Synthesis and in vitro Anticancer Activity of Ruthenium-Cymene Complexes with Cyclohexyl-Functionalized Ethylenediamine-N,N′-diacetate-Type Ligands

• Published in: ChemMedChem Vol. 6; no. 10; pp. 1884 - 1891
• Main Authors: Savić, Aleksandar, Dulović, Marija, Poljarević, Jelena M., Misirlić-Denčić, Sonja, Jovanović, Maja, Bogdanović, Andrija, Trajković, Vladimir, Sabo, Tibor J., Grgurić-Šipka, Sanja, Marković, Ivanka
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 04.10.2011; WILEY‐VCH Verlag
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; cancer; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - pharmacology; Ethylenediamines - chemistry; Humans; leukemia; Ligands; mitochondrial depolarization; Neoplasms - drug therapy; ruthenium; Ruthenium - chemistry; Stereoisomerism; Structure-Activity Relationship
• DOI: 10.1002/cmdc.201100232
• ISSN: 1860-7179

Herein we describe the synthesis, characterization, and anticancer activity of novel p‐cymeneruthenium(II) complexes containing methyl, ethyl, n‐propyl, and n‐butyl esters of (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, 1H, and 13C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL‐60, K562, and REH cells (IC50: 1.0–20.2 μM), with the n‐butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n‐butyl ester complex is more effective against leukemic patients′ blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of RuII‐based compounds. Mitochondria depolarized! Novel ruthenium(II) arene complexes containing alkyl esters of (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoic acid as chelating agents show potent selective antitumor activity. They induce apoptosis via a mitochondrial pathway involving mechanisms different from those induced by platinum‐based drugs.