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首页> 外文期刊>Chemistry: A European journal >DNA Cross-Linking Patterns Induced by an Antitumor-Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue
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DNA Cross-Linking Patterns Induced by an Antitumor-Active Trinuclear Platinum Complex and Comparison with Its Dinuclear Analogue

机译：抗肿瘤活性三核铂复合物诱导的DNA交联模式及其与双核类似物的比较

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The DNA binding and crosslinking modes of a trinuclear platinum complex [Pt_3Cl_3A(hptab)][ClO_4]_3 (1; hptab=N,N,N’,N’,N’’,N’’-hexakis(2-pyridylmethyl)- 1,3,5-tris(aminomethyl)- benzene) and its dinuclear analogue [Pt_2Cl_2(m-tpxa)]Cl_2 (2; m-tpxa= N,N,N’,N’-tetra(2-pyridylmethyl)-m-xylylene diamine) are reported and compared. The adducts of 1 and 2 with 18- mer duplex N1, 5’-d(GAAGAAGTCACAAAATGT)- 3’·5’-d(ACATTTTGTGACTTCTTC)- 3’, have been characterized by means of denaturing polyacrylamide 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-inactive complex 2 preferentially forms 1,4-intrastrand rather than 1,3-intraand -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 residues on the opposite strand, a feature that appears to be unprecedented in antitumor platinum complexes. In the case of 2, the cleavage bypasses the first platinated guanine 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.
机译：三核铂配合物[Pt_3Cl_3A（hptab）] [ClO_4] _3（1; hptab = N，N，N'，N'，N''，N''-N''-六（2-吡啶基甲基）的DNA结合和交联模式-1,3,5-三（氨基甲基）-苯）及其双核类似物[Pt_2Cl_2（m-tpxa）] Cl_2（2; m-tpxa = N，N，N'，N'-四（2-吡啶基甲基） -间亚二甲苯基二胺）已被报道并进行了比较。 1和2与18-mer双链体N1、5'-d（GAAGAAGAGTCACAAAATGT）-3'·5'-d（ACATTTTGTGACTTCTTCTTC）-3'的加合物已通过变性聚丙烯酰胺凝胶，Maxam–Gilbert测序， MALDI-TOF质谱与酶促降解相结合，以深入了解造成其抗肿瘤活性差异的结构特征。具有细胞毒活性的复合物1容易形成各种DNA加合物，例如通过1，3-和1，4-链内交联，特别是独特且前所未有的链间交联的三加合物。相反，无细胞毒性的复合物2优先形成1，4-链内而不是1，3-链内-交联。 1的DNA加合物的消化表明，在一个相反的链上交联的鸟嘌呤残基之前，切割在一个核苷酸处完全被阻断，这在抗肿瘤铂络合物中似乎是空前的。在2的情况下，切割会绕过第一个镀金鸟嘌呤位点，并在第二个镀金位点之前的一个核苷酸处终止，从而证实2形成的1，3-内链交联极少。双链N1与1和2的链内和链间交联的模型研究。DNA结合和交联中1和2之间的显着差异为它们对肿瘤细胞系的不同细胞毒性提供了机械学见识;这些见解对于设计未来的抗肿瘤药物很有用。

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