Synthesis of 2-deoxy-2-fluoro and 1,2-ene derivatives of the naturally occurring glycosidase inhibitor, salacinol, and their inhibitory activities against recombinant human maltase glucoamylase.
2-Deoxy-2-fluorosalacinol and a 1,2-ene derivative of the naturally occurring glycosidase inhibitor salacinol were synthesized for structure activity studies with human maltase glucoamylase (MGA). 2-Deoxy-2-fluorosalacinol was synthesized through the coupling reaction of 2-deoxy-2-fluoro-3,5-di-O-p-methoxybenzyl-1,4-anhydro-4-thio-D-arabinitol with 2,4-O-benzylidene-l-erythritol-1,3-cyclic sulfate in hexafluoroisopropanol (HFIP) containing 0.3 equiv of K(2)CO(3). Excess of K(2)CO(3) resulted in the elimination of HF from the coupled product, and the formation of an alkene derivative of salacinol. Nucleophilic attack of the 1,4-anhydro-4-thio-D-arabinitol moiety on the cyclic sulfate did not proceed in the absence of K(2)CO(3). No reaction was observed in acetonitrile containing K(2)CO(3). The target compounds were obtained by deprotection with TFA. The 2-deoxy-1-ene derivative of salacinol and 2-deoxy-2-fluorosalacinol inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose, with an IC(50) value of 150 microM and a K(i) value of 6+/-1 microM, respectively.
Choubdar
Niloufar
N
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Sim
Lyann
L
Rose
David R
DR
Pinto
B Mario
BM
D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013402:Sugar Alcohols / Q000737:chemistry*; D013431:Sulfates / Q000737:chemistry*; D000520:alpha-Glucosidases / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D011994:Recombinant Proteins; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D005461:Fluorine; D006026:Glycoside Hydrolases; D000520:alpha-Glucosidases