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A Structure-Activity Relationship Study of Novel Hydroxamic Acid Inhibitors around the S1 Subsite of Human Aminopeptidase N.
ChemMedChem ( IF 3.4 ) Pub Date : 2020-09-18 , DOI: 10.1002/cmdc.202000527
Jisook Lee 1 , Nyssa Drinkwater 2 , Sheena McGowan 2 , Peter Scammells 1
Affiliation  

Aminopeptidase N (APN/CD13) is a zinc‐dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti‐cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously, we identified a potent and selective APN inhibitor, N‐(2‐(Hydroxyamino)‐2‐oxo‐1‐(3′,4′,5′‐trifluoro‐[1,1′‐biphenyl]‐4‐yl)ethyl)‐4‐(methylsulfonamido)benzamide (3). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical properties. A series of hydroxamic acid analogues were synthesised, and the pharmacological activities were evaluated in vitro. N‐(1‐(3′‐Fluoro‐[1,1′‐biphenyl]‐4‐yl)‐2‐(hydroxyamino)‐2‐oxoethyl)‐4‐(methylsulfonamido)benzamide (6 f) was found to display an extremely potent inhibitory activity in the sub‐nanomolar range.

中文翻译:

人氨肽酶N S1亚位点周围新型异羟肟酸抑制剂的构效关系研究。

氨肽酶 N (APN/CD13) 是一种锌依赖性普遍存在的跨膜胞外酶,广泛存在于不同类型的细胞中。APN 是研究最广泛的金属氨基肽酶之一,作为抗癌靶点,由于其在调节转移和血管生成中的重要作用。之前,我们确定了一种有效的选择性 APN 抑制剂N- (2-(Hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl )乙基)-4-(甲基磺酰氨基)苯甲酰胺 ( 3 )。在此,我们报告了为探索 APN 的 S1 子位点周围的 SAR 并改善理化特性而进行的进一步修改。合成了一系列异羟肟酸类似物,并进行了体外药理活性评价。N-(1-(3'-Fluoro-[1,1'-biphenyl]-4-yl)-2-(hydroxyamino)-2-oxoethyl)-4-(methylsulfonamido)benzamide ( 6f ) 被发现显示出在亚纳摩尔范围内具有极强的抑制活性。
更新日期:2020-09-18
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