Synthesis and Evaluation of Piperazine‐Tethered Derivatives of Alepterolic Acid as Anticancer Agents

Abstract

AbstractAlepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea with potential anti‐cancer activity. In this study, alepterolic acid was modified to construct a series of arylformyl piperazinyl derivatives (3a–3p). The synthesized derivatives were fully characterized with HRMS, NMR, and IR. Four compounds with inhibition rate higher than 30 % at 10 μM (3f, 3n, 3g and 3k) were further measured to obtain the IC50 values against four cancer cell lines, including hepatoma cell lines HepG2, lung cancer cell lines A549, estrogen receptor‐positive cell lines MCF7, and triple‐negative breast cancer (TNBC) cell lines MDA‐MB‐231 by MTT assay. It was found that these compounds were more effective to HepG2 and MDA‐MB‐231 cells, while less toxic to A549 and MCF7 cells, and compound 3n as the most toxic derivatve against MDA‐MB‐231 cell lines, with IC50 value of 5.55±0.56 μM. Trypan blue staining and colony formation assay showed that compound 3n inhibited the growth of MDA‐MB‐231 cells and prevented colony formation. Hoechst staining, flow cytometry and western blot analysis revealed that compound 3n induced caspase‐dependent apoptosis in MDA‐MB‐231 cells. Conclusively, compound 3n was demonstrated to be a potential anti‐cancer lead compound for further investigation.