Reactions of Potent Antitumor Complextrans-[Ru^IIICl₄(indazole)₂]^-with a DNA-Relevant Nucleobase and Thioethers:  Insight into Biological Action

Abstract

Reactions of the complex trans-[RuCl(4)(Hind)(2)](-) (Hind = indazole), which is of clinical relevance today, with both the DNA model nucleobase 9-methyladenine (made) and the thioethers R(2)S (R = Me, Et), as models of the methionine residue in biological molecules possibly acting as nitrogen-competing sulfur-donor ligands for ruthenium atom, have been investigated to get insight into details of mechanism leading to antitumor activity. Three novel ruthenium complexes, viz., [Ru(III)Cl(3)(Hind)(2)(made)], 1, [Ru(II)Cl(2)(Hind)(2)(Me(2)S)(2)], 2, and [Ru(II)Cl(2)(Hind)(2)(Et(2)S)(2)], 3, have been isolated as solids. Oxidation of 2 and 3 with hydrogen peroxide in the presence of 12 M HCl in chloroform afforded the monothioether adducts, viz., [Ru(III)Cl(3)(Hind)(2)(Me(2)S)], 4, and [Ru(III)Cl(3)(Hind)(2)(Et(2)S)], 5. By dissolution of 2 or 3 in DMSO, replacement of both R(2)S ligands by DMSO molecules occurred with isolation of trans,trans,trans-[Ru(II)Cl(2)(Hind)(2)(DMSO)(2)], 6. The products were characterized by elemental analysis, IR, UV-vis, electrospray mass spectrometry, cyclic voltammetry, and X-ray crystallography (1.CH(2)Cl(2).CH(3)OH and 1.1.1H(2)O.0.9CH(3)OH, 2, and 5). The first crystallographic evidence for the monofunctional coordination of the 9-methyladenine ligand to ruthenium via N7 and the self-pairing of the complex molecules via H-bonding, using the usual Watson-Crick pairing donor and acceptor sites of two adjacent 9-methyladenine ligands, is reported. The electrochemical behavior of 1-5 has been studied in DMF and DMSO by cyclic voltammetry. The redox potential values have been interpreted on the basis of the Lever's parametrization method. The E(L) parameter was estimated for 9-methyladenine at 0.18 V, showing that this ligand behaves as a weaker net electron donor than imidazole (E(L) = 0.12 V). The kinetics of the reductively induced stepwise replacement of chlorides by DMF in 4 and 5 were studied by digital simulation of the cyclic voltammograms. The rate constant k(1) has been determined as 0.9 +/- 0.1 s(-)(1), which obeys the first-order rate law, while k(2) is concentration dependent (0.2 +/- 0.1 M(1)(-)(n)().s(-)(1) with n > 1 for 4 mM solutions of 4 and 5), indicating higher-order reactions mechanism.

In Vitro Anticancer Activity and Biologically Relevant Metabolization of Organometallic Ruthenium Complexes with Carbohydrate‐Based Ligands

“…Moreover, the formation of aqua species plays a critical role in the mode of action of metal-based drugs with respect to drug activation by facilitating the reaction of the complex with the biomolecular target. [15,38,39] Hydrolysis of 1 was studied by 31 …”

Studies on the reactivity of organometallic Ru–, Rh– and Os–pta complexes with DNA model compounds

“…For platinum compounds, the binding to DNA is thought to be the most important event leading to inhibition of transcription and replication, and ultimately cell death. Ru(III) complexes [25][26][27] and organometallic Ru(II) compounds with intercalating or other simple ligands were shown by NMR to be capable of forming covalent bonds with DNA and DNA model compounds [28][29][30][31][32][33], as are (Cp * )Rh derivatives [34][35][36][37][38]. 1 H NMR spectroscopy was shown to be a useful tool for studying the reaction of such compounds with single nucleosides or purine bases.…”

CZE–ICP-MS as a tool for studying the hydrolysis of ruthenium anticancer drug candidates and their reactivity towards the DNA model compound dGMP

“…The binding of novel anticancer drugs towards nucleotides, utilized as model systems for indicating the affinity of a compound to bind to DNA, has been studied by means of capillary electrophoresis [34][35][36] and other methods [28,[37][38][39][40]. The interaction of metal complexes with dGMP is of particular interest since the N7 position has been identified as the primary binding site for cisplatin [8] and is therefore considered a possible target for other metallodrugs.…”