Electronic structure and mechanism for the uptake of nitric oxide by the Ru(iii) antitumor complex NAMI-A

Nitric oxide (NO) has well known vasodilation effects in living organisms and its participation in the metastasis of cancer cells through the angiogenesis process has been demonstrated experimentally. Therefore, the uptake of NO has become one focus of investigation to produce anti-metastatic drugs. In this article we have investigated the uptake of NO by the ruthenium based metallodrug trans-tetrachloride(dimethylsulfoxide)imidazole ruthenate(iii) [Im]trans-[RuCl₄(Im)(DMSO)], known as New Anti-tumor Metastasis Inhibitor-A (NAMI-A). Electronic structure calculations using Density Functional Theory, DFT, and State-Averaged Complete Active Space Self Consistent Field, SA-CASSCF, with second order perturbation theory corrections, NEVPT2 were carried out to investigate the mechanism involved in the uptake of NO by the Ru-based anticancer metallodrug NAMI-A. The calculations revealed that the reaction takes place at the triplet potential energy surface, with the singlet surface being ∼15 kcal mol^-1 shifted to higher energies, and there is a surface crossing to form the most stable singlet product after the reaction takes place at the triplet surface. The spin pairing and electron transfer from the nitric oxide to the metallic fragment takes place at the region of the minimum energy crossing point between the two surfaces. The Ru-NO bond in the {Ru-NO}⁶ product has ∼10% of the Ru^III-NO⁰ character. The SA-CASSCF/NEVPT2 calculations revealed that the uptake of NO by NAMI-A has a small energy barrier of ∼8 kcal mol^-1 and, therefore a rate constant of 11.3 × 10⁶ s^-1 at 300 K. In addition, the reaction is thermodynamically favorable, with a Gibbs free energy of ∼30 kcal mol^-1. These results show that the uptake of nitric oxide by the NAMI-A complex is kinetically and thermodynamically feasible in biological medium and, therefore, gives support to the anti-angiogenesis theory associated to the mode of action of NAMI-A and other related compounds.