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

Autor: Horley NJ; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Beresford KJ; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Chawla T; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., McCann GJ; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Ruparelia KC; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Gatchie L; CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK., Sonawane VR; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Williams IS; CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK., Tan HL; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK., Joshi P; Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India., Bharate SS; Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India., Kumar V; Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India., Bharate SB; Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India. Electronic address: sbharate@iiim.ac.in., Chaudhuri B; Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK; CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK. Electronic address: bchaudhuri@dmu.ac.uk.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2017 Mar 31; Vol. 129, pp. 159-174. Date of Electronic Publication: 2017 Feb 09.
DOI: 10.1016/j.ejmech.2017.02.016
Abstrakt: 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 9 nM, 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, 4 nM, respectively. Furthermore, the synthesized pyridylchalcones possess better solubility and lipophilicity values than ANF. Both compounds overcome cisplatin-resistance in HEK293 and A2780 cells 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.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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