Wen Xianghui, Crick Dean C, Brennan Patrick J, Hultin Philip G
Department of Chemistry, University of Manitoba, R3T 2N2, Winnipeg, MB, Canada.
Bioorg Med Chem. 2003 Aug 15;11(17):3579-87. doi: 10.1016/s0968-0896(03)00366-3.
The mycobacterial arabinogalactan linkage disaccharide [alpha-L-Rha-(1-->3)-alpha-D-GlcNAc] provides a basis for the design of new antitubercular drugs, since it supports a key skeletal structure in the bacterial cell wall. A series of analogues of the linker was synthesized by coupling appropriate thiorhamnosyl donors modified at their 4-positions, with an N-acetyl glucosamine acceptor. In a cell-free enzyme inhibition assay, three analogues inhibited the activity of the galactosyltransferase that adds a Galf residue to the linkage disaccharide. Although the compounds were modest inhibitors, these data confirm the viability of this approach to anti-mycobacterial agents. It is especially significant that the three effective compounds are modified at the site of the acceptor atom in the natural substrate.
分枝杆菌阿拉伯半乳聚糖连接二糖[α-L-鼠李糖-(1→3)-α-D-氨基葡萄糖]为新型抗结核药物的设计提供了基础，因为它支撑着细菌细胞壁中的关键骨架结构。通过将在其4位修饰的合适硫代鼠李糖基供体与N-乙酰葡糖胺受体偶联，合成了一系列连接体类似物。在无细胞酶抑制试验中，三种类似物抑制了向连接二糖添加一个Galf残基的半乳糖基转移酶的活性。尽管这些化合物是适度的抑制剂，但这些数据证实了这种抗分枝杆菌药物方法的可行性。特别重要的是，这三种有效化合物是在天然底物中受体原子的位点进行修饰的。
