Highly Brominated Quinolines: Synthesis, Characterization, and Investigation of Anticancer Activities Supported by Molecular Dynamics

Abstract

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 (IC₅₀ 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.