Synthesis And Structure-activity Relationship Of Pseudo-ginsenoside Rh₂and Its Isomer

Ginseng, which is well-known as the king of herbs, has been an important medicinalresource all over the world. A large number of experimental studies have shown this herb tohave antidiabetic, anti-HIV protease, and antitumor activities. Ginsenosides are considered asthe major pharmacologically active ingredient of ginseng, which are defined as types ofprotopanaxadiol (PPD), protopanaxatriol (PPT), and oleanolic acid according to aglyconeskeleton.Previous studies on the structure–activity relationships of ginsenosides suggested that theanti-tumor activities were affected by the positions of the hydroxyl group and double band inthe side chain, and the stereochemistry of the double bond also played a crucial role for theiranti-tumor activities. For example, the relationships of inhibit-ory rate on HSC-T6cell forginsenoside Rh2with different side chain at C20were that20(S)-Rh2＞20(R)-Rh2,20(S)-25-OH-Rh2＞20(R)-25-OH-Rh2,20(S)-Rh2＞20(R)-25-OH-Rh2. Moreover, theoctillol-type derivatives of ginsenoside Rh2had higher inhibitory rate on CK, LDH and MDAcells; lower inhibitory rate on SOD, GSH-PX and T-AOC cells compared by team ofginsenoside Rh2.Based on the previous study, we wanted to synthesize new ginsenosides with ginsenosideRh2and proved the data for the structure–activity relationship, which can be used for thedeveloping of new medicine. In current, many dammarane-type derivatives have been preparedand investigated for their activities, such as25-OH-Rh2and the octillol-type derivatives ofginsenoside Rh2. In our plan, we have described the synthesis of two dammarane-typederivatives, namely, β-D-Glucopyranoside,(3β,12β,20E)-12,25-dihydroxydammar-20(22)-en-3-yl (Pseudo-G-Rh2) and β-D-Glucopyranoside,(3β,12β,20Z)-12,25-dihydroxydammar-20(22)-en-3-yl (20Z-isomer), both of which bear a different side chain at C-17by comparing withginsenoside Rh2. Because of the low product of ginsenoside Rh2in the nature products, we have decided tosynthesize it by alkaline and acid hydrolysis. In a series of experiments, we found that we canget only one kind of ginsenoside Rh2(20S) by alkaline hydrolysis, while we can get two kinds(20S,20R) with acid hydrolysis, which can be explained by the reaction mechanism in ourhypothesis.Here we proposed a low-temperature synthesis of Pseudo-G-Rh2and its20Z-isomer.Through the elimination and addition at different positions in a one-step reaction, the excellentyields of the title compounds were achieved conveniently. In addition, we found that if raisethe temperature or alter the acid medium, the reaction was unsatisfactory and often resulted in acomplicated mixture of products, which indirectly indicated the irreplaceability of thelow-temperature and the acid catalysis.Pseudo-G-Rh2, its20Z-isomer and ginsenoside Rh2were evaluated on eight differenthuman tumor cell lines using MTT assay. Results indicated that the reaction in the side chainmight greatly enhance the anti-proliferative activity of ginsenosides.We have proved a synthesis of Pseudo-G-Rh2and its20Z-isomer on the high yields andtheir activities were evaluated by eight different human tumor cells, compared withginsenoside Rh2group, which can be used for the developments of medicine.