have been used to investigate the magneto-structural phase transitions in 20% Cu substituted multiferroic CoCr2O4 spinel. The Jahn-Teller active Cu2+ ion in the tetrahedral A-site of the spinel configuration induces the Jahn-Teller distortion slightly above the Néel temperature. In this compound, we observe a Jahn-Teller distortion of the crystal structure at 90 K. It was further observed that the high temperature cubic (Fd 3 ‾ m) structure coexists with the low temperature orthorhombic (Fddd) structure till the lowest temperature of measurement.

Compound edaravone alleviates lipopolysaccharide (LPS)-induced acute lung injury in mice.

PubMed

Zhang, Zhengping; Luo, Zhaowen; Bi, Aijing; Yang, Weidong; An, Wenji; Dong, Xiaoliang; Chen, Rong; Yang, Shibao; Tang, Huifang; Han, Xiaodong; Luo, Lan

2017-09-15

Acute lung injury (ALI) represents an unmet medical need with an urgency to develop effective pharmacotherapies. Compound edaravone, a combination of edaravone and borneol, has been developed for treatment of ischemia stroke in clinical phase III study. The purpose of the present study is to investigate the anti-inflammatory effect of compound edaravone on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and the therapeutic efficacy on LPS-induced ALI in mice. Edaravone and compound edaravone concentration-dependently decreased LPS-induced interleukin-6 (IL-6) production and cyclooxygenase-2 (COX-2) expression in RAW264.7 cells. The efficiency of compound edaravone was stronger than edaravone alone. In the animal study, compound edaravone was injected intravenously to mice after intratracheal instillation of LPS. It remarkably alleviated LPS-induced lung injury including pulmonary histological abnormalities, polymorphonuclear leukocyte (PMN) infiltration and extravasation. Further study demonstrated that compound edaravone suppressed LPS-induced TNF-α and IL-6 increase in mouse serum and bronchoalveolar lavage (BAL) fluid, and inhibited LPS-induced nuclear factor-κB (NF-κB) activation and COX-2 expression in mice lung tissues. Importantly, our findings demonstrated that the compound edaravone showed a stronger protective effect against mouse ALI than edaravone alone, which suggested the synergies between edaravone and borneol. In conclusion, compound edaravone could be a potential novel therapeutic drug for ALI treatment and borneol might produce a synergism with edaravone. Copyright © 2017 Elsevier B.V. All rights reserved.

Gold(III) bis(thiosemicarbazonate) compounds in breast cancer cells: Cytotoxicity and thioredoxin reductase targeting.

PubMed

Rodríguez-Fanjul, Vanessa; López-Torres, Elena; Mendiola, M Antonia; Pizarro, Ana María

2018-03-25

Gold(III) compounds have received increasing attention in cancer research. Three gold complexes of general formula [Au III L]Cl, where L is benzil bis(thiosemicarbazonate), compound 1, benzil bis(4-methyl-3-thiosemicarbazonate), compound 2, or benzil bis(4-cyclohexyl-3-thiosemicarbazonate), compound 3, have been synthesized and fully characterized, including the X-ray crystal structure of compound 3, confirming square-planar geometry around the gold(III) centre. Compound 1 showed moderate cytotoxicity and accumulation in MCF7 breast cancer cells but did not inhibit thioredoxin reductase (TrxR) activity and did not induce reactive oxygen species (ROS) production. Compound 2, the least cytotoxic, was found to be capable of modestly inhibiting TrxR activity and produced low levels of ROS in the MCF7 cell line. The most cytotoxic compound, 3, had the highest cellular accumulation and its distribution pattern showed a clear preference for the cytosol and mitochondria of MCF7 cells. It readily hampered intracellular TrxR activity leading to a dramatic alteration of the cellular redox state and to the induction of cell death. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Antioxidant and Anti-Osteoporotic Activities of Aromatic Compounds and Sterols from Hericium erinaceum.

PubMed

Li, Wei; Lee, Sang Hyun; Jang, Hae Dong; Ma, Jin Yeul; Kim, Young Ho

2017-01-11

Hericium erinaceum , commonly called lion's mane mushroom, is a traditional edible mushroom widely used in culinary applications and herbal medicines in East Asian countries. In this study, a new sterol, cerevisterol 6-cinnamate ( 6 ), was isolated from the fruiting bodies of H. erinaceum together with five aromatic compounds 1 - 5 and five sterols 7 - 11 . The chemical structures of these compounds were elucidated using chemical and physical methods and comparison of HRESIMS, ¹D-NMR (¹H, 13 C, and DEPT) and 2D-NMR (COSY, HMQC, HMBC, and NOESY) spectra with previously reported data. The antioxidant and anti-osteoporotic activities of extracts and the isolated compounds 1 - 11 were investigated. All compounds exhibited peroxyl radical-scavenging capacity but only compounds 1 , 3 , and 4 showed potent reducing capacity. Moreover, compounds 1 , 2 , 4 , and 5 showed moderate effects on cellular antioxidant activity and inhibited the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastic differentiation. These results suggested that H. erinaceum could be utilized in the development of natural antioxidant and anti-osteoporotic nutraceuticals and functional foods.

Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes.

PubMed

Zhang, Xiangming; Liu, Huijuan; Sun, Bo; Sun, Yan; Zhong, Weilong; Liu, Yanrong; Chen, Shuang; Ling, Honglei; Zhou, Lei; Jing, Xiangyan; Qin, Yuan; Xiao, Ting; Sun, Tao; Zhou, Honggang; Yang, Cheng

2016-11-17

Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus.

Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.

PubMed

McKoy, Angela F; Chen, Jermont; Schupbach, Trudi; Hecht, Michael H

2014-11-01

Inhibiting aggregation of the amyloid-beta (Aβ) peptide may be an effective strategy for combating Alzheimer's disease. As the high-resolution structure of the toxic Aβ aggregate is unknown, rational design of small molecule inhibitors is not possible, and inhibitors are best isolated by high-throughput screening. We applied high-throughput screening to a collection of 65,000 compounds to identify compound D737 as an inhibitor of Aβ aggregation. D737 diminished the formation of oligomers and fibrils, and reduced Aβ42-induced cytotoxicity. Most importantly, D737 increased the life span and locomotive ability of transgenic flies in a Drosophila melanogaster model of Alzheimer's disease (J Biol Chem, 287, 2012, 38992). To explore the chemical features that make D737 an effective inhibitor of Aβ42 aggregation and toxicity, we tested a small collection of eleven analogues of D737. Overall, the ability of a compound to inhibit Aβ aggregation was a good predictor of its efficacy in prolonging the life span and locomotive ability of transgenic flies expressing human Aβ42 in the central nervous system. Two compounds (D744 and D830) with fluorine substitutions on an aromatic ring were effective inhibitors of Aβ42 aggregation and increased the longevity of transgenic flies beyond that observed for the parent compound, D737. © 2014 John Wiley & Sons A/S.

Isoprenylated flavonoids from the root bark of Morus alba and their hepatoprotective and neuroprotective activities.

PubMed

Jung, Jae-Woo; Ko, Won-Min; Park, Ji-Hae; Seo, Kyeong-Hwa; Oh, Eun-Ji; Lee, Dae-Young; Lee, Dong-Sung; Kim, Youn-Chul; Lim, Dong-Wook; Han, Daeseok; Baek, Nam-In

2015-11-01

A new isoprenylated flavonoid, 2S-5,7,2',4'-tetrahydroxy-3',5'-di-(γ,γ-dimethylallyl)flavanone, sanggenol Q (1), along with seven known isoprenylated flavonoids, sanggenol A (2), sanggenol L (3), kuwanon T (4), cyclomorusin (5), sanggenon F (6), sanggenol O (7), and sanggenon N (8), three known Diels-Alder type adducts, sanggenon G (9), mulberrofuran G (10), and mulberrofuran C (11), and a known benzofuran, moracin E (12), were isolated from the root bark of Morus alba using silica gel, ODS, and Sephadex LH-20 column chromatography. Chemical structures were determined based on spectroscopic data analyses including NMR, MS, CD, and IR. For the first time, compounds 1 and 7 were isolated from the root bark of M. alba. All compounds were evaluated for hepatoprotective activity on t-BHP-induced oxidative stress in HepG2 cells and neuroprotective activity on glutamate-induced cell death in HT22 cells. Compounds 1, 4, 8, 10, and 11 showed protective effects on t-BHP-induced oxidative stress with EC50 values of 6.94 ± 0.38, 30.32 ± 6.82, 23.45 ± 4.72, 15.31 ± 2.21, and 0.41 ± 0.48 μM, respectively, and compounds 1, 2, 10, 11, and 12 showed protective effects on glutamate-induced cell death with EC50 values of 5.54 ± 0.86, 34.03 ± 7.71, 19.71 ± 0.71, 16.50 ± 7.82, and 1.02 ± 0.13 μM, respectively.

Exploring bacteria-induced growth and morphogenesis in the green macroalga order Ulvales (Chlorophyta)

PubMed Central

Wichard, Thomas

2015-01-01

Green macroalgae, such as Ulvales, lose their typical morphology completely when grown under axenic conditions or in the absence of the appropriate microbiome. As a result, slow growing aberrant phenotypes or even callus-like morphotypes are observed in Ulvales. The cross-kingdom interactions between marine algae and microorganisms are hence not only restricted by the exchange of macronutrients, including vitamins and nutrients, but also by infochemicals such as bacterial morphogenetic compounds. The latter are a fundamental trait mediating the mutualism within the chemosphere where the organisms interact with each other via compounds in their surroundings. Approximately 60 years ago, pilot studies demonstrated that certain bacteria promote growth, whereas other bacteria induce morphogenesis; this is particularly true for the order of Ulvales. However, only slow progress was made towards the underlying mechanism due to the complexity of, for example, algal cultivation techniques, and the lack of standardized experiments in the laboratory. A breakthrough in this research was the discovery of the morphogenetic compound thallusin, which was isolated from an epiphytic bacterium and induces normal germination restoring the foliaceous morphotypes of Monostroma. Owing to the low concentration, the purification and structure elucidation of highly biologically active morphogenetic compounds are still challenging. Recently, it was found that only the combination of two specific bacteria from the Rhodobacteraceae and Flavobacteriaceae can completely recover the growth and morphogenesis of axenic Ulva mutabilis cultures forming a symbiotic tripartite community by chemical communication. This review combines literature detailing evidences of bacteria-induced morphogenesis in Ulvales. A set of standardized experimental approaches is further proposed for the preparation of axenic algal tissues, bacteria isolation, co-cultivation experiments, and the analysis of the chemosphere. PMID:25784916

Camptosorus sibiricus rupr aqueous extract prevents lung tumorigenesis via dual effects against ROS and DNA damage.

PubMed

He, Shugui; Ou, Rilan; Wang, Wensheng; Ji, Liyan; Gao, Hui; Zhu, Yuanfeng; Liu, Xiaomin; Zheng, Hongming; Liu, Zhongqiu; Wu, Peng; Lu, Linlin

2018-06-28

Camptosorus sibiricus Rupr (CSR) is a widely used herbal medicine with antivasculitis, antitrauma, and antitumor effects. However, the effect of CSR aqueous extract on B[a]P-initiated tumorigenesis and the underlying mechanism remain unclear. Moreover, the compounds in CSR aqueous extract need to be identified and structurally characterized. We aim to investigate the chemopreventive effect of CSR and the underlying molecular mechanism. A B[a]P-stimulated normal cell model (BEAS.2B) and lung adenocarcinoma animal model were established on A/J mice. In B[a]P-treated BEAS.2B cells, the protective effects of CSR aqueous extract on B[a]P-induced DNA damage and ROS production were evaluated through flow cytometry, Western blot, real-time quantitative PCR, single-cell gel electrophoresis, and immunofluorescence. Moreover, a model of B[a]P-initiated lung adenocarcinoma was established on A/J mice to determine the chemopreventive effect of CSR in vivo. The underlying mechanism was analyzed via immunohistochemistry and microscopy. Furthermore, the new compounds in CSR aqueous extract were isolated and structurally characterized using IR, HR-ESI-MS, and 1D and 2D NMR spectroscopy. CSR effectively suppressed ROS production by re-activating Nrf2-mediated reductases HO-1 and NQO-1. Simultaneously, CSR attenuated the DNA damage of BEAS.2B cells in the presence of B[a]P. Moreover, CSR at 1.5 and 3 g/kg significantly suppressed tumorigenesis with tumor inhibition ratios of 36.65% and 65.80%, respectively. The tumor volume, tumor size, and multiplicity of B[a]P-induced lung adenocarcinoma were effectively decreased by CSR in vivo. After extracting and identifying the compounds in CSR aqueous extract, three new triterpene saponins were isolated and characterized structurally. CSR aqueous extract prevents lung tumorigenesis by exerting dual effects against ROS and DNA damage, suggesting that CSR is a novel and effective agent for B[a]P-induced carcinogenesis. Moreover, by isolating and structurally characterizing three new triterpene saponins, our study further standardized the quality of CSR aqueous extract, which could widen CSR clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Antimicrobial metabolites from the plant endophytic fungus Penicillium sp.

PubMed

Yang, Ming-Hua; Li, Tian-Xiao; Wang, Ying; Liu, Rui-Huan; Luo, Jun; Kong, Ling-Yi

2017-01-01

Five rare dichloro aromatic polyketides (1-5) were obtained from an endophytic fungus Penicillium sp., along with five known metabolites (6-10). Their structures were elucidated by extensive spectroscopic analysis, Mosher methods, as well as [Rh 2 (OCOCF 3 ) 4 ]-induced electronic circular dichroism (ECD) experiments. Compounds 2-4 and 6 structurally involved acyclic 1.3-diols, the uneasy configuration determinations of which were well carried out by double-derivation NMR methods. Compounds 1-10 were evaluated for their antibacterial and antifungal activities against five strains of human pathogenic microorganisms. Helvolic acid (7) showed potent inhibitory effects against Staphylococcus aureus and Pseudomonas aeruginosa with MIC (minimum inhibitory concentration) values of 5.8 and 4.6μg/mL, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-inflammatory steroidal glycosides from the berries of Solanum nigrum L. (European black nightshade).

PubMed

Xiang, Limin; Wang, Yihai; Yi, Xiaomin; He, Xiangjiu

2018-04-01

Seven previously undescribed steroidal glycosides, along with three known congeners were isolated from the unripe berries of Solanum nigrum L. (Solanaceae). Their structures were elucidated on basis of 1D and 2D NMR, HR-ESI-MS spectroscopic data and GC analysis after acid hydrolysis. The potential inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide in RAW 264.7 cell line and the anti-proliferative activities against five cancer cell lines (HL-60, U-937, Jurkat, K562 and HepG2) were evaluated. Seven compounds exhibited inhibition activities on NO production with IC 50 values ranging from 11.33 to 49.35 μM. Structure-activity relationships of the isolated compounds were also discussed. Copyright © 2018 Elsevier Ltd. All rights reserved.

CLEFMA- An Anti-Proliferative Curcuminoid from Structure Activity Relationship Studies on 3,5-bis(benzylidene)-4-piperidones

PubMed Central

Lagisetty, Pallavi; Vilekar, Prachi; Sahoo, Kaustuv; Anant, Shrikant; Awasthi, Vibhudutta

2010-01-01

3,5-bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC50 < 30 μM), and sixteen compounds possessed reduced cell-killing efficacy (IC50 > 50 μM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers. PMID:20638855

Bent CNN bond of diazo compounds, RR'(Cdbnd N+dbnd N-)

NASA Astrophysics Data System (ADS)

Akita, Motoko; Takahashi, Mai; Kobayashi, Keiji; Hayashi, Naoto; Tukada, Hideyuki

2013-02-01

The reaction of ninhydrin with benzophenone hydrazone afforded 2-diazo-3-diphenylmethylenehydrazono-1-indanone 1 and 2-diazo-1,3-bis(diphenylmethylenehydrazono)indan 2. X-ray crystal structure analyses of these products showed that the diazo functional group Cdbnd N+dbnd N- of 1 is bent by 172.9°, while that of 2 has a linear geometry. The crystal structure data of diazo compounds have been retrieved from the Cambridge Structural Database (CSD), which hit 177 entries to indicate that the angle of 172.9° in 1 lies in one of the most bent structures. The CSD search also indicated that diazo compounds consisting of a distorted diazo carbon tend to bend the Cdbnd N+dbnd N- bond. On the basis of DFT calculations (B3LYP/6-311++G(d,p)) of model compounds, it was revealed that the bending of the CNN bond is principally induced by steric factors and that the neighboring carbonyl group also plays a role in bending toward the carbonyl side owing to an electrostatic attractive interaction. The potential surface along the path of Cdbnd N+dbnd N- bending in 2-diazopropane shows a significantly shallow profile with only 4 kcal/mol needed to bend the Cdbnd N+dbnd N- bond from 180° to 160°. Thus, the bending of the diazo group in 1 is reasonable as it is provided with all of the factors for facile bending disclosed in this investigation.

Design of co-existence parallel periodic surface structure induced by picosecond laser pulses on the Al/Ti multilayers

NASA Astrophysics Data System (ADS)

Petrović, Suzana; Peruško, D.; Kovač, J.; Panjan, P.; Mitrić, M.; Pjević, D.; Kovačević, A.; Jelenković, B.

2017-09-01

Formation of periodic nanostructures on the Ti/5x(Al/Ti)/Si multilayers induced by picosecond laser pulses is studied in order to better understand the formation of a laser-induced periodic surface structure (LIPSS). At fluence slightly below the ablation threshold, the formation of low spatial frequency-LIPSS (LSFL) oriented perpendicular to the direction of the laser polarization is observed on the irradiated area. Prolonged irradiation while scanning results in the formation of a high spatial frequency-LIPSS (HSFL), on top of the LSFLs, creating a co-existence parallel periodic structure. HSFL was oriented parallel to the incident laser polarization. Intermixing between the Al and Ti layers with the formation of Al-Ti intermetallic compounds was achieved during the irradiation. The intermetallic region was formed mostly within the heat affected zone of the sample. Surface segregation of aluminium with partial ablation of the top layer of titanium was followed by the formation of an ultra-thin Al2O3 film on the surface of the multi-layered structure.

Synthesis and Cytotoxic Activities of Difluoro-Dimethoxy Chalcones.

PubMed

Yamali, Cem; Gul, Halise Inci; Ozgun, Dilan Ozmen; Sakagam, Hiroshi; Umemura, Naoki; Kazaz, Cavit; Gul, Mustafa

2017-01-01

Although anticancer chemotherapeutics are available in markets, side effects related to the drugs in clinical use lead to researchers to investigate new drug candidates which are more safe, potent and selective than others. Chalcones are popular with their anticancer activities with the several reported mechanisms including inhibition of angiogenesis, inhibition of tubulin polymerization, and induction of apoptosis etc. This study was focused on to synthesize of 1-(2,4/2,6-difluorophenyl)-3-(2,3/2,4/2,5/3,4- dimethoxyphenyl)-2-propen-1-ones (1-8) and investigate their cytotoxic properties with possible mechanism of action. The compounds were synthesized by Claisen-Schmidt condensation. The chemical structures were confirmed by 1H NMR, 13C NMR, DEPT, COSY, HMQC, HMBC, 19F NMR and HRMS. In vitro cytotoxic effects of the compounds against human tumour cell lines [gingival carcinoma (Ca9-22), oral squamous cell carcinoma (HSC-2)] and human normal oral cells [gingival fibroblasts (HGF), periodontal ligament fibroblasts (HPLF)] were evaluated via MTT test. All compounds had higher cytotoxicity than reference compound 5-Fluorouracil (5-FU). The compounds 3-7 had higher potency selectivity expression values (PSE) than 5-FU and PSE values of the compounds were over 100. All chalcone derivatives seem good candidates for further studies according to very remarkable and high PSE values. It was clearly demonstrated that compound 7 can induce early apoptosis at a concentration of 10 µM and dose-dependent late apoptosis starting at 10 µM. Compound 7 induced cleavage of the apoptosis marker PARP. The results indicate that new chalcones reported here can promote apoptosis in human tumour cell lines. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mechanisms of inhibition of zinc-finger transcription factors by selenium compounds ebselen and selenite.

PubMed

Larabee, Jason L; Hocker, James R; Hanas, Jay S

2009-03-01

The anti-inflammatory selenium compounds, ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) and selenite, were found to alter the DNA binding mechanisms and structures of cysteine-rich zinc-finger transcription factors. As assayed by DNase I protection, DNA binding by TFIIIA (transcription factor IIIA, prototypical Cys(2)His(2) zinc finger protein), was inhibited by micromolar amounts of ebselen. In a gel shift assay, ebselen inhibited the Cys(2)His(2) zinc finger-containing DNA binding domain (DBD) of the NF-kappaB mediated transcription factor Sp1. Ebselen also inhibited DNA binding by the p50 subunit of the pro-inflammatory Cys-containing NF-kappaB transcription factor. Electrospray ionization mass spectrometry (ESI-MS) was utilized to elucidate mechanisms of chemical interaction between ebselen and a zinc-bound Cys(2)His(2) zinc finger polypeptide modeled after the third finger of Sp1 (Sp1-3). Exposing Sp1-3 to micromolar amounts of ebselen resulted in Zn(2+) release from this peptide and the formation of a disulfide bond by oxidation of zinc finger SH groups, the likely mechanism for DNA binding inhibition. Selenite was shown by ESI-MS to also eject zinc from Sp1-3 as well as induce disulfide bond formation through SH oxidation. The selenite-dependent inhibition/oxidation mechanism differed from that of ebselen by inducing the formation of a stable selenotrisulfide bond. Selenite-induced selenotrisulfide formation was dependent upon the structure of the Cys(2)His(2) zinc finger as alteration in the finger structure enhanced this reaction as well as selenite-dependent zinc release. Ebselen and selenite-dependent inhibition/oxidation of Cys-rich zinc finger proteins, with concomitant release of zinc and finger structural changes, points to mechanisms at the atomic and protein level for selenium-induced alterations in Cys-rich proteins, and possible amelioration of certain inflammatory, neurodegenerative, and oncogenic responses.

Designing of Protein Kinase C β-II Inhibitors against Diabetic complications: Structure Based Drug Design, Induced Fit docking and analysis of active site conformational changes

PubMed Central

Vijayakumar, Balakrishnan; Velmurugan, Devadasan

2012-01-01

Protein Kinase C β-II (PKC β-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC β-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC β-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC β-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC β-II. Based on the HTVs results and the nature of active site residues of PKC β-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC β-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC β-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC β-II were observed for the back bone Cα atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC β-II. PMID:22829732

Isolation of bergenin from the root bark of Securinega virosa and evaluation of its potential sleep promoting effect.

PubMed

Magaji, Mohammed Garba; Musa, Aliyu Muhammad; Abdullahi, Musa Ismail; Ya'u, Jamilu; Hussaini, Isa Marte

2015-01-01

Securinega virosa Roxb (Ex Willd) Baill (Euphorbaiceae) root bark has been reportedly used in African traditional medicine in the management of mental illnesses. Previously, the sleep-inducing potential of the crude methanol root bark of Securinega virosa extract and its butanol fraction have been reported. The study aimed to isolate and characterize the bioactive constituent that may be responsible for the sleep inducing property of the root of the plant. The phytochemical investigation of the S. virosa root bark was carried out leading to the isolation of a compound from the butanol-soluble fraction of the methanol extract. The structure of the compound was elucidated on the basis of its spectral data, including IR, 1D and 2D NMR, mass spectrometry as well as X-ray diffraction analysis. The compound was investigated for sleep-inducing potential using diazepam-induced sleeping time test and beam walking assay in mice. This is the first report on the isolation of bergenin from the root of the plant. It significantly decreased the mean onset of sleep [F (2, 15) =7.167; p< 0.01] at the dose of 10 mg/kg, without significantly affecting the total sleep duration [F (2, 15) = 0.090, p=0.914]. Conversely, it did not significantly affect the number of foot slips at the doses of 5 and 10 mg/kg tested. Bergenin isolated from the root bark of S. virosa possesses sleep-inducing property and could be partly responsible for the sedative potential of the root of S. virosa.

Sesquiterpenoids from the cultured mycelia of Ganoderma capense.

PubMed

Tan, Zhen; Zhao, Jinlian; Liu, Jimei; Zhang, Min; Chen, Ridao; Xie, Kebo; Dai, Jungui

2017-04-01

Eleven new sesquiterpenoids, including eight cadinane-type sesquiterpenoids, Ganodermanol A-H (1-8), and three eudesmane-type sesquiterpenoids, Ganodermanol I-K (9-11), together with three known compounds (12-14), were isolated from the cultured mycelia of Ganoderma capense. Their structures and absolute configurations were identified through combined extensive spectroscopic analysis, circular dichroism (CD), and Mo 2 (AcO) 4 -induced CD. Compounds 4 and 9 exhibited moderate cytotoxic activity against the human cancer cell line HCT116 with IC 50 values of 16.6 and 12.2μM, respectively. Copyright © 2017 Elsevier B.V. All rights reserved.

Cochlearoids F-K: Phenolic meroterpenoids from the fungus Ganoderma cochlear and their renoprotective activity.

PubMed

Wang, Xin-Long; Zhou, Feng-Jiao; Dou, Man; Yan, Yong-Ming; Wang, Shu-Mei; Di, Lei; Cheng, Yong-Xian

2016-11-15

Ganoderma mushrooms are of great nutritious and medicinal values. This study was designed to characterize compounds from the fruiting bodies of Ganoderma cochlear and investigate their protective effects against kidney disorders. Six novel meroterpenoids cochlearoids F-K (1-6) were isolated by utilizing phytochemical approaches. Their structures were identified on the basis of extensive spectroscopic data and calculation methods. Biological evaluation shows that compounds 1-4 and 6 exhibit potent inhibitory activity on fibronectin overproduction in TGF-β1-induced HKC-8 cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

UV-visible degradation of boscalid--structural characterization of photoproducts and potential toxicity using in silico tests.

PubMed

Lassalle, Yannick; Kinani, Aziz; Rifai, Ahmad; Souissi, Yasmine; Clavaguera, Carine; Bourcier, Sophie; Jaber, Farouk; Bouchonnet, Stéphane

2014-05-30

Boscalid is a carboximide fungicide mainly used for vineyard protection as well as for tomato, apple, blueberry and various ornamental cultivations. The structural elucidation of by-products arising from the UV-visible photodegradation of boscalid has been investigated by gas chromatography/multi-stage mass spectrometry (GC/MS(n) ) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) couplings. The potential toxicities of transformation products were estimated by in silico calculations. Aqueous solutions of boscalid were irradiated up to 150 min in a self-made reactor equipped with a mercury lamp. Analyses were carried out using a gas chromatograph coupled with an ion trap mass spectrometer operated in both electron ionization (EI) and chemical ionization (CI) modes and a liquid chromatograph coupled with a quadrupole time-of-flight (Q-TOF) mass spectrometer operated in electrospray ionization (ESI) mode. Multiple-stage collision-induced dissociation (CID) experiments were performed to establish dissociation pathways of ions. The QSAR (Quantitative Structure-Activity Relationship) T.E.S.T. program allowed the estimation of the toxicities of the by-products. Eight photoproducts were investigated. Chemical structures were proposed not only on the interpretation of multi-stage CID experiments, but also on kinetics data. These structures led us to suggest photodegradation pathways. Three photoproducts were finally detected in Lebanon in a real sample of grape leaves for which routine analysis had led to the detection of boscalid at 4 mg kg(-1). With one exception, the structures proposed for the photoproducts on the basis of mass spectra interpretation have not been reported in previous studies. In silico toxicity predictions showed that two photoproducts are potentially more toxic than the parent compound considering oral rat LD50 while five photoproducts may induce mutagenic toxicity. With the exception of one compound, all photoproducts may potentially induce developmental toxicity. Copyright © 2014 John Wiley & Sons, Ltd.

Cytotoxic and apoptosis-inducing activities against human lung cancer cell lines of cassaine diterpenoids from the bark of Erythrophleum fordii.

PubMed

Ha, Manh Tuan; Tran, Manh Hung; Phuong, Thien Thuong; Kim, Jeong Ah; Woo, Mi Hee; Choi, Jae Sue; Lee, Suhyun; Lee, Jeong Hyung; Lee, Hyeong Kyu; Min, Byung Sun

2017-07-01

A phytochemical investigation into the bark of Erythrophleum fordii yielded four new compounds, two new cassaine diterpenoids (erythrofordin T and U, 1 and 2) and two new cassaine diterpenoid amines (erythroformine A and B, 6 and 7), as well as nine known compounds. We report for the first time the isolation of erythrofordin V (3) from a natural source and that of the remaining eight known diterpenoids (4-5, 8-13) from E. fordii. All structures were elucidated using spectroscopic analysis. Cytotoxic activity of the isolated compounds (1-13) was examined in vitro against three non-small cell lung cancer cell lines (A549, NCI-H1975, and NCI-H1229) using the MTT assay. Cassaine diterpene amines (6-10, 12, 13) exhibited potent cytotoxic activity against all three cell lines with IC 50 values between 0.4μM and 5.9μM. Erythroformine B (7) significantly induced apoptosis in all three cancer cells in a concentration-dependent manner. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genotoxicity and Cytotoxicity Evaluation of the Neolignan Analogue 2-(4-Nitrophenoxy)-1Phenylethanone and its Protective Effect Against DNA Damage

PubMed Central

Hanusch, Alex Lucas; de Oliveira, Guilherme Roberto; de Sabóia-Morais, Simone Maria Teixeira; Machado, Rafael Cosme; dos Anjos, Murilo Machado; Chen Chen, Lee

2015-01-01

Neolignans are secondary metabolites found in various groups of Angiosperms. They belong to a class of natural compounds with great diversity of chemical structures and pharmacological activities. These compounds are formed by linking two phenylpropanoid units. Several compounds that have ability to prevent genetic damage have been isolated from plants, and can be used to prevent or delay the development of tumor cells. Genetic toxicology evaluation is widely used in risk assessment of new drugs in preclinical screening tests. In this study, we evaluated the genotoxicity and cytotoxicity of the neolignan analogue 2-(4-nitrophenoxy)-1-phenylethanone (4NF) and its protective effect against DNA damage using the mouse bone marrow micronucleus test and the comet assay in mouse peripheral blood. Our results showed that this neolignan analogue had no genotoxic activity and was able to reduce induced damage both in mouse bone marrow and peripheral blood. Although the neolignan analogue 4NF was cytotoxic, it reduced cyclophosphamide-induced cytotoxicity. In conclusion, it showed no genotoxic action, but exhibited cytotoxic, antigenotoxic, and anticytotoxic activities. PMID:26554835

Novel pyrimidinic selenourea induces DNA damage, cell cycle arrest, and apoptosis in human breast carcinoma.

PubMed

Barbosa, Flavio A R; Siminski, Tâmila; Canto, Rômulo F S; Almeida, Gabriela M; Mota, Nádia S R S; Ourique, Fabiana; Pedrosa, Rozangela Curi; Braga, Antonio Luiz

2018-06-11

Novel pyrimidinic selenoureas were synthesized and evaluated against tumour and normal cell lines. Among these, the compound named 3j initially showed relevant cytotoxicity and selectivity for tumour cells. Three analogues of 3j were designed and synthesized keeping in view the structural requirements of this compound. Almost all the tested compounds displayed considerable cytotoxicity. However, 8a, one of the 3j analogues, was shown to be highly selective and cytotoxic, especially for breast carcinoma cells (MCF-7) (IC 50  = 3.9 μM). Furthermore, 8a caused DNA damage, inhibited cell proliferation, was able to arrest cell cycle in S phase, and induced cell death by apoptosis in human breast carcinoma cells. Moreover, predictions of pharmacokinetic properties showed that 8a may present good absorption and permeation characteristics for oral administration. Overall, the current study established 8a as a potential drug prototype to be employed as a DNA interactive cytotoxic agent for the treatment of breast cancer. Copyright © 2018. Published by Elsevier Masson SAS.

Pharmacological insight into the anti-inflammatory activity of sesquiterpene lactones from Neurolaena lobata (L.) R.Br. ex Cass.

PubMed

McKinnon, R; Binder, M; Zupkó, I; Afonyushkin, T; Lajter, I; Vasas, A; de Martin, R; Unger, C; Dolznig, H; Diaz, R; Frisch, R; Passreiter, C M; Krupitza, G; Hohmann, J; Kopp, B; Bochkov, V N

2014-10-15

Neurolaena lobata is a Caribbean medicinal plant used for the treatment of several conditions including inflammation. Recent data regarding potent anti-inflammatory activity of the plant and isolated sesquiterpene lactones raised our interest in further pharmacological studies. The present work aimed at providing a mechanistic insight into the anti-inflammatory activity of N. lobata and eight isolated sesquiterpene lactones, as well as a structure-activity relationship and in vivo anti-inflammatory data. The effect of the extract and its compounds on the generation of pro-inflammatory proteins was assessed in vitro in endothelial and monocytic cells by enzyme-linked immunosorbent assay. Their potential to modulate the expression of inflammatory genes was further studied at the mRNA level. In vivo anti-inflammatory activity of the chemically characterized extract was evaluated using carrageenan-induced paw edema model in rats. The compounds and extract inhibited LPS- and TNF-α-induced upregulation of the pro-inflammatory molecules E-selectin and interleukin-8 in HUVECtert and THP-1 cells. LPS-induced elevation of mRNA encoding for E-selectin and interleukin-8 was also suppressed. Furthermore, the extract inhibited the development of acute inflammation in rats. Sesquiterpene lactones from N. lobata interfered with the induction of inflammatory cell adhesion molecules and chemokines in cells stimulated with bacterial products and cytokines. Structure-activity analysis revealed the importance of the double bond at C-4-C-5 and C-2-C-3 and the acetyl group at C-9 for the anti-inflammatory activity. The effect was confirmed in vivo, which raises further interest in the therapeutic potential of the compounds for the treatment of inflammatory diseases. Copyright © 2014 Elsevier GmbH. All rights reserved.

Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

PubMed

Pérez-Rodríguez, Maribel; García-Mendoza, Esperanza; Farfán-García, Eunice D; Das, Bhaskar C; Ciprés-Flores, Fabiola J; Trujillo-Ferrara, José G; Tamay-Cach, Feliciano; Soriano-Ursúa, Marvin A

2017-09-01

Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

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

Huang, C.-P.; Fang, W.-H.; Lin, L.-I.

2008-03-15

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II{alpha} activity through the accumulation of Topomore » II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC{sub 50} of 0.9 {mu}M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC{sub 50} of 9.6 {mu}M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 {mu}M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC{sub 50} about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.« less

The chemical nature of phenolic compounds determines their toxicity and induces distinct physiological responses in Saccharomyces cerevisiae in lignocellulose hydrolysates

PubMed Central

2014-01-01

We investigated the severity of the inhibitory effects of 13 phenolic compounds usually found in spruce hydrolysates (4-hydroxy-3-methoxycinnamaldehyde, homovanilyl alcohol, vanillin, syringic acid, vanillic acid, gallic acid, dihydroferulic acid, p-coumaric acid, hydroquinone, ferulic acid, homovanillic acid, 4-hydroxybenzoic acid and vanillylidenacetone). The effects of the selected compounds on cell growth, biomass yield and ethanol yield were studied and the toxic concentration threshold was defined for each compound. Using Ethanol Red, the popular industrial strain of Saccharomyces cerevisiae, we found the most toxic compound to be 4-hydroxy-3-methoxycinnamaldehyde which inhibited growth at a concentration of 1.8 mM. We also observed that toxicity did not generally follow a trend based on the aldehyde, acid, ketone or alcohol classification of phenolic compounds, but rather that other structural properties such as additional functional groups attached to the compound may determine its toxicity. Three distinctive growth patterns that effectively clustered all the compounds involved in the screening into three categories. We suggest that the compounds have different cellular targets, and that. We suggest that the compounds have different cellular targets and inhibitory mechanisms in the cells, also compounds who share similar pattern on cell growth may have similar inhibitory effect and mechanisms of inhibition. PMID:24949277

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Watanabe, Hitoshi; Honda, Yayoi; Deguchi, Jiro; Yamada, Toru; Bando, Kiyoko

2017-01-01

Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a β-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery.

Tuning of chain chirality by interchain stacking forces and the structure-property relationship in coordination systems constructed by meridional FeIII cyanide and MnIII Schiff bases.

PubMed

Sohn, Ah Ram; Lim, Kwang Soo; Kang, Dong Won; Song, Jeong Hwa; Koh, Eui Kwan; Moon, Dohyun; Hong, Chang Seop

2016-12-06

We synthesized six Fe(iii)-Mn(iii) bimetallic compounds by self-assembling the newly developed mer-Fe cyanide PPh 4 [Fe(Clqpa)(CN) 3 ]·H 2 O (1) and PPh 4 [Fe(Brqpa)(CN) 3 ]·H 2 O (2) with Mn Schiff base Mn(5-Xsalen) + cations. These compounds include [Fe(Xqpa)(CN) 3 ][Mn(5-Ysalen)]·pMeOH·qH 2 O [qpaH 2 = N-(quinolin-8-yl)picolinamide; salen = N,N'-ethylenebis(salicylideneiminato) dianion; X = Cl, Y = H (3); X = Cl, Y = Br (4); X = Br, Y = H (5); X = Br, Y = F (6); X = Br, Y = Cl (7); X = Br, Y = Br (8)]. When precursor 1 was used, compounds 3 and 4 were isolated to give a dinuclear entity and a linear chain structure, respectively. The reaction of precursor 2 with the Schiff bases afforded four linear Fe(iii)-Mn(iii) chain complexes. Chain chirality with P- and M-helicity emerges in 4, 7, and 8, while 5 exhibits chain helicity opposite to the previous chain complexes and 6 presents no chain helicity. Such a structural feature is heavily dependent on the interchain π-π contacts and the Fe precursor bridging unit. Chiral induction from a local ethylenediamine link of Y-salen is propagated over the chain via noncovalent π-π interactions. All the bimetallic compounds show antiferromagnetic interactions transmitted by the cyanide linkage. A field-induced metamagnetic transition is involved in 4, 7, and 8, while a field-induced two-step transition is evident in 6. From a magnetostructural viewpoint, the coupling constant is primarily governed by the Mn-N ax -C ax angle (ax = axial) in the bimetallic chain complexes composed of mer-Fe(iii) tricyanides, although the torsion angle plays a role.

Electronic modification of Cu-based chalcopyrite semiconductors induced by lattice deformation and composition alchemy

NASA Astrophysics Data System (ADS)

Jiang, F. D.; Feng, J. Y.

2008-02-01

Using first principles calculation, we systematically investigate the electronic modification of Cu-based chalcopyrite semiconductors induced by lattice deformation and composition alchemy. It is shown that the optical band gap Eg is remarkably sensitive to the anion displacement μ, resulting from the opposite shifts of conduction band minimum and valence band maximum. Meanwhile, the dependence of structural parameters of alloyed compounds on alloy composition x is demonstrated for both cation and anion alloying. The d orbitals of group-III cations are found to be of great importance in the calculation. Abnormal changes in the optical band gap Eg induced by anion alloying are addressed.

Hepatoprotective glycosides from the rhizomes of Imperata cylindrical.

PubMed

Ma, Jie; Sun, Hua; Liu, Hui; Shi, Gao-Na; Zang, Ying-Da; Li, Chuang-Jun; Yang, Jing-Zhi; Chen, Fang-You; Huang, Ji-Wu; Zhang, Dan; Zhang, Dong-Ming

2018-05-01

Three new C-methylated phenylpropanoid glycosides (1, 2), a new 8-4'-oxyneolignan (3), together with two known analogs (4, 5), were isolated from the rhizomes of Imperata cylindrical Beauv. var. major (Nees) C. E. Hubb. Their structures were determined by spectroscopic and chemical methods. Compounds 1, 2, and 5 (10 μM) exhibited pronounced hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell damage in vitro assays. Furthermore, their antioxidant activities against Fe 2+ -cysteine-induced rat liver microsomal lipid peroxidation and the effects on the secretion of TNF-α in murine peritoneal macrophages (RAW264.7) induced by lipopolysaccharides were evaluated.

Evaluation of the effects of several zoanthamine-type alkaloids on the aggregation of human platelets.

PubMed

Villar, Rosa M; Gil-Longo, José; Daranas, Antonio H; Souto, María L; Fernández, José J; Peixinho, Solange; Barral, Miguel A; Santafé, Gilmar; Rodríguez, Jaime; Jiménez, Carlos

2003-05-15

Ten zoanthamine-type alkaloids from two marine zoanthids belonging to the Zoanthus genus (Zoanthus nymphaeus and Zoanthus sp.) along with one semisynthetic derivative were evaluated for their antiplatelet activities on human platelet aggregation induced by several stimulating agents. 11-Hydroxyzoanthamine (11) and a synthetic derivative of norzoanthamine (16) showed strong inhibition against thrombin-, collagen- and arachidonic acid-induced aggregation, zoanthenol (15) displayed a selective inhibitory activity induced by collagen, while zoanthaminone (10) behaved as a potent aggregant agent. These evaluations allowed us to deduce several structure-activity relationships and suggest some mechanisms of action for this type of compounds.

Origin of negative thermal expansion in Zn2GeO4 revealed by high pressure study

NASA Astrophysics Data System (ADS)

Cheng, Xuerui; Yuan, Jie; Zhu, Xiang; Yang, Kun; Liu, Miao; Qi, Zeming

2018-03-01

Zn2GeO4, as an open-framework structure compound, exhibits negative thermal expansion (NTE) below room temperature. In this work, we investigated the structural stability and phonon modes employing the x-ray diffraction and Raman spectroscopy under high pressure up to 23.0 GPa within a diamond anvil cell, and we observed that a pressure-induced irreversible amorphization took place around 10.1 GPa. Bulk modulus, pressure coefficients, and Grüneisen parameters were measured for the initial rhombohedral structure. Several low-frequency rigid-unit modes are found to have negative Grüneisen parameter, which accounts for the primary part of NTE in Zn2GeO4. These results further confirm the hypothesis that the pressure-induced amorphization and the negative thermal expansion are correlated phenomena.

The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

PubMed

Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

2017-08-01

Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

Thermoelectric power factor of La0.9M0.1FeO3 (M = Ca and Ba) system: Structural, band gap and electrical transport evaluations

NASA Astrophysics Data System (ADS)

Karthikeyan, N.; Kumar, R. Ramesh; Jaiganesh, G.; Sivakumar, K.

2018-01-01

The search for thermoelectric materials has been incredibly increased due to the increase in global energy demand. Hence the present work focus on preparation and characterization of thermal transport phenomena of pure and Ba/Ca substituted perovskite LaFeO3 orthoferrite system. The conventional solid state reaction technique is utilized for the preparation of LaFeO3 and La0.9M0.1FeO3 (M = Ca and Ba) compounds. Crystal structure analyses of the prepared samples are analyses using Rietveld refinement process which confirms the orthoferrite crystal structure of all the prepared compounds with induced distortion in position of atoms by the incorporation of substituent atoms. The electronic structure calculations are performed by VASP. As the LaFeO3 compound is a strongly energy correlated system, the Density Functional Theory (DFT) calculations are performed by DFT + U (Hubbard function) method. The computed band gap values are compared with the energy gap values calculated from UV-Vis spectral analysis. Electrical conductivity measurement and Arrhenius behavior for the temperature range of room temperature to 650 K are analyzed and the drift increase in conductivity with respect to temperature is due to the thermally activated mobility of charge carriers. Temperature dependent thermopower analysis is also examined using homemade seebeck coefficient measurement system. The calculation of thermoelectric power factor reveals that the Ba substituted LaFeO3 compound show highest power factor value of 3.73 μW/K2 cm at higher temperature and the superior power factor values observed in the Ba substituted compound determine the material's capability in power generating devices based on thermoelectric effect.

Discovering ligands for a microRNA precursor with peptoid microarrays

PubMed Central

Chirayil, Sara; Chirayil, Rachel; Luebke, Kevin J.

2009-01-01

We have screened peptoid microarrays to identify specific ligands for the RNA hairpin precursor of miR-21, a microRNA involved in cancer and heart disease. Microarrays were printed by spotting a library of 7680 N-substituted oligoglycines (peptoids) onto glass slides. Two compounds on the array specifically bind RNA having the sequence and predicted secondary structure of the miR-21 precursor hairpin and have specific affinity for the target in solution. Their binding induces a conformational change around the hairpin loop, and the most specific compound recognizes the loop sequence and a bulged uridine in the proximal duplex. Functional groups contributing affinity and specificity were identified, and by varying a critical methylpyridine group, a compound with a dissociation constant of 1.9 μM for the miR-21 precursor hairpin and a 20-fold discrimination against a closely-related hairpin was created. This work describes a systematic approach to discovery of ligands for specific pre-defined novel RNA structures. It demonstrates discovery of new ligands for an RNA for which no specific lead compounds were previously known by screening a microarray of small molecules. PMID:19561197

Quantum interference in coherent tunneling through branched molecular junctions containing ferrocene centers

NASA Astrophysics Data System (ADS)

Zhao, Xin; Kastlunger, Georg; Stadler, Robert

2017-08-01

In our theoretical study where we combine a nonequilibrium Green's function approach with density functional theory we investigate branched compounds containing ferrocene moieties in both branches which, due to their metal centers, are designed to allow for asymmetry induced by local charging. In these compounds the ferrocene moieties are connected to pyridyl anchor groups either directly or via acetylenic spacers in a metaconnection, where we also compare our results with those obtained for the respective single-branched molecules with both meta- and paraconnections between the metal center and the anchors. We find a destructive quantum interference (DQI) feature in the transmission function slightly below the lowest unoccupied molecular orbital, which dominates the conductance even for the uncharged branched compound with spacer groups inserted. In an analysis based on mapping the structural characteristics of the range of molecules in our article onto tight-binding models, we identify the structural source of the DQI minimum as the through-space coupling between the pyridyl anchor groups. We also find that local charging in one of the branches changes the conductance only by about one order of magnitude, which we explain in terms of the spatial distributions of the relevant molecular orbitals for the branched compounds.

Research in Computational Astrobiology

NASA Technical Reports Server (NTRS)

Chaban, Galina; Colombano, Silvano; Scargle, Jeff; New, Michael H.; Pohorille, Andrew; Wilson, Michael A.

2003-01-01

We report on several projects in the field of computational astrobiology, which is devoted to advancing our understanding of the origin, evolution and distribution of life in the Universe using theoretical and computational tools. Research projects included modifying existing computer simulation codes to use efficient, multiple time step algorithms, statistical methods for analysis of astrophysical data via optimal partitioning methods, electronic structure calculations on water-nuclei acid complexes, incorporation of structural information into genomic sequence analysis methods and calculations of shock-induced formation of polycylic aromatic hydrocarbon compounds.

Dihydro-β-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

PubMed

Núñez, Marvin J; Jiménez, Ignacio A; Mendoza, Cristina R; Chavez-Sifontes, Marvin; Martinez, Morena L; Ichiishi, Eiichiro; Tokuda, Ryo; Tokuda, Harukuni; Bazzocchi, Isabel L

2016-03-23

Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-β-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of β-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Impact of high hydrostatic pressure and pasteurization on the structure and the extractability of bioactive compounds of persimmon “Rojo Brillante”.

PubMed

Hernández-Carrión, M; Vázquez-Gutiérrez, J L; Hernando, I; Quiles, A

2014-01-01

Rojo Brillante is an astringent oriental persimmon variety with high levels of bioactive compounds such as soluble tannins, carotenoids, phenolic acids, and dietary fiber. The purpose of this study was to investigate the effects of high hydrostatic pressure (HHP) and pasteurization on the structure of the fruit and on the extractability of certain bioactive compounds. The microstructure was studied using light microscopy, transmission electron microscopy, and low temperature scanning electron microscopy, and certain physicochemical properties (carotenoid and total soluble tannin content, antioxidant activity, fiber content, color, and texture properties) were measured. The structural changes induced by HHP caused a rise in solute circulation in the tissues that could be responsible for the increased carotenoid level and the unchanged antioxidant activity in comparison with the untreated persimmon. In contrast, the changes that took place during pasteurization lowered the tannin content and antioxidant activity. Consequently, HHP treatment could improve the extraction of potentially bioactive compoundsxsts from persimmons. A high nutritional value ingredient to be used when formulating new functional foods could be obtained using HHP. © 2013 Institute of Food Technologists®

Signals of Systemic Immunity in Plants: Progress and Open Questions

PubMed Central

Ádám, Attila L.; Nagy, Zoltán Á.; Kátay, György; Mergenthaler, Emese; Viczián, Orsolya

2018-01-01

Systemic acquired resistance (SAR) is a defence mechanism that induces protection against a wide range of pathogens in distant, pathogen-free parts of plants after a primary inoculation. Multiple mobile compounds were identified as putative SAR signals or important factors for influencing movement of SAR signalling elements in Arabidopsis and tobacco. These include compounds with very different chemical structures like lipid transfer protein DIR1 (DEFECTIVE IN INDUCED RESISTANCE1), methyl salicylate (MeSA), dehydroabietinal (DA), azelaic acid (AzA), glycerol-3-phosphate dependent factor (G3P) and the lysine catabolite pipecolic acid (Pip). Genetic studies with different SAR-deficient mutants and silenced lines support the idea that some of these compounds (MeSA, DIR1 and G3P) are activated only when SAR is induced in darkness. In addition, although AzA doubled in phloem exudate of tobacco mosaic virus (TMV) infected tobacco leaves, external AzA treatment could not induce resistance neither to viral nor bacterial pathogens, independent of light conditions. Besides light intensity and timing of light exposition after primary inoculation, spectral distribution of light could also influence the SAR induction capacity. Recent data indicated that TMV and CMV (cucumber mosaic virus) infection in tobacco, like bacteria in Arabidopsis, caused massive accumulation of Pip. Treatment of tobacco leaves with Pip in the light, caused a drastic and significant local and systemic decrease in lesion size of TMV infection. Moreover, two very recent papers, added in proof, demonstrated the role of FMO1 (FLAVIN-DEPENDENT-MONOOXYGENASE1) in conversion of Pip to N-hydroxypipecolic acid (NHP). NHP systemically accumulates after microbial attack and acts as a potent inducer of plant immunity to bacterial and oomycete pathogens in Arabidopsis. These results argue for the pivotal role of Pip and NHP as an important signal compound of SAR response in different plants against different pathogens. PMID:29642641

Benzyl alcohol derivatives from the mushroom Hericium erinaceum attenuate LPS-stimulated inflammatory response through the regulation of NF-κB and AP-1 activity.

PubMed

Noh, Hyung Jun; Yoon, Ju Young; Kim, Geum Sook; Lee, Seung Eun; Lee, Dae Young; Choi, Je Hun; Kim, Seung Yu; Kang, Ki Sung; Cho, Jae Youl; Kim, Ki Hyun

2014-10-01

On the search for anti-inflammatory compounds from natural Korean medicinal sources, a bioassay-guided fractionation and chemical investigation of the MeOH extract from the fruiting bodies of Hericium erinaceum resulted in the isolation and identification of five benzyl alcohol derivatives (1-5). In this study, their anti-inflammatory effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators were examined using RAW 264.7 macrophage cells. The structures of isolates were identified by comparing their spectroscopic data with previously reported values. The analysis of their inhibitory activities on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 macrophage cells showed that erinacerin B (2) and hericenone E (4) decreased the levels of NO and PGE2 production in a concentration-dependent manner. Next, this study was performed to examine their mechanism of action on the regulation of NO and PGE2 production. Compounds 2 and 4 were found to block the LPS-induced phosphorylation of two major inflammatory transcription factors, NF-κB (p65/p50) and AP-1 (c-Jun and c-Fos). Taken together, these results suggest that down-regulation of LPS-induced NO and PGE2 production by compounds 2 and 4 is mediated through the modulation of NF-κB and AP-1 activation in macrophage cells. These results impact the development of potential health products for preventing and treating inflammatory diseases.

Ganoboninketals A-C, Antiplasmodial 3,4-seco-27-Norlanostane Triterpenes from Ganoderma boninense Pat.

PubMed

Ma, Ke; Ren, Jinwei; Han, Junjie; Bao, Li; Li, Li; Yao, Yijian; Sun, Chen; Zhou, Bing; Liu, Hongwei

2014-08-22

Three new nortriterpenes, ganoboninketals A-C (1-3), featuring rearranged 3,4-seco-27-norlanostane skeletons and highly complex polycyclic systems were isolated from the medicinal mushroom Ganoderma boninense. The structures of the new metabolites were established by spectroscopic methods. The absolute configurations in 1-3 were assigned by electronic circular dichroism (ECD) calculations. Compounds 1-3 showed antiplasmodial activity against Plasmodium falciparum with IC50 values of 4.0, 7.9, and 1.7 μM, respectively. Compounds 1 and 3 also displayed weak cytotoxicity against A549 cell line with IC50 values of 47.6 and 35.8 μM, respectively. Compound 2 showed weak cytotoxicity toward HeLa cell line with an IC50 value of 65.5 μM. Compounds 1-3 also presented NO inhibitory activity in the LPS-induced macrophages with IC50 values of 98.3, 24.3, and 60.9 μM, respectively.

Magnetically induced electrical transport and dielectric properties of 3d transition elemental substitution at the Mn-site in Nd0.67Ba0.33MnO3 manganites

NASA Astrophysics Data System (ADS)

Sudakshina, B.; Arun, B.; Chandrasekhar, K. Devi; Yang, H. D.; Vasundhara, M.

2018-05-01

We have investigated the temperature dependence of electrical transport and dielectric properties along with magnetoresistance and magneto dielectric behavior in Nd0.67Ba0.33Mn0.9TR0.1O3 (TR= Cr, Fe, Co, Ni, Cu) manganites. All the compounds crystallized into an orthorhombic structure with Imma space group. Nd0.67Ba0.33MnO3 shows insulating to metallic behavior at intermediate temperatures, but, with the substitution of transitional elements it shows insulating in nature, down to lowest temperature measured for all the compounds. Dielectric measurement shows the intrinsic behavior of these lossy materials. A large value of magneto resistance is obtained for all the compounds and considerable amount of magneto-dielectric effect is shown for all the substituted compounds at lower temperatures.

Withanolides derived from Physalis peruviana (Poha) with potential anti-inflammatory activity.

PubMed

Sang-Ngern, Mayuramas; Youn, Ui Joung; Park, Eun-Jung; Kondratyuk, Tamara P; Simmons, Charles J; Wall, Marisa M; Ruf, Michael; Lorch, Sam E; Leong, Ethyn; Pezzuto, John M; Chang, Leng Chee

2016-06-15

Three new withanolides, physaperuvin G (1), with physaperuvins I (2), and J (3), along with seven known derivatives (4-10), were isolated from the aerial parts of Physalis peruviana. The structures of 1-3 were determined by NMR, X-ray diffraction, and mass spectrometry. Compounds 1-10 were evaluated in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. Compounds 4, 5, and 10 with potent nitric oxide inhibitory activity in LPS-activated RAW 264.7 cells, with IC50 values in the range of 0.32-7.8μM. In addition, all compounds were evaluated for potential to inhibit tumor necrosis factor-alpha (TNF-α)-activated nuclear factor-kappa B (NF-κB) activity with transfected human embryonic kidney cells 293. Compounds 4-7 inhibited TNF-α-induced NF-κB activity with IC50 values in the range of 0.04-5.6μM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis, anti-inflammatory evaluation in vivo and docking studies of some new 5-(benzo[b]furan-2-ylmethyl)-6-methyl-pyridazin-3(2H)-one derivatives

NASA Astrophysics Data System (ADS)

Boukharsa, Youness; Lakhlili, Wiame; El harti, Jaouad; Meddah, Bouchra; Tiendrebeogo, Ramata Yvette; Taoufik, Jamal; El Abbes Faouzi, My; Ibrahimi, Azeddine; Ansar, M'hammed

2018-02-01

Seven novel 5-(benzo[b]furan-2-ylmethyl)-6-methyl-pyridazin-3(2H)-one derivatives (6a to 6g) have been synthesized by the condensation of appropriate 3-(benzofuran-2-ylmethylene)-4-oxopentanoic acid and hydrazine hydrate in ethanol. Structures of all compounds were elucidated by elemental analysis, IR, 1H NMR and 13C NMR. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. In silico molecular docking study has been executed to study the binding interactions of the synthesized compounds with COX-2 protein. Compounds 6a, 6b, 6e and 6g showed a good anti-inflammatory activity at 50 mg/kg compared with the indometacin at 10 mg/kg and the aspirin at 150 mg/kg and good binding affinity with COX-2.

Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells.

PubMed

Kim, Hyeon Ho; Sik Bang, Sung; Seok Choi, Jin; Han, Hogyu; Kim, Ik-Hwan

2005-06-08

Protein kinase C (PKC) plays an important role in the proliferation and differentiation of various cell types including normal and leukemic hematopoietic cells. Recently, various PKC modulators were used as a chemotherapeutic agent of leukemia. Decursin (1), a pyranocoumarin from Angelica gigas, exhibits the cytotoxic effects on various human cancer cell lines and in vitro PKC activation. For the development of more effective anticancer agents with PKC modulation activity, 11 decursin derivatives 2-12 were chemically synthesized and evaluated for their ability to act as a tumor-suppressing PKC activator and as an antagonist to phorbol 12-myristate 13-acetate (PMA), a tumor-promoting PKC activator. In the presence of phosphatidylserine (PS), all of 12 compounds 1-12 activated PKC (mainly alpha, beta, and gamma isozymes) but only three compounds 1-3 activated PKC even in the absence of PS. Six compounds 1-6 containing the coumarin structure were cytotoxic to human K562 erythroleukemia and U937 myeloleukemia cells. A cytotoxic mechanism of decursin and its derivatives was investigated using TUR cells, a PKC betaII-deficient variant of U937 cells. Among six compounds 1-6 with cytotoxicity to K562 and U937 leukemia cells, only three compounds 1-3 were cytotoxic to TUR cells. Therefore, compounds 1-3 and 4-6 inhibit the proliferation of leukemia cells in a PKC betaII-independent and dependent manner, respectively, indicating that the side chain of compounds determines the dependency of their cytotoxicity on PKC betaII. To further elucidate the cytotoxic mechanism of compounds 1 and 2, levels of PKC isozymes and generation of reactive oxygen species (ROS) were investigated. Compounds 1-2 induced the down-regulation of PKC alpha and betaII in K562 cells and the production of ROS in U937 cells. Thus, PKC and ROS are probably important factors in the cytotoxic mechanism of compounds 1-2. From these results, the structure-activity relationship of decursin and its derivatives is as follows: (i) the coumarin structure is required for anti-leukemic activity and (ii) the side chain is a determinant of PKC activation and the cytotoxic mechanism in leukemia cells.

Fast dynamic electron transfer along infinite anion-cation chains in technetium and rhenium acido clusters

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

Antipov, B.G.; Kryuchkov, S.V.; Grigor`ev, M.S.

1995-09-01

New technetium and rhenium compounds with ferricenium cations - [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 3}[Tc{sub 6}I{sub 14}], [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 3}[Tc{sub 6}Cl{sub 14}], [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 2}[Tc{sub 8}Br{sub 14}], and [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 2}[Re{sub 2}Br{sub 8}] - are synthesized and identified. The compounds are characterized by the methods of static magnetic susceptibility and differential scanning calorimetry; solid-state conductivity measurements; and IR, EPR, {sup 57}Fe Moessbauer, and X-ray photoelectron spectroscopic data. These data are compared with the physicochemical characteristics of ferricenium pertechnetate and hexachlorotechnetate, as well as of a number of reference technetium and rhenium compounds containing the samemore » anions but different cations. The structure of [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 3}[Tc{sub 6}I{sub 14}] is determined by X-ray diffraction analysis of a single crystal [space group P6/m, a = 15.34(2), c = 12.70(1) {angstrom}]. The structures of the remaining compounds were confirmed by comparing their spectroscopic properties with corresponding properties of compounds with known composition and structure. None of the compounds with ferricenium cations exhibit covalent or other localized bonds between anions and cations. However, the physicochemical properties of these compounds indicate the occurrence of a fast dynamic electron transfer along infinite anion-cation chains. Compounds [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 3}[Tc{sub 6}Cl{sub 14}] and [Fe(C{sub 5}H{sub 5}){sub 2}]{sub 2}[Tc{sub 8}Br{sub 14}] were found to exhibit a new phenomenon of X-ray-induced low-temper ature high-energy electron emission.« less

Bioactive metabolites from an endophytic Cryptosporiopsis sp. inhabiting Clidemia hirta.

PubMed

Zilla, Mahesh K; Qadri, Masroor; Pathania, Anup S; Strobel, Gary A; Nalli, Yedukondalu; Kumar, Sunil; Guru, Santosh K; Bhushan, Shashi; Singh, Sanjay K; Vishwakarma, Ram A; Riyaz-Ul-Hassan, Syed; Ali, Asif

2013-11-01

An endophytic Cryptosporiopsis sp. was isolated from Clidemia hirta and analyzed for its secondary metabolites that lead to the isolation of three bioactive molecules. The compounds were purified from the culture broth of the fungus and their structures were determined by spectroscopic methods as (R)-5-hydroxy-2-methylchroman-4-one (1), 1-(2,6-dihydroxyphenyl)pentan-1-one (2) and (Z)-1-(2-(2-butyryl-3-hydroxyphenoxy)-6-hydroxyphenyl)-3-hydroxybut-2-en-1-one (3). Compound 1 exhibited significant cytotoxic activity against the human leukemia cell line, HL-60 with an IC50 of 4 μg/ml. This compound induced G2 arrest of the HL-60 cell cycle significantly. In addition, out of these compounds, 2 and 3 were active against several bacterial pathogens. Compound 2 was active against Bacillus cereus, Escherichia coli and Staphylococcus aureus with IC50 values varying from 18 to 30 μg/ml, and compound 3 displayed activity against Pseudomonas fluorescens with an IC50 value of 6 μg/ml. Compounds 2 and 3 are novel whereas compound 1 was reported earlier but the stereochemistry of its C-2 methyl is established for the first time. Copyright © 2013 Elsevier Ltd. All rights reserved.

Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.

PubMed

Simoni, Elena; Daniele, Simona; Bottegoni, Giovanni; Pizzirani, Daniela; Trincavelli, Maria L; Goldoni, Luca; Tarozzo, Glauco; Reggiani, Angelo; Martini, Claudia; Piomelli, Daniele; Melchiorre, Carlo; Rosini, Michela; Cavalli, Andrea

2012-11-26

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).

Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres.

PubMed

Alafeefy, Ahmed M; Bakht, Mohammed A; Ganaie, Majid A; Ansarie, Mohd N; El-Sayed, Nahed N; Awaad, Amani S

2015-01-15

A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and (VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no hepatocyte necrosis or liver degeneration. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of Potential Thrombin Inhibitors from the White Mangrove (Laguncularia racemosa (L.) C.F. Gaertn.)

PubMed Central

Rodrigues, Caroline Fabri Bittencourt; Gaeta, Henrique Hessel; Belchor, Mariana Novo; Ferreira, Marcelo José Pena; Pinho, Marcus Vinícius Terashima; de Oliveira Toyama, Daniela; Toyama, Marcos Hikari

2015-01-01

The aim of this work was to verify the effects of methanol (MeOH) and hydroalcoholic (HA) extracts and their respective partition phases obtained from white mangrove (Laguncularia racemosa (L.) C.F. Gaertn.) leaves on human thrombin activity. Among the extracts and phases tested, only the ethyl acetate and butanolic partitions significantly inhibited human thrombin activity and the coagulation of plasma in the presence of this enzyme. Chromatographic analyses of the thrombin samples incubated with these phases revealed that different compounds were able to interact with thrombin. The butanolic phase of the MeOH extract had the most potent inhibitory effects, reducing enzymatic activity and thrombin-induced plasma coagulation. Two glycosylated flavonoids in this partition were identified as the most potent inhibitors of human thrombin activity, namely quercetin-3-O-arabinoside (QAra) and quercetin-3-O-rhamnoside (Qn). Chromatographic analyses of thrombin samples incubated with these flavonoids demonstrated the chemical modification of this enzyme, suggesting that the MeOH extract contained other compounds that both induced structural changes in thrombin and diminished its activity. In this article, we show that despite the near absence of the medical use of mangrove compounds, this plant contains natural compounds with potential therapeutic applications. PMID:26197325

Synthesis, biological evaluation and molecular modeling of novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic agents

NASA Astrophysics Data System (ADS)

Helal, M. H.; El-Awdan, S. A.; Salem, M. A.; Abd-elaziz, T. A.; Moahamed, Y. A.; El-Sherif, A. A.; Mohamed, G. A. M.

2015-01-01

This paper presents a combined synthesis; characterization, computational and biological activity studies of novel series of pyridines heterocyclic compounds. The compounds have been characterized by elemental analyses and spectral like IR, 1H NMR, 13C NMR and MS studies. Michael addition of substituted-2-methoxycarbonylacetanilide 2a,b on the α-substituted cinnamonitriles 3a-d gave the corresponding 2-pyridone derivatives 5-10. Structures of the titled compounds cited in this article were elucidated by spectrometric data (IR, 1H NMR, 13C NMR and MS). The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from the calculation of molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Various in vitro antitumor as well as in vivo anti-inflammatory and analgesic activities of the synthesized compounds were investigated. Evaluation of anti-inflammatory activity of test compounds was performed using carrageenan induced paw edema in rats. All the tested compounds showed moderate to good activity. The SAR results indicate that all compounds showed moderate to good activity, among these 7 and 10 compounds having -N(CH3)2 group are most effective.

Discovery of Indeno[1,2-c]quinoline Derivatives as Potent Dual Antituberculosis and Anti-Inflammatory Agents.

PubMed

Tseng, Chih-Hua; Tung, Chun-Wei; Wu, Chen-Hsin; Tzeng, Cherng-Chyi; Chen, Yen-Hsu; Hwang, Tsong-Long; Chen, Yeh-Long

2017-06-16

A series of indeno[1,2- c ]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H 37 R V . Among the tested compounds, ( E )- N '-[6-(4-hydroxypiperidin-1-yl)-11 H -indeno[1,2- c ]quinolin-11-ylidene]isonicotino-hydrazide ( 12 ), exhibited significant activities against the growth of M. tuberculosis (MIC values of 0.96 μg/mL) with a potency approximately equal to that of isoniazid (INH), an anti-TB drug. Important structure features were analyzed by quantitative structure-activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the anti-TB activity. The anti-inflammatory activity was induced by superoxide anion generation and neutrophil elastase (NE) release using the formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils method. Results indicated that compound 12 demonstrated a potent dual inhibitory effect on NE release and superoxide anion generation with IC 50 values of 1.76 and 1.72 μM, respectively. Our results indicated that compound 12 is a potential lead compound for the discovery of dual anti-TB and anti-inflammatory drug candidates. In addition, 6-[3-(hydroxymethyl)piperidin-1-yl]-9-methoxy-11 H -indeno[1,2- c ]quinolin-11-one ( 4g ) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC 50 values of 0.46 and 0.68 μM, respectively, and is a potential lead compound for the discovery of anti-inflammatory drug candidates.

The predatory mite Phytoseiulus persimilis does not perceive odor mixtures as strictly elemental objects.

PubMed

van Wijk, Michiel; de Bruijn, Paulien J A; Sabelis, Maurice W

2010-11-01

Phytoseiulus persimilis is a predatory mite that in absence of vision relies on the detection of herbivore-induced plant odors to locate its prey, the two-spotted spider-mite Tetranychus urticae. This herbivorous prey is feeding on leaves of a wide variety of plant species in different families. The predatory mites respond to numerous structurally different compounds. However, typical spider-mite induced plant compounds do not attract more predatory mites than plant compounds not associated with prey. Because the mites are sensitive to many compounds, components of odor mixtures may affect each other's perception. Although the response to pure compounds has been well documented, little is known how interactions among compounds affect the response to odor mixtures. We assessed the relation between the mites' responses elicited by simple mixtures of two compounds and by the single components of these mixtures. The preference for the mixture was compared to predictions under three conceptual models, each based on one of the following assumptions: (1) the responses elicited by each of the individual components can be added to each other; (2) they can be averaged; or (3) one response overshadows the other. The observed response differed significantly from the response predicted under the additive response, average response, and overshadowing response model in 52, 36, and 32% of the experimental tests, respectively. Moreover, the behavioral responses elicited by individual compounds and their binary mixtures were determined as a function of the odor concentration. The relative contribution of each component to the behavioral response elicited by the mixture varied with the odor concentration, even though the ratio of both compounds in the mixture was kept constant. Our experiments revealed that compounds that elicited no response had an effect on the response elicited by binary mixtures that they were part of. The results are not consistent with the hypothesis that P. persimilis perceives odor mixtures as a collection of strictly elemental objects. They suggest that odor mixtures rather are perceived as one synthetic whole.

Synthesis, structural characterization and effect on human granulocyte intracellular cAMP levels of abscisic acid analogs.

PubMed

Bellotti, Marta; Salis, Annalisa; Grozio, Alessia; Damonte, Gianluca; Vigliarolo, Tiziana; Galatini, Andrea; Zocchi, Elena; Benatti, Umberto; Millo, Enrico

2015-01-01

The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure-activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2' and C-3' abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti-inflammatory compounds. Copyright © 2014 Elsevier Ltd. All rights reserved.

Disruption of crystalline structure of Sn3.5Ag induced by electric current

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

Huang, Han-Chie; Lin, Kwang-Lung, E-mail: matkllin@mail.ncku.edu.tw; Wu, Albert T.

2016-03-21

This study presented the disruption of the Sn and Ag{sub 3}Sn lattice structures of Sn3.5Ag solder induced by electric current at 5–7 × 10{sup 3} A/cm{sup 2} with a high resolution transmission electron microscope investigation and electron diffraction analysis. The electric current stressing induced a high degree of strain on the alloy, as estimated from the X-ray diffraction (XRD) peak shift of the current stressed specimen. The XRD peak intensity of the Sn matrix and the Ag{sub 3}Sn intermetallic compound diminished to nearly undetectable after 2 h of current stressing. The electric current stressing gave rise to a high dislocation density ofmore » up to 10{sup 17}/m{sup 2}. The grain morphology of the Sn matrix became invisible after prolonged current stressing as a result of the coalescence of dislocations.« less

A cytotoxic and apoptosis-inducing sesquiterpenoid isolated from the aerial parts of Artemisia princeps PAMPANINI (Sajabalssuk).

PubMed

Bang, Myun-Ho; Han, Min-Woo; Song, Myoung-Chong; Cho, Jin-Gyeong; Chung, Hae-Gon; Jeong, Tae-Sook; Lee, Kyung-Tae; Choi, Myung-Sook; Kim, Se-Young; Baek, Nam-In

2008-08-01

Repeated silica gel and octadecyl silica gel (ODS) column chromatography of the aerial parts of Artemisia princeps PAMPANINI (Sajabalssuk) led to the isolation of a new sesquiterpenoid, 3-((S)-2-methylbutyryloxy)-costu-1(10),4(5)-dien-12,6 alpha-olide (2), along with two previously reported sesquiterpenoids: 8 alpha-angeloyloxy-3beta,4 beta-epoxy-6 beta H,7 alpha H,8 beta H-guaia-1(10),11(13)-dien-12,6 alpha-olide (1, carlaolide B) and 3beta,4 beta-epoxy-8 alpha-isobutyryloxy-6 beta H,7 alpha H,8 beta H-guaia-1(10),11(13)-dien-12,6 alpha-olide (3, carlaolide A). The structure of compound 2 was elucidated by spectroscopic data analysis, including one dimensional (1D) and two dimensional (2D) nuclear magnetic resonance (NMR) experiments. Of the isolates, compound 2 exhibited potent cytotoxicity against human cervix adenocarcinoma cells and induced apoptosis.

Formation of organobromine and organoiodine compounds by engineered TiO2 nanoparticle-induced photohalogenation of dissolved organic matter in environmental waters.

PubMed

Hao, Zhineng; Yin, Yongguang; Wang, Juan; Cao, Dong; Liu, Jingfu

2018-08-01

There are increasing concerns about the adverse effects of released engineered nanoparticles and photochemically formed organohalogen compounds (OHCs) on human health and the environment. Herein, we report that titanium dioxide nanoparticles (TiO 2 NPs) can photocatalytically halogenate dissolved organic matter (DOM) to form a large number of organobromine compounds (OBCs) and organoiodine compounds (OICs), as characterized by negative ion electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry. Compared with no OHCs produced in control samples in darkness and/or without TiO 2 NPs under sunlight irradiation, various OBCs and OICs were detected in freshwater and seawater under sunlight irradiation for 12h and 24h even in the presence of 1mgL -1 TiO 2 NPs, indicating the photocatalytic roles TiO 2 NPs played in DOM halogenation. Furthermore, TiO 2 NPs could result in the photodegradation of newly formed OHCs, as evidenced by the intensity and the number of some OHCs decreased with reaction time. In addition, many TiO 2 NP-induced OBCs contained two or three bromine atoms, and/or nitrogen and sulfur elements, belonging to lignin-like, tannin-like, unsaturated hydrocarbon and aliphatic compounds. While the OICs were primarily contained one iodine, and very few consisted of nitrogen and sulfur elements, most were lignin-like and tannin-like compounds. Finally, the OBCs in freshwater were found to be formed mainly via a substitution reaction or addition reaction and were accompanied by other reactions such as photooxidation, while the OBCs in seawater and OICs were formed primarily via substitution reactions. Given the abundance of produced OHCs and their toxicity, our findings call for further studies on the exact structure and toxicity of the formed OHCs, taking account the TiO 2 NP-induced DOM photohalogenation in aquatic environments during the evaluation of the environmental effects of engineered TiO 2 NPs. Copyright © 2018 Elsevier B.V. All rights reserved.

Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.

PubMed

Schöffmann, Angela; Wimmer, Laurin; Goldmann, Daria; Khom, Sophia; Hintersteiner, Juliane; Baburin, Igor; Schwarz, Thomas; Hintersteininger, Michael; Pakfeifer, Peter; Oufir, Mouhssin; Hamburger, Matthias; Erker, Thomas; Ecker, Gerhard F; Mihovilovic, Marko D; Hering, Steffen

2014-07-10

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators.

Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest.

PubMed

Duran, Leidy Tatiana Díaz; Rincón, Nathalia Olivar; Galvis, Carlos Eduardo Puerto; Kouznetsov, Vladimir V; Lorenzo, Jorge Luis Fuentes

2015-03-01

Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis. © 2013 Wiley Periodicals, Inc.

Natural dietary compound naringin prevents azoxymethane/dextran sodium sulfate-induced chronic colorectal inflammation and carcinogenesis in mice.

PubMed

Zhang, Yu-Sheng; Wang, Feng; Cui, Shu-Xiang; Qu, Xian-Jun

2018-03-26

Naringin, a natural occurring flavonoid compound, enriches in citrus fruits. We aimed to evaluate the inhibitory effect of naringin on colitis and chronic inflammation-driven carcinogenesis. Male C57BL/6 mice were exposed to AOM/DSS to induce colorectal inflammation and carcinogenesis. Naringin by oral administration prevented AOM/DSS-induced ulcerative colitis and carcinogenesis without significant side effects. Naringin attenuated the severity of colitis and colorectal adenomas through inhibiting myeloid-derived suppressor cells (MDSCs), pro-inflammatory mediators GM-CSF/M-CSF, IL-6 and TNF-α and the NF-κB/IL-6/STAT3 cascades in colorectal tissues. Naringin-treated mice exhibited normalized structures of colorectal tissues. Electron microscopy analysis showed the suppression of robust endoplasmic reticulum (ER) stress-induced autophagy. Naringin inhibited the secretion of the ER-spanning transmembrane proteins, such as GRP78 ATF6, IRE1α and activated PERK phosphorylated eIF-2α and complex of autophagosomes ATG3, ATG5, ATG7, ATG12, ATG16 and ATG16L1 in the colorectal mucosal cells. Naringin prevented colitis and colorectal carcinogenesis through suppressing robust ER stress-induced autophagy in colorectal mucosal cells. Naringin could develop a promising therapeutic agent for the prevention of ulcerative colitis and colorectal tumor.

Hydrothermal synthesis of zinc(II)-phosphonate coordination polymers with different dimensionality (0D, 2D, 3D) and dimensionality change in the solid phase (0D→3D) induced by temperature

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

Fernández-Zapico, Eva; Montejo-Bernardo, Jose; Fernández-González, Alfonso

2015-05-15

Three new zinc(II) coordination polymers, [Zn(HO{sub 3}PCH{sub 2}CH{sub 2}COO)(C{sub 12}H{sub 8}N{sub 2})(H{sub 2}O)] (1), [Zn{sub 3}(O{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(C{sub 12}H{sub 8}N{sub 2})](H{sub 2}O){sub 3.40} (2) and [Zn{sub 5}(HO{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(O{sub 3}PCH{sub 2}CH{sub 2}COO){sub 2}(C{sub 12}H{sub 8}N{sub 2}){sub 4}](H{sub 2}O){sub 0.32} (3), with different structural dimensionality (0D, 2D and 3D, respectively) have been prepared by hydrothermal synthesis, and their structures were determined by single-crystal X-ray diffraction. Compound 1 crystallizes in the monoclinic system (P2{sub 1}/c) forming discrete dimeric units bonded through H-bonds, while compounds 2 and 3 crystallize in the triclinic (P−1) and the monoclinic (C2/c) systems, respectively.more » Compound 3, showing three different coordination numbers (4, 5 and 6) for the zinc atoms, has also been obtained by thermal treatment of 1 (probed by high-temperature XRPD experiments). The crystalline features of these compounds, related to the coordination environments for the zinc atoms in each structure, provoke the increase of the relative fluorescence for 2 and 3, compared to the free phenanthroline. Thermal analysis (TG and DSC) and XPS studies have been also carried out for all compounds. - Graphical abstract: Three new coordination compounds of zinc with 2-carboxyethylphosphonic acid (H{sub 2}PPA) and phenanthroline have been obtained by hydrothermal synthesis. The crystalline structure depends on the different coordination environments of the zinc atoms (see two comparative Zn{sub 6}-moieties). The influence of the different coordination modes of H{sub 2}PPA with the central atom in all structures have been studied, being found new coordination modes for this ligand. Several compounds show a significant increase in relative fluorescence with respect to the free phenanthroline. - Highlights: • Compounds have been obtained modifying the reaction time and the rate of reagents. • Dimensionality and crystalline structure is a function of the zinc environments. • New coordination modes for 2-carboxyethylphosphonic acid are reported. • 3D-compound presents three different coordination environments for the zinc atoms. • Fluorescence properties are related to the structural dimensionality.« less

2D-1D structural phase transformation of Co(II) 3,5-pyridinedicarboxylate frameworks with chromotropism.

PubMed

Cheansirisomboon, Achareeya; Pakawatchai, Chaveng; Youngme, Sujittra

2012-09-21

Two new metal-organic frameworks [Co(pydc)(H(2)O)(2)](n) (1) and [Co(pydc)(H(2)O)(4)](n)(H(2)O)(n) (2), (pydc = 3,5-pyridinedicarboxylate) have been synthesized by a diffusion method and characterized by single-crystal X-ray diffraction. The structure of 1 reveals an infinite 2D layer with honeycomb-like cavities in which each pydc ligand bridges three Co(II) ions. The adjacent 2D layers are orderly packed in an ABAB-type array via intermolecular interactions of the combined π-π stacking and hydrogen bonds to form a 3D supramolecular architecture. Interestingly, compound 1 exhibits a water induced crystal-to-amorphous transformation with chromotropism confirmed by spectroscopic techniques, elemental analysis, TGA and XRPD. When this amorphous phase (1A) was exposed to water vapor, it was readily converted into the second crystalline phase 1B with a color change. Moreover, a reversible process between 1A and 1B was performed. In the case of compound 2, pydc acts as didentate bridging ligand connecting two Co(II) ions, leading to a 1D zig-zag chain. Guest water molecules fill the gaps in between chains and form hydrogen bonds with the host chains stabilizing the 3D network of 2. Additionally, compound 2 also exhibits a water induced crystal-to-amorphous transformation with chromotropism and the reversible process was also performed between the dehydrated (2A) and rehydrated (2') forms. Surprisingly, the IR and UV-vis spectra, elemental analysis, TGA curve and XRPD pattern of the rehydrated second phase 1B are found to be identical to that of 2 and 2', these results confirm that 2, 2' and 1B are the same compound.

Carrier doping into a superconducting BaPb0.7Bi0.3O3‑δ epitaxial film using an electric double-layer transistor structure

NASA Astrophysics Data System (ADS)

Komori, S.; Kakeya, I.

2018-06-01

Doping evolution of the unconventional superconducting properties in BaBiO3-based compounds has yet to be clarified in detail due to the significant change of the oxygen concentration accompanied by the chemical substitution. We suggest that the carrier concentration of an unconventional superconductor, BaPb0.7Bi0.3O3‑δ , is controllable without inducing chemical or structural changes using an electric double-layer transistor structure. The critical temperature is found to decrease systematically with increasing carrier concentration.

Method for making surfactant-templated, high-porosity thin films

DOEpatents

Brinker, C. Jeffrey; Lu, Yunfeng; Fan, Hongyou

2001-01-01

An evaporation-induced self-assembly method to prepare a surfactant-templated thin film by mixing a silica sol, a surfactant, and a hydrophobic polymer and then evaporating a portion of the solvent during coating onto a substrate and then heating to form a liquid-phase, thin film material with a porosity greater than approximately 50 percent. The high porosity thin films can have dielectric constants less than 2 to be suitable for applications requiring low-dielectric constants. An interstitial compound can be added to the mixture, with the interstitial compound either covalently bonded to the pores or physically entrapped within the porous structure. The selection of the interstitial compound provides a means for developing thin films for applications including membranes, sensors, low dielectric constant films, photonic materials and optical hosts.

Organic photovoltaic cell incorporating electron conducting exciton blocking layers

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

Forrest, Stephen R.; Lassiter, Brian E.

2014-08-26

The present disclosure relates to photosensitive optoelectronic devices including a compound blocking layer located between an acceptor material and a cathode, the compound blocking layer including: at least one electron conducting material, and at least one wide-gap electron conducting exciton blocking layer. For example, 3,4,9,10 perylenetetracarboxylic bisbenzimidazole (PTCBI) and 1,4,5,8-napthalene-tetracarboxylic-dianhydride (NTCDA) function as electron conducting and exciton blocking layers when interposed between the acceptor layer and cathode. Both materials serve as efficient electron conductors, leading to a fill factor as high as 0.70. By using an NTCDA/PTCBI compound blocking layer structure increased power conversion efficiency is achieved, compared to anmore » analogous device using a conventional blocking layers shown to conduct electrons via damage-induced midgap states.« less

Cycloartanes from Euphorbia aellenii Rech. f. and their Antiproliferative Activity

PubMed Central

Ayatollahi, Abdul Majid; Ghanadian, Mustafa; Afsharypuor, Suleiman; Mesaik, M. Ahmad; Abdalla, Omer Mohamed; Shahlaei, Mohsen; Farzandi, Gholamhossein; Mostafavi, Hamid

2011-01-01

The cytotoxic chloroform fraction of Euphorbia aellenii afforded two cycloartane type triterpenes-cycloart-25-en-3β,24-diol (1) and 24-methylene-cycloartan-3β-ol (2)-for the first time from this plant. Preparation of cycloartane derivatives, 3β, 24-O-diacetyl-cycloart-25-en as compound 3 and 3β-O-acetyl-24-methylene-cycloartan (4) were conducted by acetylating of 1 and 2, respectively. The structures of the isolated compounds were elucidated by spectroscopic methods and their activities evaluated by proliferation assay on human peripheral blood lymphocytes (PBLs). Comparing the results suggested that anti-proliferation effect of these compounds on PBLs might be due to the presence of free 3-OH group while masking the free OH groups by acetylation, could induce proliferation activity. PMID:24363688

A novel icariin type flavonoid from Epimedium pseudowushanense.

PubMed

Ti, Huihui; Wu, Ping; Xu, Liangxiong; Wei, Xiaoyi

2018-06-06

A novel icariin type flavonoid glycoside with a malonaldehydic acid intramolecular ester and two known flavonoid glycosides were isolated from Epimedium pseudowushanense. Their structures were elucidated on the basis of spectroscopic analysis and comparison of their data to the values reported in the literatures. The anti-inflammatory activities of these compounds icariin 3'''-O-malonaldehydic acid intramolecular 1'''', 2''' ester (1), icariin (2) and epimedin C (3) were tested. The results indicated that compounds 1, 2 and 3 showed maximal inhibitory ratio of 27.91, 44.80 and 46.61%, respectively in in vitro anti-inflammatory activity on LPS-induced TNF-α secretion in RAW264.7 cells. Compounds icariin (2) and epimedin C (3) were found to inhibit the secretion of TNF-α to a comparable degree as quercetin.

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

PubMed

Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Surfactant-induced assembly of enzymatically-stable peptide hydrogels

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

Jones, Brad H.; Martinez, Alina M.; Wheeler, Jill S.

The secondary structure of peptides in the presence of interacting additives is an important topic of study, having implications in the application of peptide science to a broad range of modern technologies. Surfactants constitute a class of biologically relevant compounds that are known to influence both peptide conformation and aggregation or assembly. In addition, we have characterized the secondary structure of a linear nonapeptide composed of a hydrophobic alanine/phenylalanine core flanked by hydrophilic acid/amine units. We show that the anionic surfactant sodium dodecyl sulfate (SDS) induces the formation of β-sheets and macroscopic gelation in this otherwise unstructured peptide. Through comparisonmore » to related additives, we propose that SDS-induced secondary structure formation is the result of amphiphilicity created by electrostatic binding of SDS to the peptide. In addition, we demonstrate a novel utility of surfactants in manipulating and stabilizing peptide nanostructures. SDS is used to simultaneously induce secondary structure in a peptide and to inhibit the activity of a model enzyme, resulting in a peptide hydrogel that is impervious to enzymatic degradation. These results complement our understanding of the behavior of peptides in the presence of interacting secondary molecules and provide new potential pathways for programmable organization of peptides by the addition of such components.« less

Surfactant-induced assembly of enzymatically-stable peptide hydrogels

DOE PAGES

Jones, Brad H.; Martinez, Alina M.; Wheeler, Jill S.; ...

2015-04-07

The secondary structure of peptides in the presence of interacting additives is an important topic of study, having implications in the application of peptide science to a broad range of modern technologies. Surfactants constitute a class of biologically relevant compounds that are known to influence both peptide conformation and aggregation or assembly. In addition, we have characterized the secondary structure of a linear nonapeptide composed of a hydrophobic alanine/phenylalanine core flanked by hydrophilic acid/amine units. We show that the anionic surfactant sodium dodecyl sulfate (SDS) induces the formation of β-sheets and macroscopic gelation in this otherwise unstructured peptide. Through comparisonmore » to related additives, we propose that SDS-induced secondary structure formation is the result of amphiphilicity created by electrostatic binding of SDS to the peptide. In addition, we demonstrate a novel utility of surfactants in manipulating and stabilizing peptide nanostructures. SDS is used to simultaneously induce secondary structure in a peptide and to inhibit the activity of a model enzyme, resulting in a peptide hydrogel that is impervious to enzymatic degradation. These results complement our understanding of the behavior of peptides in the presence of interacting secondary molecules and provide new potential pathways for programmable organization of peptides by the addition of such components.« less

Competition between the compound and the pre-compound emission processes in α-induced reactions at near astrophysical energy to well above it

NASA Astrophysics Data System (ADS)

Sharma, Manoj Kumar; Sharma, Vijay Raj; Yadav, Abhiskek; Singh, Pushpendra P.; Singh, B. P.; Prasad, R.

2016-04-01

The study of pre-compound emission in α-induced reactions, particularly at the low incident energies, is of considerable interest as the pre-compound emission is more likely to occur at higher energies. With a view to study the competition between the compound and the pre-compound emission processes in α-induced reactions at different energies and with different targets, a systematics for neutron emission channels in targets 51V, 55Mn, 93Nb, 121, 123Sb and 141Pr at energy ranging from astrophysical interest to well above it, has been developed. The off-line γ-ray-spectrometry based activation technique has been adopted to measure the excitation functions. The experimental excitation functions have been analysed within the framework of the compound nucleus mechanism based on the Weisskopf-Ewing model and the pre-compound emission calculations based on the geometry dependent hybrid model. The analysis of the data shows that experimental excitation functions could be reproduced only when the pre-compound emission, simulated theoretically, is taken into account. The strength of pre-compound emission process for each system has been obtained by deducing the pre-compound fraction. Analysis of data indicates that in α-induced reactions, the pre-compound emission process plays an important role, particularly at the low incident energies, where the pure compound nucleus process is likely to dominate.

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.

PubMed

Gong, Hua; Weinstein, David S; Lu, Zhonghui; Duan, James J-W; Stachura, Sylwia; Haque, Lauren; Karmakar, Ananta; Hemagiri, Hemalatha; Raut, Dhanya Kumar; Gupta, Arun Kumar; Khan, Javed; Camac, Dan; Sack, John S; Pudzianowski, Andrew; Wu, Dauh-Rurng; Yarde, Melissa; Shen, Ding-Ren; Borowski, Virna; Xie, Jenny H; Sun, Huadong; D'Arienzo, Celia; Dabros, Marta; Galella, Michael A; Wang, Faye; Weigelt, Carolyn A; Zhao, Qihong; Foster, William; Somerville, John E; Salter-Cid, Luisa M; Barrish, Joel C; Carter, Percy H; Dhar, T G Murali

2018-01-15

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y max in the PXR assay for long term preclinical pharmacokinetic (PK) studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Triterpenoid saponins from Anemone flaccida induce apoptosis activity in HeLa cells.

PubMed

Han, Lin-Tao; Li, Juan; Huang, Fang; Yu, Shang-Gong; Fang, Nian-Bai

2009-01-01

Five triterpenoid saponins were isolated from Anemone flaccida Fr. Schmidt. Their structures were identified as glycoside St-I4a (1), glycoside St-J (2), anhuienoside E (3), hederasaponin B (4), and flaccidoside II (5). Compounds 1-2 were isolated from Anemone family for the first time, and compounds 3-4 were isolated from this plant for the first time. The inhibitory effects of saponins on proliferation of HeLa cells were studied by MTT assay, the apoptosis-induction activity was observed by cell-cycle analysis and caspase-3 expression assay. The antitumor activities of the saponins were ranked in the following order: 5 > 3 > 4 > 1 > 2. The data presented here indicated that naturally occurring triterpenoid saponins can be regarded as excellent structures for the potential development of new anticancer agents.

Assay development and case history of a 32K-biased library high-content MK2-EGFP translocation screen to identify p38 mitogen-activated protein kinase inhibitors on the ArrayScan 3.1 imaging platform.

PubMed

Trask, Oscar J; Baker, Audrey; Williams, Rhonda Gates; Nickischer, Debra; Kandasamy, Ramani; Laethem, Carmen; Johnston, Patricia A; Johnston, Paul A

2006-01-01

This chapter describes the conversion and assay development of a 96-well MK2-EGFP translocation assay into a higher density 384-well format high-content assay to be screened on the ArrayScan 3.1 imaging platform. The assay takes advantage of the well-substantiated hypothesis that mitogen-activated protein kinase-activating protein kinase-2 (MK2) is a substrate of p38 MAPK kinase and that p38-induced phosphorylation of MK-2 induces a nucleus-to-cytoplasm translocation. This chapter also presents a case history of the performance of the MK2-EGFP translocation assay, run as a "high-content" screen of a 32K kinase-biased library to identify p38 inhibitors. The assay performed very well and a number of putative p38 inhibitor hits were identified. Through the use of multiparameter data provided by the nuclear translocation algorithm and by checking images, a number of compounds were identified that were potential artifacts due to interference with the imaging format. These included fluorescent compounds, or compounds that dramatically reduced cell numbers due to cytotoxicity or by disrupting cell adherence. A total of 145 compounds produced IC(50) values <50.0 muM in the MK2-EGFP translocation assay, and a cross target query of the Lilly-RTP HTS database confirmed their inhibitory activity against in vitro kinase targets, including p38a. Compounds were confirmed structurally by LCMS analysis and profiled in cell-based imaging assays for MAPK signaling pathway selectivity. Three of the hit scaffolds identified in the MK2-EGFP translocation HCS run on the ArrayScan were selected for a p38a inhibitor hit-to-lead structure activity relationship (SAR) chemistry effort.

Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity.

PubMed

Koksal, Meric; Ozkan-Dagliyan, Irem; Ozyazici, Tugce; Kadioglu, Beril; Sipahi, Hande; Bozkurt, Ayhan; Bilge, Suleyman S

2017-09-01

Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4-oxadiazole bioisostere is a generally used strategy to obtain an anti-inflammatory agent devoid of GI side effects. In the present work, a novel group of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one Mannich bases were synthesized and characterized on the basis of IR, 1 H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non-toxic concentration for anti-inflammatory screening. Anti-inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)-induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS-induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti-inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti-inflammatory data scoring showed that compounds 5a-d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively. © 2017 Deutsche Pharmazeutische Gesellschaft.

Viper and cobra venom neutralization by beta-sitosterol and stigmasterol isolated from the root extract of Pluchea indica Less. (Asteraceae).

PubMed

Gomes, A; Saha, Archita; Chatterjee, Ipshita; Chakravarty, A K

2007-09-01

We reported previously that the methanolic root extract of the Indian medicinal plant Pluchea indica Less. (Asteraceae) could neutralize viper venom-induced action [Alam, M.I., Auddy, B., Gomes, A., 1996. Viper venom neutralization by Indian medicinal plant (Hemidesmus indicus and P. indica) root extracts. Phytother. Res. 10, 58-61]. The present study reports the neutralization of viper and cobra venom by beta-sitosterol and stigmasterol isolated from the root extract of P. indica Less. (Asteraceae). The active fraction (containing the major compound beta-sitosterol and the minor compound stigmasterol) was isolated and purified by silica gel column chromatography and the structure was determined using spectroscopic analysis (EIMS, (1)H NMR, (13)C NMR). Anti-snake venom activity was studied in experimental animals. The active fraction was found to significantly neutralize viper venom-induced lethal, hemorrhagic, defibrinogenation, edema and PLA(2) activity. Cobra venom-induced lethality, cardiotoxicity, neurotoxicity, respiratory changes and PLA(2) activity were also antagonized by the active component. It potentiated commercial snake venom antiserum action against venom-induced lethality in male albino mice. The active fraction could antagonize venom-induced changes in lipid peroxidation and superoxide dismutase activity. This study suggests that beta-sitosterol and stigmasterol may play an important role, along with antiserum, in neutralizing snake venom-induced actions.

Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents.

PubMed

Savjani, Jignasa K; Mulamkattil, Suja; Variya, Bhavesh; Patel, Snehal

2017-04-15

Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Cyclooxygenase-2 (COX-2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti-inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID-4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4-Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure-Activity Relationships) software. The study indicated most of the compounds under safe category. In-vitro pharmacological assessment of heterocyclic compounds was done for COX-1 and COX-2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti-inflammatory activity and ED 50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX-2 enzyme. The pharmacological screening uncovered that compound substituted with p-bromophenyl indicated maximum potency. Copyright © 2017 Elsevier B.V. All rights reserved.

Virtual screening and biological evaluation of novel antipyretic compounds.

PubMed

Froes, Thamires Quadros; Melo, Miriam C C; Souza, Gloria E P; Castilho, Marcelo Santos; Soares, Denis M

2017-11-01

Due to the absence of safety of the antipyretics to patients with cardiovascular dysfunction, new targets to treat inflammation have been pursued. mPGES-1 is a promising target because its inhibition would not cause the side-effects related to COX inhibition. To identify novel inhibitors of mPGES-1, we developed a ligand-based pharmacophore model that differentiates true inhibitors from decoys and enlightens the structure-activity relationships for known mPGES-1 inhibitors. The model (four hydrophobic centers, two hydrogen bond acceptor and two hydrogen bond donor points) was employed to select lead-like compounds from ZINC database for in vivo evaluation. Among the 18 compounds selected, five inhibited the fever induced by LPS. The most potent compound (5-(4-fluorophenyl)-3-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-2,3dihydro-1,3,4-oxadiazol-2-one) is active peripherally (i.v.) or centrally (i.c.v.) (82.18% and 112% reduction, respectively) and reduces (69.13%) hypothalamic PGE 2 production, without significant COX-1/2 inhibition. In conclusion, our in silico approach leads to the selection of a compound that presents the chemical features to inhibit mPGES-1 and reduces fever induced by LPS. Furthermore, the in vivo and in vitro results support the hypothesis that its mechanism of action does not depend on COX inhibition. Hence, it can be considered a promising lead compound for antipyretic development, once it would not have the side-effects of COX-1/2 inhibitors. © 2017 John Wiley & Sons A/S.

Atom-based 3D-QSAR, induced fit docking, and molecular dynamics simulations study of thieno[2,3-b]pyridines negative allosteric modulators of mGluR5.

PubMed

Vijaya Prabhu, Sitrarasu; Singh, Sanjeev Kumar

2018-05-28

Atom-based three dimensional-quantitative structure-activity relationship (3D-QSAR) model was developed on the basis of 5-point pharmacophore hypothesis (AARRR) with two hydrogen bond acceptors (A) and three aromatic rings for the derivatives of thieno[2,3-b]pyridine, which modulates the activity to inhibit the mGluR5 receptor. Generation of a highly predictive 3D-QSAR model was performed using the alignment of predicted pharmacophore hypothesis for the training set (R 2  = 0.84, SD = 0.26, F = 45.8, N = 29) and test set (Q 2  = 0.74, RMSE = 0.235, Pearson-R = 0.94, N = 9). The best pharmacophore hypothesis AARRR was selected, and developed three dimensional-quantitative structure activity relationship (3D-QSAR) model also supported the outcome of this study by means of favorable and unfavorable electron withdrawing group and hydrophobic regions of most active compound 42d and least active compound 18b. Following, induced fit docking and binding free energy calculations reveals the reliable binding orientation of the compounds. Finally, molecular dynamics simulations for 100 ns were performed to depict the protein-ligand stability. We anticipate that the resulted outcome could be supportive to discover potent negative allosteric modulators for metabotropic glutamate receptor 5 (mGluR5).

Fragmentation study of iridoid glucosides through positive and negative electrospray ionization, collision-induced dissociation and tandem mass spectrometry.

PubMed

Es-Safi, Nour-Eddine; Kerhoas, Lucien; Ducrot, Paul-Henri

2007-01-01

Mass spectrometric methodology based on the combined use of positive and negative electrospray ionization, collision-induced dissociation (CID) and tandem mass spectrometry (MS/MS) has been applied to the mass spectral study of a series of six naturally occurring iridoids through in-source fragmentation of the protonated [M+H]+, deprotonated [M--H]- and sodiated [M+Na]+ ions. This led to the unambiguous determination of the molecular masses of the studied compounds and allowed CID spectra of the molecular ions to be obtained. Valuable structural information regarding the nature of both the glycoside and the aglycone moiety was thus obtained. Glycosidic cleavage and ring cleavages of both aglycone and sugar moieties were the major fragmentation pathways observed during CID, where the losses of small molecules, the cinnamoyl and the cinnamate parts were also observed. The formation of the ionized aglycones, sugars and their product ions was thus obtained giving information on their basic skeleton. The protonated, i.e. [M+H]+ and deprotonated [M--H]-, ions were found to fragment mainly by glycosidic cleavages. MS/MS spectra of the [M+Na]+ ions gave complementary information for the structural characterization of the studied compounds. Unlike the dissociation of protonated molecular ions, that of sodiated molecules also provided sodiated sugar fragments where the C0+ fragment corresponding to the glucose ion was obtained as base peak for all the studied compounds. Copyright (c) 2007 John Wiley & Sons, Ltd.

Molecular characterization of low molecular weight dissolved organic matter in water reclamation processes using Orbitrap mass spectrometry.

PubMed

Phungsai, Phanwatt; Kurisu, Futoshi; Kasuga, Ikuro; Furumai, Hiroaki

2016-09-01

Reclaimed water has recently become an important water source for urban use, but the composition of dissolved organic matter (DOM) in reclaimed water has rarely been characterized at the compound level because of its complexity. In this study, the transformation and changes in composition of low molecular weight DOM in water reclamation processes, where secondary effluent of the municipal wastewater treatment plant was further treated by biofiltration, ozonation and chlorination, were investigated by "unknown" screening analysis using Orbitrap mass spectrometry (Orbitrap MS). The intense ions were detected over an m/z range from 100 to 450. In total, 2412 formulae with various heteroatoms were assigned, and formulae with carbon (C), hydrogen (H) and oxygen (O) only and C, H, O and sulfur (S) were the most abundant species. During biofiltration, CHO-only compounds with relatively high hydrogen to carbon (H/C) ratio or with saturated structure were preferentially removed, while CHOS compounds were mostly removed. Ozonation induced the greatest changes in DOM composition. CHOS compounds were mostly decreased after ozonation while ozone selectively removed CHO compounds with relatively unsaturated structure and produced compounds that were more saturated and with a higher degree of oxidation. After chlorination, 168 chlorine-containing formulae, chlorinated disinfection by-products (DBPs), were additionally detected. Candidate DBP precursors were determined by tracking chlorinated DBPs formed via electrophilic substitution, half of which were generated during the ozonation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design and synthesis of small molecule agonists of EphA2 receptor.

PubMed

Petty, Aaron; Idippily, Nethrie; Bobba, Viharika; Geldenhuys, Werner J; Zhong, Bo; Su, Bin; Wang, Bingcheng

2018-01-01

Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure-activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is very different to the parental compound. Compound 27 with a twelve-carbon linker of the dimer activated the kinase and induced receptor internalization and cell death with the best potency. Another dimer with a six-carbon linker has significantly reduced potency compared to the dimer with a longer linker, suggesting that the length of the linker is critical for the activity of the dimeric agonist. To explore the receptor binding characteristics of the new molecules, we applied a docking study to examine how the small molecule binds to the EphA2 receptor. The results reveal that compounds 24 and 27 form more hydrogen bonds to EphA2 than Doxazosin, suggesting that they may have higher binding affinity to the receptor. Published by Elsevier Masson SAS.

Food processing strategies to enhance phenolic compounds bioaccessibility and bioavailability in plant-based foods.

PubMed

Ribas-Agustí, Albert; Martín-Belloso, Olga; Soliva-Fortuny, Robert; Elez-Martínez, Pedro

2017-06-13

Phenolic compounds are important constituents of plant-based foods, as their presence is related to protective effects on health. To exert their biological activity, phenolic compounds must be released from the matrix during digestion in an absorbable form (bioaccessible) and finally absorbed and transferred to the bloodstream (bioavailable). Chemical structure and matrix interactions are some food-related factors that hamper phenolic compounds bioaccessibility and bioavailability, and that can be counteracted by food processing. It has been shown that food processing can induce chemical or physical modifications in food that enhance phenolic compounds bioaccessibility and bioavailability. These changes include: (i) chemical modifications into more bioaccessible and bioavailable forms; (ii) cleavage of covalent or hydrogen bonds or hydrophobic forces that attach phenolic compounds to matrix macromolecules; (iii) damaging microstructural barriers such as cell walls that impede the release from the matrix; and (iv) create microstructures that protect phenolic compounds until they are absorbed. Indeed, food processing can produce degradation of phenolic compounds, however, it is possible to counteract it by modulating the operating conditions in favor of increased bioaccessibility and bioavailability. This review compiles the current knowledge on the effects of processing on phenolic compounds bioaccessibility or bioavailability, while suggesting new guidelines in the search of optimal processing conditions as a step forward towards the design of healthier foods.

The novel cyclophilin D inhibitor compound 19 protects retinal pigment epithelium cells and retinal ganglion cells from UV radiation.

PubMed

Xie, Laiqing; Cheng, Long; Xu, Guoxu; Zhang, Ji; Ji, Xiaoyan; Song, E

2017-06-10

Excessive Ultra violet (UV) radiation induces injuries to retinal pigment epithelium (RPE) cells (RPEs) and retinal ganglion cells (RGCs), causing retinal degeneration. Cyclophilin D (Cyp-D)-dependent mitochondrial permeability transition pore (mPTP) opening mediates UV-induced cell death. In this study, we show that a novel Cyp-D inhibitor compound 19 efficiently protected RPEs and RGCs from UV radiation. Compound 19-mediated cytoprotection requires Cyp-D, as it failed to further protect RPEs/RGCs from UV when Cyp-D was silenced by targeted shRNAs. Compound 19 almost blocked UV-induced p53-Cyp-D mitochondrial association, mPTP opening and subsequent cytochrome C release. Further studies showed that compound 19 inhibited UV-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage. Together, compound 19 protects RPEs and RGCs from UV radiation, possibly via silencing Cyp-D-regulated intrinsic mitochondrial death pathway. Compound 19 could a lead compound for treating UV-associated retinal degeneration diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure-Function Correlation of G6, a Novel Small Molecule Inhibitor of Jak2

PubMed Central

Majumder, Anurima; Govindasamy, Lakshmanan; Magis, Andrew; Kiss, Róbert; Polgár, Tímea; Baskin, Rebekah; Allan, Robert W.; Agbandje-McKenna, Mavis; Reuther, Gary W.; Keserű, György M.; Bisht, Kirpal S.; Sayeski, Peter P.

2010-01-01

Somatic mutations in the Jak2 protein, such as V617F, cause aberrant Jak/STAT signaling and can lead to the development of myeloproliferative neoplasms. This discovery has led to the search for small molecule inhibitors that target Jak2. Using structure-based virtual screening, our group recently identified a novel small molecule inhibitor of Jak2 named G6. Here, we identified a structure-function correlation of this compound. Specifically, five derivative compounds of G6 having structural similarity to the original lead compound were obtained and analyzed for their ability to (i) inhibit Jak2-V617F-mediated cell growth, (ii) inhibit the levels of phospho-Jak2, phospho-STAT3, and phospho-STAT5; (iii) induce apoptosis in human erythroleukemia cells; and (iv) suppress pathologic cell growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Additionally, we computationally examined the interactions of these compounds with the ATP-binding pocket of the Jak2 kinase domain. We found that the stilbenoid core-containing derivatives of G6 significantly inhibited Jak2-V617F-mediated cell proliferation in a time- and dose-dependent manner. They also inhibited phosphorylation of Jak2, STAT3, and STAT5 proteins within cells, resulting in higher levels of apoptosis via the intrinsic apoptotic pathway. Finally, the stilbenoid derivatives inhibited the pathologic growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Collectively, our data demonstrate that G6 has a stilbenoid core that is indispensable for maintaining its Jak2 inhibitory potential. PMID:20667821

Characterization of the Apoptotic Response Induced by the Cyanine Dye D112: A Potentially Selective Anti-Cancer Compound

PubMed Central

Yang, Ning; Gilman, Paul; Mirzayans, Razmik; Sun, Xuejun; Touret, Nicolas; Weinfeld, Michael; Goping, Ing Swie

2015-01-01

Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation. PMID:25927702

Conserved Binding Mode of Human [beta subscript 2] Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography

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

Wacker, Daniel; Fenalti, Gustavo; Brown, Monica A.

2010-11-15

G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the {beta}{sub 2} adrenergic receptor ({beta}{sub 2}AR) is one of the most extensively studied. Previously, the X-ray crystal structure of {beta}{sub 2}AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational differences, we determined the crystal structures of a previously described engineered {beta}{sub 2}AR construct in complex with two inverse agonists: ICI 118,551 (2.8 {angstrom}),more » a recently described compound (2.8 {angstrom}) (Kolb et al, 2009), and the antagonist alprenolol (3.1 {angstrom}). The structures show the same overall fold observed for the previous {beta}{sub 2}AR structures and demonstrate that the ligand binding site can accommodate compounds of different chemical and pharmacological properties with only minor local structural rearrangements. All three compounds contain a hydroxy-amine motif that establishes a conserved hydrogen bond network with the receptor and chemically diverse aromatic moieties that form distinct interactions with {beta}{sub 2}AR. Furthermore, receptor ligand cross-docking experiments revealed that a single {beta}{sub 2}AR complex can be suitable for docking of a range of antagonists and inverse agonists but also indicate that additional ligand-receptor structures may be useful to further improve performance for in-silico docking or lead-optimization in drug design.« less

A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera.

PubMed

Bivén, K; Erdal, H; Hägg, M; Ueno, T; Zhou, R; Lynch, M; Rowley, B; Wood, J; Zhang, C; Toi, M; Shoshan, M C; Linder, S

2003-06-01

We have developed an apoptosis assay based on measurement of a neoepitope of cytokeratin-18 (CK18-Asp396) exposed after caspase-cleavage and detected by the monoclonal antibody M30. The total amount of caspase-cleaved CK18 which has accumulated in cells and tissue culture media during apoptosis is measured by ELISA. The sensitivity is sufficient for use in the 96-well format to allow high-through-put screening of drug libraries. We here describe strategies allowing classification of pro-apoptotic compounds according to their profiles of induction of apoptosis in the presence of pharmacological inhibitors. The time course of induction of CK18 cleavage can furthermore be used to distinguish structurally similar compounds. We propose that compounds that induce rapid CK18 cleavage have mechanisms of actions distinct from conventional genotoxic and microtubuli-targeting agents, and we present one example of an agent that induces almost immediate mitochondrial depolarization and cytochrome c release. Finally, CK18-Asp396 cleavage products are released from cells in tissue culture, and presumably from tumor cells in vivo. These products can be measured in sera from cancer patients. We present evidence suggesting that it will be possible to use the M30-ELISA assay for measuring chemotherapy-induced apoptosis in patient sera, opening possibilities for monitoring therapy.

Cinnamaldehyde--a potential antidiabetic agent.

PubMed

Subash Babu, P; Prabuseenivasan, S; Ignacimuthu, S

2007-01-01

Cinnamonum zeylanicum (cinnamon) is widely used in traditional system of medicine to treat diabetes in India. The present study was carried out to isolate and identify the putative antidiabetic compounds based on bioassay-guided fractionation; the compound identified decreased the plasma glucose levels. The active compound was purified by repeat column and structure of cinnamaldehyde was determined on the basis of chemical and physiochemical evidence. The LD(50) value of cinnamaldehyde was determined as 1850+/-37 mg/kg bw. Cinnamaldehyde was administered at different doses (5, 10 and 20 mg/kg bw) for 45 days to streptozotocin (STZ) (60 mg/kg bw)-induced male diabetic wistar rats. It was found that plasma glucose concentration was significantly (p<0.05) decreased in a dose-dependent manner (63.29%) compared to the control. In addition, oral administration of cinnamaldehyde (20 mg/kg bw) significantly decreased glycosylated hemoglobin (HbA(1C)), serum total cholesterol, triglyceride levels and at the same time markedly increased plasma insulin, hepatic glycogen and high-density lipoprotein-cholesterol levels. Also cinnamaldehyde restored the altered plasma enzyme (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase and acid phosphatase) levels to near normal. Administration of glibenclamide, a reference drug (0.6 mg/kg bw) also produced a significant (p<0.05) reduction in blood glucose concentration in STZ-induced diabetic rats. The results of this experimental study indicate that cinnamaldehyde possesses hypoglycemic and hypolipidemic effects in STZ-induced diabetic rats.

Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Aβ-induced mitochondrial dysfunction

NASA Astrophysics Data System (ADS)

Park, Insun; Londhe, Ashwini M.; Lim, Ji Woong; Park, Beoung-Geon; Jung, Seo Yun; Lee, Jae Yeol; Lim, Sang Min; No, Kyoung Tai; Lee, Jiyoun; Pae, Ae Nim

2017-10-01

Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to β amyloid (Aβ) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD). In this study, we generated an energy-based pharmacophore model by using the crystal structure of CypD—cyclosporine A (CsA) complex and performed virtual screening of ChemDiv database, which yielded forty-five potential hit compounds with novel scaffolds. We further tested those compounds using mitochondrial functional assays in neuronal cells and identified fifteen compounds with excellent protective effects against Aβ-induced mitochondrial dysfunction. To validate whether these effects derived from binding to CypD, we performed surface plasmon resonance (SPR)—based direct binding assays with selected compounds and discovered compound 29 was found to have the equilibrium dissociation constants (KD) value of 88.2 nM. This binding affinity value and biological activity correspond well with our predicted binding mode. We believe that this study offers new insights into the rational design of small molecule CypD inhibitors, and provides a promising lead for future therapeutic development.

Fermentation, Isolation, Structure, and antidiabetic activity of NFAT-133 produced by Streptomyces strain PM0324667

PubMed Central

2011-01-01

Type-2 diabetes is mediated by defects in either insulin secretion or insulin action. In an effort to identify extracts that may stimulate glucose uptake, similar to insulin, a high throughput-screening assay for measuring glucose uptake in skeletal muscle cells was established. During the screening studies to discover novel antidiabetic compounds from microbial resources a Streptomyces strain PM0324667 (MTCC 5543, the Strain accession number at Institute of Microbial Technology, Chandigarh, India), an isolate from arid soil was identified which expressed a secondary metabolite that induced glucose uptake in L6 skeletal muscle cells. By employing bioactivity guided fractionation techniques, a tri-substituted simple aromatic compound with anti-diabetic potential was isolated. It was characterized based on MS and 2D NMR spectral data and identified as NFAT-133 which is a known immunosuppressive agent that inhibits NFAT-dependent transcription in vitro. Our investigations revealed the antidiabetic potential of NFAT-133. The compound induced glucose uptake in differentiated L6 myotubes with an EC50 of 6.3 ± 1.8 μM without activating the peroxisome proliferator-activated receptor-γ. Further, NFAT-133 was also efficacious in vivo in diabetic animals and reduced systemic glucose levels. Thus it is a potential lead compound which can be considered for development as a therapeutic for the treatment of type-2 diabetes. We have reported herewith the isolation of the producer microbe, fermentation, purification, in vitro, and in vivo antidiabetic activity of the compound. PMID:22104600

Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent-resistant membrane compartments.

PubMed

Klingenstein, Ralf; Löber, Stefan; Kujala, Pekka; Godsave, Susan; Leliveld, S Rutger; Gmeiner, Peter; Peters, Peter J; Korth, Carsten

2006-08-01

Prion diseases are invariably fatal, neurodegenerative diseases transmitted by an infectious agent, PrPSc, a pathogenic, conformational isoform of the normal prion protein (PrPC). Heterocyclic compounds such as acridine derivatives like quinacrine abolish prion infectivity in a cell culture model of prion disease. Here, we report that these compounds execute their antiprion activity by redistributing cholesterol from the plasma membrane to intracellular compartments, thereby destabilizing membrane domains. Our findings are supported by the fact that structurally unrelated compounds with known cholesterol-redistributing effects - U18666A, amiodarone, and progesterone - also possessed high antiprion potency. We show that tricyclic antidepressants (e.g. desipramine), another class of heterocyclic compounds, displayed structure-dependent antiprion effects and enhanced the antiprion effects of quinacrine, allowing lower doses of both drugs to be used in combination. Treatment of ScN2a cells with quinacrine or desipramine induced different ultrastructural and morphological changes in endosomal compartments. We synthesized a novel drug from quinacrine and desipramine, termed quinpramine, that led to a fivefold increase in antiprion activity compared to quinacrine with an EC50 of 85 nm. Furthermore, simvastatin, an inhibitor of cholesterol biosynthesis, acted synergistically with both heterocyclic compounds to clear PrPSc. Our data suggest that a cocktail of drugs targeting the lipid metabolism that controls PrP conversion may be the most efficient in treating Creutzfeldt-Jakob disease.

Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors.

PubMed

Song, Jeong Uk; Jang, Jae Wan; Kim, Tae Hun; Park, Heuisul; Park, Wan Su; Jung, Sang-Hun; Kim, Geun Tae

2016-02-01

Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl)thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl)thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy-indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model. Copyright © 2016. Published by Elsevier Ltd.

New isoxazolidinone and 3,4-dehydro-β-proline derivatives as antibacterial agents and MAO-inhibitors: A complex balance between two activities.

PubMed

Ferrazzano, Lucia; Viola, Angelo; Lonati, Elena; Bulbarelli, Alessandra; Musumeci, Rosario; Cocuzza, Clementina; Lombardo, Marco; Tolomelli, Alessandra

2016-11-29

Among the different classes of antibiotics, oxazolidinone derivatives represent important drugs, since their unique mechanism of action overcomes commonly diffused multidrug-resistant bacteria. Anyway, the structural similarity of these molecules to monoamino oxidase (MAO) inhibitors, like toloxatone and blefoxatone, induces in many cases loss of selectivity as a major concern. A small library of compounds based on isoxazolidinone and dehydro-β-proline scaffold was designed with the aim to obtain antibacterial agents, evaluating at the same time the potential effects of structural features on MAO inhibitory behaviour. The structural modification introduced in the backbone, starting from Linezolid model, lead to a significant loss in antibiotic activity, while a promising inhibitory effect could be observed on monoamino oxidases. These interesting results are also in agreement with docking experiments suggesting a good binding pose of the synthesized compounds into the pocket of the oxidase enzymes, in particular of MAO-B. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pyridine radical cation and its fluorine substituted derivatives

USGS Publications Warehouse

Bondybey, V.E.; English, J.H.; Shiley, R.H.

1982-01-01

The spectra and relaxation of the pyridine cation and of several of its fluorinated derivatives are studied in low temperature Ne matrices. The ions are generated by direct photoionization of the parent compounds. Of the compounds studied, laser induced → and → fluorescence is observed only for the 2, 6‐difluoropyridine cation. The analysis of the spectrum indicates that the ion is planar both in the and states. The large variety in the spectroscopic and relaxation behavior of fluoropyridine radical cations is explained in terms of their electronic structure and of the differential shifts of the individual electronic states caused by the fluorine substitution.

Observation of Vacancies, Faults, and Superstructures in Ln5Mo2O12 (Ln = La, Y, and Lu) Compounds with Direct Mo-Mo Bonding.

PubMed

Colabello, Diane M; Sobalvarro, Elizabeth M; Sheckelton, John P; Neuefeind, Joerg C; McQueen, Tyrel M; Khalifah, Peter G

2017-11-06

Among oxide compounds with direct metal-metal bonding, the Y 5 Mo 2 O 12 (A 5 B 2 O 12 ) structural family of compounds has a particularly intriguing low-dimensional structure due to the presence of bioctahedral B 2 O 10 dimers arranged in one-dimensional edge-sharing chains along the direction of the metal-metal bonds. Furthermore, these compounds can have a local magnetic moment due to the noninteger oxidation state (+4.5) of the transition metal, in contrast to the conspicuous lack of a local moment that is commonly observed when oxide compounds with direct metal-metal bonding have integer oxidation states resulting from the lifting of orbital degeneracy typically induced by the metal-metal bonding. Although a monoclinic C2/m structure has been previously proposed for Ln 5 Mo 2 O 12 (Ln = La-Lu and Y) members of this family based on prior single crystal diffraction data, it is found that this structural model misses many important structural features. On the basis of synchrotron powder diffraction data, it is shown that the C2/m monoclinic unit cell represents a superstructure relative to a previously unrecognized orthorhombic Immm subcell and that the superstructure derives from the ordering of interchangeable Mo 2 O 10 and LaO 6 building blocks. The superstructure for this reason is typically highly faulted, as evidenced by the increased breadth of superstructure diffraction peaks associated with a coherence length of 1-2 nm in the c* direction. Finally, it is shown that oxygen vacancies can occur when Ln = La, producing an oxygen deficient stoichiometry of La 5 Mo 2 O 11.55 and an approximately 10-fold reduction in the number of unpaired electrons due to the reduction of the average Mo valence from +4.5 to +4.05, a result confirmed by magnetic susceptibility measurements. This represents the first observation of oxygen vacancies in this family of compounds and provides an important means of continuously tuning the magnetic interactions within the one-dimensional octahedral chains of this system.

Observation of Vacancies, Faults, and Superstructures in Ln 5Mo 2O 12 (Ln = La, Y, and Lu) Compounds with Direct Mo–Mo Bonding

DOE PAGES

Colabello, Diane M.; Sobalvarro, Elizabeth M.; Sheckelton, John P.; ...

2017-10-26

Among oxide compounds with direct metal–metal bonding, the Y 5Mo 2O 12 (A 5B 2O 12) structural family of compounds has a particularly intriguing low-dimensional structure due to the presence of bioctahedral B 2O 10 dimers arranged in one-dimensional edge-sharing chains along the direction of the metal–metal bonds. Furthermore, these compounds can have a local magnetic moment due to the noninteger oxidation state (+4.5) of the transition metal, in contrast to the conspicuous lack of a local moment that is commonly observed when oxide compounds with direct metal–metal bonding have integer oxidation states resulting from the lifting of orbital degeneracymore » typically induced by the metal–metal bonding. Although a monoclinic C2/m structure has been previously proposed for Ln 5Mo 2O 12 (Ln = La–Lu and Y) members of this family based on prior single crystal diffraction data, it is found that this structural model misses many important structural features. On the basis of synchrotron powder diffraction data, it is shown in this paper that the C2/m monoclinic unit cell represents a superstructure relative to a previously unrecognized orthorhombic Immm subcell and that the superstructure derives from the ordering of interchangeable Mo 2O 10 and LaO 6 building blocks. The superstructure for this reason is typically highly faulted, as evidenced by the increased breadth of superstructure diffraction peaks associated with a coherence length of 1–2 nm in the c* direction. Finally, it is shown that oxygen vacancies can occur when Ln = La, producing an oxygen deficient stoichiometry of La 5Mo 2O 11.55 and an approximately 10-fold reduction in the number of unpaired electrons due to the reduction of the average Mo valence from +4.5 to +4.05, a result confirmed by magnetic susceptibility measurements. Finally, this represents the first observation of oxygen vacancies in this family of compounds and provides an important means of continuously tuning the magnetic interactions within the one-dimensional octahedral chains of this system.« less

Observation of Vacancies, Faults, and Superstructures in Ln 5Mo 2O 12 (Ln = La, Y, and Lu) Compounds with Direct Mo–Mo Bonding

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

Colabello, Diane M.; Sobalvarro, Elizabeth M.; Sheckelton, John P.

Among oxide compounds with direct metal–metal bonding, the Y 5Mo 2O 12 (A 5B 2O 12) structural family of compounds has a particularly intriguing low-dimensional structure due to the presence of bioctahedral B 2O 10 dimers arranged in one-dimensional edge-sharing chains along the direction of the metal–metal bonds. Furthermore, these compounds can have a local magnetic moment due to the noninteger oxidation state (+4.5) of the transition metal, in contrast to the conspicuous lack of a local moment that is commonly observed when oxide compounds with direct metal–metal bonding have integer oxidation states resulting from the lifting of orbital degeneracymore » typically induced by the metal–metal bonding. Although a monoclinic C2/m structure has been previously proposed for Ln 5Mo 2O 12 (Ln = La–Lu and Y) members of this family based on prior single crystal diffraction data, it is found that this structural model misses many important structural features. On the basis of synchrotron powder diffraction data, it is shown in this paper that the C2/m monoclinic unit cell represents a superstructure relative to a previously unrecognized orthorhombic Immm subcell and that the superstructure derives from the ordering of interchangeable Mo 2O 10 and LaO 6 building blocks. The superstructure for this reason is typically highly faulted, as evidenced by the increased breadth of superstructure diffraction peaks associated with a coherence length of 1–2 nm in the c* direction. Finally, it is shown that oxygen vacancies can occur when Ln = La, producing an oxygen deficient stoichiometry of La 5Mo 2O 11.55 and an approximately 10-fold reduction in the number of unpaired electrons due to the reduction of the average Mo valence from +4.5 to +4.05, a result confirmed by magnetic susceptibility measurements. Finally, this represents the first observation of oxygen vacancies in this family of compounds and provides an important means of continuously tuning the magnetic interactions within the one-dimensional octahedral chains of this system.« less

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates.

PubMed

Deeg, Andreas A; Reiner, Anne M; Schmidt, Felix; Schueder, Florian; Ryazanov, Sergey; Ruf, Viktoria C; Giller, Karin; Becker, Stefan; Leonov, Andrei; Griesinger, Christian; Giese, Armin; Zinth, Wolfgang

2015-09-01

Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of α-synuclein and prion-protein aggregation related to these diseases. Photophysical and photochemical properties of the diphenyl-pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated α-synuclein were studied by fluorescence techniques. The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with α-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric α-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity (Kd=190±120nM) for anle138b. Several α-synuclein proteins form a hydrophobic binding pocket for the diphenyl-pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar α-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes. Copyright © 2015 Elsevier B.V. All rights reserved.

Anti-Tumor Activity of a Novel HS-Mimetic-Vascular Endothelial Growth Factor Binding Small Molecule

PubMed Central

Sugahara, Kazuyuki; Thimmaiah, Kuntebommanahalli N.; Bid, Hemant K.; Houghton, Peter J.; Rangappa, Kanchugarakoppal S.

2012-01-01

The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF) pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl)-3H-imidazole-4-carbaldehyde) was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS), which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7) which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor. PMID:22916091

Effect of green tea catechins and hydrolyzable tannins on benzo[a]pyrene-induced DNA adducts and structure-activity relationship.

PubMed

Cao, Pengxiao; Cai, Jian; Gupta, Ramesh C

2010-04-19

Green tea catechins and hydrolyzable tannins are gaining increasing attention as chemopreventive agents. However, their mechanism of action is poorly understood. We investigated the effects of four green tea catechins and two hydrolyzable tannins on microsome-induced benzo[a]pyrene (BP)-DNA adducts and the possible structure-activity relationship. BP (1 microM) was incubated with rat liver microsomes and DNA in the presence of the test compound (1-200 microM) or vehicle. The purified DNA was analyzed by (32)P-postlabeling. The inhibitory activity of the catechins was in the following descending order: epigallocatechin gallate (IC(50) = 16 microM) > epicatechin gallate (24 microM) > epigallocatechin (146 microM) > epicatechin (462 microM), suggesting a correlation between the number of adjacent aromatic hydroxyl groups in the molecular structure and their potencies. Tannic acid (IC(50) = 4 microM) and pentagalloglucose (IC(50) = 26 microM) elicited as much DNA adduct inhibitory activity as the catechins or higher presumably due to the presence of more functional hydroxyl groups. To determine if the activity of these compounds was due to direct interaction of phenolic groups with electrophilic metabolite(s) of BP, DNA was incubated with anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE) (0.5 microM) in the presence of test compounds (200 microM) or vehicle. Significant inhibition of DNA adduct formation was found (tannic acid > pentagalloglucose > epigallocatechin gallate > epicatechin gallate). This notion was confirmed by analysis of the reaction products of anti-BPDE with the catechins and pentagalloglucose by electrospray ionization mass spectrometry and liquid chromatography-mass spectrometry. In conclusion, our data demonstrate that green tea catechins and the hydrolyzable tannins are highly effective in inhibiting BP-DNA adduct formation at least, in part, due to direct interaction of adjacent hydroxyl groups in their structures and that the activity is higher with an increasing number of functional hydroxyl groups.

Plant secondary metabolite-induced shifts in bacterial community structure and degradative ability in contaminated soil.

PubMed

Uhlik, Ondrej; Musilova, Lucie; Ridl, Jakub; Hroudova, Miluse; Vlcek, Cestmir; Koubek, Jiri; Holeckova, Marcela; Mackova, Martina; Macek, Tomas

2013-10-01

The aim of the study was to investigate how selected natural compounds (naringin, caffeic acid, and limonene) induce shifts in both bacterial community structure and degradative activity in long-term polychlorinated biphenyl (PCB)-contaminated soil and how these changes correlate with changes in chlorobiphenyl degradation capacity. In order to address this issue, we have integrated analytical methods of determining PCB degradation with pyrosequencing of 16S rRNA gene tag-encoded amplicons and DNA-stable isotope probing (SIP). Our model system was set in laboratory microcosms with PCB-contaminated soil, which was enriched for 8 weeks with the suspensions of flavonoid naringin, terpene limonene, and phenolic caffeic acid. Our results show that application of selected plant secondary metabolites resulted in bacterial community structure far different from the control one (no natural compound amendment). The community in soil treated with caffeic acid is almost solely represented by Proteobacteria, Acidobacteria, and Verrucomicrobia (together over 99 %). Treatment with naringin resulted in an enrichment of Firmicutes to the exclusion of Acidobacteria and Verrucomicrobia. SIP was applied in order to identify populations actively participating in 4-chlorobiphenyl catabolism. We observed that naringin and limonene in soil foster mainly populations of Hydrogenophaga spp., caffeic acid Burkholderia spp. and Pseudoxanthomonas spp. None of these populations were detected among 4-chlorobiphenyl utilizers in non-amended soil. Similarly, the degradation of individual PCB congeners was influenced by the addition of different plant compounds. Residual content of PCBs was lowest after treating the soil with naringin. Addition of caffeic acid resulted in comparable decrease of total PCBs with non-amended soil; however, higher substituted congeners were more degraded after caffeic acid treatment compared to all other treatments. Finally, it appears that plant secondary metabolites have a strong effect on the bacterial community structure, activity, and associated degradative ability.

Targeting SDF-1/CXCL12 with a ligand that prevents activation of CXCR4 through structure based drug design

PubMed Central

Veldkamp, Christopher T.; Ziarek, Joshua J.; Peterson, Francis C.; Chen, Yu; Volkman, Brian F.

2010-01-01

CXCL12 is an attractive target for clinical therapy because of its involvement in autoimmune diseases, cancer growth, metastasis, and neovascularization. Tyrosine sulfation at three positions in the CXCR4 N-terminus is crucial for specific, high-affinity CXCL12 binding. An NMR structure of the complex between the CXCL12 dimer and a sulfotyrosine-containing CXCR4 fragment enabled high-throughput in silico screening for inhibitors of the chemokine-receptor interface. A total of 1.4 million compounds from the ZINC database were docked into a cleft on the CXCL12 surface normally occupied by sulfotyrosine 21 (sY21), and five were selected for experimental screening. NMR titrations with CXCL12 revealed that four compounds occupy the sY21 site, one of which binds with a Kd of 64 µM. This compound selectively inhibits SDF1-induced CXCR4 signaling in THP1 cells. Our results suggest that sulfotyrosine recognition sites can be targeted for the development of novel chemokine inhibitors. PMID:20459090

Structure of 7,12-dimethylbenz(a)anthracene-guanosine adducts.

PubMed

Jeffrey, A M; Blobstein, S H; Weinstein, I B; Beland, F A; Harvey, R G; Kasai, H; Nakanishi, K

1976-07-01

Arene oxides have been proposed as the reactive intermediates in the process of carcinogenesis induced by polycyclic aromatic hydrocarbons. The present study defines the structures of four guanosine adducts formed by the reaction of 7,12-dimethylbenz[a]anthracene-5,6-oxide with polyguanylic acid. The modified polymer was hydrolyzed to nucleotides and the hydrophobic guanosine adducts separated from unmodified guanosine by LH-20 column chromatograhy. The adducts were further resolved into four components (I-IV) by reverse phase high pressure liquid chromatography. Analysis of the ultraviolet, circular dichroism, mass, and proton magnetic resonance spectra of these compounds, or their acetate and free base derivatives, indicates that in all four compounds the aromatic hydrocarbon is present on the 2 amino group of guanine. Compounds I and IV, and II and III constitute diastereoisomeric pairs, respectively. In the I and IV pair, the adducts result from addition at the 6 position of the original dimethylbenz[a]anthracene oxide, whereas in the II and III pair, the addition occurs at the 5 position. Indirect evidence suggests that trans opening of the oxide occurred in all cases but this remains to be established.

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.

Digestibility of Bovine Serum Albumin and Peptidomics of the Digests: Effect of Glycation Derived from α-Dicarbonyl Compounds.

PubMed

Sheng, Bulei; Larsen, Lotte Bach; Le, Thao T; Zhao, Di

2018-03-21

α-Dicarbonyl compounds, which are widely generated during sugar fragmentation and oil oxidation, are important precursors of advanced glycation end products (AGEs). In this study, the effect of glycation derived from glyoxal (GO), methylglyoxal (MGO) and diacetyl (DA) on the in vitro digestibility of bovine serum albumin (BSA) was investigated. Glycation from α-dicarbonyl compounds reduced digestibility of BSA in both gastric and intestinal stage of digestion according to measurement of degree of hydrolysis. Changes in peptide composition of digests induced by glycation were displayed, showing absence of peptides, occurrence of new peptides and formation of peptide-AGEs, based on the results obtained using liquid chromatography electron-spray-ionization tandem mass spectrometry (LC-ESI-MS/MS). Crosslinked glycation structures derived from DA largely reduced the sensitivity of glycated BSA towards digestive proteases based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results. Network structures were found to remain in the digests of glycated samples by transmission electron microscope (TEM), thus the impact of AGEs in unabsorbed digests on the gut flora should be an interest for further studies.

Effects of skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones.

PubMed

Zhang, Dongjian; Jiang, Cuihua; Yang, Shengwei; Gao, Meng; Huang, Dejian; Wang, Xiaoning; Shao, Haibo; Feng, Yuanbo; Sun, Ziping; Ni, Yicheng; Zhang, Jian; Yin, Zhiqi

2016-01-01

Necrosis avid agents (NAAs) can be used for diagnose of necrosis-related diseases, evaluation of therapeutic responses and targeted therapeutics of tumor. In order to probe into the effects of molecular skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones, four dianthrone compounds with the same substituents but different skeletal structures, namely Hypericin (Hyp), protohypericin (ProHyp), emodin dianthrone mesomer (ED-1) and emodin dianthrone raceme (ED-2) were synthesized and radioiodinated. Then radioiodinated dianthrones were evaluated in vitro for their necrosis avidity in A549 lung cancer cells untreated and treated with H2O2. Their biodistribution and pharmacokinetic properties were determined in rat models of induced necrosis. In vitro cell assay revealed that destruction of rigid skeleton structure dramatically reduced their necrosis targeting ability. Animal studies demonstrated that destruction of rigid skeleton structure dramatically reduced the necrotic tissue uptake and speed up the clearance from the most normal tissues for the studied compounds. Among these (131)I-dianthrones, (131)I-Hyp exhibited the highest uptake and persistent retention in necrotic tissues. Hepatic infarction could be clearly visualized by SPECT/CT using (131)I-Hyp as an imaging probe. The results suggest that the skeleton structure of Hyp is the lead structure for further structure optimization of this class of NAAs.

Electrolyte-induced surface transformation and transition-metal dissolution of fully delithiated LiNi 0.8Co 0.15Al 0.05O 2

DOE PAGES

Faenza, Nicholas V.; Lebens-Higgins, Zachary W.; Mukherjee, Pinaki; ...

2017-06-08

Here, enabling practical utilization of layered Rmore » $$\\bar{3}$$ m positive electrodes near full delithiation requires an enhanced understanding of the complex electrode–electrolyte interactions that often induce failure. Using Li[Ni 0.8Co 0.15Al 0.05]O 2 (NCA) as a model layered compound, the chemical and structural stability in a strenuous thermal and electrochemical environment was explored. Operando microcalorimetry and electrochemical impedance spectroscopy identified a fingerprint for a structural decomposition and transition-metal dissolution reaction that occurs on the positive electrode at full delithiation. Surface-sensitive characterization techniques, including X-ray absorption spectroscopy and high-resolution transmission electron microscopy, measured a structural and morphological transformation of the surface and subsurface regions of NCA. Despite the bulk structural integrity being maintained, NCA surface degradation at a high state of charge induces excessive transition-metal dissolution and significant positive electrode impedance development, resulting in a rapid decrease in electrochemical performance. Additionally, the impact of electrolyte salt, positive electrode surface area, and surface Li 2CO 3 content on the magnitude and character of the dissolution reaction was studied.« less

Electrolyte-Induced Surface Transformation and Transition-Metal Dissolution of Fully Delithiated LiNi0.8Co0.15Al0.05O2.

PubMed

Faenza, Nicholas V; Lebens-Higgins, Zachary W; Mukherjee, Pinaki; Sallis, Shawn; Pereira, Nathalie; Badway, Fadwa; Halajko, Anna; Ceder, Gerbrand; Cosandey, Frederic; Piper, Louis F J; Amatucci, Glenn G

2017-09-19

Enabling practical utilization of layered R3̅m positive electrodes near full delithiation requires an enhanced understanding of the complex electrode-electrolyte interactions that often induce failure. Using Li[Ni 0.8 Co 0.15 Al 0.05 ]O 2 (NCA) as a model layered compound, the chemical and structural stability in a strenuous thermal and electrochemical environment was explored. Operando microcalorimetry and electrochemical impedance spectroscopy identified a fingerprint for a structural decomposition and transition-metal dissolution reaction that occurs on the positive electrode at full delithiation. Surface-sensitive characterization techniques, including X-ray absorption spectroscopy and high-resolution transmission electron microscopy, measured a structural and morphological transformation of the surface and subsurface regions of NCA. Despite the bulk structural integrity being maintained, NCA surface degradation at a high state of charge induces excessive transition-metal dissolution and significant positive electrode impedance development, resulting in a rapid decrease in electrochemical performance. Additionally, the impact of electrolyte salt, positive electrode surface area, and surface Li 2 CO 3 content on the magnitude and character of the dissolution reaction was studied.

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

PubMed Central

Fujino, Aiko; Fukushima, Kei; Kubota, Takaharu; Matsumoto, Yoshiyuki; Takimoto-Kamimura, Midori

2013-01-01

Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2), a serine/threonine kinase from the p38 mitogen-activated protein kinase signalling pathway, plays an important role in the production of TNF-α and other cytokines. In a previous report, it was shown that MK2 in complex with the selective inhibitor TEI-I01800 adopts an α-helical glycine-rich loop that is induced by the stable nonplanar conformer of TEI-I01800. To understand the mechanism of the structural change, the structure of MK2 bound to TEI-L03090, which lacks the key substituent found in TEI-I01800, was determined. MK2–TEI-L03090 has a β-sheet glycine-rich loop in common with other kinases, as predicted. This result suggests that a small compound can induce a drastic conformational change in the target protein structure and can be used to design potent and selective inhibitors. PMID:24316826

X-ray targeted bond or compound destruction

DOEpatents

Pravica, Sr., Michael G.

2016-11-01

This document provides methods, systems, and devices for inducing a decomposition reaction by directing x-rays towards a location including a particular compound. The x-rays can have an irradiation energy that corresponds to a bond distance of a bond in the particular compound in order to break that bond and induce a decomposition of that particular compound. In some cases, the particular compound is a hazardous substance or part of a hazardous substance. In some cases, the particular compound is delivered to a desired location in an organism and x-rays induce a decomposition reaction that creates a therapeutic substance (e.g., a toxin that kills cancer cells) in the location of the organism. In some cases, the particular compound decomposes to produce a reactant in a reactor apparatus (e.g., fuel cell or semiconductor fabricator).

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

Efthimiopoulos, I.; Tsurkan, V.; Loidl, A.

We have conducted high-pressure measurements on the CuCr2O4 and CuCr2Se4 spinels to unravel the structural systematics of these materials under compression. Our studies have revealed diverse structural behavior in these two compounds. In particular, CuCr2O4 retains its ambient-pressure I41/amd structure up to 50 GPa. Close inspection of the lattice and interatomic parameters reveals a compressibility change near 23 GPa, which is accompanied by an expansion of the apical Cr–O bond distances. We speculate that an outer Cr3+ 3d orbital reorientation might be at play in this system, manifesting as the change in compressibility at that pressure point. On the othermore » hand, CuCr2Se4 undergoes a structural transformation from the starting Fd3¯m phase toward a monoclinic structure initiated at ~8 GPa and completed at ~20 GPa. This high-pressure behavior resembles that of ZnCr2Se4, and it appears that, unlike similar chalcogenide Cr spinels, steric effects take a leading role in this pressure-induced Fd3¯m → monoclinic transition. Close comparison of our results with the reported literature yields significant insights behind the pressure-induced structural systematics of this important family of materials, thus both allowing for the careful manipulation of the structural/physical properties of these systems by strain and promoting our understanding of similar pressure-induced effects in relevant systems.« less

Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1.

PubMed

Wang, Yan-Xiang; Pang, Wei-Qiang; Zeng, Qing-Xuan; Deng, Zhe-Song; Fan, Tian-Yun; Jiang, Jian-Dong; Deng, Hong-Bin; Song, Dan-Qing

2018-01-01

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation. Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Effect of Thermochemical Synthetic Conditions on the Structure and Dielectric Properties of Ga1.9Fe0.1O3 Compounds.

PubMed

Roy, Swadipta; Ramana, C V

2018-02-05

We report on the tunable and controlled dielectric properties of iron (Fe)-doped gallium oxide (Ga 2 O 3 ; Ga 1.9 Fe 0.1 O 3 , referred to as GFO) inorganic compounds. The GFO materials were synthesized using a standard high-temperature, solid-state chemical reaction method by varying the thermochemical processing conditions, namely, different calcination and sintering environments. Structural characterization by X-ray diffraction revealed that GFO compounds crystallize in the β-Ga 2 O 3 phase. The Fe doping has induced slight lattice strain in GFO, which is evident in structural analysis. The effect of the sintering temperature (T sint ), which was varied in the range of 900-1200 °C, is significant, as revealed by electron microscopy analysis. T sint influences the grain size and microstructure evolution, which, in turn, influences the dielectric and electrical properties of GFO compounds. The energy-dispersive X-ray spectrometry and mapping data demonstrate the uniform distribution of the elemental composition over the microstructure. The temperature- and frequency-dependent dielectric measurements indicate the characteristic features that are specifically due to Fe doping in Ga 2 O 3 . The spreading factor and relaxation time, calculated using Cole-Cole plots, are in the ranges of 0.65-0.76 and 10 -4 s, respectively. The results demonstrate that densification and control over the microstructure and properties of GFO can be achieved by optimizing T sint .

Antioxidant, anti-glycation and anti-inflammatory activities of phenolic constituents from Cordia sinensis.

PubMed

Al-Musayeib, Nawal; Perveen, Shagufta; Fatima, Itrat; Nasir, Muhammad; Hussain, Ajaz

2011-12-08

Nine compounds have been isolated from the ethyl acetate soluble fraction of C. sinensis, namely protocatechuic acid (1), trans-caffeic acid (2), methyl rosmarinate (3), rosmarinic acid (4), kaempferide-3-O-β-D-glucopyranoside (5), kaempferol-3-O-β-D-glucopyranoside (6), quercetin-3-O-β-D-glucopyranoside (7), kaempferide-3-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (8) and kaempferol-3-O-α-L-rhamno-pyranosyl (1→6)-β-D-glucopyranoside (9), all reported for the first time from this species. The structures of these compounds were deduced on the basis of spectroscopic studies, including 1D and 2D NMR techniques. Compounds 1-9 were investigated for biological activity and showed significant anti-inflammatory activity in the carrageen induced rat paw edema test. The antioxidant activities of isolated compounds 1-9 were evaluated by the DPPH radical scavenging test, and compounds 1, 2, 4 and 7-9 exhibited marked scavenging activity compared to the standard BHA. These compounds were further studied for their anti-glycation properties and some compounds showed significant anti-glycation inhibitory activity. The purity of compounds 2-5, 8 and 9 was confirmed by HPLC. The implications of these results for the chemotaxonomic studies of the genus Cordia have also been discussed.

Theoretical prediction of sandwiched two-dimensional phosphide binary compound sheets with tunable bandgaps and anisotropic physical properties

NASA Astrophysics Data System (ADS)

Zhang, C. Y.; Yu, M.

2018-03-01

Atomic layers of GaP and InP binary compounds with unique anisotropic structural, electronic and mechanical properties have been predicted from first-principle molecular dynamics simulations. These new members of the phosphide binary compound family stabilize to a sandwiched two-dimensional (2D) crystalline structure with orthorhombic lattice symmetry and high buckling of 2.14 Å-2.46 Å. Their vibration modes are similar to those of phosphorene with six Raman active modes ranging from ˜80 cm-1 to 400 cm-1. The speeds of sound in their phonon dispersions reflect anisotropy in their elastic constants, which was further confirmed by their strong directional dependence of Young’s moduli and effective nonlinear elastic moduli. They show wide bandgap semiconductor behavior with fundamental bandgaps of 2.89 eV for GaP and 2.59 eV for InP, respectively, even wider than their bulk counterparts. Such bandgaps were found to be tunable under strain. In particular, a direct-indirect bandgap transition was found under certain strains along zigzag or biaxial orientations, reflecting their promising applications in strain-induced bandgap engineering in nanoelectronics and photovoltaics. Feasible pathways to realize these novel 2D phosphide compounds are also proposed.

Mechanical and magneto-opto-electronic investigation of transition metal based fluoro-perovskites: An ab-initio DFT study

NASA Astrophysics Data System (ADS)

Erum, Nazia; Azhar Iqbal, Muhammad

2017-09-01

Detailed ab-initio calculations are performed to investigate structural, elastic, mechanical, magneto-electronic and optical properties of the KXF3 (X = V, Fe, Co, Ni) fluoro-perovskites using Full Potential Linearized Augmented Plane Wave (FP-LAPW) method within the framework of density functional theory (DFT). The calculated structural parameters by DFT and analytical methods are found consistent with the experimental results. From the elastic and mechanical properties, it can be inferred that these compounds are elastically stable and anisotropic while KCoF3 is harder than rest of the compounds. Furthermore, thermal behavior of these compounds is analyzed by calculating Debye temperature (θD). The calculated spin dependent magneto-electronic properties in these compounds reveal that exchange splitting is dominated by N-3d orbital. The stable magnetic phase optimizations verify the experimental observations at low temperature. Type of chemical bonding is analyzed with the help of variations in electron density difference distribution that is induced due to changes of the second cation. The linear optical properties are also discussed in terms of optical spectra. The present methodology represents an influential approach to calculate the whole set of mechanical and magneto-opto-electronic parameters, which would support to understand various physical phenomena and empower device engineers for implementing these materials in spintronic applications.

Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

PubMed

Parise-Filho, Roberto; Pasqualoto, Kerly Fernanda Mesquita; Magri, Fátima Maria Motter; Ferreira, Adilson Kleber; da Silva, Bárbara Athayde Vaz Galvão; Damião, Mariana Celestina Frojuello Costa Bernstorff; Tavares, Maurício Temotheo; Azevedo, Ricardo Alexandre; Auada, Aline Vivian Vatti; Polli, Michelle Carneiro; Brandt, Carlos Alberto

2012-12-01

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50)  = 69.3 µM) and Leishmania brasiliensis (IC(50)  = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50)  = 99.9 µM for L. amazonensis and IC(50)  = 90.5 µM for L. braziliensis) and 3 (IC(50)  = 122.9 µM for L. amazonensis and IC(50)  = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arbuscular Mycorrhizal Fungi and Plant Chemical Defence: Effects of Colonisation on Aboveground and Belowground Metabolomes.

PubMed

Hill, Elizabeth M; Robinson, Lynne A; Abdul-Sada, Ali; Vanbergen, Adam J; Hodge, Angela; Hartley, Sue E

2018-02-01

Arbuscular mycorrhizal fungal (AMF) colonisation of plant roots is one of the most ancient and widespread interactions in ecology, yet the systemic consequences for plant secondary chemistry remain unclear. We performed the first metabolomic investigation into the impact of AMF colonisation by Rhizophagus irregularis on the chemical defences, spanning above- and below-ground tissues, in its host-plant ragwort (Senecio jacobaea). We used a non-targeted metabolomics approach to profile, and where possible identify, compounds induced by AMF colonisation in both roots and shoots. Metabolomics analyses revealed that 33 compounds were significantly increased in the root tissue of AMF colonised plants, including seven blumenols, plant-derived compounds known to be associated with AMF colonisation. One of these was a novel structure conjugated with a malonyl-sugar and uronic acid moiety, hitherto an unreported combination. Such structural modifications of blumenols could be significant for their previously reported functional roles associated with the establishment and maintenance of AM colonisation. Pyrrolizidine alkaloids (PAs), key anti-herbivore defence compounds in ragwort, dominated the metabolomic profiles of root and shoot extracts. Analyses of the metabolomic profiles revealed an increase in four PAs in roots (but not shoots) of AMF colonised plants, with the potential to protect colonised plants from below-ground organisms.

Surface patterning by pulsed-laser-induced transfer of metals and compounds

NASA Astrophysics Data System (ADS)

Toth, Zsolt; Mogyorosi, Peter; Szoerenyi, Tamas

1990-08-01

Besults of a systematic study on Q-switched nthy laser induced rrrn2 area transfer of supported titanium and chranium thin films and Ge/Se multilayer structures are reported. The appearance of the prints is governed by film-support adhesion and source-target spacing. Best quality prints are produced by ablating well adhering ntal films in close proximity ( spacing < 15 pm) to the target to be patterned. Transfer fran stacked elenntaxy layers as a source offers a unique possibility of depositing acinpound films by mixing the constituents and transferring the material onto the target substrate in a single step.

[Amiodarone and thyroid].

PubMed

Capraro, Joël; Thalmann, Sébastien

2011-06-01

Amiodarone is a widely used antiarrythmic drug and can lead either to hypothyroidism or hyperthyroidism due to its molecular structure which is similar to levothyroxin. Amiodarone induced hypothyroidism can be treated easely with hormonal subsitution. Hyperthyroidism is more challenging. There exist two forms of amiodarone-induced Hyperthyroidism (AIT): AIT type 1 is directly related to the iodine compound of amiodarone and responds to thyreostatic therapy. Type 2 is a consequence of the direct toxicity of amiodarone to the thyroid gland and is treated primarily with glucocorticoids. However, this differentiation often is impossible in clinical settings and a pragmatic approach is needed.

Synthesis of Five Known Brassinosteroid Analogs from Hyodeoxycholic Acid and Their Activities as Plant-Growth Regulators.

PubMed

Duran, María Isabel; González, Cesar; Acosta, Alison; Olea, Andrés F; Díaz, Katy; Espinoza, Luis

2017-03-08

Brassinosteroids (BRs) are plant hormones that promote growth in different plant organs and tissues. The structural requirements that these compounds should possess to exhibit this biological activity have been studied. In this work, a series of known BR analogs 5 - 15 , were synthesized starting from hyodeoxycholic acid 4 , and maintaining the alkyl side chain as cholic acid or its methyl ester. The growth-promoting effects of brassinolide ( 1 ) and synthesized analogs were evaluated by using the rice lamina inclination assay at concentrations ranging from 1 × 10 -8 -1 × 10 -6 M. Our results indicate that in this concentration range the induced bending angle of rice seedlings increases with increasing concentration of BRs. Analysis of the activities, determined at the lowest tested concentration, in terms of BR structures shows that the 2α,3α-dihydroxy-7-oxa-6-ketone moiety existing in brassinolide is required for the plant growing activity of these compounds, as it has been proposed by some structure-activity relationship studies. The effect of compound 8 on cell elongation was assessed by microscopy analysis, and the results indicate that the growth-promoting effect of analog 8 is mainly due to cell elongation of the adaxial sides, instead of an increase on cell number.

Synthesis of Five Known Brassinosteroid Analogs from Hyodeoxycholic Acid and Their Activities as Plant-Growth Regulators

PubMed Central

Duran, María Isabel; González, Cesar; Acosta, Alison; Olea, Andrés F.; Díaz, Katy; Espinoza, Luis

2017-01-01

Brassinosteroids (BRs) are plant hormones that promote growth in different plant organs and tissues. The structural requirements that these compounds should possess to exhibit this biological activity have been studied. In this work, a series of known BR analogs 5–15, were synthesized starting from hyodeoxycholic acid 4, and maintaining the alkyl side chain as cholic acid or its methyl ester. The growth-promoting effects of brassinolide (1) and synthesized analogs were evaluated by using the rice lamina inclination assay at concentrations ranging from 1 × 10−8–1 × 10−6 M. Our results indicate that in this concentration range the induced bending angle of rice seedlings increases with increasing concentration of BRs. Analysis of the activities, determined at the lowest tested concentration, in terms of BR structures shows that the 2α,3α-dihydroxy-7-oxa-6-ketone moiety existing in brassinolide is required for the plant growing activity of these compounds, as it has been proposed by some structure-activity relationship studies. The effect of compound 8 on cell elongation was assessed by microscopy analysis, and the results indicate that the growth-promoting effect of analog 8 is mainly due to cell elongation of the adaxial sides, instead of an increase on cell number. PMID:28282853

Bioactive steroids and sorbicillinoids isolated from the endophytic fungus Trichoderma sp. Xy24.

PubMed

Zhao, Jin-Lian; Zhang, Min; Liu, Ji-Mei; Tan, Zhen; Chen, Ri-Dao; Xie, Ke-Bo; Dai, Jun-Gui

2017-10-01

A new steroid glucoside (1), along with nine known steroids (2-10) and four known sorbicillinoids (11-14), were isolated from the endophytic fungus Trichoderma sp. Xy24. Their structures were elucidated on the basis of spectroscopic data analyses and by comparison with reported data. Compounds 3, 5-7, 9, 10, and 13 exhibited significant inhibitory effects on HIV-1 virus with IC 50 values ranging 1.9-9.3 μM; compounds 10, 13, and 14 showed potent inhibitory activity on LPS-induced NO production in BV2 microglia cells with inhibitory rates of 108.2, 100, and 75.1% at 10 μM, respectively. In addition, compound 10 displayed moderate cytotoxicity against BCG823 and HePG2 cell lines with IC 50 values of 11.1 and 17.7 μM, respectively.

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

PubMed

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

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

Zhang, Lianying; College of Life Science, Dezhou University, Dezhou 253023; Ren, Xiao-Min

2014-09-15

Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group.more » For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.« less

Using fragmentation trees and mass spectral trees for identifying unknown compounds in metabolomics.

PubMed

Vaniya, Arpana; Fiehn, Oliver

2015-06-01

Identification of unknown metabolites is the bottleneck in advancing metabolomics, leaving interpretation of metabolomics results ambiguous. The chemical diversity of metabolism is vast, making structure identification arduous and time consuming. Currently, comprehensive analysis of mass spectra in metabolomics is limited to library matching, but tandem mass spectral libraries are small compared to the large number of compounds found in the biosphere, including xenobiotics. Resolving this bottleneck requires richer data acquisition and better computational tools. Multi-stage mass spectrometry (MSn) trees show promise to aid in this regard. Fragmentation trees explore the fragmentation process, generate fragmentation rules and aid in sub-structure identification, while mass spectral trees delineate the dependencies in multi-stage MS of collision-induced dissociations. This review covers advancements over the past 10 years as a tool for metabolite identification, including algorithms, software and databases used to build and to implement fragmentation trees and mass spectral annotations.

Spin-orbit coupling enhanced superconductivity in Bi-rich compounds ABi3 (A = Sr and Ba)

PubMed Central

Shao, D. F.; Luo, X.; Lu, W. J.; Hu, L.; Zhu, X. D.; Song, W. H.; Zhu, X. B.; Sun, Y. P.

2016-01-01

Recently, Bi-based compounds have attracted attentions because of the strong spin-orbit coupling (SOC). In this work, we figured out the role of SOC in ABi3 (A = Sr and Ba) by theoretical investigation of the band structures, phonon properties, and electron-phonon coupling. Without SOC, strong Fermi surface nesting leads to phonon instabilities in ABi3. SOC suppresses the nesting and stabilizes the structure. Moreover, without SOC the calculation largely underestimates the superconducting transition temperatures (Tc), while with SOC the calculated Tc are very close to those determined by measurements on single crystal samples. The SOC enhanced superconductivity in ABi3 is due to not only the SOC induced phonon softening, but also the SOC related increase of electron-phonon coupling matrix elements. ABi3 can be potential platforms to construct heterostructure of superconductor/topological insulator to realize topological superconductivity. PMID:26892681

Spin-orbit coupling enhanced superconductivity in Bi-rich compounds ABi₃ (A = Sr and Ba).

PubMed

Shao, D F; Luo, X; Lu, W J; Hu, L; Zhu, X D; Song, W H; Zhu, X B; Sun, Y P

2016-02-19

Recently, Bi-based compounds have attracted attentions because of the strong spin-orbit coupling (SOC). In this work, we figured out the role of SOC in ABi3 (A = Sr and Ba) by theoretical investigation of the band structures, phonon properties, and electron-phonon coupling. Without SOC, strong Fermi surface nesting leads to phonon instabilities in ABi3. SOC suppresses the nesting and stabilizes the structure. Moreover, without SOC the calculation largely underestimates the superconducting transition temperatures (Tc), while with SOC the calculated Tc are very close to those determined by measurements on single crystal samples. The SOC enhanced superconductivity in ABi3 is due to not only the SOC induced phonon softening, but also the SOC related increase of electron-phonon coupling matrix elements. ABi3 can be potential platforms to construct heterostructure of superconductor/topological insulator to realize topological superconductivity.

Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.

PubMed

Delfosse, Vanessa; Dendele, Béatrice; Huet, Tiphaine; Grimaldi, Marina; Boulahtouf, Abdelhay; Gerbal-Chaloin, Sabine; Beucher, Bertrand; Roecklin, Dominique; Muller, Christina; Rahmani, Roger; Cavaillès, Vincent; Daujat-Chavanieu, Martine; Vivat, Valérie; Pascussi, Jean-Marc; Balaguer, Patrick; Bourguet, William

2015-09-03

Humans are chronically exposed to multiple exogenous substances, including environmental pollutants, drugs and dietary components. Many of these compounds are suspected to impact human health, and their combination in complex mixtures could exacerbate their harmful effects. Here we demonstrate that a pharmaceutical oestrogen and a persistent organochlorine pesticide, both exhibiting low efficacy when studied separately, cooperatively bind to the pregnane X receptor, leading to synergistic activation. Biophysical analysis shows that each ligand enhances the binding affinity of the other, so the binary mixture induces a substantial biological response at doses at which each chemical individually is inactive. High-resolution crystal structures reveal the structural basis for the observed cooperativity. Our results suggest that the formation of 'supramolecular ligands' within the ligand-binding pocket of nuclear receptors contributes to the synergistic toxic effect of chemical mixtures, which may have broad implications for the fields of endocrine disruption, toxicology and chemical risk assessment.

Novel drift structures for silicon and compound semiconductor X-ray and gamma-ray detectors

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

Patt, B.E.; Iwanczyk, J.S.

Recently developed silicon- and compound-semiconductor-based drift detector structures have produced excellent performance for charged particles, X-rays, and gamma rays and for low-signal visible light detection. The silicon drift detector (SDD) structures that the authors discuss relate to direct X-ray detectors and scintillation photon detectors coupled with scintillators for gamma rays. Recent designs include several novel features that ensure very low dark current and hence low noise. In addition, application of thin window technology ensures a very high quantum efficiency entrance window on the drift photodetector. The main features of the silicon drift structures for X rays and light detection aremore » very small anode capacitance independent of the overall detector size, low noise, and high throughput. To take advantage of the small detector capacitance, the first stage of the electronics needs to be integrated into the detector anode. In the gamma-ray application, factors other than electronic noise dominate, and there is no need to integrate the electronics into the anode. Thus, a different drift structure is needed in conjunction with a high-Z material. The main features in this case are large active detector volume and electron-only induced signal.« less

Flavonoids from acai (Euterpe oleracea Mart.) pulp and their antioxidant and anti-inflammatory activities.

PubMed

Kang, Jie; Xie, Chenghui; Li, Zhimin; Nagarajan, Shanmugam; Schauss, Alexander G; Wu, Tong; Wu, Xianli

2011-09-01

Five flavonoids, (2S,3S)-dihyrokaempferol 3-O-β-d-glucoside (1) and its isomer (2R,3R)-dihydrokaempferol 3-O-β-d-glucoside (2) , isovitexin (3), velutin (4) and 5,4'-dihydroxy-7,3',5'-trimethoxyflavone (5), were isolated from acai (Euterpe oleracea Mart.) pulp. The structures of these compounds were elucidated based upon spectroscopic and chemical analyses. To our knowledge, compounds 1, 2, 4 and 5 were identified from acai pulp for the first time. The in vitro antioxidant activities of these compounds were evaluated by the oxygen radial absorbance capacity (ORAC) assay. The ORAC values varied distinctly (4458.0-22404.5μmol Trolox equivalent (TE)/g) from 5,4'-dihydroxy-7,3',5'-trimethoxyflavone (5) to isovitexin (3) and were affected by the numbers/positions of hydroxyl groups, substitute groups, as well as stereo configuration. The anti-inflammatory effects of these compounds were screened by the secreted embryonic alkaline phosphatase (SEAP) reporter assay, which is designed to measure NF-κB activation. Velutin (4) was found to dose-dependently inhibit SEAP secretion in RAW-blue cells induced by LPS, with an IC50 value of 2.0μM. Velutin (4) also inhibited SEAP secretion induced by oxidised LDL, indicating potential athero-protective effects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.

PubMed

Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A; Dicker, David T; Wu, Gen Sheng; El-Deiry, Wafik S

2015-05-01

We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

Fluorine-Induced Chemiluminescence Detection of Biologically Methylated Tellurium, Selenium, and Sulfur Compounds and Methyldithiocarbhydrazide as a Formaldehyde Derivatization Reagent

NASA Astrophysics Data System (ADS)

Chasteen, Thomas Girard

1990-01-01

The first part of this dissertation describes capillary chromatography coupled to a fluorine-induced chemiluminescence detector as a sensitive method by which biologically methylated metalloids can be determined in the presence of high concentrations of potentially interfering molecules. With a wide linear range and excellent sensitivity, this method was applied to the detection of dimethyl selenide (DMSe), dimethyl diselenide (DMDSe), and dimethyl telluride (DMTe), often found in biological environments in the presence of interfering methylated sulfur gases, such as methanethiol, dimethyl sulfide, dimethyl disulfide, and dimethyl trisulfide. Detection limits for DMSe, DMDSe, and DMTe were 30, 9, and 7 picograms, respectively. This DMTe detection limit is the lowest reported to date for a volatile tellurium gas. A variety of selenium-resistant bacteria emitted mixtures of methylated sulfur/selenium gases when dosed with inorganic selenium salts in the presence of sulfur containing growth media. One of the gases detected was dimethyl selenenyl sulfide, CH_3SeSCH _3, reported here for the first time in headspace above microorganisms. In addition, this detector responded to reduced phosphorus compounds such as phosphine. The detection limit for this compound was 2.8 picograms. Detection limits for alkylated phosphines trimethyl and triethyl phosphine were 0.5 and 17 picograms respectively, based on the relative response of these compounds compared to dimethyl sulfide. This method can be used for the simultaneous determination of methylated sulfur, selenium, tellurium compounds found in biological systems. Part II of this dissertation describes work with methyldithiocarbhydrazide, a compound that has been synthesized for use as a derivatization reagent to capture formaldehyde in the gas phase. Chosen for its ability to react in a manner similar to 2,4-dinitrophenylhydrazine, this molecule was selected based on two structural characteristics: a hydrazine tag to react with and thereby capture carbonyls and a methyl sulfide group to allow for sensitive detection by fluorine-induced chemiluminescence. Although in the final analysis methyldithiocarbohydrazide failed as a successful means by which formaldehyde can be determined using gas chromatography in conjunction with fluorine-induced chemiluminescence, it did successfully derivatize formaldehyde in both solution and the gas phase without the need for low pH conditions.

Synthesis, Characterization, and Anti-Inflammatory Activities of Methyl Salicylate Derivatives Bearing Piperazine Moiety.

PubMed

Li, Jingfen; Yin, Yong; Wang, Lisheng; Liang, Pengyun; Li, Menghua; Liu, Xu; Wu, Lichuan; Yang, Hua

2016-11-23

In this study, a new series of 16 methyl salicylate derivatives bearing a piperazine moiety were synthesized and characterized. The in vivo anti-inflammatory activities of target compounds were investigated against xylol-induced ear edema and carrageenan-induced paw edema in mice. The results showed that all synthesized compounds exhibited potent anti-inflammatory activities. Especially, the anti-inflammatory activities of compounds M15 and M16 were higher than that of aspirin and even equal to that of indomethacin at the same dose. In addition, the in vitro cytotoxicity activities and anti-inflammatory activities of four target compounds were performed in RAW264.7 macrophages, and compound M16 was found to significantly inhibit the release of lipopolysaccharide (LPS)-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a dose-dependent manner. In addition, compound M16 was found to attenuate LPS induced cyclooxygenase (COX)-2 up-regulation. The current preliminary study may provide information for the development of new and safe anti-inflammatory agents.

Novel pyrrole derivatives bearing sulfonamide groups: Synthesis in vitro cytotoxicity evaluation, molecular docking and DFT study

NASA Astrophysics Data System (ADS)

Bavadi, Masoumeh; Niknam, Khodabakhsh; Shahraki, Omolbanin

2017-10-01

The synthesis of new derivatives of pyrrole substituted sulfonamide groups is described. The in vitro anticancer activity of these pyrroles was evaluated against MCF7, MOLT-4 and HL-60 cells using MTT assay. The target compounds showed inhibitory activity against tested cell lines. Among the compounds, compound 1a exhibited good cytotoxic activity. The potential of this analog to induce apoptosis was confirmed in a nuclear morphological assay by Hoechst 33258 staining in the PC-12 cells. Finally, molecular docking was performed to determine the probable binding mode of the designed pyrrole derivatives into the active site of FGFR1 protein. DFT calculations were carried out at the B3LYP levels of theory with 6-31+G (d,p) basis set for compound 1a. The point group (C1) of it was obtained based on the optimized structures; the calculation of the FT-IR vibrational frequencies, 1H NMR and 13C NMR chemical shifts of the compound were carried out and compared with those obtained experimentally.

Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.

PubMed

Matralis, Alexios N; Kourounakis, Angeliki P

2014-03-27

Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.

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

Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes.

PubMed

Gul, Halise Inci; Yamali, Cem; Bulbuller, Merve; Kirmizibayrak, Petek Ballar; Gul, Mustafa; Angeli, Andrea; Bua, Silvia; Supuran, Claudiu T

2018-08-01

In this study, new dibenzensulfonamides, 7-9, having the chemical structure 4,4'-(5'-chloro-3'-methyl-5-aryl-3,4-dihydro-1'H,H-[3,4'-bipyrazole]-1',2-diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1 H NMR, 13 C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7-9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7-28.1 nM and 4.5-9.3 nM, respectively. Copyright © 2018 Elsevier Inc. All rights reserved.

A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells

PubMed Central

Kim, A D; Kang, K A; Kim, H S; Kim, D H; Choi, Y H; Lee, S J; Kim, H S; Hyun, J W

2013-01-01

Compound K (20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol) is an active metabolite of ginsenosides and induces apoptosis in various types of cancer cells. This study investigated the role of autophagy in compound K-induced cell death of human HCT-116 colon cancer cells. Compound K activated an autophagy pathway characterized by the accumulation of vesicles, the increased positive acridine orange-stained cells, the accumulation of LC3-II, and the elevation of autophagic flux. Whereas blockade of compound K-induced autophagy by 3-methyladenein and bafilomycin A1 significantly increased cell viability. In addition, compound K augmented the time-dependent expression of the autophagy-related proteins Atg5, Atg6, and Atg7. However, knockdown of Atg5, Atg6, and Atg7 markedly inhibited the detrimental impact of compound K on LC3-II accumulation and cell vitality. Compound K-provoked autophagy was also linked to the generation of intracellular reactive oxygen species (ROS); both of these processes were mitigated by the pre-treatment of cells with the antioxidant N-acetylcysteine. Moreover, compound K activated the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas downregulation of JNK by its specific inhibitor SP600125 or by small interfering RNA against JNK attenuated autophagy-mediated cell death in response to compound K. Compound K also provoked apoptosis, as evidenced by an increased number of apoptotic bodies and sub-G1 hypodiploid cells, enhanced activation of caspase-3 and caspase-9, and modulation of Bcl-2 and Bcl-2-associated X protein expression. Notably, compound K-stimulated autophagy as well as apoptosis was induced by disrupting the interaction between Atg6 and Bcl-2. Taken together, these results indicate that the induction of autophagy and apoptosis by compound K is mediated through ROS generation and JNK activation in human colon cancer cells. PMID:23907464

Alterations in Red Blood Cell Functionality Induced by an Indole Scaffold Containing a Y-Iminodiketo Moiety: Potential Antiproliferative Conditions

PubMed Central

Scala, Angela; Ficarra, Silvana; Russo, Annamaria; Giunta, Elena; Galtieri, Antonio; Tellone, Ester

2016-01-01

We have recently proposed a new erythrocyte-based model of study to predict the antiproliferative effects of selected heterocyclic scaffolds. Starting from the metabolic similarity between erythrocytes and cancer cells, we have demonstrated how the metabolic derangement induced by an indolone-based compound (DPIT) could be related to its antiproliferative effects. In order to prove the validity of our biochemical approach, in the present study the effects on erythrocyte functionality of its chemical precursor (PID), whose synthesis we reported, were investigated. The influence of the tested compound on band 3 protein (B3), oxidative state, ATP efflux, caspase 3, metabolism, intracellular pH, and Ca2+ homeostasis has been evaluated. PID crosses the membrane localizing into the cytosol, increases anion exchange, induces direct caspase activation, shifts the erythrocytes towards an oxidative state, and releases less ATP than in normal conditions. Analysis of phosphatidylserine externalization shows that PID slightly induces apoptosis. Our findings indicate that, due to its unique features, erythrocyte responses to exogenous molecular stimuli can be fruitfully correlated at structurally more complex cells, such as cancer cells. Overall, our work indicates that erythrocyte is a powerful study tool to elucidate the biochemical/biological effects of selected heterocycles opening considerable perspectives in the field of drug discovery. PMID:27651854

Identification of natural products with neuronal and metabolic benefits through autophagy induction.

PubMed

Fan, Yuying; Wang, Nan; Rocchi, Altea; Zhang, Weiran; Vassar, Robert; Zhou, Yifa; He, Congcong

2017-01-02

Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.

Genotoxicity analysis of two halonitromethanes, a novel group of disinfection by-products (DBPs), in human cells treated in vitro

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

Liviac, Danae; Creus, Amadeu; Marcos, Ricard

Halonitromethanes (HNMs) constitute an emerging class of disinfection by-products (DBPs) produced when chlorine and/or ozone are used for water treatment. The HNMs are structurally similar to halomethanes, but have a nitro-group in place of hydrogen bonded to the central carbon atom. Since little information exists on the genotoxic potential of HNMs, a study has been carried out with two HNM compounds, namely trichloronitromethane (TCNM) and bromonitromethane (BNM) by using human cells. Primary damage induction has been measured with the Comet assay, which is used to determine both the repair kinetics of the induced damage and the proportion of induced oxidativemore » damage. In addition, the fixed DNA damage has been evaluated by using the micronucleus (MN) assay. The results obtained indicate that both compounds are genotoxic, inducing high levels of DNA breaks in the Comet assay, and that this DNA damage repairs well over time. In addition, oxidized bases constitute a high proportion of DNA-induced damage (50-75%). Contrarily, no positive effects were observed in the frequency of micronucleus, which measures both clastogenic and aneugenic effects, neither using TK6 cells nor peripheral blood lymphocytes. This lack of fixed genetic damage would minimize the potential mutagenic risk associated with HNMs exposure.« less

Activation of the proapoptotic Bcl-2 protein Bax by a small molecule induces tumor cell apoptosis.

PubMed

Zhao, Guoping; Zhu, Yanglong; Eno, Colins O; Liu, Yanlong; Deleeuw, Lynn; Burlison, Joseph A; Chaires, Jonathan B; Trent, John O; Li, Chi

2014-04-01

The proapoptotic Bcl-2 protein Bax by itself is sufficient to initiate apoptosis in almost all apoptotic paradigms. Thus, compounds that can facilitate disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. In our study, we have identified small-molecule compounds predicted to associate with the Bax hydrophobic groove by a virtual-screen approach. Among these, one lead compound (compound 106) promotes Bax-dependent but not Bak-dependent apoptosis. Importantly, this compound alters Bax protein stability in vitro and promotes the insertion of Bax into mitochondria, leading to Bax-dependent permeabilization of the mitochondrial outer membrane. Furthermore, as a single agent, compound 106 inhibits the growth of transplanted tumors, probably by inducing apoptosis in tumors. Our study has revealed a compound that activates Bax and induces Bax-dependent apoptosis, which may lead to the development of new therapeutic agents for cancer.

Activation of the Proapoptotic Bcl-2 Protein Bax by a Small Molecule Induces Tumor Cell Apoptosis

PubMed Central

Zhao, Guoping; Zhu, Yanglong; Eno, Colins O.; Liu, Yanlong; DeLeeuw, Lynn; Burlison, Joseph A.; Chaires, Jonathan B.; Trent, John O.

2014-01-01

The proapoptotic Bcl-2 protein Bax by itself is sufficient to initiate apoptosis in almost all apoptotic paradigms. Thus, compounds that can facilitate disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. In our study, we have identified small-molecule compounds predicted to associate with the Bax hydrophobic groove by a virtual-screen approach. Among these, one lead compound (compound 106) promotes Bax-dependent but not Bak-dependent apoptosis. Importantly, this compound alters Bax protein stability in vitro and promotes the insertion of Bax into mitochondria, leading to Bax-dependent permeabilization of the mitochondrial outer membrane. Furthermore, as a single agent, compound 106 inhibits the growth of transplanted tumors, probably by inducing apoptosis in tumors. Our study has revealed a compound that activates Bax and induces Bax-dependent apoptosis, which may lead to the development of new therapeutic agents for cancer. PMID:24421393

Change of choline compounds in sodium selenite-induced apoptosis of rats used as quantitative analysis by in vitro 9.4T MR spectroscopy.

PubMed

Cao, Zhen; Wu, Lin-Ping; Li, Yun-Xia; Guo, Yu-Bo; Chen, Yao-Wen; Wu, Ren-Hua

2008-06-28

To study liver cell apoptosis caused by the toxicity of selenium and observe the alteration of choline compounds using in vitro 9.4T high resolution magnetic resonance spectroscopy. Twenty male Wistar rats were randomly divided into two groups. The rats in the treatment group were intraperitoneally injected with sodium selenite and the control group with distilled water. All rats were sacrificed and the livers were dissected. (1)H-MRS data were collected using in vitro 9.4T high resolution magnetic resonance spectrometer. Spectra were processed using XWINNMR and MestRe-c 4.3. HE and TUNEL staining was employed to detect and confirm the change of liver cells. Good (1)H-MR spectra of perchloric acid extract from liver tissue of rats were obtained. The conventional metabolites were detected and assigned. Concentrations of different ingredient choline compounds in treatment group vs control group were as follows: total choline compounds, 5.08 +/- 0.97 mmol/L vs 3.81 +/- 1.16 mmol/L (P = 0.05); and free choline, 1.07 +/- 0.23 mmol/L vs 0.65 +/- 0.20 mmol/L (P = 0.00). However, there was no statistical significance between the two groups. The hepatic sinus and cellular structure of hepatic cells in treatment group were abnormal. Apoptosis of hepatic cells was confirmed by TUNEL assay. High dose selenium compounds can cause the rat liver lesion and induce cell apoptosis in vivo. High resolution (1)H-MRS in vitro can detect diversified metabolism. The changing trend for different ingredient of choline compounds is not completely the same at early period of apoptosis.

Nuclear Factor Kappa B Activation and Peroxisome Proliferator-activated Receptor Transactivational Effects of Chemical Components of the Roots of Polygonum multiflorum.

PubMed

Sun, Ya Nan; Li, Wei; Song, Seok Bean; Yan, Xi Tao; Yang, Seo Young; Kim, Young Ho

2016-01-01

Polygonum multiflorum is well-known as "Heshouwu" in traditional Chinese herbal medicine. In Northeast Asia, it is often used as a tonic to prevent premature aging of the kidney and liver, tendons, and bones and strengthening of the lower back and knees. To research the anti-inflammatory activities of components from P. multiflorum. The compounds were isolated by a combination of silica gel and YMC R-18 column chromatography, and their structures were identified by analysis of spectroscopic data (1D, 2D-nuclear magnetic resonance, and mass spectrometry). The anti-inflammatory activities of the isolated compounds 1-15 were evaluated by luciferase reporter gene assays. Fifteen compounds (1-15) were isolated from the roots of P. multiflorum. Compounds 1-5 and 14-15 significantly inhibited tumor necrosis factor-α-induced nuclear factor kappa B-luciferase activity, with IC50 values of 24.16-37.56 μM. Compounds 1-5 also greatly enhanced peroxisome proliferator-activated receptors transcriptional activity with EC50 values of 18.26-31.45 μM. The anthraquinone derivatives were the active components from the roots of P. multiflorum as an inhibitor on inflammation-related factors in human hepatoma cells. Therefore, we suggest that the roots of P. multiflorum can be used to treat natural inflammatory diseases. This study presented that fifteen compounds (1-15) isolated from the roots of Polygonum multiflrum exert signifiant anti inflmmatory effects by inhibiting TNF α induced NF κB activation and PPARs transcription. Abbreviation used: NF κB: Nuclear factor kappa B, PPARs: Peroxisome proliferator activated receptors, PPREs: Peroxisome proliferator response elements, TNF α: Tumor necrosis factor α, ESI-MS: Electrospray ionization mass spectrometry, HepG2: Human hepatoma cells.

Bis-Cyclic-Guanidine as a Novel Class of Compounds Potent Against Clostridium Difficile.

PubMed

Li, Chunhui; Teng, Peng; Peng, Zhong; Sang, Peng; Sun, Xingmin; Cai, Jianfeng

2018-05-16

Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infections in the USA. To combat the pathogen, the new structural class of pseudo peptides that exhibit antimicrobial activities could play an important role. Herein, we report that bis-cyclic guanidine compounds that exhibit potent antibacterial activity against C. difficile with decent selectivity. Eight compounds showed high in vitro potency against C. difficile UK6 with MIC of 1.0 μg/mL, and cytotoxic selectivity index (SI) up to 37. Moreover, the most selective compound 13 is also effective upon the treatment of C. difficile-induced diseases in the mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical Characterization of Beer Aging Products Derived from Hard Resin Components in Hops (Humulus lupulus L.).

PubMed

Taniguchi, Yoshimasa; Yamada, Makiko; Taniguchi, Harumi; Matsukura, Yasuko; Shindo, Kazutoshi

2015-11-25

The bitter taste of beer originates from resins in hops (Humulus lupulus L.), which are classified into two subtypes (soft and hard). Whereas the nature and reactivity of soft-resin-derived compounds, such as α-, β-, and iso-α-acids, are well studied, there is only a little information on the compounds in hard resin. For this work, hard resin was prepared from stored hops and investigated for its compositional changes in an experimental model of beer aging. The hard resin contained a series of α-acid oxides. Among them, 4'-hydroxyallohumulinones were unstable under beer storage conditions, and their transformation induced primary compositional changes of the hard resin during beer aging. The chemical structures of the products, including novel polycyclic compounds scorpiohumulinols A and B and dicyclohumulinols A and B, were determined by HRMS and NMR analyses. These compounds were proposed to be produced via proton-catalyzed cyclization reactions of 4'-hydroxyallohumulinones. Furthermore, they were more stable than their precursor 4'-hydroxyallohumulinones during prolonged storage periods.

Antioxidant and anti-inflammatory caffeoyl phenylpropanoid and secoiridoid glycosides from Jasminum nervosum stems, a Chinese folk medicine.

PubMed

Guo, Zhi-Yong; Li, Ping; Huang, Wen; Wang, Jian-Jun; Liu, Yu-Jing; Liu, Bo; Wang, Ye-Ling; Wu, Shi-Biao; Kennelly, Edward J; Long, Chun-Lin

2014-10-01

Eight compounds including four caffeoyl phenylpropanoid glycosides, jasnervosides A-D (1-4), one monoterpenoid glycoside, jasnervoside E (5), and three secoiridoid glycosides, jasnervosides F-H (10-12), were isolated from the stems of Jasminum nervosum Lour. (Oleaceae), along with four known compounds, poliumoside (6), verbascoside (7), α-l-rhamnopyranosyl-(1→3)-O-(α-l-rhamnopyranosyl(1→6)-1-O-E-caffeoyl-β-d-glucopyranoside (8), and jaspolyanthoside (9). Their structures were elucidated on the basis of their physicochemical and spectroscopic properties. Compounds 1, 2, 4 and 11 displayed potent antioxidant activities in the DPPH assay, while 2 and 3 displayed good activities against LPS-induced TNF-α and IL-1β production in BV2 cells. Compounds 1-5 and 10-12 were evaluated for their cytotoxic activities against three human cancer cell lines (A-549, Bel-7402, and HCT-8), but none displayed significant activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ferromagnetism in UCo1-xMnxAl and UCo1-xVxAl

NASA Astrophysics Data System (ADS)

Izmaylov, M.; Rafaja, D.; Sechovský, V.; Andreev, A. V.

2002-01-01

UCoAl is an itinerant 5 f-electron metamagnet with a tiny critical field of transition B c≈0.4 T (at 1.3 K). Critical magnetic parameters of this material are strongly sensitive to chemical environment of U atoms. We present results of a pilot study of formation, crystal structure and magnetism of UCo1-xTxAl compounds for T=Mn and V, x≤0.1. All these compounds have been found to be isostructural with the parent compound. Already for x=0.01 in both systems a spontaneous magnetization M s has been observed at low temperatures. Anomalies in the AC susceptibility as a function of temperature point to T c≈28 and 25 K respectively for Mn and V doping. The ferromagnetism induced in UCo1-xTxAl compounds due to a substitution of light transition metal for Co is discussed within a model considering effects of varying 5 f-ligand hybridization on the stability of U 5 f-moment and on exchange interactions.

Chalcone derivatives from the fern Cyclosorus parasiticus and their anti-proliferative activity.

PubMed

Wei, Han; Zhang, Xuenong; Wu, Guanghua; Yang, Xian; Pan, Songwei; Wang, Yanyan; Ruan, Jinlan

2013-10-01

Three new chalcone derivatives, named parasiticins A-C (1-3), were isolated from the leaves of Cyclosorus parasiticus, together with four known chalcones, 5,7-dihydroxy-4-phenyl-8-(3-phenyl-trans-acryloyl)-3,4-dihydro-1-benzopyran-2-one (4), 2'-hydroxy-4',6'-dimethoxychalcone (5), 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (6), 2',4'-dihydroxy-6'-methoxy-3'-methylchalcone (7). The chemical structures of the new isolated compounds were elucidated unambiguously by spectroscopic data analysis. The cytotoxic activities of compounds 1-7 were evaluated against six human cancer cell lines in vitro. Compounds 3 and 6 exhibited substantial cytotoxicity against all six cell lines, especially toward HepG2 with the IC₅₀ values of 1.60 and 2.82 μM, respectively. Furthermore, we demonstrated that compounds 3 and 6 could induce apoptosis in the HepG2 cell line, which may contribute significantly to their cytotoxicity. Copyright © 2013 Elsevier Ltd. All rights reserved.

EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1

PubMed Central

Thomas, Shala L.; Zhong, Diansheng; Zhou, Wei; Malik, Sanna; Liotta, Dennis; Snyder, James P.; Hamel, Ernest; Giannakakou, Paraskevi

2008-01-01

Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin’s low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1α protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1α gene transcription, EF24 exerted its activity by inhibiting HIF-1α posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24. PMID:18682687

EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1.

PubMed

Thomas, Shala L; Zhong, Diansheng; Zhou, Wei; Malik, Sanna; Liotta, Dennis; Snyder, James P; Hamel, Ernest; Giannakakou, Paraskevi

2008-08-01

Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.

Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

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

Doherty, Kimberly R., E-mail: kimberly.doherty@quintiles.com; Talbert, Dominique R.; Trusk, Patricia B.

Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks.more » Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. - Highlights: • 24 drugs were tested for cardiac liability using an in vitro multi-parameter screen. • Changes in beating activity were the most sensitive in predicting cardiac risk. • Structural effects add in-depth insight towards mechanism of cardiac toxicity. • Testing functional and structural endpoints enhances early cardiac risk assessment.« less

Experimental and ab Initio Study of Catena(bis(μ2-iodo)-6-methylquinoline-copper(I)) under Pressure: Synthesis, Crystal Structure, Electronic, and Luminescence Properties.

PubMed

Aguirrechu-Comerón, Amagoia; Hernández-Molina, Rita; Rodríguez-Hernández, Plácida; Muñoz, Alfonso; Rodríguez-Mendoza, Ulises R; Lavín, Vı́ctor; Angel, Ross J; Gonzalez-Platas, Javier

2016-08-01

Copper(I) iodine compounds can exhibit interesting mechanochromic and thermochromic luminescent properties with important technological applications. We report the synthesis and structure determination by X-ray diffraction of a new polymeric staircase copper(I) iodine compound catena(bis(μ2-iodo)-6-methylquinoline-copper(I), [C10H9CuIN]. The structure is composed of isolated polymeric staircase chains of copper-iodine coordinated to organic ligands through Cu-N bonds. High pressure X-ray diffraction to 6.45 GPa shows that the material is soft, with a bulk modulus K0 = 10.2(2)GPa and a first derivative K'0 = 8.1(3), typical for organometallic compounds. The unit-cell compression is very anisotropic with the stiffest direction [302] arising from a combination of the stiff CuI ladders and the shear of the planar quinolone ligands over one another. Full structure refinements at elevated pressures show that pressures reduce the Cu···Cu distances in the compound. This effect is detected in luminescence spectra with the appearance of four sub-bands at 515, 600, 647, and 712 nm above 3.5 GPa. Red-shifts are observed, and they are tentatively associated with interactions between copper(I) ions due to the shortening of the Cu···Cu distances induced by pressure, below twice the van der Waals limit (2.8 Å). Additionally, ab initio simulations were performed, and they confirmed the structure and the results obtained experimentally for the equation of state. The simulation allowed the band structure and the electronic density of states of this copper(I) iodine complex to be determined. In particular, the band gap decreases slowly with pressure in a quadratic way with dEg/dP = -0.011 eV/GPa and d(2)Eg/dP(2) = 0.001 eV/GPa(2).

Core-level photoabsorption study of defects and metastable bonding configurations in boron nitride

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

Jimenez, I.; Jankowski, A.F.; Terminello, L.J.

1997-04-01

Boron nitride is an interesting material for technological applications and for fundamental solid state physics investigations. It is a compound isoelectronic with carbon and, like carbon can possess sp{sup 2} and sp{sup 3} bonded phases resembling graphite and diamond. BN crystallizes in the sp{sup 2}-bonded hexagonal (h-BN), rhombohedral (r-BN) and turbostratic phases, and in the sp{sup 3}-bonded cubic (c-BN) and wurtzite (w-BN) phases. A new family of materials is obtained when replacing C-C pairs in graphite with isoelectronic B-N pairs, resulting in C{sub 2}BN compounds. Regarding other boron compounds, BN is exceptional in the sense that it has standard two-centermore » bonds with conventional coordination numbers, while other boron compounds (e.g. B{sub 4}C) are based on the boron icosahedron unit with three-center bonds and high coordination numbers. The existence of several allotropic forms and fullerene-like structures for BN suggests a rich variety of local bonding and poses the questions of how this affects the local electronic structure and how the material accommodates the stress induced in the transition regions between different phases. One would expect point defects to play a crucial role in stress accommodation, but these must also have a strong influence in the electronic structure, since the B-N bond is polar and a point defect will thus be a charged structure. The study of point defects in relationship to the electronic structure is of fundamental interest in these materials. Recently, the authors have shown that Near-Edge X-ray Absorption Fine Structure (NEXAFS) is sensitive to point defects in h-BN, and to the formation of metastable phases even in amorphous materials. This is significant since other phase identification techniques like vibrational spectroscopies or x-ray diffraction yield ambiguous results for nanocrystalline and amorphous samples. Serendipitously, NEXAFS also combines chemical selectivity with point defect sensitivity.« less

E-Cadherin/β-Catenin Complex: A Target for Anticancer and Antimetastasis Plants/Plant-derived Compounds.

PubMed

Tafrihi, Majid; Nakhaei Sistani, Roohollah

2017-07-01

Plants reputed to have cancer-inhibiting potential and putative active components derived from those plants have emerged as an exciting new field in cancer study. Some of these compounds have cancer-inhibiting potential in different clinical staging levels, especially metastasis. A few of them which stabilize cell-cell adhesions are controversial topics. This review article introduces some effective herbal compounds that target E-cadherin/β-catenin protein complex. In this article, at first, we briefly review the structure and function of E-cadherin and β-catenin proteins, Wnt signaling pathway, and its target genes. Then, effective compounds of the Teucrium persicum, Teucrium polium, Allium sativum (garlic), Glycine max (soy), and Brassica oleracea (broccoli) plants, which influence stability and cellular localization of E-cadherin/β-catenin complex, were studied. Based on literature review, there are some compounds in these plants, including genistein of soy, sulforaphane of broccoli, organosulfur compounds of garlic, and the total extract of Teucrium genus that change the expression of variety of Wnt target genes such as MMPs, E-cadherin, p21, p53, c-myc, and cyclin D1. So they may induce cell-cycle arrest, apoptosis and/or inhibition of Epithelial-Mesenchymal Transition (EMT) and metastasis.

Synthesis of biologically active N-methyl derivatives of amidines and cyclized five-membered products of amidines with oxalyl chloride.

PubMed

Sondhi, Sham M; Dinodia, Monica; Jain, Shubhi; Kumar, Ashok

2008-12-01

A series of substituted N-methylisonicotinamidine (2a-f), N-methylpyrazine-2-carboxamidine (2g-i) derivatives were synthesized by reaction of amidine derivatives (1a-i) with methyl iodide in presence of triethylamine. Five-membered condensed dihydroimidazolylbenzenesulfonamide derivatives (3a-i) were obtained by the reaction of amidine derivatives (1a-i) with acylating agent oxalyl chloride. All the compounds, i.e. 2a-i and 3a-i were purified by crystallization. Structures of all the synthesized compounds are supported by correct IR, (1)H NMR, mass spectral and analytical data. Anti-inflammatory activity evaluation was carried out using carrageenan-induced paw oedema assay and compounds 2e, 3a and 3d exhibited good anti-inflammatory activity (44%, 31% and 37% activity at 50 mg/kg p.o., respectively). Analgesic activity evaluation was carried out using acetic acid writhing assay and compounds 2a and 3f gave 75% activity each at 100 mg/kg p.o.; on the other hand compounds 3a and 3d exhibited 60% analgesic activity each at 50 mg/kg p.o. Compounds 3a and 3d exhibited good anti-inflammatory and analgesic activities.

A Dinitroaniline-Resistant Mutant of Eleusine indica Exhibits Cross-Resistance and Supersensitivity to Antimicrotubule Herbicides and Drugs 1

PubMed Central

Vaughn, Kevin C.; Marks, M. David; Weeks, Donald P.

1987-01-01

A dinitroaniline-resistant (R) biotype of Eleusine indica (L.) Gaertner. (goosegrass) is demonstrated to be cross-resistant to a structurally non-related herbicide, amiprophosmethyl, and supersensitive to two other classes of compounds which disrupt mitosis. These characteristics of the R biotype were discovered in a comparative test of the effects of 24 different antimitotic compounds on the R biotype and susceptible (S) wild-type Eleusine. The compounds tested could be classified into three groups based upon their effects on mitosis in root tips of the susceptible (S) biotype. Class I compounds induced effects like the well known mitotic disrupter colchicine: absence of cortical and spindle microtubules, mitosis arrested at prometaphase, and the formation of polymorphic nuclei after arrested mitosis. The R biotype was resistant to treatment with some class I inhibitors (all dinitroaniline herbicides and amiprophosmethyl) but not all (e.g. colchicine, podophyllotoxin, vinblastine, and pronamide). Roots of the R biotype, when treated with either dinitroaniline herbicides or amiprophosmethyl, exhibited no or only small increases in the mitotic index nor were the spindle and cortical microtubules affected. Compounds of class II (carbamate herbicides and griseofulvin) cause misorientation of microtubules which results in multinucleated cells. Compounds of class III (caffeine and structually related alkaloids) cause imcomplete cell walls to form at telophase. Each of these last two classes of compounds affected the R biotype more than the S biotype (supersensitivity). The cross-resistance and high levels of resistance of the R biotype of Eleusine to the dinitroaniline herbicides and the structurally distinct herbicide, amiprophosmethyl, indicate that a mechanism of resistance based upon metabolic modification, translocation, or compartmentation of the herbicides is probably not operative. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 Fig. 6 PMID:16665371

A Dinitroaniline-Resistant Mutant of Eleusine indica Exhibits Cross-Resistance and Supersensitivity to Antimicrotubule Herbicides and Drugs.

PubMed

Vaughn, K C; Marks, M D; Weeks, D P

1987-04-01

A dinitroaniline-resistant (R) biotype of Eleusine indica (L.) Gaertner. (goosegrass) is demonstrated to be cross-resistant to a structurally non-related herbicide, amiprophosmethyl, and supersensitive to two other classes of compounds which disrupt mitosis. These characteristics of the R biotype were discovered in a comparative test of the effects of 24 different antimitotic compounds on the R biotype and susceptible (S) wild-type Eleusine. The compounds tested could be classified into three groups based upon their effects on mitosis in root tips of the susceptible (S) biotype. Class I compounds induced effects like the well known mitotic disrupter colchicine: absence of cortical and spindle microtubules, mitosis arrested at prometaphase, and the formation of polymorphic nuclei after arrested mitosis. The R biotype was resistant to treatment with some class I inhibitors (all dinitroaniline herbicides and amiprophosmethyl) but not all (e.g. colchicine, podophyllotoxin, vinblastine, and pronamide). Roots of the R biotype, when treated with either dinitroaniline herbicides or amiprophosmethyl, exhibited no or only small increases in the mitotic index nor were the spindle and cortical microtubules affected. Compounds of class II (carbamate herbicides and griseofulvin) cause misorientation of microtubules which results in multinucleated cells. Compounds of class III (caffeine and structually related alkaloids) cause imcomplete cell walls to form at telophase. Each of these last two classes of compounds affected the R biotype more than the S biotype (supersensitivity). The cross-resistance and high levels of resistance of the R biotype of Eleusine to the dinitroaniline herbicides and the structurally distinct herbicide, amiprophosmethyl, indicate that a mechanism of resistance based upon metabolic modification, translocation, or compartmentation of the herbicides is probably not operative.

Synergetic effect and structure-activity relationship of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors from Crataegus pinnatifida Bge.

PubMed

Ye, Xiao-Li; Huang, Wen-Wen; Chen, Zhu; Li, Xue-Gang; Li, Ping; Lan, Ping; Wang, Liang; Gao, Ying; Zhao, Zhong-Qi; Chen, Xin

2010-03-10

The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors from hawthorn fruit ( Crataegus pinnatifida Bge.) were isolated and evaluated for their antihyperlipidemic effect induced by high-fat diet in mice. After being further purified with silica and polyamide column chromatography from the fractions (fractions A, F, H, and G) with a high inhibitory rate (IR) to HMGR, 24 chromatographic fractions were obtained, including 8 active fractions with a high IR to HMGR. However, the total inhibitory activity of 24 fractions was decreased by about 70%. From eight active fractions, four compounds were obtained by recrystallization and identified as quercetin (a), hyperoside (b), rutin (c), and chlorogenic acid (d), the contents of which in hawthorn EtOH extract were 0.16, 0.32, 1.45, and 0.95%, respectively. The IR values of compounds a-d to HMGR were 6.28, 9.64, 23.53, and 10.56% at the corresponding concentrations of 0.16, 0.32, 1.45, and 0.95 mg/mL, respectively. It was discovered that the IR of a mixture (2.85 mg/mL) matching the original percentage of compounds a-d in hawthorn EtOH extract was up to 79.5%, much higher than that of the single compound and the total IR of these four compounds (50.01%). The in vivo results also revealed that the mixture had a more significant lipid-lowering efficacy than the monomers. Structure-activity relationship revealed the inhibitory activity and lowering-lipid ability of compounds a-c decreased with increasing glycoside numbers. It was concluded that there were synergetic effects on inhibiting HMGR and lowering lipid among compounds a-d, and the weak hydrophilic ability benefits the inhibition to HMGR and lowering-lipid efficacy.

Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching

PubMed Central

Hevener, Kirk E.; Mehboob, Shahila; Su, Pin-Chih; Truong, Kent; Boci, Teuta; Deng, Jiangping; Ghassemi, Mahmood; Cook, James L.; Johnson, Michael E.

2011-01-01

Enoyl-acyl carrier protein (ACP) reductase, FabI, is a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is an NADH-dependent oxidoreductase that acts to reduce enoyl-ACP substrates in a final step of the pathway. The absence of this enzyme in humans makes it an attractive target for the development of new antibacterial agents. FabI is known to be unresponsive to structure-based design efforts due to a high degree of induced fit and a mobile flexible loop encompassing the active site. Here we discuss the development, validation, and careful application of a ligand-based virtual screen used for the identification of novel inhibitors of the Francisella tularensis FabI target. In this study, four known classes of FabI inhibitors were used as templates for virtual screens that involved molecular shape and electrostatic matching. The program ROCS was used to search a high-throughput screening library for compounds that matched any of the four molecular shape queries. Matching compounds were further refined using the program EON, which compares and scores compounds by matching electrostatic properties. Using these techniques, 50 compounds were selected, ordered, and tested. The tested compounds possessed novel chemical scaffolds when compared to the input query compounds. Several hits with low micromolar activity were identified and follow-up scaffold-based searches resulted in the identification of a lead series with sub-micromolar enzyme inhibition, high ligand efficiency, and a novel scaffold. Additionally, one of the most active compounds showed promising whole-cell antibacterial activity against several Gram-positive and Gram-negative species, including the target pathogen. The results of a preliminary structure-activity relationship analysis are presented. PMID:22098466

A selective plasmin inhibitor, trans-aminomethylcyclohexanecarbonyl-L-(O-picolyl)tyrosine-octylamide (YO-2), induces thymocyte apoptosis.

PubMed

Lee, Eibai; Enomoto, Riyo; Takemura, Kazu; Tsuda, Yuko; Okada, Yoshio

2002-04-01

The treatment of rat thymocytes with YO-2, a novel inhibitor of plasmin, resulted in an increase in DNA fragmentation. DNA fragmentation was also induced by another YO compounds such as YO-0, -3, -4 and -5. These YO compounds are the inhibitor of plasmin activity. On the other hand, YO-1, -6 and -8 that hardly inhibit plasmin activity had no effect on DNA fragmentation. Analysis of fragmented DNA from thymocytes treated with YO-2 by agarose gel electrophoresis revealed that the compound caused internucleosomal DNA fragmentation. In addition, judging from a laser scanning microscopy, annexin V-positive and propidium iodide-negative cells were increased by the treatment of the cells with the compound. Moreover, chromatin condensation was observed in thymocytes treated with the compound. These results demonstrated that YO-2 induces thymocyte apoptosis. There seemed to be some correlation between the apoptosis induced by YO compounds and their plasmin inhibitory effect. However, because the other protease inhibitors including pepstatin A, leupeptin, AEBSF, DFP and E-64-d did not affect DNA fragmentation, YO compounds are likely to have unique mechanism on plasmin or to show the effect on the other plasmin-like proteases. The plasmin inhibitory activity may have an important role in YO-2-induced apoptosis. Furthermore, the stimulations of caspase-8, -9 and -3-like activities were observed in thymocytes treated with YO-2. These results suggest that YO-2 induces thymocyte apoptosis via activation of caspase cascade.

Anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol and lupeol isolated from Diospyros lotus L.

PubMed

Rauf, Abdur; Uddin, Ghias; Khan, Haroon; Raza, Muslim; Zafar, Muhammad; Tokuda, Harukuni

2016-01-01

In this study, the anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol (1) and lupeol (2), isolated from Diospyros lotus L., were explored. Compound 1 showed a marked concentration-dependent inhibition against 12-O-tetradecanoylphorbol-13-acetate (20 ng/32 pmol)-induced Epstein-Barr virus early antigen activation in Raji cells with IC50 of 270 μg/ml, without significant toxicity (70% viability). Compound 2 showed significant anti-tumour-promoting effect with IC50 of 412 μg/ml, without significant toxicity (60% viability). In heat-induced protein denaturation assay, compound 1 exhibited a concentration-dependent attenuation with a maximum effect of 73.5% at 500 μg/ml with EC50 of 117 μg/ml, while compound 2 exhibited a maximum effect of 59.2% at 500 μg/ml with EC50 of 355 μg/ml. Moreover, in silico docking studies against the phosphoinositide 3-kinase enzyme also show the inhibitory potency of these compounds. In short, both the compounds exhibited a marked anti-tumour-promoting and potent inhibitory effect on thermal-induced protein denaturation.