RESUMEN
α-Oxy amides are prepared through enantioselective synthesis using a sequence beginning with a Henry addition of bromonitromethane to aldehydes and finishing with Umpolung Amide Synthesis (UmAS). Key to high enantioselection is the finding that ortho-iodo benzoic acid salts of the chiral copper(II) bis(oxazoline) catalyst deliver both diastereomers of the Henry adduct with high enantiomeric excess, homochiral at the oxygen-bearing carbon. Overall, this approach to α-oxy amides provides an innovative complement to alternatives that focus almost entirely on the enantioselective synthesis of α-oxy carboxylic acids.
Asunto(s)
Amidas/síntesis química , EstereoisomerismoRESUMEN
The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.
Asunto(s)
Proteínas Cromosómicas no Histona/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Línea Celular , Proteínas Cromosómicas no Histona/metabolismo , VIH-1/crecimiento & desarrollo , Ensayos Analíticos de Alto Rendimiento , Ratones , Bibliotecas de Moléculas Pequeñas/química , Factores de Transcripción/metabolismo , Latencia del Virus/genéticaRESUMEN
A systematic study of α-iodination and subsequent Suzuki-Miyaura couplings between non-attenuated enaminones and a wide range of aromatic boronic acids is reported. The microwave-assisted variant of this transformation furnished the α-arylenaminones in significantly shorter reaction times and slightly improved yields as compared to conventional heating.
RESUMEN
Umpolung Amide Synthesis (UmAS) provides direct access to amides from an α-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C-N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of α-bromo nitroalkane donors, this protocol realizes the goal of enantioselective α-amino amide and peptide synthesis based solely on catalytic methods.
Asunto(s)
Alcanos/química , Amidas/síntesis química , Hidrocarburos Bromados/química , Nitrocompuestos/química , Oxígeno/química , Succinimidas/química , Amidas/química , Aminas/química , Catálisis , Técnicas Químicas Combinatorias , Estructura MolecularRESUMEN
Both enantiomers of boehmeriasin A were synthesized in seven steps each, using a chiral pool approach. Key steps in the synthesis are a one-flask, two-step protocol to generate the quinolizine core and a C-H functionalization reaction between tetrahydroquinolizinones and an aryltrifluoroborate. The natural product (R)-boehmeriasin A demonstrated potent cytotoxicity against several cancer cell lines, whereas the unnatural (+)-(S)-isomer was significantly less potent.