Polymer “ruthenium-cyclopentadienyl” conjugates - New emerging anti-cancer drugs

Tiago Moreira (1, 2) , Rita Francisco (1) , Elisabeta Comsa (3) , Sophie S. Duban-Deweer (4) , Valérie Labas (5) , Ana-Paula Teixeira-Gomes (5) , Lucie Combes-Soia (5) , Fernanda Marques (1) , António Matos (6) , Audrey Favrelle (7) , Cyril Rousseau , Philippe Zinck (7) , Pierre Falson (3) , M. Helena Garcia (1) , Ana Preto (2) , Andreia Valente (7)

1 ULISBOA - Universidade de Lisboa = University of Lisbon
2 Universidade do Minho = University of Minho [Braga]
3 MMSB - Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry
4 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
5 PRC - Physiologie de la reproduction et des comportements [Nouzilly]
6 Instituto Superior de Ciências da Saúde Egas Moniz [Portugal]
7 UCCS - Unité de Catalyse et Chimie du Solide - UMR 8181

In this work, we aimed to understand the biological activity and the mechanism of action of three polymer-'ruthenium-cyclopentadienyl' conjugates (RuPMC) and a low molecular weight parental compound (Ru1) in cancer cells. Several biological assays were performed in ovarian (A2780) and breast (MCF7, MDA-MB-231) human cancer derived cell lines as well as in A2780cis, a cisplatin resistant cancer cell line. Our results show that all compounds have high activity towards cancer cells with low IC 50 values in the micromolar range. We observed that all Ru-PMC compounds are mainly found inside the cells, in contrast with the parental low molecular weight compound Ru1 that was mainly found at the membrane. All compounds induced mitochondrial alterations. PMC3 and Ru1 caused F-actin cytoskel-eton morphology changes and reduced the clonogenic ability of the cells. The conjugate PMC3 induced apoptosis at low concentrations comparing to cisplatin and could overcame the platinum resistance of A2780cis cancer cells. A proteomic analysis showed that these compounds induce alterations in several cellular proteins which are related to the phenotypic disorders induced by them. Our results suggest that PMC3 is foreseen as a lead candidate to future studies and acting through a different mechanism of action than cisplatin. Here we established the potential of these Ru compounds as new metallodrugs for cancer chemotherapy.

Mots clés: Ruthenium organometallic compounds; Polymer-metal conjugates; Proteomic analysis; Cytoskeleton

Domaines: Chimie thérapeutique; Chimie de coordination; Pharmacologie; Cancer

Tiago Moreira, Rita Francisco, Elisabeta Comsa, Sophie S. Duban-Deweer, Valérie Labas, et al.. Polymer “ruthenium-cyclopentadienyl” conjugates - New emerging anti-cancer drugs. European Journal of Medicinal Chemistry, 2019, 168, pp.373-384. ⟨10.1016/j.ejmech.2019.02.061⟩. ⟨hal-02325931⟩