The role of bridging ligands in determining DNA-binding ability and cross-linking patterns of dinuclear platinum(II) antitumour complexes.
The DNA binding ability and binding mode of platinum complexes are crucial factors that govern their cytotoxic activity. In this work, circular dichroism spectroscopy, gel electrophoresis and MALDI-TOF MS spectrometry combined with enzymatic degradation have been used to elucidate the role of bridging ligands in DNA-binding ability and cross-linking patterns of two dinuclear antitumour active platinum(II) complexes, {[cis-Pt(NH(3))(2)Cl](2)L1}(NO(3))(2) (1, L1= 4,4'-methylenedianiline) and {[cis-Pt(NH(3))(2)Cl](2)L2}(NO(3))(2) (2, L2 = alpha,alpha'-diamino-p-xylene). Although both complexes have two cis-diammine-Pt(II) moieties (1,1/c,c), complex 1 exhibits much higher DNA-binding ability than complex 2. The former readily forms both 1,3- and 1,4-intrastrand cross-links with DNA oligonucleotides, while the latter preferentially forms 1,4- rather than 1,3-intrastrand cross-links. Cytotoxicity studies against a human non-small-cell lung cancer cell line (A549) demonstrate that complex 1 has higher activity than 2. These results show that the linker properties play a critical role in controlling the DNA-binding and cross-linking abilities and in modulating the cytotoxicity of dinuclear platinum complexes.
Zhu
Jianhui
J
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China.
Lin
Miaoxin
M
Fan
Damin
D
Wu
Ziyi
Z
Chen
Yuncong
Y
Zhang
Junfeng
J
Lu
Yi
Y
Guo
Zijian
Z
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000633:toxicity; D010984:Platinum / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D008024:Ligands; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA