A phosphonamidate containing aromatic N-terminal amino group as inhibitor of leucine aminopeptidase - design, synthesis and stability
A phosphonamidate containing aromatic N-terminal amino group as inhibitor of leucine aminopeptidase - design, synthesis and stability
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DOI：
10.1016/j.ejmech.2006.03.023
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发表时间：
2006-06-01
影响因子：
6.7
通讯作者：
Kafarski, P.
中科院分区：
文献类型：
--
作者：
Mucha, A.;Kunert, A.;Kafarski, P.
完全脱保护的磷酰胺酯二肽，预测作为有效的抑制剂的胞质亮氨酸氨肽酶，在水溶液中显示出意想不到的不稳定性，在pH值低于12。它们的水解速率与N-末端氨基的碱性密切相关。为了改善这一特征，设计了在抑制剂的P1位含有较少碱性、芳香族2-氨基苯基膦酸酯残基的膦酰胺酯类似物。以2-硝基膦酸二乙酯为起始原料，经几步反应合成了目标化合物。修饰类似物的末端氨基部分的碱性的降低实际上导致P-N键的水解稳定性的令人满意的改善。所开发的磷酰胺酯被证明是完全耐水解pH 7以上。令人惊讶的是，在针对亮氨酸氨肽酶（最适pH 8.5）的酶测定中测试，其在高达毫摩尔浓度下不表现出抑制活性。这可能是因为末端氨基的碱性减弱可能导致其对锌离子的亲和力发生变化。(c)2006年爱思唯尔SAS。All rights reserved.
Fully deprotected phosphonamidate dipeptides, predicted as effective inhibitors of cytosolic leucine aminopeptidase, showed unexpected instability in water solution at pH below 12. Their hydrolysis rate was strictly correlated with basicity of the N-terminal amino group. To improve this feature a phosphonamidate analogue containing less basic, aromatic 2-aminophenylphosphonate residue in P1 position of the inhibitor was designed. The target compound was synthesised starting from diethyl 2-nitrophosphonate in several step procedure. The decrease in basicity of the terminal amino moiety of the modified analogue in fact resulted in satisfactory improvement of hydrolytic stability of the P-N bond. The developed phosphonamidate was proved to be fully resistant to hydrolysis above pH 7. Surprisingly, tested in enzymatic assays towards leucine aminopeptidase (optimum pH 8.5), it did not exhibit inhibition activity up to milimolar concentration. The explanation could be that diminishing the basic character of the terminal amino group may result in a change of its affinity towards the zinc ions. (c) 2006 Elsevier SAS. All rights reserved.