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

Abstract

A novel method for caging protease inhibitors is described. The complex [RuII(bpy)2(1)2](PF6)2 (2) was prepared from the nitrile-based peptidomimetic inhibitor Ac-Phe-NHCH2CN (1). 1H NMR, UV-vis and IR spectroscopic and mass spectrometric data confirm that two equiv of inhibitor 1 bind to RuII 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. Due to binding to the RuII 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 that inhibits the cysteine proteases papain and cathepsins B, K and L, up to two times more potently than 1 alone. Ratios for IC50 values for 2 range from 6:1 to 33:1 under dark vs. light conditions, against isolated enzymes and in human cell lysates, confirming a high level of photoinduced enzyme inhibition is obtained with this method.

Ruthenium-based PACT compounds based on an N,S non-toxic ligand: a delicate balance between photoactivation and thermal stability

“…Thioethers are excellent ligands for ruthenium(II) due to their softness, which often leads to thermally stable complexes. In addition, many ruthenium complexes coordinated to thioethers show selective photosubstitution of the thioether ligand because these types of ligands become more weakly bound in the excited states than nitrogen-based ligands [11,12]. [Ru(bpy) 2 (mtmp)]Cl 2 and [Ru(Ph 2 phen) 2 (mtmp)]Cl 2 (Ph 2 phen = 4,7-diphenyl-1,10-phenantroline and mtmp = 2-methylthiomethyl pyridine), for example, efficiently photosubstitute the non-toxic N,S ligand mtmp in water [8].…”

Cytotoxicity of cyclometallated ruthenium complexes: the role of ligand exchange on the activity

“…The compounds cis-[Ru(bpy) 2 (NH 3 ) 2 ] 2+ (bpy = 2, 2 -bipyridine) [11], cis-[Ru(bpy) 2 (5-CNU) 2 ] 2+ (5-CNU = 5-cyanouracil) [12] and cis- [Ru(bpy) 2 (NC-peptide) 2 ] 2+ (NC-peptide = nitrile-terminated cysteine protease inhibitor) [13,14] have been shown to undergo ligand exchange with solvent water molecules upon irradiation. The initial photolysis in water produces the corresponding complex, [Ru(bpy) 2 2+ , with quantum yields, Φ, of 0.018 (λ irr = 400 nm) and 0.16 (λ irr ≥ 400 nm), respectively, followed by the formation of cis- [Ru(bpy) 2 (H 2 O) 2 ] 2+ with continued irradiation [11,12].…”

Photoacoustic calorimetry study of ligand photorelease from the Ru(II)bis(2,2′-bipyridine)(6,6′-dimethyl-2,2′-bipyridine) complex in aqueous solution

“…Fits of the data followed by scaling to ˚5 32 nm (0.19 ± 0.03) (Eqs. (4) and (5)) yielded H of 42 ± 4 kcal mol −1 and V of 6 ± 1 mL mol −1 . The photoinitiated ligand exchange mechanism associated with the [Ru(bpy) 2 (dmbpy)] 2+ complex has not been reported in detail.…”

“…Octahedral Ruthenium(II) complexes containing bidentate ligands display a rich photochemistry that has been exploited in applications ranging from solar cells to drug development [1][2][3][4][5][6][7]. In general, Ruthenium(II) coordination complexes containing Nheteroaromatic ligands (e.g., 2,2 -bipyridine (bpy)), exemplified by the Ru(II)tris(2,2 -bipyridine) ([Ru(bpy) 3 ] 2+ ) complex, exhibit excited state chemistry including ligand exchange with the bulk solvent which is of interest in the development of novel photorelease compounds for bioactive molecules [7].…”