Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
Bioorg Med Chem Lett. 2021 Nov 1;51:128371. doi: 10.1016/j.bmcl.2021.128371. Epub 2021 Sep 15.
Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood-brain barrier. Moreover, preliminary structure-activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.
恶性神经胶质瘤是最常见的脑肿瘤，通常预后不良，临床早期恶化和死亡率高。最近，2-氨基喹啉支架衍生物在中枢神经系统疾病中显示出显著的活性。我们在此报告了一系列 2-氨基喹啉-3-甲酰胺作为新型非烷化剂抗神经胶质瘤药物。合成的化合物在体外对神经胶质瘤细胞系 U87 MG 的活性与顺铂相当。其中，我们发现 6a 对 A172 和 U118 MG 神经胶质瘤细胞系表现出良好的抑制活性，并通过流式细胞术分析诱导 U87 MG 细胞周期停滞和凋亡。此外，6a 对几种正常人细胞系的细胞毒性较低。计算机研究表明 6a 具有有前途的物理化学性质，并预测能够穿透血脑屏障。此外，还研究了初步的构效关系，为这一系列化合物的更有效药物的进一步修饰提供了线索。我们的结果表明，该化合物具有作为抗神经胶质瘤剂的潜在前景，在肿瘤细胞和非恶性细胞之间具有不同的作用。
