title: The 1,3-diaryltriazenido(p-cymene)ruthenium(II) complexes with a high in vitro anticancer activity.
abstract: 1,3-Diaryltriazenes (1) were let to react with [RuCl2(p-cymene)]2 in the presence of trimethylamine to give neutral 1,3-diaryltriazenido(p-cymene)ruthenium(II) complexes, [RuCl(p-cymene)(ArNNNAr)] (2). The molecular composition of the products 2 was confirmed by NMR spectroscopy and mass spectrometry. The structures of the selected complexes were confirmed by a single crystal X-ray analysis. All triazenido-ruthenium complexes were highly cytotoxic against human cervical carcinoma HeLa cells with IC50 below 6μM, as determined by a spectrophotometric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) method. The most active was [RuCl(p-cymene)(ArNNNAr)] (Ar=4-Cl-3-(CF3)-C6H3) (2g) with IC50 of 0.103±0.006μM. In comparison with the data for the non-coordinated triazenes 1, the triazenido-ruthenium complexes 2 exhibited up to 560-times higher activity. Three selected complexes were highly cytotoxic also against several tumor cell lines: laryngeal carcinoma HEp-2 cells and their drug-resistant HEp-2 subline (7T), colorectal carcinoma HCT-116 cells, lung adenocarcinoma H460 cells, and mammary carcinoma MDA-MB-435 cells. The compounds 2g and [RuCl(p-cymene)(ArNNNAr)] (Ar=4-I-C6H4) (2j) were similarly cytotoxic against parental and drug-resistant cells. Time and dose dependent accumulation of the cells in the S phase of the cell cycle was induced by the compound 2g, triggering apoptosis. Our preliminary results indicate triazenido-ruthenium complexes as promising anticancer drug candidates.
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI 1000, Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Vajs
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Steiner
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb Croatia.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Brozovic
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI 1000, Ljubljana, Slovenia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Pevec
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb Croatia.
authors.forename: Andreja
authors.initials: A
authors.lastname: Ambriović-Ristov
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Matković
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Piantanida
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI 1000, Ljubljana, Slovenia.
authors.forename: Damijana
authors.initials: D
authors.lastname: Urankar
authors.affiliation: Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb Croatia. Electronic address: Maja.Osmak@irb.hr.
authors.forename: Maja
authors.initials: M
authors.lastname: Osmak
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI 1000, Ljubljana, Slovenia. Electronic address: janez.kosmrlj@fkkt.uni-lj.si.
authors.forename: Janez
authors.initials: J
authors.lastname: Košmrlj
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D014226:Triazenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D014226:Triazenes; D004247:DNA; C427203:calf thymus DNA
keywords: Anticancer activity; Ruthenium complexes; Triazene; Triazenido