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N-Benzyl Residues as the P1′ Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases
Molecules ( IF 4.2 ) Pub Date : 2020-09-22 , DOI: 10.3390/molecules25184334
Kamila Janiszewska , Michał Talma , Bartosz Oszywa , Małgorzata Pawełczak , Paweł Kafarski , Artur Mucha

Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based on the three-component phospha-Mannich condensation of phosphinic acids, formaldehyde, and N-benzylglycines. The last-mentioned component allowed for simple and versatile introduction of functionalized P1′ residues located on the tertiary amino group. The products demonstrated moderate inhibitory activity towards porcine and plant metalloaminopeptidases, while selected derivatives appeared very potent with human alanyl aminopeptidase (Ki = 102 nM for 6a). Analysis of ligand-protein complexes obtained by molecular modelling revealed canonical modes of interactions for mono-metallic alanyl aminopeptidases, and distorted modes for di-metallic leucine aminopeptidases (with C-terminal carboxylate, not phosphinate, involved in metal coordination). In general, the method can be dedicated to examine P1′-S1′ complementarity in searching for non-evident structures of specific residues as the key fragments of perspective ligands.

中文翻译:

N-苄基残基作为金属氨基肽酶含磷扩展过渡态类似物抑制剂中的 P1' 取代基

含有内部氨甲基次膦键系统 (P(O)(OH)-CH2-NH) 的肽基酶抑制剂可通过与相应的膦酰胺酸酯 (P(O)(OH)-NH) 的相似性而被称为扩展过渡态类似物。膦酰胺假肽被广泛认为是金属酶(主要是水解酶)的基于竞争机制的抑制剂。然而,它们的实际应用受到水解不稳定性的限制,这对二肽类似物尤其受限。通过添加亚甲基来扩展膦酰胺酸酯产生完全耐受水条件的 PCN 系统。在目前的工作中,我们提出了一种基于次膦酸、甲醛和 N-苄基甘氨酸的三组分磷酸-曼尼希缩合反应的多功能合成方法来合成这种修饰的二肽。最后提到的组件允许简单和通用地引入位于叔氨基上的功能化 P1' 残基。这些产品对猪和植物金属氨基肽酶表现出中等抑制活性,而选定的衍生物对人丙氨肽酶表现出非常有效的作用(6a 的 Ki = 102 nM)。通过分子建模获得的配体-蛋白质复合物的分析揭示了单金属丙氨酰氨肽酶相互作用的典型模式,以及双金属亮氨酸氨肽酶的扭曲模式(C 端羧酸盐,而不是次膦酸盐,参与金属配位)。通常,该方法可以专门用于检查 P1'-S1' 互补性,以寻找特定残基的非明显结构作为透视配体的关键片段。
更新日期:2020-09-22
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