Design, synthesis, and biological evaluation of estratriene-based hydroxamic acid derivatives as histone deacetylase...

A series of estratriene-based hydroxamic acid derivatives were rationally designed as histone deacetylase (HDAC) inhibitors, utilizing estrone and estradiol scaffolds with hydroxamic acid groups attached at the 3-position via alkoxy linkers of varying chain lengths. Structure-activity relationship studies indicated that compounds with n = 4 exhibited optimal activity. The lead compounds CFT-2b and CEC-2b showed potent antiproliferative effects against HeLa and SKOV-3 cells (IC₅₀, 6.09-8.36 μM) and favorable selectivity indices (8.5 to >13.1 versus 293 T cells). Notably, several compounds showed superior HDAC inhibitory activity compared to SAHA. Mechanistic studies showed that CFT-2b and CEC-2b induced dose-dependent apoptosis, caused G1-phase cell-cycle arrest, and significantly increased acetylated histone H3 levels in HeLa cells, consistent with intracellular HDAC inhibition. Molecular docking supported favorable binding within the HDAC2 and HDAC6 active sites via zinc chelation and proper cap-group positioning. These findings establish estratriene-based hydroxamic acids as promising HDAC inhibitor scaffolds for cancer therapy development.