In-vitro antitumor activity evaluation of hyperforin derivatives

Abstract

The derivatives of hyperforin, namely hyperforin acetate (2), 17,18,22,23,27,28,32,33-octahydrohyperforin acetate (3), and N,N-dicyclohexylamine salt of hyperforin (4), have been investigated for their antitumor properties. In-vitro studies demonstrated that 2 and 4 were active against HeLa (human cervical cancer), A375 (human malignant melanoma), HepG2 (human hepatocellular carcinoma), MCF-7 (human breast cancer), A549 (human nonsmall cell lung cancer), K562 (human chronic myeloid leukemia), and K562/ADR (human adriamycin-resistant K562) cell lines with IC₅₀ values in the range of 3.2–64.1 μM. The energy differences between highest occupied molecular orbital and lowest unoccupied molecular orbital of 2–4 were calculated to be 0.39778, 0.43106, and 0.30900 a.u., respectively, using the Gaussian 03 software package and ab initio method with the HF/6-311 G* basis set. The result indicated that the biological activity of 4 might be the strongest and that of 3 might be the weakest, which was in accordance with their corresponding antiproliferative effects against the tested tumor cell lines. Compound 4 caused cell cycle arrest at G2/M phase in flow cytometry experiment and induced apoptosis by 4′,6-diamidino-2-phenylindole staining and Annexin V-FITC/PI (propidium iodide) double-labeled staining in HepG2 cells. The results indicated a potential for N,N-dicyclohexylamine salt of hyperforin as a new antitumor drug.

Keywords:

• hyperforin derivatives
• antiproliferative effect
• apoptosis
• quantum chemistry calculation

Acknowledgements

This work was supported by the Australia–China Special Fund for Scientific and Technological Cooperation (30470188), International Science and Technology Cooperation Program of China (2009DF31230), External Cooperation of Science and Technology of Guangdong Province, China (2009B050500002), Guangdong Natural Science Foundation (10451008901004959), China Postdoctoral Science Foundation (20090450194), and the Fundamental Research Funds for the Central Universities (21609303).

Notes

^†These authors contributed equally to this research.