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Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines

Horley, Neill J.; Beresford, Kenneth J.M.; Chawla, Tarun; McCann, Glen J.P.; Ruparelia, Ketan C.; Gatchie, Linda; Sonawane, Vinay R.; Williams, Ibidapo S.; Tan, Hoon L.; Joshi, Prashant; Bharate, Sonali S.; Kumar, Vikas; Bharate, Sandip B.; Chaudhuri, Bhabatosh

Authors

Neill J. Horley

Kenneth J.M. Beresford

Tarun Chawla

Glen J.P. McCann

Ketan C. Ruparelia

Linda Gatchie

Vinay R. Sonawane

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

Hoon L. Tan

Prashant Joshi

Sonali S. Bharate

Vikas Kumar

Sandip B. Bharate

Bhabatosh Chaudhuri



Abstract

© 2017 Elsevier Masson SAS The structure of alpha-napthoflavone (ANF), a potent inhibitor of CYP1A1 and CYP1B1, mimics the structure of chalcones. Two potent CYP1B1 inhibitors 7k (DMU2105) and 6j (DMU2139) have been identified from two series of synthetic pyridylchalcones. They inhibit human CYP1B1 enzyme bound to yeast-derived microsomes (Sacchrosomes™) with IC 50 values of 10 and 9nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC 50 values obtained with CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19 Sacchrosomes™. Both compounds also potently inhibit CYP1B1 expressed within ‘live’ recombinant yeast and human HEK293 kidney cells with IC 50 values of 63, 65, and 4, 4nM, respectively. Furthermore, the synthesized pyridylchalcones possess better solubility and lipophilicity values than ANF. Both compounds overcome cisplatin–resistance in HEK293 and A2780cells which results from CYP1B1 overexpression. These potent cell-permeable and water-soluble CYP1B1 inhibitors are likely to have useful roles in the treatment of cancer, glaucoma, ischemia and obesity.

Citation

Horley, N. J., Beresford, K. J., Chawla, T., McCann, G. J., Ruparelia, K. C., Gatchie, L., …Chaudhuri, B. (2017). Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines. European Journal of Medicinal Chemistry, 129, 159-174. https://doi.org/10.1016/j.ejmech.2017.02.016

Journal Article Type Article
Acceptance Date Feb 7, 2017
Online Publication Date Feb 9, 2017
Publication Date Jan 1, 2017
Deposit Date May 9, 2018
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 129
Pages 159-174
DOI https://doi.org/10.1016/j.ejmech.2017.02.016
Keywords pyridylchalcones, cisplatin-resistance, CYP1B1 inhibitors, live CYP1B1-expressing human cells, live CYP1B1-Expressing yeast cells, sacchrosomes™
Public URL https://uwe-repository.worktribe.com/output/890369
Publisher URL http://dx.doi.org/10.1016/j.ejmech.2017.02.016
Related Public URLs https://doi.org/10.1016/j.ejmech.2017.02.016