title: Organoplatinum(II) complexes with nucleobase motifs as inhibitors of human topoisomerase II catalytic activity.
abstract: Platinum(II) complexes bearing acetylide ligands containing nucleobase motifs are prepared and their impact on human topoisomerase II (TopoII) is evaluated. Both platinum(II) complexes [Pt(II)(C^N^N)(C≡CCH₂R)] (1a-c) and [Pt(II)(tBu₃terpy)(C≡CCH₂R)](+) (2a-c) (C^N^N=6-phenyl-2,2'-bipyridyl, tBu₃terpy=4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridyl, and R=(a) adenine, (b) thymine, and (c) 2-amino-6-chloropurine) are stable in aqueous solutions for 48 hours at room temperature. The binding constants (K) for the platinum(II) complexes towards calf thymus DNA are in the order of 10⁵ dm³ mol⁻¹ as estimated by using UV/Vis absorption spectroscopy. Of the complexes examined, only complexes 1a-c are found to behave as intercalators. Both complexes 1a-c and 2a-c inhibit TopoII-induced relaxation of supercoiled DNA, while 2c is the most potent TopoII inhibitors among the tested compounds. Inhibition of DNA relaxation is detected at nanomolar concentrations of 2c. All of the platinum(II) complexes are cytotoxic to human cancer cells with IC₅₀ values of 0.5-13.7 μM, while they are less toxic against normal cells CCD-19 Lu.
authors: Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, P.R. China.
authors: Ping
authors: P
authors: Wang
authors: Chung-Hang
authors: CH
authors: Leung
authors: Dik-Lung
authors: DL
authors: Ma
authors: Wei
authors: W
authors: Lu
authors: Chi-Ming
authors: CM
authors: Che
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D020552:Comet Assay; D003198:Computer Simulation; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D053837:DNA Cleavage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry*; D007700:Kinetics; D009944:Organoplatinum Compounds / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013941:Thymine / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000633:toxicity
chemical_list: D056831:Coordination Complexes; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D004247:DNA; D004250:DNA Topoisomerases, Type II; D013941:Thymine