title: Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines.
abstract: 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 IC50values of 10 and 9 nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC50values 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 IC50values 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.
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Neill J
authors.initials: NJ
authors.lastname: Horley
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Kenneth J M
authors.initials: KJ
authors.lastname: Beresford
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Tarun
authors.initials: T
authors.lastname: Chawla
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Glen J P
authors.initials: GJ
authors.lastname: McCann
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Ketan C
authors.initials: KC
authors.lastname: Ruparelia
authors.affiliation: CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Gatchie
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Vinay R
authors.initials: VR
authors.lastname: Sonawane
authors.affiliation: CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK.
authors.forename: Ibidapo S
authors.initials: IS
authors.lastname: Williams
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester LE1 7RH, UK.
authors.forename: Hoon L
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India.
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.affiliation: Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India. Electronic address: sbharate@iiim.ac.in.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.affiliation: 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.
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D047188:Chalcones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D057809:HEK293 Cells; D006571:Heterocyclic Compounds; D006801:Humans
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D002945:Cisplatin
keywords: CYP1B1 inhibitors; Cisplatin-resistance; Live CYP1B1-Expressing human cells; Live CYP1B1-Expressing yeast cells; Pyridylchalcones; Sacchrosomes™