Biological evaluation of de-O-sulfonated analogs of salacinol, the role of sulfate anion in the side chain on the alpha-glucosidase inhibitory activity.

De-O-sulfonated analogs (10a, Y(-)=CH(3)OSO(3) and 10b, Y(-)=Cl) of salacinol, a naturally occurring glycosidase inhibitor, and its diastereomer (12a, Y(-)=CH(3)OSO(3)) with L-thiosugar moiety (1,4-dideoxy-1,4-epithio-L-arabinitol) were prepared. Their inhibitory activities against intestinal maltase and sucrase were examined and compared with those of the parent alpha-glycosidase inhibitor, salacinol (1a). Compounds 10a and 10b showed a potent inhibitory activity equal to that of 1a against both enzymes, although 12a was a weak inhibitor against sucrase and maltase.

Synthesis of a salacinol analogue and its alpha-glucosidase inhibitory activity.

Aim: To investigate more efficient synthetic method of the nitrogen analogue 4 of salacinol (1) for searching new antidiabetic agents.

Methods: The synthesis of the key intermediate 2, 4-O-isopropylidene-L-erythritol 1,3-cyclic sulfate (2a) was accomplished by modification of reports from D-glucose via seven steps in much more less expensive. Using this method, an efficient synthesis of 4 was carried out.

Synthesis and biological evaluation of deoxy salacinols, the role of polar substituents in the side chain on the alpha-glucosidase inhibitory activity.

Three analogs (5, 6, and 7) lacking polar substituents in the side chain of a naturally occurring alpha-glucosidase inhibitor, salacinol (1a), were synthesized by the coupling reaction of a thiosugar, 1,4-dideoxy-1,4-epithio-D-arabinitol (3), with cyclic sulfates (8, 9, and 10), and their alpha-glucosidase inhibitory activities were examined. All these simpler analogs (5, 6, and 7) showed less inhibitory activity compared to 1a, and proved the importance of cooperative role of the polar substituents for the alpha-glucosidase inhibitory activity. A practical synthetic route to 3 starting from D-xylose is also described.

Mechanistic aspects of thiyl radical-promoted acyl radical cyclization of formylenoate-cyclization versus oxidation.

Treatment of formylalkenoates 1 and 7 with 2,2'-azobis(2-methylpropanenitrile) (AIBN) in the presence of dioxygen gave oxygenated carboxylic acids 5, 6, 8, 9 instead of acyl radical cyclization products, through preferential reaction of the corresponding acyl radicals with dioxygen rather than intramolecular attack to an enoate moiety. The reaction of 1 with AIBN in the absence of dioxygen recovered starting 1 in 98% yield.

Thiol-catalyzed acyl radical cyclization of alkenals.

Thiol-catalyzed direct generation of acyl radicals and their intramolecular addition to olefins of alkenals gave 2-substituted five- and six-membered cyclic ketones in reasonably good yields. The combination of odorless tert-dodecanthiol and AIBN or V-40 was the initiator of choice among surveyed radical generators for the cyclization of alkenals. Aldehydes having electron-deficient olefins cyclized more easily than those having unactivated olefins.