Design, synthesis and in vitro and in vivo antitumor activities of novel bivalent β-carbolines

A series of bivalent β-carbolines with a spacer of three to ten methylene units between the indole nitrogen was synthesized and evaluated as antitumor agents. The results demonstrated that compounds 18c, 21b, 25a and 31b exhibited strong cytotoxic activities with IC50 value of lower than 20 μM against four tumor cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 18b, 21b, 26a and 31b exhibited potent antitumor activities with tumor inhibition rate of over 40% in animal models. Preliminary structure–activity relationships analysis indicated that (1) the spacer length affected antitumor potencies, and four to six methylene units were more favorable; (2) the introduction of appropriate substituent into position-1 of β-carboline facilitated antitumor potencies.

A series of bivalent β-carbolines with a spacer between the indole nitrogen was synthesized and their cytotoxic activities in vitro and antitumor efficacies in vivo were evaluated.Figure optionsDownload as PowerPoint slideHighlights
► A series of bivalent β-carbolines was prepared and evaluated as antitumor agents.
► Compounds 18b, 21b, 26a and 31b were found to be the most potent antitumor agents.
► The length of the spacer affected antitumor efficacies of bivalent β-carbolines.
► Appropriate substituents in position-1 facilitated antitumor activities.