Synthesis of quaternary α-amino acid-based arginase inhibitors via the Ugi reaction
Synthesis of quaternary α-amino acid-based arginase inhibitors via the Ugi reaction
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DOI：
10.1016/j.bmcl.2013.06.092
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发表时间：
2013-09-01
影响因子：
2.7
通讯作者：
Schroeter, Hagen
中科院分区：
文献类型：
--
作者：
Golebiowski, Adam;Whitehouse, Darren;Schroeter, Hagen
Ugi反应已成功地应用于合成新的辅酶Ⅱ酶抑制剂。为了降低先前报道的2-氨基-6-硼己酸（ABH）类似物1的构象灵活性，我们设计并合成了一系列化合物2，其中哌啶环直接连接到季铵氨基酸中心。通过在哌啶环上添加两个碳桥，即托烷类似物11，实现了体外活性的进一步提高。通过X射线晶体学分析，这些活性的改善是合理的，这表明托烷环氮原子移动到直接接触Asp 202（天冬氨酸酶II编号）。本文所述的合成路线使得能够设计与ABH相比具有改善的效力和显著不同的物理化学性质的新型谷胱甘肽酶抑制剂。化合物11 c代表迄今为止报道的最具体外活性的脱氢酶抑制剂。(C)2013爱思唯尔有限公司保留所有权利。
The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physicochemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date. (C) 2013 Elsevier Ltd. All rights reserved.