Laboratoire de Physico-Chimie Théorique et Chimie Informatique, Faculté de Chimie, USTHB, Algiers, Algeria.
J Mol Model. 2010 Aug;16(8):1383-90. doi: 10.1007/s00894-010-0658-z. Epub 2010 Feb 14.
Density functional theory (DFT) using the B3LYP functional was applied to elucidate the molecular properties of the antitumor drug thiotepa and its main metabolite tepa. Aqueous solvent effects were introduced using the conductor-like polarizable continuum model (CPCM). The protocol for calculating the pK (a) values obtained with different cavity models was tested on a series of aziridine and phosphoramide compounds. An efficient computational scheme has been identified that uses the CPCM model of solvation with a universal force field (UFF) cavity. The method has been used to evaluate the basicities of thiotepa and its metabolite. Our calculations show that the basicities of the aziridine moiety of thiotepa and tepa are dramatically reduced compared to free aziridine, indicating that highly acidic media are needed to produce substantial yields of the N-protonated form of the drug. Finally, the mechanisms of reaction of the drug and its metabolite are discussed based on our theoretical results. The calculations reproduce the experimental trends very satisfactorily.
密度泛函理论（DFT）采用 B3LYP 函数，用于阐明抗肿瘤药物噻替哌及其主要代谢物替哌的分子性质。使用导体相似性极化连续模型（CPCM）引入水溶剂效应。通过不同空穴模型计算得到的 pK（a）值的方案在一系列氮丙啶和磷酰胺化合物上进行了测试。已经确定了一种有效的计算方案，该方案使用具有通用力场（UFF）空穴的 CPCM 模型进行溶剂化。该方法已用于评估噻替哌及其代谢物的碱性。我们的计算表明，噻替哌和替哌的氮丙啶部分的碱性与游离氮丙啶相比大大降低，这表明需要高度酸性的介质才能产生药物的 N-质子化形式的大量产率。最后，根据我们的理论结果讨论了药物及其代谢物的反应机制。计算结果非常令人满意地再现了实验趋势。
