Synthesis of 1-C-glycoside-linked lipid II analogues toward bacterial transglycosylase inhibition

Abstract

Preparation of Lipid II analogues containing an enzymatically uncleavable 1-C-glycoside linkage between the disaccharide moiety and the pyrophosphate- or pyrophosphonate-lipid moiety is described. The synthesis of a common 1-C-vinyl disaccharide intermediate has been developed that allows easy preparation of both an elongated sugar-phosphate bond and a sugar-phosphonate moiety, which are coupled with the polyprenyl phosphate to give the desired molecules. Inhibition studies show how a subtle structural modification results in dramatically different potency toward bacterial transglycosylase (TGase), and the results identify Lipid II-C-O-PP (IC 50 =25 μM) as a potential TGase inhibitor. An unbreakable bond: The preparation of Lipid II analogues containing a 1-C-glycoside linkage between a disaccharide moiety and a pyrophosphate- or pyrophosphonate-lipid moiety is described (see scheme). A synthesis of the 1-C-vinyl disaccharide intermediate has been developed that allows easy preparation of the desired molecules. The inhibition study shows how a subtle structural modification results in dramatically different potency toward bacterial transglycosylase.