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

Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme in human drug metabolism. To garner photochemical control over the inhibition of CYP3A4, a potent Ir­(III)-based inhibitor of CYP3A4 was complexed with two Ru­(II)-based photocaging groups. Chemical, photochemical, and biological properties of the photocaged inhibitors were characterized. Importantly, mixed Ru­(II)–Ir­(III) complexes strongly absorb green light, which facilitates the photochemical release of the Ir­(III) inhibitor from the Ru­(II) caging fragment [Ru­(tpy)­(Me2bpy)]2+, where tpy = 2,2′:6′,2″-terpyridine and Me2bpy = 6,6′-dimethyl-2,2′-bipyridine. Emission turn on, type II heme binding, and more potent inhibition under light vs dark conditions were observed. The study also demonstrated that a Ru­(II)–Ir­(III) conjugate can be photoactivated to exert cytotoxic effects on MCF-7 breast cancer cells upon green light exposure. Additionally, a synthesized analogue with one [Ru­(TPA)]2+ fragment (TPA = tris­(pyridin-2-ylmethyl)­amine) and two Ir­(III) centers, although resistant to photochemical release, showed strong inhibition of CYP3A4 both in purified form and in CYP3A4-overexpressing HepG2 cells, with nanomolar potency. These mixed Ru­(II)–Ir­(III) compounds can permeate cell membranes and inhibit CYP3A4, presenting a new class of bioactive compounds.