Synthesis And Antitumor Activity Evaluation Of Ginsenoside AD-2 And PD Derivatives

Hepatocellular carcinoma(HCC)is a malignant tumor with a second mortality rate in China.In the process of tumor growth,liver cancer tissue is easy to form hypoxia microenvironment and hypoxia is one of the key factors that cause the invasion and metastasis of tumor cells.Hypoxia-inducible factor(HIF-1 a)is the most significant transcription factor in tumor cells under hypoxia.It can activate and regulate the products of various hypoxia-responsive genes and control the proliferation,invasion and apoptosis of tumor cells.The importance of HIF-1? in the process of tumor development provides us ideas to find reasonable and efficient anti-hepatocellular carcinoma drugs.Naturally occurring products like ginsenosides possessing favorable advantages of biological activities and low toxicity to human body are widely investigated for the development of new anti-tumor drugs.25-Hydroxy protopanaxadiol(25-OH-PPD,AD-2),one component of the ginsenosides(Fig.1),has been reported to exhibits strong anti-tumor activity(IC50=20-60 ?M)that can inhibit the growth and proliferation of tumor cells by arresting cell cycle and inducing tumor cell differentiation and apoptosis.Compared with ginsenoside Rg3(Shenyijiaonang,an agent already being marketed for cancer therapy),AD-2 exhibits 5-15 times higher tumor growth inhibitory activity and show little host toxicity.(20R)-Panaxadiol(PD)(Fig.1),an ortho-ginseng diol type compound having an aglycone complex,has been reported to have a tumor growth inhibitory activity and has been previously used as a leader for the synthesis of novel derivatives.In this study,we report design and synthesis of the ginsenoside derivatives using 25-OH-PPD and panaxadiol(PD)as leader compounds in order to obtain more potent anti-tumor agents.Thus,a total of 19 ginsenoside derivatives were synthesized and evaluated for their anti-tumor activity by cytotoxin reporter assay and MTT assay.The results shows that five compounds showed greater antitumor activity than the leaders in which the compounds L5,L16,L10 and L17 exhibited the most significant anti-tumor activitiesSAR studies showed that(1)Antitumor activity of L17,L18,L19 was stronger than the parent drug,it could be seen that oxidation of one or two the hydroxyl groups at 3-and 12-position into carbonyl groups resulted in a significant improvement of anti-tumor activity.(2)The anti-tumor activity of derivative L4 was stronger than that of derivative L1,indicating that the chain-like substituent at 20-position might play a critical role to the activity than the ring substituent,the difference in activity may be related to free hydroxyl groups.(3)Introducing of 2,4-dinitrophenylhydrazone to the 12-position of AD-2(L5)resulted in increase of potency compared with the corresponding ketone derivative L17.