Mixed Ru(II)–Ir(III) Complexes as Photoactive\nInhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4

Cytochrome\nP450 3A4 (CYP3A4) is a crucial enzyme in human drug\nmetabolism. To garner photochemical control over the inhibition of\nCYP3A4, a potent Ir(III)-based inhibitor of CYP3A4 was complexed with\ntwo Ru(II)-based photocaging groups. Chemical, photochemical, and\nbiological properties of the photocaged inhibitors were characterized.\nImportantly, mixed Ru(II)–Ir(III) complexes strongly absorb\ngreen light, which facilitates the photochemical release of the Ir(III)\ninhibitor from the Ru(II) caging fragment [Ru(tpy)(Me<sub>2</sub>bpy)]<sup>2+</sup>, where tpy = 2,2′:6′,2″-terpyridine\nand Me<sub>2</sub>bpy = 6,6′-dimethyl-2,2′-bipyridine.\nEmission turn on, type II heme binding, and more potent inhibition\nunder light vs dark conditions were observed. The study also demonstrated\nthat a Ru(II)–Ir(III) conjugate can be photoactivated to exert\ncytotoxic effects on MCF-7 breast cancer cells upon green light exposure.\nAdditionally, a synthesized analogue with one [Ru(TPA)]<sup>2+</sup> fragment (TPA = tris(pyridin-2-ylmethyl)amine) and two Ir(III) centers,\nalthough resistant to photochemical release, showed strong inhibition\nof CYP3A4 both in purified form and in CYP3A4-overexpressing HepG2\ncells, with nanomolar potency. These mixed Ru(II)–Ir(III) compounds\ncan permeate cell membranes and inhibit CYP3A4, presenting a new class\nof bioactive compounds.