Publication in Inorganic Chemistry

Coligand-Dependent Cellular Effects and DNA/BSA Binding of Ruthenium(II) Tris(pyrazolylmethane) Complexes

Authors: Alberto Gobbo, Ján Vančo , Sara Benetti, Tomáš Malina, Zdeněk Dvořák, Christian Castelli, Alessio Chiappa, Massimo Guelfi, Stefano Zacchini, Tarita Biver, Zdeněk Trávníček, and Fabio Marchetti

Full-text: https://doi.org/10.1021/acs.inorgchem.5c04198

 

Monocationic [RuCl(k3-tpm)(L)(PPh₃)]Cl (L = PPh₃, 1; NCMe, 2; 1,3,5-triaza-7-phosphaadamantane (PTA), 3; phosphinoferrocene, 4; 3-methyl-pyrazole, 5; NH₂(CH₂)₂OH, 6; NH₂(CH₂)₂(4-C₆H₄OH) (tyramine), 7; cyclohexylamine, 8; NH₂CH₂CH₂NH₂, 9; tpm = tris-pyrazolylmethane) and biscationic ruthenium complexes [RuCl(k 3-tpm)(PPh₃)(LL’)][NO₃]₂ (LL′ = ethylenediamine, 10; 1,10-phenanthroline, 11; 2-picolylamine, 12; N-phenyl-1-(2-pyridinyl)methanimine, 13) and [RuCl(k 3-tpm)(PPh₃)(NCMe)₂][NO₃]₂ (14) were evaluated for their anticancer potential. The complexes were characterized by IR and multinuclear NMR spectroscopy, and the solid-state structures of 4, 5, 6, 7, and 14 were determined by single-crystal X-ray diffraction. Complexes 3−8 and 10−14 were further examined for solubility and stability in aqueous media, and octanol/water partition coefficients. The complexes were assessed for their in vitro cytotoxicity on a panel of six cancer and two normal cell lines. Complex 1 and the ruthenium-ferrocenyl conjugate 4 revealed significant-to-moderate activity against the cancer cells, with IC₅₀ values ranging from 1.8 to 25.2 µM. Mechanistic studies in A2780 cells included time-dependent cytotoxicity, intracellular ruthenium uptake, cell cycle analysis, autophagy induction, production of ROS (reactive oxygen species), and mitochondrial membrane potential measurements. Moreover, a detailed study was conducted to evaluate DNA and bovine results, which revealed distinct potential mechanisms of action driven by ligand, specifically mitochondrial uncoupling for 1 and 4, and apoptosis- and necrosis-induced cell death for 13 and 14.