Ruthenium(III) polyaminocarboxylate complexes: efficient and effective nitric oxide scavengers.
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.
Cameron
Beth R
BR
AnorMED Inc., 200-20353 64th Avenue, Langley, BC, Canada V2Y 1N5. bcameron@anormed.com
Darkes
Marilyn C
MC
Yee
Helen
H
Olsen
Micki
M
Fricker
Simon P
SP
Skerlj
Renato T
RT
Bridger
Gary J
GJ
Davies
Nathan A
NA
Wilson
Michael T
MT
Rose
David J
DJ
Zubieta
Jon
J
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*
C453459:AMD 6221; D009942:Organometallic Compounds; D009569:Nitric Oxide; D004369:Pentetic Acid; D012428:Ruthenium