Design, synthesis and in vitro and in vivo antitumor activities of novel β-carboline derivatives

Abstract To further our SAR study on the chemistry and antitumor activity/neurotoxicity of β-carboline alkaloids, several series of β-carboline derivatives with various substituents were designed and synthesized from the starting material l -tryptophan on the basis of harmine chemical structure. Cytotoxic activities of these compounds were investigated in vitro. The results showed that some β-carboline derivatives had significant cytotoxic activities against human tumor cell lines. Among all the synthesized β-carboline derivatives, the compounds 27 , 28 and 32 , having a benzyl substituent at both position-2 and 9, respectively, were found to be the most potent compounds with IC 50 value lower than 50 μM against all human tumor cell lines examined. Acute toxicities and antitumor activities of the selected β-carboline derivatives in mice were also evaluated. The results demonstrated that a benzyl substituent at position-2 increased the antitumor activity as well as acute toxicity significantly. However an (ethoxycarbonyl)amino substituent at position-3 reduced the acute toxicity as well as antitumor activity remarkedly. These data suggested that ( 1 ) the antitumor potencies of β-carboline derivatives were enhanced by the introduction of benzyl substituent into the position-2; ( 2 ) the acute toxicity of β-carboline derivatives reduced dramatically by the introduction of an appropriate substituent into the position-3 and 9; ( 3 ) the β-carboline structure might be an important basis for the design and synthesis of new antitumor drugs with significant antitumor activity and low toxicity.