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

Year: 2024

Type: article

Abstract: 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)(Me 2 bpy)] 2+, where tpy = 2,2′:6′,2″-terpyridine and Me 2 bpy = 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.

Source: Inorganic Chemistry

DOI: 10.1021/acs.inorgchem.4c02633