Synthesis of aza- and thia-spiroheterocycles and attempted synthesis of spiro sulfonium compounds related to salacinol.
The synthesis of aza- and thia-spiroheterocycles and the attempted synthesis of spiro sulfonium compounds related to salacinol are described. The binding of the nanomolar inhibitor swainsonine to Drosophila Golgi alpha-mannosidase II (dGMII) involves a large contribution of interactions between the six-membered ring of the inhibitor and the hydrophobic pocket within the enzyme active site. Salacinol, a naturally occurring sulfonium ion, is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. Spiro aza- and thia-heterocycles and a spiro analogue of salacinol were designed with the expectation that the hydrocarbon portions would make hydrophobic contributions to binding. The former sets of compounds were synthesized successfully but the salacinol analogue proved to be elusive. The stereochemistry of the final compounds was determined by means of 1D-NOESY experiments. The aza- and thia-heterocycles were not effective inhibitors of Golgi alpha-mannosidase II or human maltase glucoamylase.
Chen
Wang
W
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Pinto
B Mario
BM
D000818:Animals; D002236:Carbohydrate Conformation; D003920:Diabetes Mellitus / Q000628:therapy; D004330:Drosophila / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D007659:Ketones / Q000737:chemistry; D008361:Mannosidases / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013402:Sugar Alcohols / Q000737:chemistry*; D013431:Sulfates / Q000737:chemistry*; D013452:Sulfonium Compounds / Q000737:chemistry*; D017026:Swainsonine / Q000737:chemistry; D000520:alpha-Glucosidases / Q000737:chemistry
D004791:Enzyme Inhibitors; D007659:Ketones; D013402:Sugar Alcohols; D013431:Sulfates; D013452:Sulfonium Compounds; C427963:salacinol; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase; D000520:alpha-Glucosidases; D017026:Swainsonine