title: Quinazoline derivatives as selective CYP1B1 inhibitors.
abstract: CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells.
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India.
authors.forename: Mohd Usman
authors.initials: MU
authors.lastname: Mohd Siddique
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
authors.forename: Glen J P
authors.initials: GJ
authors.lastname: McCann
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
authors.forename: Vinay R
authors.initials: VR
authors.lastname: Sonawane
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
authors.forename: Neill
authors.initials: N
authors.lastname: Horley
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK; CYP Design Limited, Innovation Centre, 49 Oxford Street, Leicester, LE1 5XY, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Gatchie
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India. Electronic address: sbharate@iiim.ac.in.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India.
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Jayaprakash
authors.affiliation: Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India.
authors.forename: Barij N
authors.initials: BN
authors.lastname: Sinha
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK; CYP Design Limited, 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: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors*; D000072467:Cytochrome P450 Family 2 / Q000187:drug effects; D000072469:Cytochrome P450 Family 3 / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008958:Models, Molecular; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015003:Yeasts / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000072467:Cytochrome P450 Family 2; D000072469:Cytochrome P450 Family 3
keywords: CYP1B1; Cancer chemoprevention; Quinazoline; Sacchrosomes; Selective CYP1B1 inhibitor