Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid‐Derived Imidazoles as Inhibitors of Bovine Liver β‐Glucuronidase
Synthesis of Glucuronic, Mannuronic, and Galacturonic Acid‐Derived Imidazoles as Inhibitors of Bovine Liver β‐Glucuronidase
复制标题
葡萄糖醛酸、甘露糖醛酸和半乳糖醛酸衍生的咪唑类化合物作为牛肝 β-葡萄糖醛酸酶抑制剂的合成
DOI：
10.1002/hlca.200690137
复制
发表时间：
2006
影响因子：
1.8
通讯作者：
A. Vasella
中科院分区：
文献类型：
--
作者：
Jagadish Pabba;Narinder Mohal;A. Vasella
分别合成葡萄糖-、甘露糖-和半乳糖-构型的咪唑并吡啶-5-羧酸酯5-7，并作为牛肝β-葡萄糖醛酸酶的抑制剂进行评价。在9个步骤中，以9%和12%的总产率将阿托内酰胺15转化为葡萄糖-和甘露糖-咪唑5和6。选择性保护的葡萄糖-和甘露糖-构型的羟甲基-咪唑并吡啶23和25（均得自β-内酰胺15）的氧化和酯化分别提供二苯甲基酯24和26。氢解得到葡糖-咪唑并吡啶-羧酸5和甘露糖异构体6。类似地，将从半乳糖内酰胺27获得的羟甲基-咪唑并吡啶33进行氧化、酯化和脱保护，以10步从半乳糖内酰胺27得到半乳糖构型的咪唑并吡啶-羧酸酯7，总产率为13%。葡萄糖构型的咪唑5是已知最强的β-葡萄糖醛酸苷酶抑制剂（Ki = 12 nM），而甘露糖和半乳糖构型的咪唑6和7是牛β-葡萄糖醛酸苷酶的微摩尔抑制剂。 讨论了咪唑并吡啶羧酸5和四唑并吡啶羧酸1的抑制强度之间的微小差异，以及5-7的构型选择性与相应的内酰胺3和4的非选择性之间的差异。
The gluco-, manno-, and galacto-configured imidazopyridine-5-carboxylates 5–7, respectively, were synthesized and evaluated as inhibitors of bovine liver β-glucuronidase. The gluconolactam 15 was transformed into the gluco- and manno-imidazoles 5 and 6 in nine steps and in an overall yield of 9 and 12%, respectively. Oxidation and esterification of the selectively protected gluco- and manno-configured hydroxymethyl-imidazopyridines 23 and 25, respectively (both obtained from gluconolactam 15), provided the benzhydryl esters 24 and 26, respectively. Hydrogenolysis afforded the gluco-imidazopyridine-carboxylic acid 5 and the manno-isomer 6. Similarly, the hydroxymethyl-imidazopyridine 33, obtained from galactonolactam 27, was subjected to oxidation, esterification, and deprotection to afford the galacto-configured imidazopyridine-carboxylate 7 in ten steps from the galactonolactam 27 and in an overall yield of 13%. The gluco-configured imidazole 5 is the strongest known inhibitor of β-glucuronidases (Ki = 12 nM), while the manno- and galacto-configured imidazoles 6 and 7 are micromolar inhibitors of bovine β-glucuronidase. The small difference between the inhibitory strength of the imidazopyridine-carboxylic acid 5 and the tetrazolopyridine-carboxylic acid 1, and the difference between the configurational selectivity of 5–7 as compared to the unselectivity of the corresponding lactams 3 and 4 are discussed.