Anticancer activity of 4′-phenyl-2,2′:6′,2″-terpyridines – behind the metal complexation

• Published in: European journal of medicinal chemistry Vol. 189; p. 112039
• Main Authors: Malarz, Katarzyna, Zych, Dawid, Kuczak, Michał, Musioł, Robert, Mrozek-Wilczkiewicz, Anna
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.03.2020; Elsevier
• Subjects: Anticancer activity; Apoptosis; Cell cycle inhibition; Chemistry, Medicinal; Life Sciences & Biomedicine; Metal chelators; Pharmacology & Pharmacy; Reactive oxygen species; Science & Technology; Terpyridine; Cell cycle inhibition; Reactive oxygen species; Metal chelators; Anticancer activity; Terpyridine; Apoptosis; CANCER-CELLS; KINASE; MECHANISMS; COPPER(II) COMPLEXES; RUTHENIUM(II) COMPLEXES; IN-VITRO; DNA INTERACTION; CYTOTOXICITY; BINDING; TERPYRIDINE COMPLEXES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112039

Terpyridine complexes are known for their broad biological activities, of which their anticancer potency is the most extensively studied. Strikingly, free ligand activity has rarely been described in the literature. In this study, a lipophilic derivative of terpyridine 4’-(1-decyl-2,3-triazol-4-yl)phenyl-2,2′:6′,2″-terpyridine (L) and its complexes were investigated to determine their mechanism of anticancer activity. Our results show that a free ligand expresses the same level of activity on a panel of cancer cells with a low toxicity towards normal fibroblasts as complexes with Cd, Zn or Cu. Breast cancer (MCF-7 cell line) was the most vulnerable for the tested compounds with the IC50 values in the nanomolar range (IC50 = 40 nM for L.) The addition of Cu(II) ions increased its activity even further, thus suggesting that ligand exchange and ROS production are the main components of its activity. A cell cycle analysis indicated its inhibition at the G0/G1 phase and the subsequent apoptosis as the cell death mode. A detailed analysis of the protein level that was involved in the aforementioned processes confirmed previous results. Furthermore, the reactive oxygen species generation and DNA intercalation confirmed its cleaving activity. [Display omitted] •Complexes of 4′-phenyl-2,2’:6′,2″-terpyridine have been synthesised and tested for anticancer activity.•Anticancer activity depends on DNA intercalation and ROS generation.•Free ligand appeared to be equally active as its complexes.