|Budget Amount *help
¥3,400,000 (Direct Cost : ¥3,400,000)
Fiscal Year 2004 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 2003 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 2002 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Salacinol (1)is a potent α-glucosidase inhibitor isolated from the aqueous extracts of the roots and stems of Salacia reticulata WIGHT (known 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, three analogs (2,3,4)lacking hydroxyl and/or hydroxymethyl groups of the side chain of 1 and O-Desulfonated salacinol (5)were synthesized, and their inhibitory activities against α-glucosidase examined.
Compounds 2,3,4 were synthesized by applying the ring-opening method of the cyclic sulfate with 1,4-dideoxy-1,4-epithio-D-arabinitol (6a). The cyclic sulfates, 1,3-propanediol 1,3-cyclic sulfate (7),2-O-benzylglycerol 1,3-cyclic sulfate (8)and 4-O-tert-b
utyldimethylsilyl-2-deoxy-L-erythtitol 1,3-cyclic sulfate (9),used for the side chain of the analogs 2, 3, 4, were derived from 1,3-propanediol, glycerin and D-glucose in good yield, respectively. Coupling reaction of 7 with 6a gave the desired 2 in 61% yield. Deprotection of coupled products obtained from 7 and 8 in a manner similar to that used for 6a gave 3 and 4 in good yield. On the other hand, acidic methanolysis of 1 gave 5 in quantitatively yield. The α-glucosidase inhibitory activities of them were examined for the intestinal α-glucosidase in vitro. Three simpler analogs (2,3,4) showed less inhibitory activity compared to 1, and proved the importance of cooperative role of the polar substituents to exhibit the α-glucosidase inhibitory activity. On the other hand, O-desulfonated analogue 5 showed a potent α-glucosidase inhibitory activity equal to that of 1, and the sulfate anion moiety of 1 was found to be not essential for the inhibitory activity. Compound 5 was also alternatively synthesized by the use of coupling reaction of epoxide, (2R,3S)-1,2-epoxy- 3,4-bis(benzyloxy)butane (10), easily obtaine from D-isoascorbic acid, with O-benzylated thiosugar 6b. Hydrogenolysis of the coupled product gave 5 in good yield. Less