Ligand Photosubstitution Reactions with Ruthenium Compounds

Hopkins, Samantha L.; Bonnet, Sylvestre

doi:10.1002/9783527695225.ch5

Cited by 2 publications

(2 citation statements)

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“…Next, we probed the impact of CYP3A4 inhibition in cellinduced toxicity with vinblastine. Complex 9 was compared side-by-side with the [Ru(tpy)(Me 2 dppn)(py)](PF 6 ) 2 complex (27), which generates 1 O 2 just as efficiently 69 but serves as a control by releasing pyridine rather than the CYP3A4 inhibitor 4. Experiments with 27 were important to carry out because prior studies demonstrated that PDT can work synergistically with microtubule-targeting drugs.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…With the potential benefits in mind, we identified photocaging as a viable strategy to achieve localized CYP inhibition. Photocaging is a powerful method for blocking the action of biologically active molecules and unleashing inhibitory compounds within desired tissues, through which highly controlled and localized CYP inhibition can be achieved. , Toward this goal, Ru(II)-based photocaging can facilitate small molecule release in a noninvasive manner to provide spatial and temporal control over biological activity. − Photocaging has been exploited in basic research and for drug activation during photochemotherapy (PCT), − with recent in vivo validation of Ru(II)-PCT . In addition to PCT, Ru(II) complexes show attractive properties for photodynamic therapy (PDT) applications, including high stability and cell permeability, , low inherent toxicity, − and higher light-to-dark ratios for cell death compared to clinically approved PDT compounds. , Due to their rich photochemistry and resistance to photobleaching, a common problem with current organic photosensitizers, ruthenium complexes are emerging as a promising new class of PDT agents, ,− some of which have advanced to clinical trials. − One recent example is the Ru(II) photosensitizer TLD-1433, which is currently in phase II clinical trials for the treatment of bladder cancer. − …”

Section: Introductionmentioning

confidence: 99%

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Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4

et al. 2021

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We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, 4 and 6: [Ru(tpy)(L)(6)]Cl2 (tpy = 2,2′:6′,2″-terpyridine) with L = 6,6′-dimethyl-2,2′-bipyridine (Me2bpy; 8), dimethylbenzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (Me2dppn; 10) and 3,6-dimethyl-10,15-diphenylbenzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (Me2Ph2dppn; 11), [Ru(tpy)(Me2bpy)(4)]Cl2 (7) and [Ru(tpy)(Me2dppn)(4)]Cl2 (9). Photochemical release of 4 or 6 from 7–11 was demonstrated, and the spectrophotometric evaluation of 7 showed that it behaves similarly to free 4 (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes 7 and 8 were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors 9–11 showed dual action properties by combining photoactivated dissociation of 4 or 6 with efficient 1O2 production. In prostate adenocarcinoma DU-145 cells, compound 9 had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 in vivo. Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

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Section: ■ Results and Discussionmentioning

confidence: 99%