The Design And Synthesis Research Of Galactofuranosyltransferase2Inhibitor

Tuberculosis (TB) has been a serious hazard to human health, and this trend hasbeen intensified these years. As TB treatment is also facing the problem of multi-drugresistance, it is urgent for people to research and develop new structure characteristicsand mechanism of anti-TB drugs. The cause of tuberculosis is the infection ofmycobacterium. The cell wall of Mycobacterium tuberculosis cantains themycolyl-arabinogalactan-pepetidoglycan complex, which possesses a core galactanmoiety, composed of approximately30galactofuranosyl resides. Galactofuranosyl-transferase2is one of the enzymes involved in the synthesis of this complex. It alsoplays a crucial role in mycobacterial cell wall biosynthesis and protential new drugtargets for the treatment of tuberculosis.We mimicked the structure of the receptor substrate and designed alkylconnected glycomimetic. Since no glycomimetic connected by alkyl glycoside hasbeen designed as inhibitors of Galactofuranosyl-transferase2till now, it is worth wellfor us to do this research. The designed glycomimetic mimics the structure ofGalactofuranosyltransferase2substrate, which can be competly combined with theGlycosyltransferase2to prevent the D-galacto-furanose unit chain extension whichcan achieve a bactericidal effect. The furanosyl glycoside only presents in the cellwalls of bacteria. It does not exist in the human body and therefore will not causetoxic and side effects to the human body. The resulting compound is a potentialinhibitor of mycobacterial Glycosyltransferase2and it is worthy to do biologicalinvestigation in later investigation.The experimental procedure involved two monosaccharides chiral startingmaterials, D-glucose and L-arabinose. D-glucose was used as a raw material and itwent through with the protection of the hydroxyl group, followed by the reaction withhydroxylamine hydrochloride to introduce a nitrogen source. The regent of t-butyldimethyl chlorosilane silicon was used to protect the hydroxyl groups of oxime.Followed by the introduction of easily departed methylsulfonyl group,tetrabutylammonium was used to deprotect the silicon protecting group, and theintramolecular nucleophilic substitution occurred as an inversion of configuration toform galacto-furanose analogues to get the key intermediates of the five-membered cyclic nitrone which passed through11steps with19%yield. L-arabinose was used asanother raw material. After the protection of the hydroxyl group and columnchromatography separation, single β configuration of5-hydroxyl triphenylmethylprotected L-arabinose was obtained. Then it was passed through the deprotectionreaction to obtain a key intermediate β-methyl-2,3-di-O-benzyl-L-arabinofuranosewith39%yield from L-arabinose. These compounds had been confirmed by NMR，IRand optical rotation. The cyclic nitrone and arabinofuranose were key intermediates inthe construction of arbon-carbon bond linkage and provided a valuable method for thesynthesis of alkyl connected glycomimetic.