DNA binding and cytotoxicity of ruthenium(II) and rhenium(I) complexes of 2-amino-4-phenylamino-6-(2-pyridyl)-1,3,5-triazine.
[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.
Ma
Dik-Lung
DL
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.
Che
Chi-Ming
CM
Siu
Fung-Ming
FM
Yang
Mengsu
M
Wong
Kwok-Yin
KY
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
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D017975:Ruthenium Compounds; D004247:DNA; C427203:calf thymus DNA