Kuppala Ramakrishna, Borrelli Silvia, Slowski Kathryn, Sanders David A R, Ravindranathan Kartha K P, Pinto B Mario
Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Bioorg Med Chem Lett. 2015 May 1;25(9):1995-7. doi: 10.1016/j.bmcl.2015.03.006. Epub 2015 Mar 17.
The synthesis of 1-[5-O-(α-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione and 1-[(5-O-(β-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.
本文描述了1-[5-O-(α-D-吡喃半乳糖基)-D-葡糖基]嘧啶-2,4(3H)-二酮和1-[(5-O-(β-D-吡喃半乳糖基)-D-葡糖基]嘧啶-2,4(3H)-二酮的合成，它们是UDP-Galp的非离子型底物模拟物。UDP-Galp是Galf的前体，Galf是几种微生物细胞壁聚糖的主要成分。UDP-Galp和UDP-Galf的相互转化由UDP吡喃半乳糖变位酶（UGM）催化；对其抑制构成了一种损害微生物的方式。非离子型多羟基化链旨在模拟UDP-Galp中的离子焦磷酸基团和核糖部分，并提高候选抑制剂的生物利用度。对结核分枝杆菌的UGM进行的抑制试验表明，这些化合物对该酶仅有微弱的抑制作用。
