Synthesis and biological evaluation of new ergosterol pyridine derivatives as potential anticancer agents.

A series of novel ergosterol pyridine derivatives were synthesized via a three-component reaction and their antiproliferative activity was preliminarily evaluated against two human cancer cell lines. Structure-activity relationship (SAR) studies revealed that the pyridine ring is more favorable than the phenyl ring for enhancing biological activity. Among them, Compound 5 g displayed the most potent antiproliferative activity against MDA-MB-231 cells (IC50 = 9.28 μM), surpassing that of ergosterol (IC50 > 32 μM). Further mechanistic studies revealed that compound 5 g inhibited colony formation without altering intracellular Ca2+ levels. Molecular docking and molecular dynamics simulations revealed that compound 5 g likely binds to ACSL1, a target of ergosterol, primarily through a key hydrogen bond with GLN-155.These results suggest that compound 5 g has potential for further modification and development.