RESUMO
We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC(50) of 0.05muM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.
Assuntos
Ácidos Difenilacéticos/química , Inibidores Enzimáticos/química , Ácidos Hidroxâmicos/química , Xantenos/química , Linhagem Celular , Ácidos Difenilacéticos/síntese química , Ácidos Difenilacéticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Xantenos/síntese química , Xantenos/farmacologiaRESUMO
In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
Assuntos
Inibidores Enzimáticos/química , Inibidores de Histona Desacetilases , Histona Desacetilases/química , Acetilação , Domínio Catalítico , Química Farmacêutica/métodos , Desenho de Fármacos , Desacetilase 6 de Histona , Histona Desacetilases/metabolismo , Histonas/química , Humanos , Ácidos Hidroxâmicos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Piperazina , Piperazinas/química , Isoformas de Proteínas , Tubulina (Proteína)/químicaRESUMO
5-, 6-, and even 7-exo-trig radical cyclizations (1â2) are possible by applying a new boron-tethering approach with alkenylboronic esters. For certain substitution patterns, a subsequent intramolecular homolytic substitution (SH i) reaction at boron occurs (2â3) and leads to rearranged products. The C-B bond of the intermediate boracycles is readily oxidized to give diol products.
RESUMO
Magnesium mediated carbometalation (Grignard addition) to appropriate propargyl alcohols to synthesize a cross-section of variably substituted alpha,beta-unsaturated gamma-sultines is described. Thio-rofecoxib, a selective COX-2 inhibitor (12), is synthesized by this method and its IC(50), microM COX-1 and COX-2 inhibition, and whole blood stability values reported.