Synthesis of C3′‐Foused Aryl/Penta‐1,4‐Dien‐3‐One/Amine Hybrids as HSP90C‐Terminal Inhibitors

Abstract

24 C3′‐focused hybrids of aryl/penta‐1,4‐dien‐3‐one/amine (APDA) were designed and synthesized. Of these hybrids, 2n demonstrated improved antiproliferative effects on HER2‐positive breast cancer cells (SKBr3 and BT474) and triple‐negative breast cancer (TNBC) cells (MDA‐MB‐231 and MDA‐MB‐468) with IC50 values ranging from 7.45 to 10.75 μM, but less toxicity to normal breast cells MCF‐10A than the first generation of hybrid 1. Additionally, 2n retained its ability to inhibit HSP90 C‐terminus, leading to the degradation of HSP90 client proteins HER2, EGFR, pAKT, AKT, and CDK4, without inducing a heat‐shock response. Notably, 2n also demonstrated improved thermostability compared to 1 and maintained in vitro metabolic stability in simulated intestinal fluid. These findings will provide a scientific basis for developing HSP90 C‐terminal inhibitors in the future.