Synthesis and biological activity of a platinum(II) 6-phenyl-2,2'-bipyridine complex and its dimeric analogue.
We have synthesized (pyridyl)-(6-phenyl-2,2'-bipyridine)platinum(II) hexafluorophosphate (1) and its corresponding dimer, micro-N,N'-bis(isonicotinyl)-1,6-hexanediamino bis-[6-phenyl-2,2'-bipyridine-platinum(II)] dichloride (2). The DNA binding constants of 1 and 2 at 20 degrees C were determined by absorption titration to be 2.25 x 10(4) M(-1) and 3.07 x 10(6) M(-1), respectively. Compound 1 showed an AT preference, while 2 had no base preference. The binding site sizes of 2 for [poly(dA-dT)](2), calf thymus DNA (ctDNA), and [poly(dG-dC)](2), as determined by fluorescence titration, were 6.6, 4.0, and 2.8 bp, respectively. Compound 2 probably bound to [poly(dA-dT)](2) through bisintercalation, and to [poly(dG-dC)](2) by monointercalation. Binding of DNA by both complexes is favorable, since the binding free energies of 1 and 2 were estimated to be -5.8 and -8.7 kcal mol(-1), respectively. The results of viscosity measurements and gel mobility shift assay demonstrated that binding of 1 and 2 caused DNA lengthening. The cytotoxicities of the complexes in various human cancer cell lines were determined by MTT assay. Complex 2 exhibited cytotoxicity comparable to that of cisplatin, and was more toxic than 1 by an order of magnitude.
Chan
Hing-Leung
HL
Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong.
Ma
Dik-Lung
DL
Yang
Mengsu
M
Che
Chi-Ming
CM
D000465:Algorithms; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007202:Indicators and Reagents; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013778:Tetrazolium Salts; D013816:Thermodynamics; D013844:Thiazoles; D014407:Tumor Cells, Cultured; D014783:Viscosity
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009944:Organoplatinum Compounds; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C478898:platinum(II) 6-phenyl-2,2'-bipyridine; D004247:DNA; C022616:thiazolyl blue