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

Jingsheng Ao; Feng Zeng; Longhao Wang; Liqin Qiu; Rihui Cao; Xiangpan Li

doi:10.1016/j.ejmech.2022.114955

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

Eur J Med Chem. 2023 Jan 15:246:114955. doi: 10.1016/j.ejmech.2022.114955. Epub 2022 Nov 26.

Authors

Jingsheng Ao¹, Feng Zeng², Longhao Wang³, Liqin Qiu³, Rihui Cao⁴, Xiangpan Li⁵

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: caorihui@mail.sysu.edu.cn.
⁵ Department of Oncology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, 430072, PR China. Electronic address: rm001227@whu.edu.cn.

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.

MeSH terms

Animals
Antineoplastic Agents*
Autophagy
Carbolines
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms* / drug therapy
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Mice
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Carbolines