Systematic investigation of the antiproliferative activity of a series of ruthenium terpyridine complexes

Johannes Karges; Olivier Blacque; Marta Jakubaszek; Bruno Goud; Philippe Goldner; Gilles Gasser

doi:10.1016/j.jinorgbio.2019.110752

Systematic investigation of the antiproliferative activity of a series of ruthenium terpyridine complexes

J Inorg Biochem. 2019 Sep:198:110752. doi: 10.1016/j.jinorgbio.2019.110752. Epub 2019 Jun 17.

Authors

Johannes Karges¹, Olivier Blacque², Marta Jakubaszek³, Bruno Goud⁴, Philippe Goldner⁵, Gilles Gasser⁶

Affiliations

¹ Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.
² Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
³ Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France; Institut Curie, PSL University, CNRS UMR 144, Paris, France.
⁴ Institut Curie, PSL University, CNRS UMR 144, Paris, France.
⁵ Chimie ParisTech, PSL University, CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France.
⁶ Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France. Electronic address: gilles.gasser@chimieparistech.psl.eu.

PMID: 31242458
DOI: 10.1016/j.jinorgbio.2019.110752

Abstract

Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing attention towards the use of Ru(II) polypyridyl complexes. Most studies in the literature were made on complexes based on the coordination of N-donating bidentate ligands to the ruthenium core whereas studies on 2,2':6', 2″-terpyridine (terpy) coordinating ligands are relatively scare. However, several studies have shown that [Ru(terpy)2]²⁺ derivatives are able bind to DNA through various binding modes making these compounds potentially suitable as chemotherapeutic agents. Additionally, light irradiation of these compounds was shown to enable DNA cleavage, highlighting their potential use as photosensitizers (PSs) for photodynamic therapy (PDT). In this work, we present the systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and PDT PSs. Importantly, six of the seven complexes were found to be stable in human plasma as well as photostable in acetonitrile upon continuous light irradiation (480 nm). The determination of the distribution coefficient logP values for the 7 complexes revealed their good water solubility. Complex 7 was found to be cytotoxic in the micromolar range in the dark as well as to have some phototoxicity upon light exposure at 480 nm in non-cancerous retinal pigment epithelium (RPE-1) and cancerous human cervical carcinoma (HeLa) cells. SYNOPSIS: The systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]²⁺ (terpy: 2,2':6', 2″-terpyridine; X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and photosensitizers for photodynamic therapy is presented.

Keywords: Anticancer; Medicinal inorganic chemistry; Metals in medicine; Photodynamic therapy; Ruthenium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / radiation effects
Cell Line, Tumor
Cell Proliferation / drug effects*
Coordination Complexes / chemical synthesis
Coordination Complexes / pharmacology*
Coordination Complexes / radiation effects
Drug Screening Assays, Antitumor
Humans
Light
Pyridines / chemical synthesis
Pyridines / pharmacology*
Pyridines / radiation effects
Ruthenium / chemistry

Substances

(2,2'-6',2'')-terpyridine
Antineoplastic Agents
Coordination Complexes
Pyridines
Ruthenium