Inhibition of Escherichia coli glycosyltransferase MurG and Mycobacterium tuberculosis Gal transferase by uridine-linked transition state mimics

Abstract

Graphical abstract

The Mycobacterial Cell Wall—Peptidoglycan and Arabinogalactan

“…MurG is a GT-B glycosyltransferase that uses UDP-GlcNAc as a substrate to form a b(1 ! 4) glycosidic bond between GlcNAc and either the MurNAc or MurNGlyc sugar of lipid I. MurG from M. tuberculosis has been shown to be able to complement a murG-deficient strain of E. coli (Jha et al 2012), and because of the essential nature of MurG, it is a target for the development of new antibacterial agents (Trunkfield et al 2010). MurG marks the final "step" in the cytoplasmic pathway of PG biosynthesis, and its product is a cell wall intermediate termed lipid II.…”

Synthesis and biological evaluation of 5′-glycyl derivatives of uridine as inhibitors of 1,4-β-galactosyltransferase

“…(3) was prepared according to the published procedure [31]. 5 0 -amino-5 0 -deoxy-2 0 ,3 0 -bis-O-(tertbutyldimethylsilyl)-uridine (9) was prepared in three step synthesis by direct conversion of unprotected uridine to 5 0 -azido-5 0 -deoxyuridine [41], followed by TBDMS protection and hydrogenation [27]. 5 0 -(N-(benzyloxycarbonyl)-glycyl)-2 0 ,3 0 -O-isopropylideneuridine (4/A1) was prepared by coupling of N-benzyloxycarbonyl-glycine (1) with 2 0 ,3 0 -O-isopropylideneuridine (3) according to procedure described by Algarov et al [25] with slight modification: as coupling agent DIC was used instead of DCC.…”

“…There are many studies describing the synthesis and biological evaluation of uridine-containing analogues [23][24][25][26][27][28]. With the goal of broadening the library of uridine derivatives that could be active against glycosyltransferases, we have synthesized new 5 0 -glycyl derivatives of uridine, in which the glycine is attached via an ester or an amide linkage to the 5 0 -position of uridine (series A and B respectively, Fig.…”

“…We, therefore, synthesized amide analogs B1-B4, which are more resistant to hydrolysis. The synthetic strategy relies on the coupling of relevant uridine substrates 3 [31] or 9 [27] with commercially available glycine derivatives 1 and 2 (Schemes 1 and 2, respectively). This approach has been demonstrated in works of Alargov et al [25], who used dicyclohexylcarbodiimide (DCC) as the condensing agent.…”

Carbasugar Analogues of Galactofuranosides: Pseudodisaccharide Mimics of Fragments of Mycobacterial Arabino­galactan

“…[8][9][10][11][12][13][14][15] Two reports of moderately potent inhibitors of galactofuranosyl transferases exist in the literature. Of these, an inhibitor of GlfT2 was described this year; [16] an inhibitor of the enzyme from M. smegmatis was reported earlier. [17] It is also important to note that carbasugar mimics of pyranosides have been shown to act as substrates for glycosyl transferases.…”