2001 Fiscal Year Final Research Report Summary
Synthetic Studied on Thiosugar Suronium Sulfate Inner Salt,a Potent α-Glucosidase Inhibitor
| Project/Area Number |
11672128
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Kinki University |
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Principal Investigator |
MURAOKA Osamu Kinki University School of Pharmacy Professor, 薬学部, 教授 (20142599)
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| Co-Investigator(Kenkyū-buntansha) |
TANABE Genzoh Kinki University School of Pharmacy Lecturer, 薬学部, 講師 (40217104)
MINEMATSU Toshie Kinki University School of Pharmacy Research Assistant, 薬学部, 助手 (60088151)
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| Project Period (FY) |
1999 – 2001
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| Keywords | salacinol / Salacia reticula / antidiabetic agents / α-glucosidase inhibitor / sulfonium sulfate inner salt / azasuga / cyclic sulfate / coupling reaction |
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| Research Abstract |
Salacinol (1) is a potent α-glucosidase inhibitor isolated from the aqueous extracts of the roots and stemps of Salacia reticulata WIGHT(nows as Kotala himbutu in Singhalese), which is traditionally used in Sri Lanka and India for the treatment of diabetes. Its unique spiro-like structure of the inner salt comprised of 1-deoxy-4-thioarabinofuranosyl cation and 1'-deoxyerythrosyl-3'-sulfate anion was revealed by the authors on the basis of chemical and physicochemical evidences including the X-ray crystallographic analysis. In this study, the nitrogen analogue 2 of 1 and some related compounds were synthesized, and their inhibitory activities against α-glucosidase tested.
2, 4-Isopropylidene-L-erythritol-1, 3-cyclic sulfate precursor (3), used for the tethering arm of 2, was synthesized in 73% overall yield via seven steps starting from D-glucose. 1, 4-Dideoxy-1, 4-imino-D-arabinitol (D-4) was synthesized in good yield also from D-glucose. Coupling reaction between 3 and D-4 followed by
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hydrolysis gave the desired 2 in good yield. On the other hand, L-4 has been reported to show nearly equal inhibitory activity to that of 1.Thus, L-4 was also prepared in 42% overall yield from D-xylose (5), and was coupled with 2, 4-benzylidene-D-erythrito-1, 3-cyclic sulfate (6) to give the enantiomeric isomer 7 of 2 in good yield. The α-glucosidase inhibitory activities of them were tested for the intestinal α-glucosidase in vitro, and found to be reduced considerably upon substitution of the sulfur atom of 1 with the nitrogen. The origin of the reduced activities were attributed to the different stereosturucture of the aza-analogues, which was deduced by the single crystal X-ray measurement of the model compound 8 obtained by the coupling reaction of 3 with pyrrolidine. Different from those of 1 the two ionic centers in 8 were far apart from each other. Further structure-activity relationships concerning the α-glucosidase inhibitor activity of 1 using the related compounds synthesized have been summarized. Less
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