Design, synthesis and pharmacological evaluation of β-carboline derivatives as potential antitumor agent via targeting autophagy

  • Eur J Med Chem. 2022 Nov 26;246:114955. doi: 10.1016/j.ejmech.2022.114955.
Jingsheng Ao  1 ,  Feng Zeng  2 ,  Longhao Wang  3 ,  Liqin Qiu  3 ,  Rihui Cao  4 ,  Xiangpan Li  5
Affiliations
  • 1. School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou, 510275, PR China; Department of Oncology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, 430072, PR China.
  • 2. Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, 430072, PR China.
  • 3. School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou, 510275, PR China.
  • 4. School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou, 510275, PR China. Electronic address: [email protected].
  • 5. Department of Oncology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, 430072, PR China. Electronic address: [email protected].
PMID: 36459757 DOI: 10.1016/j.ejmech.2022.114955
Abstract

A series of novel β-carboline derivatives was designed, synthesized and evaluated as potential Anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786-0, HT-29 and 22RV1 cell lines with IC50 values of 2.71, 2.02, and 3.86 μM, respectively. The antitumor efficiency of compound 6gin vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal Cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal Cancer therapy agent.

Keywords
ATG5/ATG7; Antitumor; Autophagy; Colorectal cancer; Synthesis; β-Carboline.
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