Light Activation of a Cysteine Protease Inhibitor: Caging of a Peptidomimetic Nitrile with RuII(bpy)2

A novel method for caging protease inhibitors is described. The complex [Ru-II(bpy)(2)(1)(2)](PF6)(2) (2) was prepared from the nitrile-based peptidomimetic inhibitor Ac-Phe-NHCH2CN (1). H-1 NMR, UV-vis, and IR spectroscopic and mass spectrometric data confirmed that 2 equiv of inhibitor 1 bind to Ru-II through the nitrile functional group. Complex 2 shows excellent stability in aqueous solution in the dark and fast release of 1 upon irradiation with visible light. As a result of binding to the Ru-II center, the nitriles of complex 2 are caged, and 2 does not act as a potent enzyme inhibitor. However, when 2 is irradiated, it releases 1, which inhibits the cysteine proteases papain and cathepsins B, K and L up to 2 times more potently than 1 alone. Ratios of the IC50 values in the dark versus in the light ranged from 6:1 to 33:1 for inhibition by 2 against isolated enzymes and in human cell lysates, confirming that a high level of photoinduced enzyme inhibition can be obtained using this method.