RESUMO
The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,ß-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, iâ¯+â¯2 and iâ¯+â¯7 side chains of the BH3 α-helix.
Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Piridinas/química , Sítios de Ligação , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína , Piridinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155â¯nM. Further investigation revealed comparable inhibition of Bcl-xL (Kiâ¯=â¯90â¯nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core.
