Discovery of 8-sulfonamidoquinolines as anti-proliferative agents against colorectal cancer: design, synthesis, and biological evaluation.

Derivatives based on the marine natural product (MNP) Ammosamide B (1) exhibited potent inhibitory activity against bromodomain-containing protein 4 (BRD4), yet their anti-proliferative effects in cellular assays remained unsatisfactory. To overcome this limitation, a ring-opening strategy was employed, leading to the design and synthesis of several series of sulfonamide derivatives. Structure-activity relationship studies were conducted, from which compound II-2, an 8-sulfonamidoquinoline derivative, emerged with significantly enhanced anti-proliferative activity against HCT116 cells, showing an IC value of 1.0 μM. Moreover, compound II-2 markedly suppressed cellular migration and colony formation, while also promoting apoptosis in HCT116 cells. Preliminary mechanistic investigations indicated that II-2 might inhibit the NF-κB signaling pathway and the WNT/β-catenin pathway by binding to P65. Molecular docking and molecular dynamics simulation predicted the interactions between II-2 and P65 in detail. The findings highlight that 8-sulfonamidoquinoline derivatives may be candidate molecules for the treatment of colon cancer and worthy for further investigation.