Synthesis of phosphate derivatives related to the glycosidase inhibitor salacinol.
The syntheses of polyhydroxylated imino- and anhydro thio-alditol compounds related to the naturally occurring glycosidase inhibitor, salacinol, containing a phosphate group in the side chain are described. The compounds lack hydroxyl groups on the acyclic side chain and are prototypes of the exact salacinol analogue. The synthetic strategy relies on the Mitsunobu reaction of N- and S-hydroxyalkyl derivatives of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-anhydro-2,3,5-tri-O-benzyl-1-thio-D-arabinitol with dibenzyl phosphate to yield the corresponding protected heteroalditol phosphates. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective inhibitors of MGA and demonstrates the importance of the hydroxyl and/or sulfate substituents present on the side chain for effective inhibition. The attempted synthesis of the exact analogue of salacinol by opening of cyclic phosphates is also described.
Bhat
Ramakrishna G
RG
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
Kumar
Nag S
NS
Pinto
B Mario
BM
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007202:Indicators and Reagents; D008958:Models, Molecular; D010710:Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013402:Sugar Alcohols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013431:Sulfates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010710:Phosphates; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D006026:Glycoside Hydrolases