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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.

Authors

Naresh K. Satti

Ibidapo Williams Ibidapo.Williams@uwe.ac.uk
Research Fellow- Cell Cultural Monitoring Technology

Prashant Joshi

Linda Gatchie

Mohit Sharma

Ram A. Vishwakarma

Bhabatosh Chaudhuri

Sandip B. Bharate



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