Design, synthesis and biological evaluation of novel β-carbolines as antitumor agents via targeting autophagy in colorectal cancer

Abstract

A series of novel β-carbolines with a flexible amino side chain at positions 1 and 3, respectively, were designed, synthesized and evaluated as potential antitumor agents. The results revealed that most of the compounds exhibited a broad spectrum of antiproliferative activity with IC₅₀ value lower than 20 μM against human tumor cell lines. Among them, compound 2f was the most potent antiproliferative agent with IC₅₀ value below 5.0 μM against human tumor cell lines. Subsequent studies on the in vivo antitumor efficacy of the representative compound 2f demonstrated its ability to hinder tumor progression and significantly diminish tumor mass in a mouse model of colorectal cancer. Further investigation on mechanisms of action showed that compound 2f induced autophagy via the ATG5/ATG7 pathway in HCT116 cells. These compounds may contribute to the development of therapeutic agents for colorectal cancer.

Keywords: Antitumor; Autophagy; Synthesis; β-carbolines.