title: Metal-based paullones as putative CDK inhibitors for antitumor chemotherapy.
abstract: Paullones constitute a class of potent cyclin-dependent kinase inhibitors. To overcome the insufficient solubility and bioavailability, which hamper their potential medical application, we aim at the development of metal-based derivatives. Two types of paullone ligands, L (1) - L (3) and L (4) , with different locations of metal-binding sites, were prepared. They were found to form organometallic complexes of the general formula [M (II)Cl(eta (6)- p-cymene)L]Cl ( 1- 4, L = L (1) - L (4) ; a, M = Ru; b, M = Os). The complexes were characterized by X-ray crystallography, one- and two-dimensional NMR spectroscopy and other physical methods. Complexes 1- 3, with a coordinated amidine unit, were found to undergo E/ Z isomerization in solution. The reaction was studied by NMR spectroscopy, and activation parameters Delta H (double dagger) and Delta S (double dagger) were determined. Antiproliferative activity in the low micromolar range was observed in vitro in three human cancer cell lines by means of MTT assays. (3)H-Thymidine incorporation assays revealed the compounds to lower the rate of DNA synthesis, and flow cytometric analyses showed cell cycle arrest mainly in G 0/ G 1 phase.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Währingerstr. 42, A-1090 Vienna, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Schmid
authors.forename: Roland O
authors.initials: RO
authors.lastname: John
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mühlgassner
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Mathea Sophia
authors.initials: MS
authors.lastname: Galanski
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006157:Guanosine Monophosphate / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009992:Osmium; D012413:Rubidium; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D007211:Indoles; D009942:Organometallic Compounds; D012996:Solutions; D009992:Osmium; D006157:Guanosine Monophosphate; D018844:Cyclin-Dependent Kinases; D012413:Rubidium