The Synthesis And Bioactivities Of Series Derivatives From D-mannitol

In the recent years, the chemical modification of natural products, which lead topreparation of derivatives with high bioactivities, has attracted more and more attention. Inthis paper, a series of sulfoacid derivatives, 1,2,5,6-tetra-O-nitrate-D-mannitol derivatives and3,4-di-O-protecting mannitol derivatives were synthesized from an inexpensive sugarD-mannitolas starting materialand their preliminary biological activities were studied. Mannitol hexa-tosylate and mannitol hexa-mesylate were synthesized through theesterification reaction of D-mannitol with p-toluene sulfonylchloride and mesylchloriderespectively in one step. Additionally, the optimal conditions of this type reaction wereobtained by discussing the factors influencing this esterification reaction and the compound3,4-bis-O-tosyl-D-mannitol was prepared from D-mannitol by the selectively tosylation ofpart hydroxyls. D-mannitol was acetalated with acetone, hydroxyls of C-1, C-2, C-5 and C-6 wereprotected. Then hydroxyls of C-3 and C-4 were respectively etherealized with methyl iodide,sulfonated with mesyl chloride and tosyl chloride. After isopropylidenes were deprotected,hydroxyls of C-1, C-2, C-5 and C-6 were nitrated under low temperature, and1,2,5,6-tetra-O-nitrate-D-mannitol derivatives were synthesized in good yield. In the course ofthis whole nitric acid esterification, the optimal conditions of this type reaction were achieved. The condensation of the intermediate 3,4-bis-O-tosyl-D-mannitol with1-phenylpiperazinyl and adenine afforded 3,4-di-(4-phenyl-1-piperazinyl)-D-mannitol and3,4-di- adenine-D-mannitol respectively. By analyzing datum from IR, Element analysis,1H-NMR, C-NMR and MS(ESI), the structures of intermediums and target compounds 13were confirmed to be same as their molecular formula. The antibacterial activities of all intermediums and target compounds were studied firsttime in vitro. The research data showed some compounds had certain inhibiting effect on G+Staphylococcus aureus, G- Escherichia coli and G+ Bacillus subtilis. Studying relationshipbetween structure and effect indicated that 1,2,5,6-tetra-O-nitrate-D-mannitol derivativesbehaved selective inhibition only on G+ Staphylococcus aureus and minimal inhibitoryconcentrations (MIC) is 5 g·L-1. Among the 1,2,5,6-tetra-O-nitrate-D-mannitol derivatives,中国科学院海洋研究所 ２００４ 届博士学位论文　　　　　　　　　　　　　　　　　　　　　　　 　 ·iii·甘露醇系列衍生物的合成及其生物活性inhibition has no evident difference. Otherwise, 3,4-di-O-methyl-D-mannitol and3,4-bis-O-tosyl-D-mannitol exhibited certain inhibiting effect and MIC reached 20 g·L-1.1,2:5,6-di-o-isopropylidene-D-mannitol showed weak effect and MIC is 100 g·L-1. However,the derivatives of total esterification, mannitol hexa-tosylate, mannitol Hexanitrate andmannitol hexa-mesylate, represented no inhibition. The vitro antitumor effects of all intermediums and target compounds were investigated,which showed that only 3,4-di-O-methyl-D-mannitol had some effect and the inhibition rateson the tumor cells were directly proportional to its concentrations. However, at the sameconcentration, the antitumor effects of 3,4-di-O-methyl-D-mannitol on tumor cells KB andHela were obviously better than that on cell HL-7702. 1,2,5,6-tetra-O-nitrate-D-mannitol derivatives C1 ( mannitol Hexanitrate ), C2(1,2,5,6-tetra-O-nitrate-3,4-di-O-tosyl-D-mannitol),C3(1,2,5,6-tetra-O-nitrate-3,4-di-O-mesyl-D-mannitol)were demonstrated to be safe in the acute tocxic test. Myocardial ischemiaprotective effects of the compounds C1, C2 and C3 on mice of coronary arterial ligaturemodel were evaluated. The datum showed that the compounds C1, C2 and C3 couldsignificantly decrease the myocardial infarction area and alleviate the degree of themyocardial ischemia. The raising of ST and T in electrocardiogram attributed frommyocardial ischemia were reduced only by C1 and C2. All thre...