Ursolic Acid Water-soluble Prodrug Of A-ring Of Oleanolic Acid Derivatives Synthesis

There are two parts in this master thesis, i.e., the design, synthesis and pharmaco-logical assays of water-soluble prodrugs of ursolic acid and oleanolic acid. Part I The synthesis of water-soluble prodrugs of ursolic acidUrsolic acid (UA) is a triterpene, which is abundant in the nature. Biological and pharmacological activities of UA and its derivates exhibited antitumor, hepatoprotective, anti-inflammatory, antiviral, and many other properties. To find novel anti-tumor compounds, the modification of UA is of particular interest.The activity of hepatoprotective of UA has been validated tentatively in preclinical and clinical tests, and the problem of pilot scale production of UA has been solved. However its clinical use was limited due to its low water-solubility and poor oral bioavailability. So we intend to improve its water-solubility and heaptoprotective activity through structural modifications.Thus, two types of derivatives from UA were designed and synthesized:First, a series of amino acid conjugates of UA have been designed and synthesized, and the pharmacological test of hepatoprotective in vitro and in vivo have been done. Its poor hepatoprotective activity maybe attributed to the imide bond is hard to hydrolyze, or maybe the activity of the new derivates is not as well as UA, the activity of hepatoprotective is not very good.Second, the galactose derivates including C-3 glycoside derivates, C-28 glycoside derivates, and 3,28-bisglycoside derivates were synthesized to enhance their water solubility and liver targeting. The physiochemical properties and pharmacological activities of these derivatives are still under investigation. Part 11 The synthesis of A ring derivates of oleanolic acid.Oleanolic acid (OA) is oleanane type triterpene, which is abundant in the nature. Biological and pharmacological activities of OA have been found to span a wide variety of ranges, such as antitumor, antiviral, anti-inflammatory, hepatoprotective, gastroprotec-tive, antimicrobial, antidiabetic, hemolytic and many other properties.After analysing their structure-activity relationship (SAR), we found that OA derivatives with a polar group such as -OH or -COOH at C-23 or C-24 exhibited angiogenic activity. So the 24-OH deriviatives were designed and synthetic efforts toward them have been made.Furthermore, according to the possible relevance of anticancer activity to the planarity of the A ring observed in pentacychc triterpenoids, a series of derivates of oleanolic acid with planar structure in the A ring and different substituting groups at C-2 were designed to facilitate further SAR studies.