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首页> 外文期刊>Chemistry: A European journal >High-Affinity Inhibitors of tRNA-Guanine Transglycosylase Replacing theFunction of a Structural Water Cluster
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High-Affinity Inhibitors of tRNA-Guanine Transglycosylase Replacing theFunction of a Structural Water Cluster

机译：高亲和力的tRNA鸟嘌呤转糖基酶替代结构水簇的功能。

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摘要

The tRNA-modifyingenzyme tRNA–guanine transglycosy-lase (TGT) is essential for the patho-genic mechanism of Shigella flexneri,the causing agent of the bacterial diar-rheal disease shigellosis. Herein, thesynthesis of a new class of rationallydesigned 6-amino-imidazo[4,5-g]quina-zolin-8(7H)-one- (lin-benzoguanine)based inhibitors of TGT are reported.In order to accommodate a small hy-drophobic crevice opening near thebinding site of ribose-34, 2-aminoethylsubstituents were introduced in posi-tion 4 of the heterocyclic scaffold. For this purpose, a synthetic sequence con-sisting of iodination, Suzuki cross-cou-pling, hydroboration, Mitsunobu reac-tion, and Gabriel synthesis was em-ployed, furnishing a primary aminethat served as a common intermediatefor the preparation of a series of deriv-atives. The resulting ligands displayedvery low inhibition constants, down toK_i=2nm. Substantial additional inhibi-tory potency is gained by interaction of terminal lipophilic groups attached tothe substituent at position 4 with thehydrophobic crevice shaped by Va145and Leu68. At the same time, the sec-ondary ammonium center in the sub-stituent displaces a cluster of watermolecules, solvating the catalytic resi-dues Asp102 and Asp280, without lossin binding affinity. In addition, a syn-thetic intermediate with an unusual3,6,7,8,9,10-hexahydroimidazo[4,5-g]- [1,3]benzodiazepine core, as confirmedby X-ray analysis, is reported.
机译：tRNA修饰酶tRNA-鸟嘌呤转糖基酶（TGT）对于弗氏志贺氏菌（细菌性痢疾志贺菌病的病原体）的致病机理至关重要。本文报道了新型合理设计的新型6-氨基-咪唑并[4,5-g]喹唑啉-8（7H）-单-（lin-苯并鸟嘌呤）基TGT抑制剂的合成。在核糖-34，2-氨基乙基取代基的结合位点附近的疏水缝隙开口被引入杂环支架的位置4。为此，采用了由碘化，铃木交联，硼氢化，Mitsunobu反应和Gabriel合成组成的合成序列，提供了伯胺，该伯胺用作制备一系列衍生物。所得配体显示出非常低的抑制常数，低至K_i = 2nm。通过在4位上的取代基上连接的末端亲脂性基团与由Va145和Leu68形成的疏水缝隙的相互作用，可获得相当大的抑制力。同时，取代基中的仲氨中心取代了一簇水分子，使催化残基Asp102和Asp280溶剂化，而结合亲和力没有损失。另外，据报道，通过X射线分析证实，该合成中间体具有不寻常的3,6,7,8,9,10-六氢咪唑并[4,5-g]-[1,3]苯并二氮杂core核。

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