Conformational studies and electronic structures of tamoxifen and toremifene and their allylic carbocations proposed as reactive intermediates leading to DNA adduct formation
Conformational studies and electronic structures of tamoxifen and toremifene and their allylic carbocations proposed as reactive intermediates leading to DNA adduct formation
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DOI：
10.1021/jm960255g
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发表时间：
1996-07-19
影响因子：
7.3
通讯作者：
Kuramochi, H
中科院分区：
文献类型：
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作者：
Kuramochi, H
托瑞米芬是一种与他莫昔芬不同的化合物，其乙基中的氢原子被氯原子取代，其在引起大鼠DNA加合物形成方面的效力明显低于他莫昔芬。为了研究这些化合物的DNA加合物形成能力与它们的物理化学性质如稳定构象和化学反应性的关系，我们对这两种化合物进行了分子力学、分子动力学和量子力学计算。对于他莫昔芬，通过CFF 91力场的构象搜索确定了六种稳定的构象。分子动力学模拟表明，这些往往在1.0 ns内相互转换。托瑞米芬的稳定构象和动力学行为与他莫昔芬基本相同，但由于氯乙基上的氯原子的影响，托瑞米芬的某些构象与他莫昔芬略有不同。此外，烯丙基碳正离子的稳定性，这已被提出作为反应中间体导致DNA加合物的形成，计算与半经验和密度泛函方法。结果表明，托瑞米芬的碳正离子中间体比他莫昔芬的碳正离子中间体稳定性低4-5 kcal/mol，表明托瑞米芬被活化为中间体的频率低于他莫昔芬。此外，其他两个他莫昔芬衍生物，4-碘他莫昔芬和droxifene，没有显示出DNA加合物形成能力的碳阳离子中间体，也不太稳定，与他莫昔芬相比。这些计算结果表明，建议的碳正离子中间体的稳定性和DNA加合物形成能力之间的密切关系。
Toremifene, a compound which differs from tamoxifen by the substitution of a chlorine atom for a hydrogen atom in the ethyl group, is significantly less potent than tamoxifen in causing DNA adduct formation in rats. To examine the relationship of the DNA adduct-forming ability of these compounds with their physicochemical properties such as stable conformation and chemical reactivity, we carried out molecular mechanics, molecular dynamics, and quantum mechanics calculations for the two compounds. For tamoxifen, six stable conformers were identified by conformational search with CFF91 force field. Molecular dynamics simulations showed that these were often interconverted within 1.0 ns. On the other hand, although the conformation of stable conformers and dynamical behavior of toremifene were almost the same as those of tamoxifen, a few conformations were slightly different from those of tamoxifen owing to the effect of the chlorine atom at chloroethyl group. In addition, the stability of the allylic carbocation, which had been proposed as the reactive intermediate leading to DNA adduct formation, was calculated with both semiempirical and density functional methods. Results showed that the carbocation intermediate of toremifene was less stable than that of tamoxifen by 4-5 kcal/mol, suggesting that toremifene was less frequently activated to the intermediate than tamoxifen. Furthermore, the carbocation intermediates of two other tamoxifen derivatives, 4-iodotamoxifen and droxifene, which show no DNA adduct-forming ability, were also less stable compared with that of tamoxifen. These calculated results suggest a close relation between the stability of the proposed carbocation intermediate and DNA adduct-forming ability.