%0 Journal Article %A Perestelo, Nayra R. %A Llanos, Gabriel G. %A Reyes, Carolina P. %A Amesty, Angel %A Sooda, Kartheek %A Afshinjavid, Saeed %A Jiménez, Ignacio A. %A Javid, Farideh %A Bazzocchi, Isabel L. %D 2019 %T Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells %U https://acs.figshare.com/articles/journal_contribution/Expanding_the_Chemical_Space_of_Withaferin_A_by_Incorporating_Silicon_To_Improve_Its_Clinical_Potential_on_Human_Ovarian_Carcinoma_Cells/8063582 %R 10.1021/acs.jmedchem.9b00146.s001 %2 https://acs.figshare.com/ndownloader/files/15026129 %K reference drug %K cell cycle analysis %K carcinoma cisplatin-sensitive %K carbonyl group %K silico absorption %K drug likeness %K C -4 %K cell lines %K analogues 22 %K cell cycle arrest %K 30 analogues %K Human Ovarian Carcinoma Cells Ovarian cancer %K nanomolar potency %K selectivity index %K Chemical Space %K cytotoxic potency %K IC 50 %K Cytotoxicity assays %K WA framework %K Incorporating Silicon %K nontumoral cell line %K excretion studies %K cell death %X 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. %I ACS Publications