Çakmak Osman, Ökten Salih, Köprülü Tuğba Kul, Andac Cenk A, Tekin Şaban, Arslan Seyfullah Oktay
Department of Gastronomy, Faculty of Arts, Design and Architecture, Istanbul Rumeli University, Silivri, Istanbul, Turkey.
Department of Maths and Science Education, Faculty of Education, Kırıkkale University, Yahşihan, Kırıkkale, Turkey.
Chem Biol Drug Des. 2025 May;105(5):e70120. doi: 10.1111/cbdd.70120.
In this study, we synthesized and characterized novel brominated methoxyquinolines (7 and 11) and nitrated bromoquinoline (17) derivatives with potential antiproliferative activity against cancer cell lines. Starting from 1,2,3,4-tetrahydroquinoline (THQ, 1), a series of brominated quinoline compounds was obtained via regioselective bromination and subsequent reactions. The structure of the key compound, 3,5,6,7-tetrabromo-8-methoxyquinoline (7), was confirmed using 1D and 2D NMR techniques. Additionally, unexpected bromination of 3,6,8-trimethoxyquinoline (5) yielded 5,7-dibromo-3,6-dimethoxy-8-hydroxyquinoline (11), allowing functionalization of both rings in the quinoline. The direct nitration of 6,8-dibromoquinoline (6) yielded the corresponding 5-nitro derivative (17), a precursor to amino derivatives that activate the bromine group on the ring. Antiproliferative activities of these derivatives (7, 11, 17) were assessed against C6, HeLa, and HT29 cancer cell lines using the BCPE assay. Compounds 7, 11, and 17 exhibited significant inhibitory effects, with compound 11 showing the highest activity (IC values of 5.45-9.6 μg/mL). Furthermore, the cytotoxicity of these compounds was evaluated using the LDH assay, indicating lower cytotoxic effects compared to the control drug 5-FU. The ability of compounds 11 and 17 to induce apoptosis was confirmed through DNA laddering, while compound 7 showed no such effect. Compounds 7 and 11 inhibited human topoisomerase I, a critical enzyme for DNA replication and repair, with significant binding energies determined by MM-PBSA studies. The wound healing assay demonstrated that compound 17 effectively inhibited the migration of HT29 cells. These findings highlight the potential of these novel quinoline derivatives as effective anticancer agents, warranting further investigation into their mechanisms of action and therapeutic applications.
在本研究中，我们合成并表征了具有潜在抗癌细胞系增殖活性的新型溴化甲氧基喹啉（7和11）以及硝化溴喹啉（17）衍生物。从1,2,3,4-四氢喹啉（THQ，1）开始，通过区域选择性溴化及后续反应获得了一系列溴化喹啉化合物。使用一维和二维核磁共振技术确认了关键化合物3,5,6,7-四溴-8-甲氧基喹啉（7）的结构。此外，3,6,8-三甲氧基喹啉（5）意外发生溴化反应生成了5,7-二溴-3,6-二甲氧基-8-羟基喹啉（11），使得喹啉的两个环都能进行官能化。6,8-二溴喹啉（6）的直接硝化反应生成了相应的5-硝基衍生物（17），它是用于活化环上溴基团的氨基衍生物的前体。使用BCPE测定法评估了这些衍生物（7、11、17）对C6、HeLa和HT29癌细胞系的抗增殖活性。化合物7、11和17表现出显著的抑制作用，其中化合物11活性最高（IC值为5.45 - 9.6μg/mL）。此外，使用乳酸脱氢酶测定法评估了这些化合物的细胞毒性，结果表明与对照药物5-氟尿嘧啶相比，其细胞毒性较低。通过DNA梯状条带分析证实了化合物11和17诱导细胞凋亡的能力，而化合物7未显示出这种作用。化合物7和11抑制人拓扑异构酶I，这是一种对DNA复制和修复至关重要的酶，通过MM-PBSA研究确定了其显著的结合能。伤口愈合测定表明化合物17有效地抑制了HT29细胞的迁移。这些发现突出了这些新型喹啉衍生物作为有效抗癌剂的潜力，值得进一步研究它们的作用机制和治疗应用。
