Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 003, Lisbon, Portugal.
Department of Biochemistry & Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649 003, Lisbon, Portugal.
ChemMedChem. 2019 Jul 17;14(14):1325-1328. doi: 10.1002/cmdc.201900243. Epub 2019 Jun 14.
Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment-based approach to create new flexible G-quadruplex (G4) DNA-interactive small molecules with good calculated oral drug-like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)-stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose- and DNA sequence-dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G-quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4'-(4,4'-(1,3-phenylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(1-methylquinolin-1-ium) (1 d) showed the greater activity. Importantly, dose-response curves show that 1 d is cytotoxic in the human colon cancer HT-29 cell line enriched in cancer stem-like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells.
四链体核酸是癌症治疗的有前途的靶点。在这项研究中，我们使用基于片段的方法，基于喹啉和三唑杂环，创建了具有良好计算口服药物样性质的新型灵活的 G-四链体 (G4) DNA 相互作用的小分子。G4 熔点和聚合酶链反应 (PCR)-停止测定表明，这两种化合物是选择性的 G4 配体，因为它们能够以剂量和 DNA 序列依赖性方式诱导和稳定 G4。分子对接研究表明，两者都可能与 G-四重奏和沟结合，其中喹啉模块起主要作用。对四种癌细胞系进行了细胞毒性筛选，其中 4,4'-(4,4'-(1,3-亚苯基)双(1H-1,2,3-三唑-4,1-二基))双(1-甲基喹啉-1-鎓) (1d) 表现出更大的活性。重要的是，剂量反应曲线表明 1d 在富含癌症干细胞样细胞的人结肠癌细胞系 HT-29 中具有细胞毒性，这是一种与化疗耐药性有关的细胞亚群。总体而言，这项研究确定了一种新的小分子作为针对癌症干细胞中 G4 的药物开发的有前途的先导物。
