Design, synthesis, and cytotoxic evaluation of novel scopoletin derivatives.

A series of scopoletin derivatives were designed and synthesized by introducing α-aminoacetamide, acrylamide and β-aminopropamide, respectively, to 3-position of scopoletin, and their chemical structures were confirmed by ESI-MS, IR, 1 H NMR, and 13 C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) by MTT method. Cytotoxic assay showed that compounds 7a, 7b, 7e, 7f, 8a, and 8e exhibited more potent cytotoxicities compared to scopoletin. Besides, we have further evaluated the growth inhibitory activities of these selected compounds against normal tissue cell lines HFL-1. Although compound 8a showed the strongest antiproliferative activity in vitro, it exhibited strong cytotoxicity on normal cells HFL-1, which limited its further study. Compound 7a and 7b exhibited higher antiproliferative activity against MDA-MB-231 and HepG2 cells and weak cytotoxicity on HFL-1, which suggested that 7a and 7b might be ideal anticancer candidates. The SARs showed that the introduction of the acrylamide and its analogues β-aminopropamide could significantly improve activity, while the α-aminoacetamide failed to enhance potency obviously. Therefore, the mechanism of compound 7a and 7b is worthy of further research and the structure of compound 8a should be further optimized.