jm9b00146_si_001.pdf (2.46 MB)
Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells
journal contribution
posted on 2019-04-22, 00:00 authored by Nayra
R. Perestelo, Gabriel G. Llanos, Carolina P. Reyes, Angel Amesty, Kartheek Sooda, Saeed Afshinjavid, Ignacio A. Jiménez, Farideh Javid, Isabel L. BazzocchiOvarian
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.
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reference drugcell cycle analysiscarcinoma cisplatin-sensitivecarbonyl groupsilico absorptiondrug likenessC -4cell linesanalogues 22cell cycle arrest30 analoguesHuman Ovarian Carcinoma Cells Ovarian cancernanomolar potencyselectivity indexChemical Spacecytotoxic potencyIC 50Cytotoxicity assaysWA frameworkIncorporating Siliconnontumoral cell lineexcretion studiescell death
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