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Antiproliferative activity of novel harmirins

β-Carbolines and coumarins are two classes of phytochemicals possessing a wide variety of biological activities, including anticancer properties.[1, 2] As a continuation of our work on hybrid compounds, we have prepared a series of harmirins – novel hybrid molecules comprising harmine, a representative of β-carbolines, and coumarin moieties linked by a 1, 2, 3-triazole. Five series of harmirins, bearing coumarin substituents at positions 1, 3, 6, 7 and 9 of the β-carboline core were prepared (Figure). Their antiproliferative activity was evaluated in vitro against human cell lines (HepG2, SW620, HCT116, MCF-7, HEK293T) and SAR analysis was performed for the most susceptible ones (HCT116 and MCF-7, IC50s in the one-digit micromolar range). The activity of harmirins towards MCF-7 decreased following the pattern 3 > 4 > 5 > 2 > 1, while the activity of compounds 2-5 against HCT116 was in the same range. Series 1 was generally inactive against both MCF-7 and HCT116. Harmirins 3 and 5 with the smallest substituents (H or F) showed the highest cytotoxicity against all tested cell lines. On the other hand, harmirins 2b and 4b, bearing a methyl substituent on the coumarin ring, were the most active compounds with the most favourable selectivity indices. However, compound 4b was selected for further investigation due to its high activity against both HCT116 and MCF-7 in low micromolar range. REFERENCES [1] S. Aaghaz et al., European Journal of Medicinal Chemistry, 2021, 216, 113321. [2] A. Thakur et al., European Journal of Medicinal Chemistry, 2015, 101, 476– 495.

harmine, coumarin, hybrid molecules, antiproliferative activity

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