engleski

Synthesis of Harmirines - Novel 1- and 3-substituted Harmine-Coumarin Hybrids

The emergence of cancer drug resistance poses a significant global public health challenge leading to cancer recurrence. Thus, there remains a constant need for new effective anticancer agents. Harmine belongs to a class of naturally occurring β-carbolines – pharmacologically active alkaloids having a broad spectrum of antitumor activity through diverse mechanisms [1]. Similarly, coumarins, compounds widely distributed in plants, also exert anticancer activity [2]. Therefore, β-carboline alkaloids, as well as coumarins, might present lead compounds in the field of drug discovery. To this end, we have prepared harmirines, new hybrid molecules consisting of both pharmacophores, linked by a 1, 2, 3-triazole. The novel series of harmirines possesses substituents at positions 1 or 3 of the β-carboline core. To prepare the title compounds, we have synthesized coumarin-based terminal alkynes 1a-d and harmine-based azides 2 and 3. Alkynes were prepared in a one-step reaction by the treatment of hydroxycoumarins with propargyl bromide in the presence of cesium carbonate. The preparation of harmine-based azides 2 and 3 at positions 1 and 3 of the β-carboline ring was previously described by our research group [3]. Synthesized alkynes and azides were the starting compounds for the Cu(I)-catalyzed azide-alkyne cycloaddition resulting in two types of hybrids: 1- and 3-substituted harmirines 4a-d and 5a-d, respectively. Harmirines 5a-d were prepared using Cu(II)-acetate precatalyst in methanol. On the other hand, due to the fewer byproducts and easier purification, sodium ascorbate was a reducing agent of choice for the generation of Cu(I) from CuSO4×5H2O in the synthesis of harmirines 4a-d. The scheme outlines the general route leading to the title compounds (Figure). The structures of newly prepared compounds 4 and 5 were confirmed by standard methods (IR, 1H, 13C NMR, MS). The evaluation of their antiproliferative activity is in progress.

harmine ; coumarin ; hybrids

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