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Potent Inhibitory Activity (potent + inhibitory_activity)
Selected AbstractsNovel Diterpenoids with Potent Inhibitory Activity Against Endothelium Cell HMEC and Cytotoxic Activities from a Well-Known TCM Plant Daphne genkwa.CHEMINFORM, Issue 24 2005Zha-Jun Zhan Abstract For Abstract see ChemInform Abstract in Full Text. [source] Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): In search of potent SARS-CoV entry inhibitorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Ling-Hon Matthew Chu Abstract Severe acute respiratory coronavirus (SARS-CoV) spike (S) glycoprotein fusion core consists of a six-helix bundle with the three C-terminal heptad repeat (HR2) helices packed against a central coiled-coil of the other three N-terminal heptad repeat (HR1) helices. Each of the three peripheral HR2 helices shows prominent contacts with the hydrophobic surface of the central HR1 coiled-coil. The concerted protein,protein interactions among the HR helices are responsible for the fusion event that leads to the release of the SARS-CoV nucleocapsid into the target host-cell. In this investigation, we applied recombinant protein and synthetic peptide-based biophysical assays to characterize the biological activities of the HR helices. In a parallel experiment, we employed a HIV-luc/SARS pseudotyped virus entry inhibition assay to screen for potent inhibitory activities on HR peptides derived from the SARS-CoV S protein HR regions and a series of other small-molecule drugs. Three HR peptides and five small-molecule drugs were identified as potential inhibitors. ADS-J1, which has been used to interfere with the fusogenesis of HIV-1 onto CD4+ cells, demonstrated the highest HIV-luc/SARS pseudotyped virus-entry inhibition activity among the other small-molecule drugs. Molecular modeling analysis suggested that ADS-J1 may bind to the deep pocket of the hydrophobic groove on the surface of the central coiled-coil of SARS-CoV S HR protein and prevent the entrance of the SARS-CoV into the host cells. J. Cell. Biochem. 104: 2335,2347, 2008. © 2008 Wiley-Liss, Inc. [source] Reconstitution of anti-HIV effector functions of primary human CD8 T,lymphocytes by transfer of HIV-specific ,,,TCR genesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Takamasa Ueno Abstract We redirected the antigen specificity of primary human CD8 T,cells by retrovirus-mediated transduction of genes encoding ,,,TCR specific to HIV-1 Pol protein. A large polyclonal population of TCR-transduced CD8 T,cells showed substantial cytotoxic and cytokine production activities toward target cells either pulsed with the peptide or infected with HIV-1, and their functional activities were comparable to those of the parental CTL clone. Peptide fine-specificity and promiscuous recognition of HLA class,I supertypes of the parental CTL clone were also preserved in the TCR-transduced cells. There were no signs of allogeneic responses in these cells, although hybrid TCR dimers consisting of transduced TCR and endogenous TCR were suspected to have been formed in these cells, as the effect of transgene expression on the surface expression of the desired TCR was limited. Moreover, the TCR-transduced cells showed potent inhibitory activity against HIV-1 replication in vitro, although the differential surface expression of the desired TCR resulted in differential functional avidity of individual TCR-transduced cells toward the peptide-pulsed target cells. These data suggest that the reconstitution of HIV-specific immunoreactive T,cells engineered by genetic transfer of HIV-specific TCR is a potential alternative to immunotherapeutic applications against HIV infections. [source] Design syntheses and mitochondrial complex I inhibitory activity of novel acetogenin mimicsFEBS JOURNAL, Issue 9 2000Kaoru Kuwabara Some natural acetogenins are the most potent inhibitors of mitochondrial complex I. These compounds are characterized by two functional units [i.e. hydroxylated tetrahydrofuran (THF) and ,,,-unsaturated ,-lactone ring moieties] separated by a long alkyl spacer. To elucidate which structural factors of acetogenins, including their active conformation, are crucial for the potent inhibitory activity we synthesized a novel bis-acetogenin and its analogues possessing two ,-lactone rings connected to bis-THF rings by flexible alkyl spacers. The inhibitory potency of the bis-acetogenin with bovine heart mitochondrial complex I was identical to that of bullatacin, one of the most potent natural acetogenins. This result indicated that one molecule of the bis-acetogenin does not work as two reactive inhibitors, suggesting that a ,-lactone and the THF ring moieties act in a cooperative manner on the enzyme. In support of this, either of the two ring moieties synthesized individually showed no or very weak inhibitory effects. Moreover, combined use of the two ring moieties at various molar ratios exhibited no synergistic enhancement of the inhibitory potency. These observations indicate that both functional units work efficiently only when they are directly linked by a flexible alkyl spacer. Therefore, some specific conformation of the spacer must be important for optimal positioning of the two units in the enzyme. Furthermore, the ,,,-unsaturated ,-lactone, the 4-OH group in the spacer region, the long alkyl tail attached to the THF unit and the stereochemistry surrounding the hydroxylated bis-THF rings were not crucial for the activity, although these are the most common structural features of natural acetogenins. The present study provided useful guiding principles not only for simplification of complicated acetogenin structure, but also for further wide structural modifications of these molecules. [source] Anti-inflammatory activity of the synthetic C-C biflavonoidsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2006Haeil Park To find anti-inflammatory agents based on plant constituents, the effects of six synthetic C-C biflavonoids connecting with different positions of C-C bond between flavone monomers (a: 4,-4,, b: 4,-3,, c: 4,-6, d: 3,-6, e: 6-6, f: 4,-3) were examined on PGE2 and nitric oxide (NO) production from lipopolysaccharide (LPS)-treated macrophages, RAW 264.7. Among the compounds tested, the biflavonoids d, e, and f showed a considerable inhibition of cyclooxygenase-2 (COX-2)-mediated PGE2 production at concentrations up to 50 ,M, while the derivative c exerted cytotoxic effects on RAW cells. Especially, the biflavonoid e possessed the most potent inhibitory activity of PGE2 production with an IC50 of 3.7 ,M, compared with an IC50 of 8.2,20.7 ,M by ginkgetin (natural biflavonoid). Western blot and reverse transcriptase-polymerase chain reaction analyses have shown that the inhibition of PGE2 production by these synthetic derivatives was mediated at least in part by COX-2 inhibition, but not by COX-2 down-regulation. Meanwhile, these synthetic biflavonoids did not considerably inhibit inducible nitric oxide synthase-mediated NO production at concentrations up to 50 ,M. When intraperitoneally administered, the biflavonoid e showed a significant anti-inflammatory activity (22.2% inhibition) against rat carrageenan-induced paw oedema at 5 mg kg,1. The biflavonoid e may be used as a synthetic lead for developing new anti-inflammatory agents. [source] Sulfamates and their therapeutic potentialMEDICINAL RESEARCH REVIEWS, Issue 2 2005Jean-Yves Winum Abstract Starting from the very simple molecule sulfamic acid, O -substituted-, N -substituted-, or di-/tri-substituted sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents, which are on one hand due to the relative ease with which such compounds are synthesized, and on the other one, due to the fact that biological activity of most of them is impressive. © 2004 Wiley Periodicals, Inc. [source] ORIGINAL ARTICLE: Investigating the inhibitory activity of green coffee and cacao bean extracts on pancreatic lipaseNUTRITION BULLETIN, Issue 3 2010S. Almoosawi Summary The present study investigated the effects of green coffee bean extract and Theobroma cacao bean extract on pancreatic lipase activity in vitro. Green coffee bean extract produced a J-shaped dose-dependent inhibition of pancreatic lipase with the percentage inhibition of pancreatic lipase ranging from 11.8% to 61.5%. Similar concentrations of Theobroma cacao failed to produce any effect on pancreatic lipase. Non-linear regression analysis revealed that the concentration of green coffee bean extract required to elicit a 50% inhibition of pancreatic lipase activity (IC50) was approximately 43 µM. In conclusion, extracts of green coffee beans but not Theobroma cacao possess potent inhibitory activity against pancreatic lipase. [source] Screening of some medicinal plants from cameroon for , -Lactamase inhibitory activityPHYTOTHERAPY RESEARCH, Issue 3 2007Joseph Gangoué-Piéboji Abstract In efforts to find new bioactive , -lactamase inhibitors, this study investigated 16 Cameroonian plants belonging to 10 families which were evaluated for anti- , -lactamase activity. The investigation showed that extracts 2, 6, 3 and 5 of the 16 plants investigated presented interesting in vitro, -lactamase inhibition (over 90%), respectively, of the , -lactamases TEM-1, OXA-10, IMP-1 and P99. These extracts were from Mammea africana (all , -lactamases), Garcinia lucida, G. kola (OXA-10, IMP-1 and P99), Bridelia micrantha (OXA-10, P99), Ochna afzelii (OXA-10, P99), Prunus africana (IMP-1) and Adenia lobata (TEM-1). After elimina tion of tannins (according to the European Pharmacopoeia) the extracts from B. micrantha, G. lucida and M. africana were tested further for their anti- , -lactamase activity. The extracts from B. micrantha and G. lucida exhibited potent inhibitory activity, respectively, of , -lactamase OXA-10 (IC50 = 0.02 mg/mL) and P99 (IC50 = 0.01 mg/mL). The anti- , -lactamase activity of M. africana extract was weak. The isolation and the structural elucidation of the active constituents of G. lucida and B. micrantha will provide useful leads in the development of , -lactamase inhibitors. Copyright © 2007 John Wiley & Sons, Ltd. [source] Flavonoids from the leaves of Litsea japonica and their anti-complement activityPHYTOTHERAPY RESEARCH, Issue 4 2005Sun-Young Lee Abstract Four flavonoids, epicatechin (1), afzelin (2), quercitrin (3), and tiliroside (4), were isolated from the leaves of Litsea japonica (Thunb.) Jussieu (Lauraceae). The structures of compounds were identified by comparing their chemical and spectral data with those previously reported. The flavonoids (1,4) were tested for their anti-complement activity against classical pathway of complement system. Compounds 2,4 showed inhibitory activity against complement system with IC50 values of 258, 440, and 101 µm, respectively, whereas 1 was inactive. For the evaluation of the structure-activity relationship of 5,7-dihydroxyflavones, myricitrin (5) from Juglans mandshurica also tested for it's anti-complement activity and is inactive in this assay system. Furthermore, compounds 2, 3, and 5 were hydrolyzed with naringinase to give kaempferol (2a), quercetin (3a), and myricetin (5a), and these were also tested for their activity. Of the three aglycones, 2a exhibited anti-complement activity with an IC50 value of 730 µM, while 3a and 5a were inactive. The inhibitory potencies of 2, 2a, 3, 3a, 5, and 5a against complement activity increased in inverse proportion to number of free hydroxyls on B-ring of 5,7-dihydroxyflavone. Of the compounds tested, 4 showed the most potent inhibitory activity against the complement system. Copyright © 2005 John Wiley & Sons, Ltd. [source] Lignans from Acanthopanax chiisanensis having an inhibitory activity on prostaglandin E2 productionPHYTOTHERAPY RESEARCH, Issue 2 2005Sanghyun Lee Abstract The chloroform and the ethyl acetate fractions from the roots of Acanthopanax chiisanensis exhibited the significant inhibition of TPA-induced prostaglandin E2 (PGE2) production in rat peritoneal macrophages. Five lignans were isolated from the chloroform fraction and their structures were elucidated as l -sesamin, helioxanthin, savinin, taiwanin C, and 3-(3,4-dimethoxybenzyl)-2-(3,4-methylenedioxybenzyl)butyrolactone. Among the lignans tested, taiwanin C showed the most potent inhibitory activity (IC50 = 0.12 µM) on PGE2 production with the relative order of potency, taiwanin C , 3-(3,4-dimethoxybenzyl)-2-(3,4-methylenedioxybenzyl)butyrolactone > savinin = helioxanthin. l -Sesamin showed no inhibitory activity at 30 µM. Copyright © 2005 John Wiley & Sons, Ltd. [source] New Racemosol Derivatives as Potent Cyclooxygenase (COX) InhibitorsCHEMISTRY & BIODIVERSITY, Issue 12 2005Saiphon Songarsa Racemosol (1) and 10- O -demethylracemosol (2), natural products from Bauhinia malabaricaRoxb., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure,activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, two, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a,q were found to be critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table,1), its diacetoxy congener 3i was slightly more selective toward COX-2. In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table,2). [source] | |||||||||||||