Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis

Abstract Beta‐carboline alkaloids such as harmine are present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In our study, 9 harmine derivatives (including harmine) were investigated for their antitumor effects and acute toxicities in mice, and the structure‐activity relationship (SAR) was also analyzed. Administration of these compounds resulted in tumor inhibition rates of 15.3–49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6. Acute toxicity studies showed that all these compounds except compounds 2 and 5 caused remarkable acute neurotoxicities manifested by tremble, twitch and jumping. SAR analysis indicated that the formate substitution at R3 of the tricyclic skeleton reduced their neurotoxicity, while the short alkyl or aryl substitution at R9 increased the antitumor activity. The harmine and its derivatives resulted in in vitro cytotoxicity (IC 50 ) values of 0.011–0.021 μmol/ml in HepG2 cells, with compound 8 being the most potent among all agents tested. Compounds 1, 6, 7 and 8 induced apoptosis in HepG2 cells, with the highest apoptotic rate (55.34%) from compound 6. Western blotting analysis demonstrated that compound 6 completely inhibited the expression of Bcl‐2 gene, and compounds 1 and 8 produced a significant inhibition by 40 and 60%, respectively, compared to the control, while compound 7 did not alter the level of Bcl‐2. Compounds 1, 6, 7 and 8 upregulated the expression of death receptor Fas by approximately 50–120%. All these findings indicate that compounds with both substitutions at R3 and R9 (such as compound 5) have high antitumor activity and low toxicity, which might be chosen as lead molecules for further development. Further studies on the effects of harmine derivatives on key regulators for tumor cell apoptosis are needed. © 2004 Wiley‐Liss, Inc.