title: Biphenyl urea derivatives as selective CYP1B1 inhibitors.
abstract: Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes. The most active human CYP1B1 inhibitors were further studied for their selectivity against human CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. The meta-chloro-substituted biphenyl urea 5h was the most potent inhibitor of CYP1B1 with IC50value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC50>10 μM in the four CYP assays, indicating >2000-fold selectivity). Similarly, two methoxy-substituted biphenyl ureas 5d and 5e also displayed potent and selective inhibition of CYP1B1 with IC50values of 69 and 58 nM, respectively, showing >62 and >98-fold selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. In order to probe if the relatively insoluble biphenyl ureas were cell permeable and if they could at all be used for future cellular studies, their CYP1B1 inhibition was investigated in live recombinant human and yeast cells. Compound 5d displayed the most potent inhibition with IC50s of 20 nM and 235 nM, respectively, in the two cell-based assays. The most potent and selective CYP1B1 inhibitor (compound 5h) from Sacchrosomes, also displayed potent inhibition in live cell assays. Molecular modeling was performed to understand the trends in potency and selectivity observed in the panel of five CYP isoenzymes used for the in vitro studies.
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. bchaudhuri@dmu.ac.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. bchaudhuri@dmu.ac.uk.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sonawane
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK. bchaudhuri@dmu.ac.uk.
authors.forename: Neill
authors.initials: N
authors.lastname: Horley
authors.affiliation: Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK. bchaudhuri@dmu.ac.uk and CYP Design Limited, Innovation Centre, 49 Oxford Street, Leicester, LE1 5XY, UK.
authors.forename: Ibidapo Steven
authors.initials: IS
authors.lastname: Williams
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. sbharate@iiim.ac.in.
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. 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. bchaudhuri@dmu.ac.uk and CYP Design Limited, Innovation Centre, 49 Oxford Street, Leicester, LE1 5XY, UK.
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D065633:Cytochrome P-450 CYP1B1; D029701:Saccharomyces cerevisiae Proteins; D014508:Urea; C010574:biphenyl; C585496:CYP1B1 protein, human