Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000, Zagreb, Croatia.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P. O. Box 177, 10000, Zagreb, Croatia.
Mol Divers. 2017 Aug;21(3):621-636. doi: 10.1007/s11030-017-9753-8. Epub 2017 Jun 30.
An experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived on an available database of compounds with previously measured activities. Our QSAR analysis revealed that an increase of the antiproliferative activities towards H460, HCT 116, MCF-7 and SW 620 cells will be obtained if new compounds are charged at a pH range from 5 to 7 and if their hydrophobicity is increased compared to the dataset compounds. Novel benzimidazo[1,2-a]quinolines bearing quarternary amino groups with corresponding aliphatic chains were designed, and their antiproliferative activities were computationally predicted. Using uncatalysed microwave-assisted amination reactions, 14 novel compounds were obtained to assess their antiproliferative activities towards H460, HCT 116, MCF-7, and SW 620 tumour cell lines in vitro. Novel compounds showed antiproliferative activities at micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities validation the QSAR models showing very good agreement between experimentally measured activities and computational predictions. In an attempt to elucidate the mode of action through which benzimidazole derivatives accomplish their antiproliferative activities, thermal denaturation experiments were performed to test their DNA-binding properties.
通过 QSAR 建模成功指导了具有增强的抗增殖活性的新型苯并咪唑衍生物的实验性搜索。对具有先前测量活性的化合物的现有数据库进行了稳健的 3D-QSAR 模型推导。我们的 QSAR 分析表明，如果新化合物在 pH 值为 5 至 7 的范围内带电荷，并且与数据集化合物相比其疏水性增加，则将获得对 H460、HCT 116、MCF-7 和 SW620 细胞的抗增殖活性的提高。设计了带有季铵基团和相应脂肪链的新型苯并咪唑并[1,2-a]喹啉，并计算预测了它们的抗增殖活性。使用非催化微波辅助胺化反应，获得了 14 种新型化合物，以评估它们在体外对 H460、HCT116、MCF-7 和 SW620 肿瘤细胞系的抗增殖活性。新型化合物在微摩尔和亚微摩尔抑制浓度下表现出抗增殖活性。抗增殖活性的实验测量验证了 QSAR 模型，表明实验测量的活性与计算预测之间非常吻合。为了阐明苯并咪唑衍生物发挥其抗增殖活性的作用方式，进行了热变性实验以测试它们的 DNA 结合特性。
