Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by tuning the Electronic Structure of Dioxo Ligands

Anna Notaro (1) , Marta Jakubaszek (1) , Nils Rotthowe , Federica Maschietto (1) , Robin Vinck (2) , Patrick S Felder (3) , Bruno Goud (4) , Mickaël Tharaud (5) , Ilaria Ciofini (6) , Fethi Bedioui (7) , Rainer Winter (8) , Gilles Gasser (3)

1 ENSCP - Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL
2 ICGM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
3 iCLeHS - Institute of Chemistry for Life and Health Sciences
4 Mécanismes moléculaires du transport intracellulaire
5 IPGP - Institut de Physique du Globe de Paris
6 LECIME - Laboratoire d'Electrochimie, Chimie des Interfaces et Modélisation pour l'Energie (LECIME - UMR 7575)
7 PSL - Université Paris Sciences et Lettres
8 Institut für Anorganische Chemie

Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely Ru-sq ([Ru(DIP)2(sq)](PF6) (DIP: 4,7-diphenyl-1,10-phenanthroline, sq: semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) that involves a broader range of derivatives resulting from the coordination of different catecholate-like dioxo ligands to the same Ru(DIP)2 core. More in detail, we chose catechols carrying either electron-donating or electron-withdrawing groups EDG or EWG and investigated the physico-chemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep red positively charged complexes 1–4 in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes 5 and 6, on the other hand, are blue/violet neutral complexes which carry an EWG substituted dinegatively charged catecholate ligand. The biological investigation of complexes 1–6 led to the conclusion that the difference in their physico-chemical properties has a strong impact on their biological activity. Thus, complexes 1–4 expressed much higher cytotoxicities than complexes 5 and 6. Complex 1 constitutes the most promising compound of the series and was selected for a more in-depth biological investigation. Apart from its remarkably high cytotoxicity (IC50 = 0.07–0.7 µM in different cancerous cell lines) complex 1 was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e. nucleus, lysosomes, mitochondria and cytoplasm) is extremely advantageous in the search of a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex 1 with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex 1 a valuable candidate in the field of chemotherapy research. Noteworthy, a preliminary biodistribution study on healthy mice demonstrated the suitability of complex 1 for further in vivo studies.

Mots clés: Bioinorganic chemistry; DNA

Domaines: Chimie thérapeutique; Chimie de coordination

Anna Notaro, Marta Jakubaszek, Nils Rotthowe, Federica Maschietto, Robin Vinck, et al.. Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by tuning the Electronic Structure of Dioxo Ligands. Journal of the American Chemical Society, In press, ⟨10.1021/jacs.9b12464⟩. ⟨hal-02509374⟩