Investigation of ruthenium(ii)-based complexes as chemotherapy anticancer candidates: from design to biological/biochemical studies

Abstract

The search and development of new drugs with high cytotoxicity and low side effects is urgently needed since cancer remains a leading cause of deaths worldwide. Our research group, (LERCI, UFSCar, Brazil) has been studying Ru-based compounds containing different phosphine and bioactive ligands on coordination sphere. Since we obtained promising results from Post-doctorate research (FAPESP Project 2021/01787-0), we aiming to improve the investigation related to the anticancer profile, conducting biological/biochemical experiments with focus on cellular metabolism. For this purpose, complexes with general formula [Ru(N-S)(dppm)2]PF6 (Ru1-Ru6) will be used, where N-S represent different mercapto ligands and dppm is a phosphine bis-dimethylphosphinemethane. The in vitro cytotoxicity in different cell lines upon light irradiation will be investigated. In attempt to obtain better insight regarding the pharmacokinetic profile of these compounds, cellular uptake by inductively coupled plasma mass spectrometry and the influence on cellular metabolism will be studied. It allows obtain crucial information about the oxygen consumption and extracellular acidification rates, and the effect on oxidative phosphorylation and glycolysis processes. Furthermore, multicellular tumor spheroids will be generated and the (photo)cytotoxicity of the promising complexes will be evaluated in 3D models. The activities will be developed during 9 months, at Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences (Paris - France), under supervision of Dr. Gilles Gasser. Dr. Gasser has H-index 54 and 215 articles published. His research lies at the interface between inorganic chemistry, medicinal chemistry, chemical biology and biology, and his group hosts chemistry and biology students. He works on Ruthenium(II)- and other metal-based complexes and its application as anticancer agents, photodynamic therapy, radioimaging and antiparasitic organometallic drugs. The Brazilian-French collaboration will allow the knowledge exchange between both groups, highlighting the publication of the results in important scientific journals with high impact factor. The results obtained from the present project can serve as a guide to a better understanding of Ruthenium compounds as anticancer agents and their mechanism of action, contributing for the development of medicinal and biological inorganic areas. (AU)