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Aliphatic amines are viable pro-drug moieties in phosphonoamidate drugs
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-10-29 , DOI: 10.1016/j.bmcl.2020.127656
Victoria C Yan 1 , Cong-Dat Pham 1 , Kenisha Arthur 1 , Kristine L Yang 1 , Florian L Muller 1
Affiliation  

Phosphate and phosphonates containing a single Psingle bondN bond are frequently used pro-drug motifs to improve cell permeability of these otherwise anionic moieties. Upon entry into the cell, the Psingle bondN bond is cleaved by phosphoramidases to release the active agent. Here, we apply a novel mono-amidation strategy to our laboratory’s phosphonate-containing glycolysis inhibitor and show that a diverse panel of phosphonoamidates may be rapidly generated for in vitro screening. We show that, in contrast to the canonical l-alanine or benzylamine moieties which have previously been reported as efficacious pro-drug moieties, small and long-chain aliphatic amines demonstrate greater drug release efficacy for our phosphonate inhibitor. These results expand the scope of possible amine pro-drugs that can be used as second pro-drug leave groups for phosphate or phosphonate-containing drugs.



中文翻译:

脂肪胺是氨基磷酸酯药物中可行的前药部分

单键经常使用含有单个P N键的磷酸酯和膦酸酯前药基序来改善这些原本阴离子部分的细胞通透性。进入细胞后,单键PN键被磷酰胺酶切割以释放活性剂。在这里,我们将一种新颖的单酰胺化策略应用于我们实验室的含膦酸酯的糖酵解抑制剂,并显示出可以快速生成用于体外筛选的多种膦酰胺盐。我们表明,相较于经典先前已被报告为有效的前药部分的-丙氨酸或苄胺部分,小的和长链的脂肪族胺对我们的膦酸酯抑制剂表现出更大的药物释放功效。这些结果扩大了可能的胺前药的范围,该胺前药可用作含磷酸盐或膦酸酯的药物的第二前药离开基团。

更新日期:2020-11-06
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