Synthesis of C3'-Foused Aryl/Penta-1,4-dien-3-one/Amine Hybrids as HSP90 C-Terminal Inhibitors.
Chem Biodivers
; : e202400870, 2024 Jun 06.
Article
in En
| MEDLINE
| ID: mdl-38842484
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Chem Biodivers
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
China