DNA cross-linking patterns induced by an antitumor-active trinuclear platinum complex and comparison with its dinuclear analogue

Jianhui Zhu, Yongmei Zhao, Yanyan Zhu, Ziyi Wu, Miaoxin Lin, Weijiang He, Yan Wang, Guangju Chen, Lei Dong, Junfeng Zhang, Yi Lu, Zijian Guo

Research output: Contribution to journalArticlepeer-review


The DNA binding and cross- linking modes of a trinuclear platinum complex [Pt3Cl3(hptab)][ClO4]3 (1. hptab = N,N,N',N',N",N"-hexakis(2-pyr- idylmethyl)-1,3,5-tris(aminomethyl)- benzene) and its dinuclear analogue [Pt2Cl2(m-tpxa)] Cl2 (2. m-tpxa = N,N,N',N'-tetra(2-pyridylmethyl)-m-xy- lylene diamine) are reported and compared. The adducts of 1 and 2 with 18- mer duplex N1,5′-d(GAAGAAGTCA- CAAAATGT)-3′ 5′-d(ACATTTTGT- GACTTCTTC)-3′, have been characterized by means of denaturing poly- acrylamide gels, Maxam-Gilbert sequencing, and MALDI-TOF mass spectrometry combined with enzymatic degradation to obtain insights into structural features responsible for the differences in their antitumor activities. The cytotoxic-active complex 1 readily forms various DNA adducts, such as through 1,3- and 1,4-intrastrand crosslinks, and in particular, the unique and unprecedented interstrand cross-linked triadducts. In contrast, the cytotoxic-in- active complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intra- and -interstrand cross-links. Digestion of the DNA adducts of 1 shows that the cleavage is completely blocked at one nucleotide before the cross-linked guanine residuesontheopposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated gua- nine site and stops at one nucleotide prior to the second platinated site, confirming that very few 1,3-intrastrand cross-links are formed by 2. These results are supported by molecular-modeling studies of intra- and interstrand cross-links of duplex N1 with 1 and 2. The remarkable differences between 1 and 2 in DNA binding and cross-linking provide mechanistic insights into their different cytotoxicity against the tumor cell lines. these insights are useful for designing future antitumor agents..

Original languageEnglish (US)
Pages (from-to)5245-5253
Number of pages9
JournalChemistry - A European Journal
Issue number21
StatePublished - May 18 2009


  • Antitumor agents
  • DNA structures
  • Mass spectrometry
  • Molecular modeling
  • Platinum

ASJC Scopus subject areas

  • General Chemistry


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