Tekiner-Gulbas B, Temiz-Arpaci O, Yildiz I, Aki-Sener E, Yalcin I
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan 06100 Ankara, Turkey.
SAR QSAR Environ Res. 2006 Apr;17(2):121-32. doi: 10.1080/10659360600636105.
Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds.
近年来，选择性拓扑异构酶II（Topo II）抑制剂在很大程度上引起了新型抗肿瘤化合物设计方面的关注。对一系列先前合成的作为真核Topo II抑制剂的苯并恶唑、苯并咪唑和恶唑并[4,5-b]吡啶衍生物进行了比较分子相似性指数分析（CoMSIA）。使用16种杂环化合物的训练集建立CoMSIA模型。它们使用SYBYL v7.0构建并进行几何优化。使用7种化合物的测试集评估模型的预测能力。最佳模型显示出良好的拟合度，r2值为0.968，交叉验证系数q2值为0.562，包括空间和疏水场。疏水相互作用对提高Topo II抑制剂活性起主导作用，并且发现在苯并恶唑部分的5位或6位上，亲水取代基比疏水取代基更重要。从本研究中获得的模型可用于修饰和/或评估作为潜在抗肿瘤化合物的新型Topo II抑制剂的开发。
