Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling
Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure-activity relationship modeling
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DOI：
10.1007/s00775-010-0676-4
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发表时间：
2010-09-01
影响因子：
3
通讯作者：
Osella, Domenico
中科院分区：
文献类型：
--
作者：
Gramatica, Paola;Papa, Ester;Osella, Domenico
合理设计并合成了通式为[Pt（L）（2）（L '）（2）（LaEuro（3））（2）] [轴向配体L为Cl-、RCOO-或OH-，赤道配体L'为两个胺或一个二胺，赤道配体LaEuro（3）为Cl-或乙醇酸]的Pt（IV）配合物，试图建立预测定量构效关系（QSAR）模型.许多理论分子描述符与物理化学数据一起使用（即，还原峰电位，E（p）和分配系数，log P（o/w）），以获得体外细胞毒性（对A2780卵巢癌和HCT 116结肠癌细胞系的半数最大抑制浓度，IC 50）和Pt（IV）络合物的一些特征之间的经验证的QSAR。在由此产生的最佳模型中，亲脂性描述符（log P（o/w）或仲sp（3）碳原子的数目）加上电子描述符（E（p），氧原子的数目，或表示为N，O极性贡献的拓扑极性表面积）对于建模是必需的，支持Pt（IV）络合物的生物学行为可以基于它们的细胞摄取，Pt（IV）→ Pt（II）还原，以及相应的Pt（II）代谢物的结构。新的化合物合成的基础上，其预测的细胞毒性的初步QSAR模型，并进行了实验测试。一个最终的QSAR模型，完全基于理论分子描述符，以确保其普遍适用性，提出。
Several Pt(IV) complexes of the general formula [Pt(L)(2)(L')(2)(LaEuro(3))(2)] [axial ligands L are Cl-, RCOO-, or OH-; equatorial ligands L' are two am(m)ine or one diamine; and equatorial ligands LaEuro(3) are Cl- or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure-activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, E (p), and partition coefficient, log P (o/w)) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log P (o/w) or the number of secondary sp (3) carbon atoms) plus an electronic descriptor (E (p), the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV) -> Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.