BIOPHYSICAL ANALYSIS OF DNA MODIFIED BY 1,2-DIAMINOCYCLOHEXANE PLATINUM(II) COMPLEXES
BIOPHYSICAL ANALYSIS OF DNA MODIFIED BY 1,2-DIAMINOCYCLOHEXANE PLATINUM(II) COMPLEXES
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DOI：
10.1093/nar/20.2.267
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发表时间：
1992-01-25
影响因子：
14.9
通讯作者：
BRABEC, V
中科院分区：
文献类型：
--
作者：
BOUDNY, V;VRANA, O;BRABEC, V
本文用物理化学方法和核酸构象化学探针研究了抗癌化合物1，2-二氨基环己烷二硝基铂（Ⅱ）（Pt-dach）配合物对DNA和双链脱氧寡核苷酸的修饰。使用三种Pt-dach络合物，其在dach非离去配体-Pt（1 R，2 R-dach）、Pt（1 S，2S-dach）和Pt（1 R，2S-dach）络合物的异构形式上不同。后者复合物具有较低的抗肿瘤活性比其他两个Pt-dach复合物。Pt（1 R，2S-dach）复合物与DNA结合的动力学最慢，单功能结合转化为双功能病变的动力学也最慢。铂化和连接的寡聚体的多聚体的电泳迁移率非常慢，这表明Pt-dach复合物与双链寡核苷酸内的d（GG）位点的双功能结合诱导寡聚体的弯曲。此外，化学探针的双螺旋脱氧寡核苷酸修饰的Pt-dach的配合物在d（GG）的网站显示，Pt（1 R，2S-dach）复合物诱导更广泛的构象变化的寡聚体比Pt（1 R，2 R-dach）和Pt（1 S，2S-dach）的配合物。提出了Pt-dach配合物对DNA的不同作用主要是由于Pt（1 R，2S-dach）配合物的DNA加合物中环己烷环的空间拥挤所致。
Modification of DNA and double-stranded deoxyoligonucleotides with antitumour 1,2-diaminocyclohexanedinitroplatinum(II) (Pt-dach) complexes was investigated with the aid of physico-chemical methods and chemical probes of nucleic acid conformation. The three Pt-dach complexes were used which differed in isomeric forms of the dach non-leaving ligand-Pt(1R,2R-dach), Pt(1S,2S-dach) and Pt(1R,2S-dach) complexes. The latter complex has lower antitumour activity than the other two Pt-dach complexes. Pt(1R,2S-dach) complex exhibits the slowest kinetics of its binding to DNA and of the conversion of monofunctional binding to bifunctional lesions. The anomalously slow electrophoretic mobility of multimers of the platinated and ligated oligomers suggests that bifunctional binding of Pt-dach complexes to a d(GG) site within double-stranded oligonucleotides induces bending of the oligomer. In addition, chemical probing of double-helical deoxyoligonucleotides modified by the Pt-dach complexes at the d(GG) sites reveals that Pt(1R,2S-dach) complex induces more extensive conformational changes in the oligomer than Pt(1R,2R-dach) and Pt(1S,2S-dach) complexes. It is proposed that different effects of the Pt-dach complexes on DNA observed in this work arise mainly from a steric crowding of the axially oriented cyclohexane ring in the DNA adduct of Pt(1R,2S-dach) complex.