Validation of Ru(II)‐caged Abiraterone as a Chemical Tool for Controlling CYP17A1 Activity with Visible Light

Abstract

Cytochromes P450 (CYP) enzymes are ubiquitous heme‐containing proteins catalyzing numerous and varied biosynthetic and detoxification transformations in biological systems. Potent and selective inhibitors have been aggressively pursued as chemical tools, drugs, and insecticides, but lack spatial and temporal control over CYP inhibition in vitro and in vivo. Metal‐caged versions of such inhibitors with photoactivated release can allow researchers to interrogate biological systems spatiotemporally. Here, a novel Ru(II)‐caged complex was designed and synthesized with the CYP17A1 inhibitor abiraterone, a prostate cancer drug. While the intact caged complex is non‐toxic and exceptionally stable in the dark, upon irradiation with low energy visible light abiraterone is rapidly released. In the dark the Ru(II) caged abiraterone does not bind to CYP17A1, but light exposure results in the released abiraterone binding to CYP17A1. This binding is observed as a type II shift consistent with the inhibitor nitrogen coordinating to the CYP17A1 heme iron with a high affinity, similar to abiraterone itself. Additionally, dark Ru(II)‐abiraterone is nontoxic to DU145 human prostate cancer cells, but light‐exposed Ru(II)‐abiraterone and abiraterone resulted in similar toxicity. Overall, this demonstrates that metal‐caged inhibitors can be designed with ideal properties as potent and selective chemical tools controlled by visible light in a biological setting.Support or Funding InformationNIH (EB 016072) and NSF (CHE1212281)