Synthetic disaccharide analogs as potential substrates and inhibitors of a mycobacterial polyprenol monophosphomannose-dependent α-(1→6)-mannosyltransferase

Abstract

Analogs of the α- d-Man p-(1→6)-α- d-Man p-O(CH 2) 7CH 3 disaccharide 4, a known substrate for a polyprenol monophosphomannose-dependent α-(1→6)-mannosyltransferase involved in mycobacterial LAM biosynthesis, have been synthesized and screened as potential substrates and inhibitors of the enzyme. In the disaccharides synthesized, the hydroxyl groups at C-2 and C-6 on the reducing end residue have been replaced by combinations of amino, fluoro, and methoxy functionalities 9– 14. In addition, a disaccharide in which the nonreducing mannopyranose residue was replaced with a 3,6-anhydromannopyranose residue 34 was synthesized from a byproduct formed during one of the reactions leading to 14. When tested against the enzyme, none were active as substrates, as would be expected as all lack the C-6′ hydroxyl group to which an additional sugar residue would be transferred. Evaluation of these compounds as inhibitors of the enzyme revealed that only three, 11, 12, and 13, all of which contain one or more amino groups, inhibited the enzyme. The most potent inhibitor was the diamino-disaccharide, 11.