Benzylpiperazinyl Derivatives of Alepterolic Acid: Synthesis and Cytotoxic Evaluation.

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 highest level of toxicity against MCF-7 cell line, with an 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/Bcl-2 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.