title: Ruthenium(III) polyaminocarboxylate complexes: efficient and effective nitric oxide scavengers.
abstract: The preparation of two Ru(III) polyaminocarboxylate complexes, AMD6245 and AMD6221, and their nitrosyl analogues, AMD6204, AMD6263, and AMD3689, is described. The compounds are characterized by IR, ES-MS, and (13)C and (15)N NMR spectroscopy where appropriate and cyclic voltammetry. The crystal structures for AMD6245, AMD6263, and AMD3689 are presented. AMD6245 (C(10)H(14)N(2)O(9)Ru) crystallized in the P2(1)/c space group with a = 8.4382(2) A, b = 8.8304(2) A, c = 17.6321(4) A, beta = 99.603(o), V = 1295.3(2) A(3), and Z = 4. AMD6263 (C(10)H(14)N(3)O(10)Ru) crystallized in the P2(1)/c space group with a = 9.9043(4) A, b = 13.1144(3) A, c = 12.0914(4) A, beta = 100.191(o), V = 1545.8(5) A(3), and Z = 4. AMD3689 (C(14)H(24.56)N(4)O(13.28)Ru) crystallized in the P1 space group with a = 8.838(2) A, b = 9.452(3) A, c = 13.419(4) A, alpha = 78.413(6)(o), beta = 75.804(6)(o), gamma = 73.562(6)(o), V = 1031.8(5) A(3), and Z = 2. The reaction of AMD6245 and AMD6221 with nitric oxide is investigated using EPR spectroscopy and stopped flow kinetics. Upon reaction with NO, a linear, diamagnetic [RuNO](6) complex is formed. The substitution reaction of AMD6245 with NO proceeds with a second-order rate constant of 2.24 x 10(7) M(-1) s(-1) at 7.3 degrees C (pH = 7.4; 50 mM phosphate buffer). The substitution reaction of AMD6221 with NO proceeds with a second-order rate constant of 3 x 10(5) M(-1) s(-1) at 20 degrees C (pH = 7.4; 50 mM phosphate buffered saline). The NO scavenging ability was assessed using a RAW264 murine macrophage assay by measuring the difference in nitrite produced between untreated control cells and treated cells. At 100 microM AMD6245 has [NO(2-)] = 12.5 microM less than the untreated cells and AMD6221 has [NO(2-)] = 37.6 microM less than the untreated cells. There is an insignificant difference in the amount of nitrite produced between AMD6263 or AMD3689 treated cells and untreated cells.
authors.affiliation: AnorMED Inc., 200-20353 64th Avenue, Langley, BC, Canada V2Y 1N5. bcameron@anormed.com
authors.forename: Beth R
authors.initials: BR
authors.lastname: Cameron
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Darkes
authors.forename: Helen
authors.initials: H
authors.lastname: Yee
authors.forename: Micki
authors.initials: M
authors.lastname: Olsen
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Rose
authors.forename: Jon
authors.initials: J
authors.lastname: Zubieta
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*
chemical_list: C453459:AMD 6221; D009942:Organometallic Compounds; D009569:Nitric Oxide; D004369:Pentetic Acid; D012428:Ruthenium