Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13
Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13
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DOI：
10.1021/jm021109f
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发表时间：
2003-08-28
影响因子：
7.3
通讯作者：
Dauzonne, D
中科院分区：
文献类型：
--
作者：
Bauvois, B;Puiffe, ML;Dauzonne, D
细胞表面氨肽酶N（APN/CD 13）在肿瘤细胞中过表达，在血管生成中起关键作用。然而，这种蛋白质的有效的，选择性的，特别是，非细胞毒性抑制剂缺乏，目前的工作进行的目的是开发新一代的非细胞毒性抑制剂，结合APN/CD 13。在此背景下，我们合成了一系列新的黄酮-8-乙酸衍生物。在本文所述和评价的化合物中，2 ′，3-二硝基黄酮-8-乙酸（19 b）被证明是最有效的，其IC 50为25 μ M，比天然已知的APN/CD 13抑制剂bestatin（1）高2.5倍。然而，与bestatin（1）相反，二硝基黄酮19 b对培养的人模型细胞不诱导任何细胞毒性。在B苯基的3 ′-或4 ′-位存在其它取代基如NO2或OCH 3基团，或存在空间限制（化合物24和29），都不能提高选择性和效力。黄酮19 b对APN/CD 13的亲和力不能用其它蛋白酶恢复，所述其它蛋白酶例如基质金属蛋白酶-9（MMP-9）、血管紧张素转化酶（ACE/CD 143）、中性内肽酶（NEP/CD 10）、γ-谷氨酰转肽酶（CD 224）或丝氨酸蛋白酶二肽基肽酶IV（DPPIV/CD 26）或组织蛋白酶G。
The cell surface aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. However, potent, selective, and, particularly, noncytotoxic inhibitors ot this protein are lacking, and the present work was undertaken with the aim of developing a new generation of noncytotoxic inhibitors that bind to APN/CD13. In this context, we have synthesized a series of novel flavone-8-acetic acid derivatives. Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC50 of 25 muM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13. However, in contrast to bestatin (1), the dinitroflavone 19b did not induce any cytotoxicity to cultured human model cells. The presence of other substituents such as NO2 or OCH3 groups at the 3'- or 4'-position of the B phenyl group, or the existence of steric constraints (compounds 24 and 29), did not improve selectivity and potency. The flavone 19b affinity for APN/CD13 is not recovered with other proteases such as matrix metalloproteinase-9 (MMP-9), angiotensin converting enzyme (ACE/CD143), neutral endopeptidase (NEP/CD10), gamma-glutamyl transpeptidase (CD224), or the serine proteases dipeptidyl peptidase IV (DPPIV/CD26) or cathepsin G.