Search for new biologically active compounds: studies of antitumor and antimicrobial activity of dirhodium(,) paddlewheel complexes

• Published in: Dalton transactions : an international journal of inorganic chemistry 2024-06, Vol.53 (22), p.933-9349
• Main Authors: Mitrovi, Marina, Djuki, Maja B, Vuki, Milena, Nikoli, Ivana, Radovanovi, Marko D, Lukovi, Jovan, Filipovi, Ignjat P, Mati, Sanja, Markovi, Tijana, Klisuri, Olivera R, Popovi, Suzana, Matovi, Zoran D, Risti, Marija S
• Format: Article
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/d4dt01082e

Four neutral Rh1-Rh4 complexes of the general formula [Rh 2 (CH 3 COO) 4 L 2 ], where L is an N -alkylimidazole ligand, were synthesized and characterized using various spectroscopic techniques, and in the case of Rh4 the crystal structure was confirmed. Investigation of the interactions of these complexes with HSA by fluorescence spectroscopy revealed that the binding constants K b are moderately strong (∼10 4 M −1 ), and site-marker competition experiments showed that the complexes bind to Heme site III (subdomain IB). Competitive binding studies for CT DNA using EB and HOE showed that the complexes bind to the minor groove, which was also confirmed by viscosity experiments. Molecular docking confirmed the experimental data for HSA and CT DNA. Antimicrobial tests showed that the Rh2-Rh4 complexes exerted a strong inhibitory effect on G + bacteria B. cereus and G − bacteria V. parahaemolyticus as well as on the yeast C. tropicalis , which showed a higher sensitivity compared to fluconazole. The cytotoxic activity of Rh1-Rh4 complexes tested on three cancer cell lines (HeLa, HCT116 and MDA-MB-231) and on healthy MRC-5 cells showed that all investigated complexes elicited more efficient cytotoxicity on all tested tumor cells than on control cells. Investigation of the mechanism of action revealed that the Rh1-Rh4 complexes inhibit cell proliferation via different mechanisms of action, namely apoptosis (increase in expression of the pro-apoptotic Bax protein and caspase-3 protein in HeLa and HCT116 cells; changes in mitochondrial potential and mitochondrial damage; release of cytochrome c from the mitochondria; cell cycle arrest in G2/M phase in both HeLa and HCT116 cells together with a decrease in the expression of cyclin A and cyclin B) and autophagy (reduction in the expression of the protein p62 in HeLa and HCT116 cells). Paddlewheel Rh1-Rh4 complexes containing N -alkylimidazole ligands inhibit the growth of B. cereus , V. parahaemolyticus and C. tropicalis and induce cell death via autophagy and mitochondrial apoptosis in the G2/M phase of the cell cycle.