Synthesis and biological evaluation of new inhibitors of UDP-Galf transferase—a key enzyme in M. tuberculosis cell wall biosynthesis

Abstract

Two iminosugars have been designed and synthesized as potential inhibitors of UDP-Galf transferase, an enzyme involved in Mycobacterium tuberculosis cell wall biosynthesis. The design is based on a proposed model of the transition state for the transferase reaction. One of the two racemic compounds is the first reported inhibitor of the target enzyme from M. smegmatis.

The First Chemical Synthesis of UDP[6‐3H]‐α‐D‐galactofuranose

“…This preparation was also analyzed for comparison ( Figure 1, B). We again confirmed by 13 C and 1 H NMR spectroscopy (Table 1) that the β-anomer (8β) spontaneously decomposes to the stable tetrabenzoate 9 (R f = 0.24). [19] This observation has been contested, [18] probably based on the fact that the β-phosphate 8β and its decomposition product, 9, could not be distinguished ( Figure 1 part B, lane 3).…”

“…The structures for the target, UDP-Galf, and for intermediate and degradation products were confirmed by the chemical shifts for the diagnostic signals in the NMR spectra (Table 1), which were in agreement with those reported in the literature. [17,19,20,28] Standard acetolysis of 6 caused partial isomerization to the pyranosic forms, according to the 13 C NMR spectrum of the nonlabeled product. Ring expansion was avoided by previous benzoylation of O-6 and mild acetolysis in CH 2 Cl 2 solution to afford 1-O-acetyl-2,3,5,6-tetra-O-benzoyl-d-galactofuranose (7).…”

“…Column chromatography was performed on silica gel 60 (230-400 mesh). The 1 H, 13 C, and 31 P NMR spectra were recorded on a Bruker AM 500 spectrometer. The chemical shift reference for 31 P was that of external phosphoric acid (85 %) in D 2 O set at 0.0 ppm.…”

“…[9][10][11] However, few studies have been reported for the transferase. [12,13] It has been only described in Mycobacterium tuberculosis, using synthetic glycosides of Galf disaccharides as acceptor substrates. [12] The transferase is a bifunctional enzyme that catalyzes the formation of β (1,5) and β(1,6) linkages (gene product of Rv 3808c).…”

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

“…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. [18] We planned to synthesise carbadisaccharides mimicking the Galf(β1Ǟ5)Galf and Galf(β1Ǟ6)Galf substructures of mycobacterial arabinogalactan to investigate the interaction of these hydrolytically stable disaccharide analogues with the enzyme GlfT2.…”