Perestelo, Nayra R. Llanos, Gabriel G. Reyes, Carolina P. Amesty, Angel Sooda, Kartheek Afshinjavid, Saeed Jiménez, Ignacio A. Javid, Farideh Bazzocchi, Isabel L. 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 (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. reference drug;cell cycle analysis;carcinoma cisplatin-sensitive;carbonyl group;silico absorption;drug likeness;C -4;cell lines;analogues 22;cell cycle arrest;30 analogues;Human Ovarian Carcinoma Cells Ovarian cancer;nanomolar potency;selectivity index;Chemical Space;cytotoxic potency;IC 50;Cytotoxicity assays;WA framework;Incorporating Silicon;nontumoral cell line;excretion studies;cell death 2019-04-22
    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
10.1021/acs.jmedchem.9b00146.s001