Synthesis and structure–activity relationships of harmine derivatives as potential antitumor agents

Harmine, a naturally occurring β-carboline alkaloid, showed good antitumor activities together with remarkable neurotoxic effects in animal models. In order to search for novel leading compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were designed and synthesized by modification of position-2, 7 and 9 of β-carboline nucleus, and their cytotoxic activities against human tumor cell lines were investigated. Acute toxicities and antitumor activities of the selected compounds in mice were also evaluated. Structure–activity relationships studies confirmed that (1) the 7-methoxy structural moiety was the pharmacophore responsible for the neurotoxic effects of this class of compounds; (2) the substituents in position-2 and 9 played a vital role in modulation of their antitumor activities.

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► A series of 2,7,9-trisubstituted harmine derivatives was synthesized.
► Compounds 5f and 5m were found to be the most potent antitumor agents.
► The 7-methoxy group was responsible for their neurotoxic effects.
► Appropriate substituents in position-2 and 9 facilitated antitumor activities.