The Synthesis Of Pentacyclic Triterpenes Derivatives And The Investigation Of Their Anti-tumor Activity

Pentacyclic triterpenes , which widely exist in natural plants, possess high efficiency as well as low side-effect in eliminating tumor and viruses. Once being properly developed and utilized, they can substitute the front line anti-tumor drugs by strengthening patients'conformance, alleviating the side-effect and improve the life standard of the patients. As a result, this sort of drugs has received unprecedented attention from pharmaceutists and researchers over the world. Here, we synthesized a series of Derivatives of pentacyclic triterpenes through chemical modification, and observed their diversification in physical and chemical character in order to deduce the direction of later chemical modification.In this experiment, we used the Oleanolic acid as substrate, protected its hydroxyl through acetylation, and get the compound No.1,namely 3-O-acetate of Oleanolic acid. Then we got the Reduction the precedent protected Lysine methyl ester as well as the hydroxyl through hydrolysis. Through research, we managed to obtain the best way of isolation and purification (including recrystalization and chromatography) so as to process the production of each step. We used the same way to process the Betulinic acid and Ursolic acid in order to get the primary information about these two compounds. And finally through the MTT experiments, we carried out the biological tests in order to compare the efficiency in the treatment against cancer among the Derivatives.The result: we finally got two derivatives of the Oleanolic acid with high purification. Through the IR, NMR and MS tests and structure certification, we are now certain that one of the derivatives is 3-O-acetate of Oleanolic acid and he output rate is 87.16%. the other one, which is a brand new compound, LNOAERT, is a dimer formed by Lysine and Oleanolic acid, with a output rate of 32.14%. The product after hydrolysis was found to be incomplete through the MS and NMR tests, and the techniques need further improvement. We also obtained two derivatives of the Betulinic acid which were highly purified. Among them, one was identified to be 3-O-acetate of Betulinic acid with the production rate of 82.5%. through MS test, it was found that the molecular weight of the other derivative was over 1000 and we deduced that it was a dimer formed by Betulinic acid and Lysine. LNBTAERT. However, due to the inadequacy of the current data of the NMR test, we failed to identify its structure. The stream line of chemical modification of the Ursolic acid is now basically mature, yet the further studies for the structure analysis and bioassay are being conducted to get more insight of Ursolic acid. After MTT bioassay in vitro, we now confirmed that the effects in anti-tumor of the derivatives of both Betulinic acid and Oleanolic acid are superior than that of the original compound.The specialty and innovation of this experiment are as following: we successfully synthesized and demonstrated the dimer consisted of ursolic acid and Lysine as well as other three Derivatives of pentacyclic triterpenes. Through MTT bioassay in vitro, we were able to document that the impact of these compounds in the tumor treatment is superior to that of the original ones. Especially for the new compound based on ursolic acid, the effect is proved to be better even than the 5 - fluorouracil, which has previously been demonstrated as a positive anti-tumor drug. Besides, we largely reduced the time needed in Amidation and Chlorination for the Derivatives of pentacyclic triterpenes. Although the output rate of these new compounds remains relatively low, the outgrowth of the Amidation still worth attention and even further investigation, for the high efficiency they presented in the experiments can be of great significance in pharmaceutical industry in the future. Moreover, theoretically speaking, there's no report for byproducts of Amidation yet, so we'll continue to make deeply reaseach.