1.
Bioorg Med Chem Lett
; 28(10): 1949-1953, 2018 06 01.
Artigo
em Inglês
| MEDLINE
| ID: mdl-29705141
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.