Ru^III complexes of edta and dtpa polyaminocarboxylate analogues and their use as nitric oxide scavengers

In this study a series of Ru^III complexes, chelated by analogues of ethylenediaminetetraacetic acid (edta) and diethylenetriaminepentaacetic acid (dtpa), were produced and tested for NO scavenging ability. Modifications to the edta and dtpa ligand frameworks were made in an effort to alter the reactivity, aqueous stability and pharmacokinetics of the resulting Ru ^III complexes. The X-ray structure of the nitrosyl complex 38 confirms that the Ru^III complex 27 reacts with NO to form a linear {Ru-NO}^[6] complex. The nitrosyl complex [C₁₅H ₁₅N₄O₁₁Ru] crystallized in the P2₁/c space group with a = 12.731(3) Å, b = 10.894(2) Å, c = 14.241 (3) Å, β= 107.320(4)°, V = 1885.6(7) ų, and Z = 4. Kinetic studies on the reactions of 14 (k = 2.38 × 10⁶ M ^-1 s^-1) and 27 (k = 2.30 × 10⁵ M ^-1 s^-1) with NO exemplify the difference in chemical properties obtained by ligand framework manipulation. Binding constants of 14 (K_B = 5×10⁶ M^-1) and 27 (K_B = 2 × 10⁵ M^-1) with NO were also measured, indicating the tight binding of NO by the Ru^III complexes. The activity of the Ru^III complexes to scavenge nitric oxide was evaluated using RAW264 murine macrophage cells. Ligand analogues of edta that have a pyridine donor as part of the N,N chelate such as 20 and 24 exhibit similar scavenging activity to the parent compound. Ligand analogues of dtpa that have R groups at the central amine in place of the carboxylic acid such as 31, 34, and 37 are also efficient NO scavengers.