4 海綿Penares sp.から得られたグルコシダーゼ阻害剤penarolide sulfate類の構造(口頭発表の部)

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Recent progresses in glycobiology have shed light on significant roles of glycosidases in various biological functions, including immune response, oncogenesis, metastasis of tumors, viral and bacterial infections, and differentiation of neural cells. Specific inhibitors of glycosidases have potentials for treatment of a variety of diseases. α-Glucosidases are involved in glycoprotein processing and glycogenolysis and their inhibitors can be applied for treatment of diabetes, obesity, viral infections, and cancer. In our screening for α-glucosidase inhibitors from Japanese marine invertebrates, we encountered a marine sponge Penares sp. collected off Hachijo-jima Island whose hydrophilic extract was highly active. Bioassay-guided fractionation led to the isolation of two active compounds, penarolide sulfates A_1 and A_2. The molecular formula of penarolide sulfate A_1 (1) was determined to be C_<35>H_<62>NO_<15>S_3Na_3 on the basis of HR-FABMS and NMR data. Interpretation of 2D NMR spectra indicated that the structure of 1 was composed of partial structures a and b which were connected through long alkyl chains. Positions of three sulfate groups and length of alkyl chain were unambiguously determined by FAB-MS/MS experiments. The absolute stereochemistry of 1 was determined by combination of Marfey analysis and modified Mosher's method. Penarolide sulfate A_2 (2) had a molecular formula identical to that of 1, as determined by the HR-FABMS and NMR data. The structure of penarolide sulfate A_2 (2) was determined following the same procedure as in the case of 1. Penarolide sulfates A_1 (1) and A_2 (2) inhibited α-glucosidase with IC_<50> values of 1.2 and 1.5μg/mL, respectively; 30-40 times more potent than a known inhibitor 1-deoxynojirimycin. Interestingly, they were only marginally active against β-glucosidase at a concentration of 100μg/mL; castanospermine and 1-deoxynojirimycin showed IC_<50> values of 15 and 96μg/mL, respectively. All four compounds did not inhibit β-galactosidase at 100μg/mL. Because penarolide sulfates inhibited thrombin as did other sulfated compounds, it is of interest to examine whether the sulfate groups in these compounds are indispensable for their enzyme inhibitory activities.
天然有機化合物討論会の論文
2000-10-01

4 海綿Penares sp.から得られたグルコシダーゼ阻害剤penarolide sulfate類の構造(口頭発表の部)

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