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

Abstract

Alepterolic 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.

• Authors: Zi Liu, Chenlu Xia, Nina Wang, Jianguo Cao, Guozheng Huang, Liang Ma
• Journal: Chemistry & biodiversity (Chem Biodivers) Vol. 20 Issue 5 Pg. e202300208 (May 2023) ISSN: 1612-1880 [Electronic] Switzerland
• PMID: 36960853 (Publication Type: Journal Article)
• Copyright: © 2023 Wiley-VHCA AG, Zurich, Switzerland.

Chemical References

• Antineoplastic Agents
• Piperazines
• alepterolic acid

Topics

• Humans
• Antineoplastic Agents (chemistry)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Drug Screening Assays, Antitumor
• MCF-7 Cells
• Piperazines (pharmacology)