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 IC value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC >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 IC values 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 ICs 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.

Biotransformation of Chrysin to Baicalein: Selective C6-Hydroxylation of 5,7-Dihydroxyflavone Using Whole Yeast Cells Stably Expressing Human CYP1A1 Enzyme

“…Microsomal CYP enzymes, isolated from these same recombinant yeast cells, have successfully been used by us earlier as drug discovery tools for screening synthetic compounds and natural product repositories to identify possible cancer chemopreventive agents. [37][38][39] Selection of CYPs for biotransformation of chrysin. In this work, use of recombinant CYPexpressing whole yeast cells has been explored for their ability to be used as biocatalysts for biotransformation reactions.…”

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

“…17β‐estradiol is metabolized by CYP1‐mediated hydroxylation, which is its first and major step in the metabolic process in human breast tumors (Figure a). Due to the importance of this pathway in prevention and treatment of human breast cancer, the inhibitory effect of CYP1B1 by exogenous compounds, including flavonoids, has received considerable attention in the past few years (Androutsopoulos et al, ; Cui et al, ; Mohd Siddique et al, ; Siddique et al, ; Takemura, Itoh, et al, ). The present study, with combining results from enzymatic, computational, and cellular studies, demonstrated that oroxylin A exhibited a more significant inhibitory effect than baicalein on the carcinogenic 4‐OHE2 formation from 17β‐estradiol mediated by CYP1B1 in MCF‐7 cells.…”

Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions

“…Compounds TKR01-TKR21 were synthesised as described methods in previous literatures (all the 1H NMR Spectra of Compounds TKR01-21 in Supporting Information) [17][18][19][20][21][22] .…”