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1.
Antimicrob Agents Chemother ; 58(7): 3679-88, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24752271

RESUMO

In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC50s], 0.029 and 0.002 µM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02) compared to ritonavir (RTV; EC50, >1.0 µM) and tipranavir (TPV; EC50, 0.364 µM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIVDRV(R)P20), with a 2.6-fold increase in its EC50 (0.097 µM) compared to its corresponding EC50 (0.038 µM) against wild-type HIV-1NL4-3 (HIVWT). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30' of HIVA02 protease (PRA02) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30' due to an absence of polar groups. The P2' thiazolyl moiety of RTV showed two conformations in the crystal structure of the PRA02-RTV complex, one of which showed loss of contacts in the S2' binding pocket of PRA02, supporting RTV's compromised antiviral activity (EC50, >1 µM). Thus, the conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30, and D30' most likely contributes to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRV(R)P20.


Assuntos
Carbamatos/farmacologia , Domínio Catalítico/efeitos dos fármacos , Farmacorresistência Viral Múltipla/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Sulfonamidas/farmacologia , Cristalização , Darunavir , Protease de HIV , Humanos , Ligação de Hidrogênio , Conformação Molecular , Dados de Sequência Molecular , Dobramento de Proteína , Piridinas/farmacologia , Pironas/farmacologia , Difração de Raios X
2.
Antimicrob Agents Chemother ; 57(10): 4920-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23877703

RESUMO

GRL007 and GRL008, two structurally related nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) as the P2 moiety and a sulfonamide isostere consisting of benzene carboxylic acid and benzene carboxamide as the P2' moiety, respectively, were evaluated for their antiviral activity and interactions with wild-type protease (PR(WT)). Both GRL007 (Ki of 12.7 pM with PR(WT)) and GRL008 (Ki of 8.9 pM) inhibited PR(WT) with high potency in vitro. X-ray crystallographic analysis of PR(WT) in complex with GRL007 or GRL008 showed that the bis-THF moiety of both compounds has three direct polar contacts with the backbone amide nitrogen atoms of Asp29 and Asp30 of PR(WT). The P2' moiety of both compounds showed one direct contact with the backbone of Asp30' and a bridging polar contact with Gly48' through a water molecule. Cell-based antiviral assays showed that GRL007 was inactive (50% effective concentration [EC50] of >1 µM) while GRL008 was highly active (EC50 of 0.04 µM) against wild-type HIV-1. High-performance liquid chromatography (HPLC)/mass spectrometry-based cellular uptake assays showed 8.1- and 84-fold higher intracellular concentrations of GRL008 than GRL007 in human MT-2 and MT-4 cell extracts, respectively. Thus, GRL007, in spite of its favorable enzyme-inhibitory activity and protease binding profile, exhibited a lack of antiviral activity in cell-based assays, most likely due to its compromised cellular uptake associated with its P2' benzene carboxylic acid moiety. The anti-HIV-1 potency, favorable toxicity, and binding profile of GRL008 suggest that further optimization of the P2' moiety may improve its antiretroviral features.


Assuntos
Benzeno/química , Benzoatos/química , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/química , Indóis/química , Domínio Catalítico , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Difração de Raios X
3.
Org Biomol Chem ; 9(1): 154-64, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21085738

RESUMO

Structure-energy relationships for a small group of pyranose and septanose mono-saccharide ligands are developed for binding to Concanavalin A (ConA). The affinity of ConA for methyl "manno"ß-septanoside 7 was found to be higher than any of the previously reported mono-septanoside ligands. Isothermal titration calorimetry (ITC) in conjunction with docking simulations and quantum mechanics/molecular mechanics (QM/MM) modeling established the specific role of binding enthalpy in the structure-energy relations of ConA bound to natural mono-saccharides and unnatural mono-septanosides. An important aspect in the differential binding among ligands is the deformation energy required to reorganize internal hydroxyl groups upon binding of the ligand to ConA.


Assuntos
Carboidratos/química , Concanavalina A/química , Termodinâmica , Concanavalina A/metabolismo , Ligantes , Metilação , Modelos Moleculares , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade
4.
Chem Commun (Camb) ; (34): 4028-30, 2008 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-18758615

RESUMO

Analysis of a series of unsaturated [13]-macro-dilactones showed that the configuration of a single carbon dictates the planar chirality of a macrocycle backbone and in turn remotely switches the facial display of an embedded alkene unit.

5.
ChemMedChem ; 12(23): 1942-1952, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29110408

RESUMO

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite.


Assuntos
Darunavir/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Cristalografia por Raios X , Darunavir/síntese química , Darunavir/química , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Ligantes , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
6.
Org Lett ; 7(21): 4709-12, 2005 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-16209516

RESUMO

[reaction: see text] An S-phenyl alpha-D-idoseptanoside donor was used in the selective preparation of a series of alpha-D-idoseptanosyl glycosides. Glycosylation of a methyl beta-D-glycero-D-guloseptanoside acceptor with the new donor constituted the first synthesis of a septanose disaccharide.


Assuntos
Dissacarídeos/síntese química , Tioglicosídeos/química , Configuração de Carboidratos , Dissacarídeos/química , Glicosilação , Estrutura Molecular , Estereoisomerismo
7.
Carbohydr Res ; 339(14): 2363-70, 2004 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-15388351

RESUMO

Oxidative glycosylations of the D-xylose-based oxepine 1,6-anhydro-3,4,5-tri-O-benzyl-2-deoxy-D-xylosept-1-enitol (1) using N-iodosuccinimide (NIS) are reported. The reaction produced 2-deoxy-2-iodo-alpha-D-idoseptanosides and 2-deoxy-2-iodo-beta-D-guloseptanosides 2-9 in good yields. When limited equivalents of a glycosyl acceptor were used, or in the absence of a glycosyl acceptor, an intramolecular cyclization predominated to form 1,6-anhydro-3,4-di-O-benzyl-2-deoxy-2-iodo-alpha-D-idopyranose (10).


Assuntos
Glicosídeos/síntese química , Compostos Heterocíclicos com 1 Anel/química , Ciclização , Glicosídeos/química , Glicosilação , Hexoses/síntese química , Hexoses/química , Oxepinas/síntese química , Oxirredução , Succinimidas/química , Xilose/química
8.
J Org Chem ; 73(9): 3626-9, 2008 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-18363373

RESUMO

DMDO epoxidation of carbohydrate fused [13]-macro-dilactones was found to be highly diastereoselective. Facial selectivity of the epoxidation depended on the identity of the fused carbohydrate. Gluco-configured macro-dilactones gave the R, R epoxide, whereas the galacto- configuration gave the S, S epoxide. The epoxide stereochemisty was confirmed by independent syntheses of dimethyl 4 R,5R-epoxyoctanedioate via Shi epoxidation of dimethyl E-oct-4-enedioate and by transesterification of the epoxide derived from the gluco-[13]-macro-dilactone. We demonstrate diastereoselectivity in alkene reactivity driven by remote rather than adjacent stereocenters.

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