Synthesis and anticancer activity of novel coumarin-stilbene hybrids with different hydrocarbon chains as linkers

Abstract

Stilbene derivatives (pterostilbene and resveratrol) and 4-methylumbelliferone occur naturally in plants. These compounds and coumarin-stilbene hybrids have a variety of biological activities. It was envisioned that the molecular hybridization strategy would produce new bioactive molecules. Thus, six new coumarin-stilbene hybrids (3a-b, 4a-b, and 5a-b) with different hydrocarbon chains as linkers were synthesized by the O-alkylation reaction and characterized using FTIR, ¹H NMR, ¹³C NMR, DEPT-135, and HRMS (ESI+) spectral analysis. An MTT assay was used to test the synthesized hybrids against breast cancer (MCF-7 and T47D) and liver cancer (HepG2) cell lines. The results showed that the synthesis of coumarin-stilbene hybrids via the O-alkylation reaction requires the presence of KI in addition to K₂CO₃ as a base to complete the reaction. On the other hand, the synthesis of coumarin-pterostilbene hybrids (3a-b) via the O-alkylation reaction with DMF as a solvent and an excess of base (K₂CO₃) and catalyst (KI) improved the yield significantly (65.43 and 73.71%, respectively). The biological results exhibited that all hybrids showed moderate to weak anticancer activities, much lower than the medication (cisplatin). However, most compounds showed superior activities than parent compounds against three different human cell lines. Among them, compounds 4a and 4b exhibited the best cytotoxic activity against T47D and MCF-7, with IC₅₀ values of 102.05 and 23.12 µM, respectively. Compound (3a) showed the most cytotoxic activity against HepG2, with an IC₅₀ value of 80.09 µM. To conclude, due to the simplicity of synthesis, hybridization is a promising strategy for producing new hybrid compounds with hydrocarbon chains as linkers and improving biological activity compared with their parent compounds.