Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells PeresteloNayra R. LlanosGabriel G. ReyesCarolina P. AmestyAngel SoodaKartheek AfshinjavidSaeed JiménezIgnacio A. JavidFarideh BazzocchiIsabel L. 2019 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 (IC<sub>50</sub> 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 <b>22</b>, <b>23</b>, and <b>25</b> as potential candidates for clinical translation in patients with relapsed ovarian cancer.