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Harmirins, Novel Harmine-Coumarin Hybrids as Potential Anticancer Agents

Novel anticancer agents are constantly needed as cancer remains one of the greatest global health burdens. As a continuation of our work on harmine derivatives, we have prepared five series of harmirins – novel hybrid molecules of 1, 2, 3-triazole-type comprising harmine and coumarin pharmacophores (Figure). Harmine, a β-carboline representative, and coumarins are two important classes of natural products both possessing anticancer properties. Here, we report their synthesis, antiproliferative activity, cell localization, and influence on the cell cycle. Harmirins were obtained by applying the standard Cu(I) catalyzed azide-alkyne cycloaddition. Their antiproliferative activity was evaluated in vitro against four human cancer cell lines (HepG2, SW620, HCT116, MCF-7) and one human non-cancer cell line (HEK293T). Harmirins 3 and 5 with the smallest substituents (H or F) on the coumarin ring showed the highest cytotoxicity against all tested cell lines. SAR analysis revealed that seven harmirins display activities in the single-digit micromolar range against MCF-7 and HCT116. Among them, harmirins 2b and 4b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at the position 6 of the coumarin ring, were the most active compounds with the highest selectivity towards cancer cells, in comparison to HEK293T. Harmirin 4b and MCF-7 cell line were chosen for further investigation. Cell localization experiments demonstrated that 4b remains exclusively in the cytoplasm. Furthermore, cell cycle analysis has shown that the treatment of MCF-7 cells with harmirin 4b induced a strong G1 arrest, accompanied by a drastic reduction in the percentage of cells in the S phase. These results might suggest that harmirin 4b exerts its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. Our future experiments will focus on the elucidation of molecular mechanisms involved in the anticancer activities of harmirins.

harmine ; coumarin ; hybrids ; anticancer activity

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