%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