RESUMO
Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4(+) T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4(+) T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4(+) T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD4-Positivos/virologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Ésteres de Forbol/química , Ésteres de Forbol/farmacologia , Ativação Viral/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Citometria de Fluxo , Humanos , Lectinas Tipo C/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ésteres de Forbol/síntese química , Ésteres de Forbol/uso terapêutico , Ligação Proteica , Proteína Quinase C/metabolismo , Ativação Viral/fisiologiaRESUMO
A new convergent synthetic approach to a pyran motif common to many naturally occurring structures is described. In this approach, two fragments are joined by esterification, and a subsequent intramolecular reductive cyclization affords the 2-hydroxypyran.
Assuntos
Piranos/química , Acilação , Briostatinas , Ciclização , Compostos Heterocíclicos/química , Macrolídeos/química , Estrutura Molecular , Oxirredução , Piranos/síntese químicaRESUMO
A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters.
Assuntos
Compostos de Boro/síntese química , Compostos de Sulfidrila/síntese química , Compostos de Boro/química , Catálise , Técnicas de Química Combinatória , Ésteres , Estrutura Molecular , Estereoisomerismo , Compostos de Sulfidrila/químicaRESUMO
A method amenable to the gram scale synthesis of (R)-H 4-BINOL, a derivative of (R)-BINOL and ligand of interest in asymmetric catalysis, is described. The key step is the net partial hydrogenation of (R)-BINOL made possible by prior bis-etherification of the parent BINOL.