Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells

Ovarian
cancer represents the seventh most commonly diagnosed cancer
worldwide. Herein, we report on the development of a withaferin A
(WA)-silyl ether library with 30 analogues reported for the first
time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive
and -resistant cell lines identified eight analogues displaying nanomolar
potency (IC50 ranging from 1 to 32 nM), higher than that
of the lead compound and reference drug. This cytotoxic potency is
also coupled with a good selectivity index on a nontumoral cell line.
Cell cycle analysis of two potent analogues revealed cell death by
apoptosis without indication of cell cycle arrest in G0/G1 phase.
The structure–activity relationship and in silico absorption,
distribution, metabolism, and excretion studies demonstrated that
the incorporation of silicon and a carbonyl group at C-4 in the WA
framework enhances potency, selectivity, and drug likeness. These
findings reveal analogues 22, 23, and 25 as potential candidates for clinical translation in patients
with relapsed ovarian cancer.