NO Releasing and Anticancer Properties of Octahedral Ruthenium-Nitrosyl Complexes with Equatorial 1 H-Indazole Ligands.

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)(NO)]Cl·HO ([3]Cl·HO) and trans-[RuOH(Hind)(NO)]Cl·HO ([4]Cl·HO), have been prepared from trans-[Ru(NO)(Hind)] ([2]). When the pH-dependent solution behavior of [3]Cl·HO and [4]Cl·HO was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)(Hind)(NO)] ([5]) and [RuOH(ind)(Hind)(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, H NMR) techniques. Compound [2], as well as [3]Cl·2(CH)CO, [4]Cl·2(CH)CO, and [5]·0.8CHCl, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl and [4]Cl was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl and [4]Cl showed considerable antiproliferative activity in human cancer cell lines with IC values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl and [4]Cl was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.