Theoretical analysis on the transition state of the anticancer drug trans-[PtCl2(isopropylamine)2] and its cis isomer binding to DNA purine bases.
Theoretical analysis on the transition state of the anticancer drug trans-[PtCl2(isopropylamine)2] and its cis isomer binding to DNA purine bases.
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DOI：
10.1021/jp806661g
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发表时间：
2009-01
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影响因子：
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通讯作者：
Lixin Zhou
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文献类型：
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作者：
Lixin Zhou
利用B3 LYP杂化泛函和IEF-PCM溶剂化模型研究了水解的trans/cis-[PtCl（2）（isopropylamine）（2）]、trans/cis-[Pt（isopropylamine）（2）Cl（H（2）O）]（+）和trans/cis- [Pt（isopropylamine）（2）（H（2）O）（2）]（2+）与嘌呤碱基鸟嘌呤和腺嘌呤之间的第一和第二取代反应.对于第一个取代基，鸟嘌呤和腺嘌呤的最低自由能势垒分别为11.4/12.2kcal/mol（从trans-Pt-氯水络合物到trans-cis-单加合物）和14.2/14.2kcal/mol（从trans-Pt-氯水络合物到trans-cis-单加合物）。在第一次取代反应中，单水合配合物的最低自由能势垒总是低于双水合配合物。我们的计算表明，第一次，反式反应物复合物（或分离的反应物）可以通过相同或非常相似的三角双锥过渡态结构产生反式或顺式单加合物，这表明单加合物可以随后关闭形成双功能链内Pt-DNA加合物，同时扭曲DNA以相同的方式作为顺铂。我们的计算证实，transplatin类似物导致双螺旋DNA的构象变化类似于顺铂诱导的那些。换句话说，很可能反铂类似物与顺铂结合DNA靶标具有相同的作用机制。对于第二次替换，Pt（2）GA（2+）头-尾路径的活化自由能最低，为17.2 kcal/mol，其次是Pt（2+），（异丙胺）（2）GG（2+）头-尾路径，当单官能cis-Pt-G络合物作为反应物时，当Pt（异丙胺）（2）GA（2+）头对头加成物具有最低的势垒13.3kcal/mol，紧随其后的是Pt（异丙胺）（2）GG（2+）头对头加合物，如果单官能反式-Pt-G络合物是反应物，则为17.6 kcal/mol。理论上测得的活化能低于顺铂的活化能，证实了反式-[PtCl（2）（异丙胺）（2）]是一种潜在的抗癌药物。对反应物配合物、产物配合物和过渡态的结构分析表明，氢键在稳定这些物种的第一和第二取代中起重要作用。
The first and second substitution reactions between hydrolyzed trans/cis-[PtCl(2)(isopropylamine)(2)], trans/cis-[Pt(isopropylamine)(2)Cl(H(2)O)](+), and trans/cis- [Pt(isopropylamine)(2)(H(2)O)(2)](2+) and purine bases guanine and adenine are explored using the B3LYP hybrid functional and IEF-PCM solvation models. For the first substitution, the calculated lowest free energy barrier is 11.4/12.2kcal/mol (from trans-Pt-chloroaqua complex to trans/cis-monoadduct) for guanine, and 14.2/14.2kcal/mol (from trans-Pt-chloroaqua complex to trans/cis-monoadduct) for adenine. The computed lowest free energy barrier of monoaquated complexes is always lower than that of diaquated complexes in the first substitution. Our calculations for the first substitution demonstrate, for the first time, that the trans reactant complexes (or isolated reactants) can generate trans- or cis-monoadducts via identical or very similar trigonal-bipyramidal transition-state structures, suggesting that the monoadducts can subsequently close to form the bifunctional intrastrand Pt-DNA adducts and simultaneously distort DNA in the same way as cisplatin. Our calculations confirm that the transplatin analogue leads to conformational alterations in double-helical DNA similar to those induced by cisplatin. In other words, it is likely that the transplatin analogue has the same mechanism of action as cisplatin binding to DNA targets. For the second substitution, the Pt(isopropylamine)(2)GA(2+) head-to-tail path has the lowest free energy of activation at 17.2 kcal/mol, closely followed by the Pt(isopropylamine)(2)GG(2+) head-to-tail path at 23.7 kcal/mol when the monofunctional cis-Pt-G complex serves as the reactant, while the Pt(isopropylamine)(2)GA(2+) head-to-head adduct has the lowest barrier of 13.3kcal/mol, closely followed by the Pt(isopropylamine)(2)GG(2+) head-to-head adduct at 17.6 kcal/mol if the monofunctional trans-Pt-G complex is the reactant. The theoretically determined activation energy is lower than that of cisplatin, which confirms that trans-[PtCl(2)(isopropylamine)(2)] is a potential anticancer drug as suggested by experiment. The structural analysis for reactant complexes, product complexes, and transition states shows that hydrogen bonds play an important role in stabilizing these species for the first and second substitution.