Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance

Satti, Naresh K.; Williams, Ibidapo S.; Joshi, Prashant; Gatchie, Linda; Sharma, Mohit; Vishwakarma, Ram A.; Chaudhuri, Bhabatosh; Bharate, Sandip B.

Abstract

© 2017 Elsevier Ltd Inhibitors of CYP1 enzymes may play vital roles in the prevention of cancer and overcoming chemo-resistance to anticancer drugs. In this letter, we report synthesis of twenty-three pyrrole based heterocyclic chalcones which were screened for inhibition of CYP1 isoforms. Compound 3n potently inhibited CYP1B1 with an IC50 of ∼0.2μM in Sacchrosomes™ and CYP1B1-expressing live human cells. However, compound 3j which inhibited both CYP1A1 and CYP1B1 with an IC50 of ∼0.9µM, using the same systems, also potently antagonized B[a]P-mediated induction of AhR signaling in yeast (IC50, 1.5µM), fully protected human cells from B[a]P toxicity and completely reversed cisplatin resistance in human cells that overexpress CYP1B1 by restoring cisplatin's cytotoxicity. Molecular modeling studies were performed to rationalize the observed potency and selectivity of enzyme inhibition by compounds 3j and 3n.

Citation

Satti, N. K., Williams, I. S., Joshi, P., Gatchie, L., Sharma, M., Vishwakarma, R. A., …Bharate, S. B. (2017). Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance. Bioorganic and Medicinal Chemistry Letters, 27(16), 3683-3687. https://doi.org/10.1016/j.bmcl.2017.07.010

• Journal Article Type: Article
• Acceptance Date: Jul 3, 2017
• Online Publication Date: Jul 4, 2017
• Publication Date: Jan 1, 2017
• Journal: Bioorganic and Medicinal Chemistry Letters
• Print ISSN: 0960-894X
• Electronic ISSN: 1464-3405
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 16
• Pages: 3683-3687
• DOI: https://doi.org/10.1016/j.bmcl.2017.07.010
• Keywords: heterocyclic chalcones, AhR antagonism, CYP1A1, chemoprevention, CYP1B1, cisplatin chemo-resistance
• Public URL: https://uwe-repository.worktribe.com/output/882944
• Publisher URL: http://dx.doi.org/10.1016/j.bmcl.2017.07.010
• Related Public URLs: http://dx.doi.org/10.1016/j.bmcl.2017.07.010