To explore the effect of the introduction of the amino and substituted amino groups on the antitumor activity of harmine, twenty-five novel 6-amino substituted harmine derivatives (3a-3j and 5a-5o) were synthesized and evaluated for anti-proliferative activity on a panel of cancer cell lines. Compounds 3i and 5n exhibited the most potent antiproliferative activity with IC50 values lower than 2.2 μM. Especially, compound 5n possessed extremely potent antitumor activity with IC50 values of 0.34 μM and 0.65 μM against HL-60 and A549 cell lines, respectively. Further, the preliminary studies of mechanisms showed that compound 5n could significantly induce cell apoptosis in a dose-dependent manner, cause cell cycle arrest at the G2/M phase and intercalate into ct-DNA via the competition with EB, while displaying very weak topoisomerase I (Topo I) inhibition activity. More importantly, 5n showed mild cytotoxicity against human normal lung epithelial cells BEAS-2B. Based on these considerations, 5n may be a good antitumor candidate compound for further exploration.
Keywords: Antitumor activity; Harmine; Structural modification; β-Carbolines.
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