title: 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 [Ru(II)(bpy)(2)(1)(2)](PF(6))(2) (2) was prepared from the nitrile-based peptidomimetic inhibitor Ac-Phe-NHCH(2)CN (1). (1)H 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 IC(50) 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.
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Respondek
authors.forename: Robert N
authors.initials: RN
authors.lastname: Garner
authors.forename: Mackenzie K
authors.initials: MK
authors.lastname: Herroon
authors.forename: Izabela
authors.initials: I
authors.lastname: Podgorski
authors.forename: Claudia
authors.initials: C
authors.lastname: Turro
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Kodanko
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry*; D057056:Cysteine Proteases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D008027:Light; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D057786:Peptidomimetics; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009570:Nitriles; D009942:Organometallic Compounds; D057786:Peptidomimetics; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D057056:Cysteine Proteases