title: DNA binding and cytotoxicity of ruthenium(II) and rhenium(I) complexes of 2-amino-4-phenylamino-6-(2-pyridyl)-1,3,5-triazine.
abstract: [Ru(tBu2bpy)2(2-appt)](PF6)2 [1.(PF6)2, tBu2bpy = 4,4'-di-tert-butyl-2,2'-bipyridine, 2-appt = 2-amino-4-phenylamino-6-(2-pyridyl)-1,3,5-triazine] and [Re(CO)3(2-appt)Cl] (2) were prepared and characterized by X-ray crystal analysis. The binding of 1.(PF6)2 and 2 to calf thymus DNA (ct DNA) led to increases in the DNA melting temperature (Delta Tm = +12 degrees C), modest hypochromism (29% and 5% of the absorption bands at lambda max = 450 and 376 nm, respectively), and insignificant shifts in the absorption maxima. The binding constants of 1.(PF6)2 and 2 with ct DNA, as determined by absorption titration, are (8.9 +/- 0.5) x 104 and (3.6 +/- 0.1) x 104 dm3 mol-1, respectively. UV-vis absorption titration, DNA melting studies, and competition dialysis using synthetic oligonucleotides [poly(dA-dT)2 and poly(dG-dC)2] revealed that 1.(PF6)2 and 2 exhibit a binding preference for AT sequences. A modeling study on the interaction between 1 or 2 and B-DNA revealed that the minor groove is the most favored binding site and an extensive hydrogen-bonding network is formed. As determined by MTT assays, 1.(PF6)2 and 2 exhibited moderate cytotoxicities toward several human cancer cell lines (KB-3-1, HepG2, and HeLa), as well as a multi-drug-resistant cancer cell line (KB-V-1). According to confocal microscopic and flow cytometric studies, 1.(PF6)2 and 2 induced apoptosis (50-60%) in cancer cells with <5% necrosis detected.
authors.affiliation: 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, Hong Kong SAR, China.
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
authors.forename: Fung-Ming
authors.initials: FM
authors.lastname: Siu
authors.forename: Mengsu
authors.initials: M
authors.lastname: Yang
authors.forename: Kwok-Yin
authors.initials: KY
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D009691:Nucleic Acid Denaturation; D009841:Oligonucleotides / Q000737:chemistry; D017975:Ruthenium Compounds / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D017975:Ruthenium Compounds; D004247:DNA; C427203:calf thymus DNA