Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity

Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for in vitro anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC₅₀ of compound HL22 against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound HL22 significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by HL22. The ¹H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.