Benzylpiperazinyl Derivatives of Alepterolic Acid: Synthesis and Cytotoxic Evaluation

Abstract

Natural products play a significant role in the development of modern drugs. Alepterolic acid, a labdane‐type diterpenoid firstly isolated from Aleuritopteris argentea (Gmél.) Fée, has been identified as a valuable template for the synthesis of potent anticancer agents by structural modification. In this study, a series of new derivatives was obtained by coupling alepterolic acid with benzylpiperazines. It was found that (3,4‐dichlorobenzyl)piperazinyl alepterolic acid (compound 6p) displayed the most toxic against MCF‐7 cell line, with IC50 value of 8.31±0.67 μM. Further investigations demonstrated that compound 6p induced morphological changes in MCF‐7 cells, inhibited proliferation in a time‐ and dose‐dependent manner. Furthermore, western blot analysis revealed that compound 6p induced a significant increase in cleaved caspase‐9, cleaved caspase‐3, cleaved poly (ADP‐ribose) polymerase (PARP) and Bax/Bcl2 ratio in MCF‐7 cells. All of these results confirmed that compound 6p induced endogenous apoptosis in MCF‐7 cells. Conclusively, the findings suggest that the incorporation of benzylpiperazine to alepterolic acid represents a promising approach for the discovery of new drug candidates.