A dinuclear monofunctional platinum(II) complex with an aromatic linker shows low reactivity towards glutathione but high DNA binding ability and antitumor activity.
Multinuclear Pt(II) complexes represent a novel class of antitumor agents. In this work, a dinuclear monofunctional Pt(II) complex {[cis-Pt(NH(3))(2)Cl](2)(4,4'-methylenedianiline)}(NO(3))(2) (1) was synthesized and characterized by (1)H NMR, electrospray mass spectrometry, and elemental analysis. The 2D [(1)H,(15)N] heteronuclear single quantum coherence NMR spectra of (15)N-labeled 1 revealed that the cationic core of this water-soluble complex hardly hydrolyzes in aqueous solution and reacts very slowly with glutathione. Hydrolysis appears not to be an essential step for the formation of Pt-guanosine-5'-monophosphate (5'-GMP) or Pt-DNA adducts because the complex can react readily with 5'-GMP and partially transform B-DNA into its Z form. Such properties are desired to achieve the goal of enhancing cytotoxicity and lowering side effects of Pt(II) complexes. In fact, complex 1 is highly cytotoxic against the murine leukemia (P-388) and the human non-small-cell lung cancer (A-549) cell lines, and it is more cytotoxic than cisplatin at most concentrations tested.
Fan
Damin
D
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, People's Republic of China.
Yang
Xiaoliang
X
Wang
Xiaoyong
X
Zhang
Shouchun
S
Mao
Jiafei
J
Ding
Jian
J
Lin
Liping
L
Guo
Zijian
Z
D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D001559:Benzhydryl Compounds
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004247:DNA; D005978:Glutathione; D006157:Guanosine Monophosphate; D007202:Indicators and Reagents; D009944:Organoplatinum Compounds; C009505:4,4'-diaminodiphenylmethane; D001559:Benzhydryl Compounds; C114062:BBR 3464