Expanding the Chemical Space of Withaferin A by Incorporating Silicon to Improve its Clinical Potential on Human Ovarian Carcinoma Cells

Nayra R. Perestelo, Gabriel G. LLanos, Carolina P. Reyes, Angel Amesty, Kartheek Sooda, Saeed Afshinjavid, Ignacio A. Jiménez, Farideh Javid, Isabel L. Bazzocchi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 50 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.

LanguageEnglish
Pages4571-4585
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
Early online date22 Apr 2019
DOIs
Publication statusPublished - 9 May 2019

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Silicon
Ovarian Neoplasms
Carcinoma
Cell Line
Cell Cycle Resting Phase
G1 Phase
Structure-Activity Relationship
Cell Cycle Checkpoints
Pharmaceutical Preparations
Computer Simulation
Ether
Cisplatin
Cell Cycle
Cell Death
Apoptosis
Neoplasms
withaferin A
Lead

Cite this

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. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 9. pp. 4571-4585.
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abstract = "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 50 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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Perestelo, NR, LLanos, GG, Reyes, CP, Amesty, A, Sooda, K, Afshinjavid, S, Jiménez, IA, Javid, F & Bazzocchi, IL 2019, 'Expanding the Chemical Space of Withaferin A by Incorporating Silicon to Improve its Clinical Potential on Human Ovarian Carcinoma Cells', Journal of Medicinal Chemistry, vol. 62, no. 9, pp. 4571-4585. https://doi.org/10.1021/acs.jmedchem.9b00146

Expanding the Chemical Space of Withaferin A by Incorporating Silicon to Improve its Clinical Potential on Human Ovarian Carcinoma Cells. / Perestelo, Nayra R.; LLanos, Gabriel G.; Reyes, Carolina P.; Amesty, Angel; Sooda, Kartheek; Afshinjavid, Saeed; Jiménez, Ignacio A.; Javid, Farideh; Bazzocchi, Isabel L.

In: Journal of Medicinal Chemistry, Vol. 62, No. 9, 09.05.2019, p. 4571-4585.

Research output: Contribution to journalArticle

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