The Design Of New Non-cyclic Nucleoside Analogues Acid Synthesis And New Coffee Pentacyclic Triterpenoid Esters And Drug Activity

This thesis consists of two parts: the first part is about the studies on the design and synthesis of the novel acyclic nucleoside analogues, and the second part is about the synthesis and bioactivity of the novel caffeyl terpenic esters.(1) Infective viral diseases are seriously threaten human health, therefor, the development of new antiviral drugs has become a world-wide scientific research hotspot. The nucleoside ananlogues occupy the vast majority of currently available antiviral drugs. Their inhibition of viral replication is achieved by blocking the combination of viral enzyme and substrate as competitive inhibitors. Structural modification of nucleoside analogues to find new lead compounds with better antiviral activities has attracted more and more research concerns.Acyclic nucleoside is an important kind of nucleoside analogues, it has been investigated for thirty years since the exposure of ACV. So far, there are several acyclic nucleoside analogues used in the clinical treatment of viral diseases. Among these drugs, the compounds with dihydroxylalkyl substitution showed better anti-viral activity, so we designed and synthesized one series of 3,4-dihydroxyl-2-substituentbutylpyrimidine or purine acyclic nucleoside analogues in order to look for novel antivirus candidates..The first synthetic procedure, a pair of chiral pre-nucleoside analogues which were enantiomers, (2'R, 3'R)-1-(3',4'-dihydroxylisopropylidenation-2'-Phenylthio-butyl)cytosine(13) and (2'S, 3'S)-1-(3',4'-dihydroxylisopropylidenation-2'-phenylthio-butyl)cytosine(19), were synthesized in 10 steps and 11 steps respectively from cis 2-butene-1,4-diol. Due to the low yield of key step, these pre-nucleoside analogues were not been extended. The second synthetic procedure, 14 novel nucleoside analogues (26a-n) were achieved through a 8-step procedure. Their structures have been confirmed by ¹HNMR, ¹³CNMR and LC-MS analysis, and their anti-viral activities are going to be tested.(2) Glycyrrhetinic acid and oleanolic acid are typical terpenoids. These compounds widely exist in a variety of natural plants, and they have good anti-inflammatory, antibacterial, antiviral, liver protective activities. In recent years, structural modification of these compounds in order to improve their solubility and absorbability and reduce their side effects and toxicity has attracted more and more research concerns. Caffeic acid is a natural dihydroxylphenyl acrylic acid, and has good antibacterial, antiviral and antioxidant activities samely. We coupled these two kinds of natural compounds together directly, expecting to find new lead compounds with good activity and low toxicity.Finally, caffeoyl and reduced caffeoyl were introduced to 3-hydroxyl of terpenoid through several steps. 3-O-caffeoyl glycyrrhetinic acid methyl ester(9a), 3-O-caffeoyl oleanolic acid ethyl ester(9b), 3-O-dihydrocaffeoyl glycyrrhetinic acid methyl ester(9c), 3-O-dihydrocaffeoyl oleanolic acid ethyl ester(9d) were prepared in high yields. Liver protective testing of these compounds compared with glycyrrhetinic acid, oleanolic acid, caffeic acid and the mixtures of caffeic acid and terpenoid showed that our products are with much better activity. Compound 9c reduced ALT, AST and DB efficiently. It also showed renal protective effects.