The Hydrolysis Mechanism of the Anticancer Ruthenium Drugs NAMI-A and ICR Investigated by DFT−PCM Calculations

Abstract

(ImH)[trans-RuCl(4)(DMSO-S)(Im)], (Im = imidazole, DMSO-S = S-bonded dimethylsulfoxide), NAMI-A, is the first anticancer ruthenium compound that successfully completed Phase I clinical trials. NAMI-A shows a remarkable activity against lung metastases of solid tumors, but is not effective in the reduction of primary cancer. The structurally similar (ImH)[trans-RuCl(4)(Im)(2)], ICR (or KP418), and its indazole analog (KP1019) are promising candidate drugs in the treatment of colorectal cancers, but have no antimetastatic activity. Despite the pharmacological relevance of these compounds, no rationale has been furnished to explain their markedly different activity. While the nature of the chemical species responsible for their antimetastatic/anticancer activity has not been determined, it has been suggested that the difference between reduction potentials of NAMI-A and ICR may be the key to the different biological responses they induce. In this work, Density Functional Theory calculations were performed to investigate the hydrolysis of NAMI-A and ICR in both Ru(III) and Ru(II) oxidation states, up to the third aquation. In line with experimental findings, our calculations provide a picture of the hydrolysis of NAMI-A and ICR mainly as a stepwise loss of chloride ligands. While dissociation of Im is unlikely under neutral conditions, that of DMSO becomes competitive with the loss of chloride ions as the hydrolysis proceeds. Redox properties of NAMI-A and ICR and of their most relevant hydrolytic intermediates were also studied in order to monitor the effects of biological reductants on the mechanism of action. Our findings may contribute to the identification of the active compounds that interact with biological targets, and to explain the different biological activity of NAMI-A and ICR.

Control of ligand-exchange processes and the oxidation state of the antimetastatic Ru(iii) complex NAMI-A by interactions with human serum albumin

“…These calculations are limited by the accuracy of solvent models, but specific studies of chloride ligand exchange have provided rate calculations in reasonable agreement with experimental reports. 41, 43 In the most recent of these studies, Vargiu et al 42 report that the activation free energy of Cl -dissociation from NAMI-A in water is larger than that of DMSO, consistent with our observation that the latter is replaced more rapidly under physiological conditions.…”

The interaction of native calf thymus DNA with FeIII-dipyrido[3,2-a:2′,3′-c]phenazine

“…On the other hand, (ImH)[trans-RuCl 4 (DMSO-S)(Im)] (known as Ru-NAMI-A) has successfully completed Phase I clinical trials as anticancer agent [16] and, interestingly, it has been recently inferred that its hydrolysis is a crucial step for the mechanism of its anticancer activity [17]. Finally, ruthenium complexes have been extensively studied also because of their ability of mimicking the binding of iron to molecules of biological significance, to exploit in such a way the mechanisms that the body has evolved for the transport of iron [18].…”

Review on supermolecules as chemical drugs

“…Supermolecule 32b was octahedral complex, displayed significant inhibition of solid tumor metastasis, and no activity at the reduction of primary tumor [88] . However, complex 32b could induce apoptosis on var human epithelium ECV304 [89] .…”