Dardonville Christophe, Rinaldi Eliana, Hanau Stefania, Barrett Michael P, Brun Reto, Gilbert Ian H
Welsh School of Pharmacy, Redwood building, Cardiff University, King Edward VII Avenue, CF10 3XF, Cardiff, UK.
Bioorg Med Chem. 2003 Jul 17;11(14):3205-14. doi: 10.1016/s0968-0896(03)00191-3.
The synthesis and biological evaluation of three series of 6-phosphogluconate (6PG) analogues is described. (2R)-2-Methyl-4,5-dideoxy, (2R)-2-methyl-4-deoxy and 2,4-dideoxy analogues of 6PG were tested as inhibitors of 6-phosphogluconate dehydrogenase (6PGDH) from sheep liver and also Trypanosoma brucei where the enzyme is a validated drug target. Among the three series of analogues, seven compounds were found to competitively inhibit 6PGDH from T. brucei and sheep liver enzymes at micromolar concentrations. Six inhibitors belong to the (2R)-2-methyl-4-deoxy series (6, 8, 10, 12, 21, 24) and one is a (2R)-2-methyl-4,5-dideoxy analogue (29b). The 2,4-dideoxy analogues of 6PG did not inhibit both enzymes. The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani).
本文描述了三个系列6-磷酸葡萄糖酸（6PG）类似物的合成及生物学评价。对6PG的（2R）-2-甲基-4,5-二脱氧、（2R）-2-甲基-4-脱氧和2,4-二脱氧类似物作为绵羊肝脏6-磷酸葡萄糖酸脱氢酶（6PGDH）以及布氏锥虫6PGDH抑制剂进行了测试，该酶是一个已验证的药物靶点。在这三个系列的类似物中，发现有七种化合物在微摩尔浓度下能竞争性抑制布氏锥虫和绵羊肝脏酶的6PGDH。六种抑制剂属于（2R）-2-甲基-4-脱氧系列（6、8、10、12、21、24），一种是（2R）-2-甲基-4,5-二脱氧类似物（29b）。6PG的2,4-二脱氧类似物对这两种酶均无抑制作用。还在体外评估了这些化合物对罗德西亚布氏锥虫以及其他相关锥虫寄生虫（即克氏锥虫和杜氏利什曼原虫）的杀锥虫作用。
