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Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4

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journal contribution
posted on 10.06.2021, 20:36 authored by Nicholas Toupin, Sean J. Steinke, Sandeep Nadella, Ao Li, Thomas N. Rohrabaugh, Eric R. Samuels, Claudia Turro, Irina F. Sevrioukova, Jeremy J. Kodanko
We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru­(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru­(tpy)­(L)­(6)]­Cl2 (tpy = 2,2′:6′,2″-terpyridine) with L = 6,6′-dimethyl-2,2′-bipyridine (Me2bpy; 8), dimethylbenzo­[i]­dipyrido­[3,2-a:2′,3′-c]­phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo­[i]­dipyrido­[3,2-a:2′,3′-c]­phenazine (Me2Ph2dppn; 11), [Ru­(tpy)­(Me2bpy)­(4)]­Cl2 (7) and [Ru­(tpy)­(Me2dppn)­(4)]­Cl2 (9). Photochemical release of 4 or 6 from 711 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru­(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 911 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.