title: A SAR study of novel antiproliferative ruthenium and osmium complexes with quinoxalinone ligands in human cancer cell lines.
abstract: A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Ginzinger
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mühlgassner
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Alexander
authors.initials: A
authors.lastname: Roller
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.forename: Michael
authors.initials: M
authors.lastname: Reithofer
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009992:Osmium; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D052160:Benzothiazoles; D001583:Benzoxazoles; D056831:Coordination Complexes; D011810:Quinoxalines; D009992:Osmium; D012428:Ruthenium