Zhou Lixin
Department of Chemistry, Jinan University, Guangzhou, Guangdong 510632, P R China.
J Phys Chem B. 2009 Feb 19;113(7):2110-27. doi: 10.1021/jp806661g.
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) 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.
使用B3LYP杂化泛函和IEF - PCM溶剂化模型，研究了水解的反式/顺式 - [PtCl₂(异丙胺)₂]、反式/顺式 - [Pt(异丙胺)₂Cl(H₂O)]⁺和反式/顺式 - [Pt(异丙胺)₂(H₂O)₂]²⁺与嘌呤碱鸟嘌呤和腺嘌呤之间的首次和第二次取代反应。对于首次取代反应，计算得出的最低自由能垒，鸟嘌呤为11.4/12.2千卡/摩尔（从反式铂 - 氯水络合物到反式/顺式单加合物），腺嘌呤为14.2/14.2千卡/摩尔（从反式铂 - 氯水络合物到反式/顺式单加合物）。在首次取代反应中，计算得出的单水合络合物的最低自由能垒总是低于二水合络合物的。我们对首次取代反应的计算首次表明，反式反应物络合物（或孤立反应物）可以通过相同或非常相似的三角双锥过渡态结构生成反式或顺式单加合物，这表明单加合物随后可以闭合形成双功能链内铂 - DNA加合物，并同时以与顺铂相同的方式使DNA扭曲。我们的计算证实，反式铂类似物会导致双螺旋DNA发生构象改变，类似于顺铂所诱导的改变。换句话说，反式铂类似物很可能具有与顺铂结合DNA靶点相同的作用机制。对于第二次取代反应，当单功能顺式铂 - G络合物作为反应物时，Pt(异丙胺)₂GA²⁺头对头路径的活化自由能最低，为17.2千卡/摩尔，紧随其后的是Pt(异丙胺)₂GG²⁺头对头路径，为23.7千卡/摩尔；而当单功能反式铂 - G络合物为反应物时，Pt(异丙胺)₂GA²⁺头对头加合物的能垒最低，为13.3千卡/摩尔，紧随其后的是Pt(异丙胺)₂GG²⁺头对头加合物，为17.6千卡/摩尔。理论确定的活化能低于顺铂的活化能，这证实了反式 - [PtCl₂(异丙胺)₂]如实验所表明的那样是一种潜在的抗癌药物。对反应物络合物、产物络合物和过渡态的结构分析表明，氢键在稳定首次和第二次取代反应中的这些物种方面起着重要作用。
