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

  • Bioorg Chem. 2026 Jun 5:173:109689. doi: 10.1016/j.bioorg.2026.109689.
Yanfeng Sun  1 ,  Yanmei Chen  1 ,  Zhenhao Wang  1 ,  Yue Zhou  1 ,  Xinxin Zhang  2 ,  Liangzhou Li  1 ,  Jinbo Yang  2 ,  Pingyuan Wang  3 ,  Zhiqing Liu  4 ,  Chang-Yun Wang  5
Affiliations
  • 1. MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 2. MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China.
  • 3. MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China. Electronic address: [email protected].
  • 4. MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China. Electronic address: [email protected].
  • 5. MOE Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China. Electronic address: [email protected].
PMID: 41763019 DOI: 10.1016/j.bioorg.2026.109689
Abstract

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 IC50 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.

Keywords
8-Sulfonamidoquinolines; Anti-proliferative activity; Colorectal cancer; Molecular docking; Structure-activity relationship.
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