Consequences of nucleic acid conformation on the binding of a trinuclear platinum drug.
Consequences of nucleic acid conformation on the binding of a trinuclear platinum drug.
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DOI：
10.1021/bi991202e
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发表时间：
1999-11
期刊：
影响因子：
2.9
通讯作者：
M. Kloster;J. Hannis;D. Muddiman;N. Farrell
中科院分区：
文献类型：
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作者：
M. Kloster;J. Hannis;D. Muddiman;N. Farrell
BBR 3464是一种带电的三核铂化合物，是第一个进入I期临床试验的一类新型抗癌药物的代表。BBR 3464的结构特征为两个[trans-PtCl（NH（3））（2）]单元通过四胺[trans-Pt（NH（3））（2）<$H（2）N（CH（2））（6）NH（2）<$（2）]单元连接。BBR 3464的+4电荷和铂化单元的分离表明DNA结合模式将明显不同于经典单核药物如顺铂，顺式-[PtCl（2）（NH（3））（2）]。通过凝胶电泳评估BBR 3464与三种不同核酸构象的反应。单链DNA、RNA和双链DNA的比较表明，BBR 3464与单链DNA和RNA的反应比与双链DNA的反应快，并且产生更多的药物-DNA和药物-RNA加合物。采用电喷雾离子化傅立叶变换离子回旋共振质谱进一步表征BBR 3464与DNA底物的结合模式。BBR 3464与不同核酸构象的结合提高了单链DNA和RNA的加合物可能在这种新药与顺铂相比的不同抗肿瘤功效中发挥作用的可能性。
BBR3464, a charged trinuclear platinum compound, is the first representative of a new class of anticancer drugs to enter phase I clinical trials. The structure of BBR3464 is characterized by two [trans-PtCl(NH(3))(2)] units linked by a tetraamine [trans-Pt(NH(3))(2)¿H(2)N(CH(2))(6)NH(2)¿(2)] unit. The +4 charge of BBR3464 and the separation of the platinating units indicate that the mode of DNA binding will be distinctly different from those of classical mononuclear drugs such as cisplatin, cis-[PtCl(2)(NH(3))(2)]. The reaction of BBR3464 with three different nucleic acid conformations was assessed by gel electrophoresis. Comparison of single-stranded DNA, RNA, and double-stranded DNA indicated that the reaction of BBR3464 with single-stranded DNA and RNA was faster than that with duplex DNA, and produced more drug-DNA and drug-RNA adducts. Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry was used to further characterize the binding modes of BBR3464 with the DNA substrates. BBR3464 binding to different nucleic acid conformations raises the possibility that the adducts of single-stranded DNA and RNA may play a role in the different antitumor efficacies of this novel drug as compared with cisplatin.