RESUMO
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
Assuntos
Antivirais/síntese química , Éteres Cíclicos/química , Hepacivirus/efeitos dos fármacos , Nucleosídeos/química , Antivirais/química , Antivirais/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismoRESUMO
Syntheses and structure-antiproliferative relationship for oxyphenisatin analogues are described. The cell proliferation data showed that the presence of substituents (especially F, Cl, Me, CF(3), and OMe) in the 6- and 7-position of oxyphenisatin markedly enhanced the potency in the MDA-468 cell line without affecting the MDA-231 cell line. The best compounds from this series showed low nanomolar antiproliferative activity towards the MDA-468 cell line and a 1000-fold selectivity over the MDA-231 cell line.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Acetato de Oxifenisatina/análogos & derivados , Acetato de Oxifenisatina/síntese química , Acetato de Oxifenisatina/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A stereocontrolled approach to alpha-alkyl beta-alkynyl cyclohexanones is reported through a Lewis acid mediated rearrangement reaction of enol ethers bearing an Co-alkyne moiety. The reaction proceeds with high levels of stereoselectivity in the presence of Ti- and B-Lewis acids to provide a range of alpha,beta-disubstituted cyclohexanones in high yield although the products are prone to epimerization at the alpha-position in the presence of the B-promoter system. The potential for an enantioselective variant of this process is outlined, and a rationale for the observed stereochemical trends and detailed structural analyses of the ketone products are described.