Study On Synthesis Of Two Kinds Of Glycosides Compounds And Two Different Series Of Heterocycle Compounds And Biological Activities

Nowadays, in order to search new active moleculars, the common methods of constructing the compound library have been adopted. Thus, it is not only extensive studies of many kinds of bioactivities, but also even more establishing some structure-activity relationship based on a lot of testing datas, and establishing the basic for Pharmaprojeccts, too.1. Synthesis and pharmacological evaluation of novel saponin derivatives with antiviral H5N1 activitySaponins are complex glycosides of steroids and triterpenes, with significant pharmacological activities, not only show wide spectrum of cytotoxicity against various cancer cells, but also exhibit good antiviral activities and pharmacological effects. Our paper described that an HIV-based pseudotyping system was used to screen our semi-synthesized saponin library for the entry inhibitors against high pathogenic H5N1 infection. The first two small molecule inhibitors chlorogenin 3-O-β-chacotrioside YC-72 and chlorogenin 6-α-O-actyl-3-O-β-chacotrioside GC-29, were discovered. In order to develop additional small molecule inhibitors with enhanced activity, compound YC-72 was chosen as the lead compound to design and synthesize a series of analogs 1-7 to explore the preliminary structure-activity relations of such these designed molecules around the aglycone and sugar chain. It was found that ursolate saponin 5 showed the similar inhibitory activity as YC-72. These results suggest that the aglycone with more fused rings is favored for the inhibitory activity and the 3-O-β-chacotriosyl residue plays a very important role in antiviral activity, suggesting that attachment of such t sugar chain to some steroids and triterpenes can contribute to enhance inhibitory activity against H5N1 entry. 2. Synthesis and biological evaluation on antitumor activity of novel anthracene L-rhamnopyranoside derivativesEmodin with many kinds of pharmacological activities, has low DNA binding affinity, low or insignificant cytotoxicity against various cancer cells though it could induce the apoptosis of certain cancer cells. It is proved that the addition of side chain sugar to emodin is usually effective to gain higher antitumor activities. Our paper reported that three different series of anthracene L-rhamnopyranosides including emodin L-rhamnopyranosides,anthrone L-rhamnopyranosides and xanthrone rhamnopyranosides were designed and synthesized, which were evaluated on their cytotoxicity against various cancer cells for study on the structure-activity relationship.Anthrone L-rhamnopyranosides were synthesized on the basis of the synthesis of emodin L-rhamnopyranosides. In order to reduce side effects of anthrone L-rhamnopyranosides, the introduction of Ac group into methylene proton at C-10 of anthrone was carried out. It was found the introduction of Ac group into methylene proton at C-10 of anthrone not only was helpful to enhance antitumor activities but also could reduce side effects. In addition, three different series of xanthrone L-rhamnopyranosides were designed and synthesized by taking the place of methylene proton at C-10 with O or S-isosteres of the chromophore. Then this thesis made some research on antitumor activities and came to a rude conclusion. Compound 2-[4-O-(2',3'-Di-O-acetyl-α-L-rhamnopyranosy l)-8-methyl-2H-chromeno[4,3,2-c,d]indazol-2-yl]-1-N,N-diethylethanamine(119)with novel structure, exhibited a broad specturm of antitumor activities.Our paper described that competitive displacement (C50) fluorometric assays with DNA-bound ethidium can be used21 to determine the DNA binding capacity with anthracene L-rhamnopyranosides synthesized. It was proved that anthracene L-rhamnopyranosides could bind with DNA by insertion model, which insert directly double-stranded and bind with base group of DNA to lead to inability of further replication. These results provided some experimental datas which were helpful to develop some new antitumor drugs from molecure level.3. Synthesis and Biological Evaluation on Activities of Novel, Potent, and Selective PDE4 InhibitorsIt was reported that selective PDE4 inhibitors could be used to efficiently therapy COPD, but selective PDE4 inhibitors in clinic showed some side effects such as vomiting and so on. This paper reported that the combination of cavity characteristics and active cite combination of PDE4 have been confirmed and pharmacophore features of the selective PDE4 inhibitors has been defined. Tetrahydroisowuinolin derivatives and phthalide derivatives were designed and synthesized on the basis of a PDE4 inhibitor pharmacophore model set up through computer simulation. Some tetrahydroisowuinolin derivatives synthesized were evaluated on their activity against PDE4 for study on the structure-activity relationship. (7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxyphenyl)methanone (155) and Methyl 7-(cyclopentyloxy)-6-methoxy-2-(4-methoxy- benzoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (170) showed good activity against PDE4, which were chosen as the lead compounds to design and synthesize another analogs in order to develop selective PDE4 inhibitors with better activity. The further studies on the SAR are in progress.