RESUMEN
UDP-galactofuranose (UDP-Galf) is the donor substrate for both bifunctional galactofuranosyltransferases, GlfT1 and GlfT2, which are involved in the biosynthesis of mycobacterial galactan. In this paper, a group of UDP-Galf mimics were synthesized via reductive amination of a bicyclo[3.1.0]hexane-based amine by reacting with aromatic, linear, or uridine-containing aldehydes. These compounds were evaluated against GlfT2 using a coupled spectrophotometric assay, and were shown to be weak inhibitors of the enzyme.
Asunto(s)
Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Galactosa/análogos & derivados , Hexanos/química , Mycobacterium/enzimología , Uridina Difosfato/análogos & derivados , Diseño de Fármacos , Galactosa/síntesis química , Galactosa/química , Galactosa/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Mycobacterium/efectos de los fármacos , Uridina Difosfato/síntesis química , Uridina Difosfato/química , Uridina Difosfato/farmacologíaRESUMEN
The synthesis of 1-[5-O-(α-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione and 1-[(5-O-(ß-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione as non-ionic substrate mimics of UDP-Galp are described. UDP-Galp is a precursor of Galf, which is a primary component of the cell-wall glycans of several microorganisms. The interconversion of UDP-Galp and UDP-Galf is catalyzed by UDP galactopyranose mutase (UGM); its inhibition comprises a mode of compromising the microorganisms. The nonionic polyhydroxylated chain was intended to mimic the ionic pyrophosphate group and the ribose moiety in UDP-Galp and increase the bioavailabilities of the candidate inhibitors. Inhibition assays with UGM of Mycobacterium tuberculosis showed only weak inhibition of the enzyme by these compounds.