Synthesis And Anti-Tumor Effect Evaluation Of Some Novel Panaxadiol And Dhea Derivatives

Cancer is a term used for diseases in which abnormal cells divide uncontrollably and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. For most of chemotherapeutic agents, a direct correlation between the antitumor efficacy and the ability to induce normal cell apoptosis was established, so it is a challenge to search a kind of new anticancer agents, possessing strong anticancer activity against various cancer cells with low toxicity in normal cells.Ginsenosides are considered to be the main bioactive constituents of Panax ginseng which has a range of biological properties including anti-tumor [1-3], antioxidative [4], immunomodulatory [5], analgesic and anti-inflammatory activities [6] and neuroprotective effects [7]. It was reported that panaxadiol (PD, Fig.1), one of the protopanaxadiol-type of ginsenoside with a dammarane skeleton, could enhance its anti-tumor effects when co-administrated with cyclophosphamide [8] and 5-fluorouracil [9,10] in human cancer cell lines.Dehydroepiandrosterone (DHEA), a major steroid secreted by the adrenal gland which decreases with age after adolescence, is available as a nutritional supplement [11] and the most abundant steroid in humans [12]. In addition to serving as a precursor of both androgens and estrogens, DHEA has various other beneficial biological effects. In experimental animals, DHEA decreases body fat without altering food intake, enhances the immune system, suppresses spontaneous decreases in blood glucose in diabetic mice and increases the memory of old mice [13]. In recent years, it has been reported that DHEA possesses an anti-proliferative effect on animal tumor models and malignant cell lines [14], although the mechanisms of altered tumor growth have not been established.In the present work, we aim to increase the antitumor effects of PD and DHEA, 27 derivatives of panaxadiol and 58 derivatives of DHEA were synthesized. The structures of these compounds were identified using 1H-NMR,13H-NMR, MS, and IR spectroscopy. The anti-tumor activities of 69 synthesized compounds were evaluated against the different human tumor cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicated that most amino acid acylated PD compounds showed stronger activities than that of PD, and 4c,5i,5o,6a,6b and 6c showed stronger activities than that of DHEA.In conclusion, we have synthesized two series of derivatives of DHEA and PD, investigated their growth inhibitory activities against different human tumor cell lines. Several derivatives demonstrated stronger potencies than PD, DHEA. The most promising compounds in those series were 1b,2a,2b,2c,2d, 2e,2f,4c,5i,5o,6a,6b and 6c. Further investigations into optimizing the inhibitory activity of these compounds are in progress.