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

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.

• 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
• Contract Date: May 9, 2018