Organoplatinum(H) Complexes with Nucleobase Motifs as Inhibitors of Human Topoisomerase II Catalytic Activity

Platinum(II) complexes bearing acetylide ligands containing nucleobase motifs are prepared and their impact on human topoisomerase II (TopoII) is evaluated. Both platinum(11) complexes [Pt(II)(C boolean AND N boolean AND N)-(C CCH(2)R)] (la-c) and [Pt(II)(tBu(3)terpy)(C CCH(2)R)](+) (2a-c) (C boolean AND N boolean AND N=6-phenyl-2,2'-bipyridyl, tBu(3)terpy=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(11) complexes towards calf thymus DNA are in the order of 10(5) dm(3)mol(-1) as estimated by using UV/Vis absorption spectroscopy. Of the complexes examined, only cornplexes la c are found to behave as intercalators. Both complexes la c and 2a-c inhibit Topo(II)-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(11) complexes are cytotoxic to human cancer cells with IC(50) values of 0.5-13.7 mu m, while they are less toxic against normal cells CCD-19 Lu.