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

Abstract

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 2CO 3. Excess of K 2CO 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 2CO 3. No reaction was observed in acetonitrile containing K 2CO 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 μM and a K i value of 6 ± 1 μM, respectively.