2. Academic Validation
  3. Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism

Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism

  • Eur J Med Chem. 2024 Jul 5:273:116509. doi: 10.1016/j.ejmech.2024.116509.
Yonghua Liu 1,  Junyi Zhang 2,  Jiaqi Tian 2,  Chengxi Wang 2,  Tianqi Wang 2,  Jianhua Gong 3,  Laixing Hu 4
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
PMID: 38781920 DOI: 10.1016/j.ejmech.2024.116509
Abstract

A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC50 values of 0.81-31.19 nM) against five different Cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high Cancer cell selectivity (IC50(L02)/average IC50: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce Apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for Cancer treatment.

Keywords

Antiproliferative activity; Antitumor; Carbazole sulfonamide; Colchicine binding site; Topo I.

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