Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells
Fecha
2019Resumen
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 cisplatinsensitive
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.