2. Academic Validation
  3. Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer

Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer

  • Bioorg Med Chem. 2024 Jun 15:108:117786. doi: 10.1016/j.bmc.2024.117786.
Jielin Tang 1,  Yuxin Zhang 1,  Lingling Zhou 1,  Xiangrui Song 1,  Yusi Wei 2,  Ji Qi 2,  Jianmin Wu 3,  Zengqiang Song 4,  Lingling Zhan 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 5 Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
PMID: 38843656 DOI: 10.1016/j.bmc.2024.117786
Abstract

An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound 3ab showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that 3ab could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and Apoptosis. Mechanistic studies revealed that compound 3ab inhibited the proliferation of CRC cells via suppressing the Akt/GSK-3β pathway. In vivo evaluation demonstrated remarkable antitumor effect of 3ab (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate 3ab could be considered as a potential CRC therapy agent for further development.

Keywords

AKT/GSK-3β; Antitumor; Colorectal cancer; Efficient synthesis; Indoline-maleimide conjugates.

Figures