Cytochrome P450s (CYPs) are involved in steroid or retinoic acid metabolism, which can promote tumor development through hormonal control. CYPs inhibition is a relatively new strategy to prevent hormonal synthesis and thus it can be used to treat reproductive cancers. Abiraterone, a 17α-hydroxylase/ C17,20 lyase (CYP17A1) inhibitor, has been approved for the treatment of castration-resistant prostate cancer.<br/>Phototherapy utilizes the application of light to produce a cytotoxic species from a chemically inert compound. Ru(II) complexes have tunable photochemical properties allowing them to be suitable cages for organic drug molecules containing nitrogen heterocycles. Visible light irradiation causes the phototriggered release of these caged organic drug molecules and simultaneously creates a ligand-deficient metal center capable of damaging DNA and producing a cytotoxic response. The production of two distinct active species will result in a synergistic mechanism of cell death.<br/>We have developed a new class of supramolecular ruthenium-based “prodrugs” bearing P450 inhibitors (metyrapone, etomidate and 2-(1-Imidazolyl)-2-methyl-1-phenyl-2−1-propanone) that are inert until activated with visible light, providing localized toxicity.<br/>Additional chemical modifications to the Ru(II) “prodrugs” were made to reduce the binding affinity for the P450s in the absence of light as well as to improve DNA interactions following irradiation.<br/>

Ruthenium-caged P450 inhibitors for dual antitumor activity

251st National Meeting (2016)

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