Synthesis of Caffeic Acid Amides Bearing 2,3,4,5-Tetra-hydrobenzo[b][1,4]dioxocine Moieties and Their Biological Evaluation as Antitumor Agents

A series of caffeic acid amides D(1)-D(17) bearing 2,3,4,5-tetrahydrobenzo-[b][1,4]dioxocine units has been synthesized and their biological activities evaluated for potential antiproliferative and EGFR inhibitory activity. Of all the compounds studied, compound D(9) showed the most potent inhibitory activity (IC(50) = 0.79 μM for HepG2 and IC(50) = 0.36 μM for EGFR). The structures of compounds were confirmed by (1)H-NMR, ESI-MS and elemental analysis. Among all, the structure of compound D(9) ((E)-N-(4-ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)acrylamide) was also determined by single-crystal X-ray diffraction analysis. Compound D(9) was found to be a potential antitumor agent according to biological activity, molecular docking, apoptosis assay and inhibition of HepG2.