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首页> 外文期刊>RSC Advances >Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)
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Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

机译：第二信使腺苷5'-二磷酸核糖（ADPR）的膦酸酯类似物的合成

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摘要

Adenosine 5′-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD ~(+) ). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate that is also sensitive to cellular pyrophosphatases. Prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described via tandem N , N ′-dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor.
机译：腺苷5'-二磷酸核糖（ADPR）是从烟酰胺腺嘌呤二核苷酸（NAD〜（+））产生的细胞内信号分子。合成的ADPR类似物可以阐明ADPR靶标的激活机制及其下游效应。然而，由于带负电的焦磷酸盐对细胞的焦磷酸酶也敏感，因此此类化学生物学研究通常具有挑战性。先前对初始ADPR靶标（瞬态受体电位阳离子通道TRPM2）的研究表明，完整的焦磷酸酯基团取代对于维持生物活性而言太过分了。因此，我们设计了通过使用膦酰基乙酸酯连接基除去了一个带负电荷的磷酸基团的ADPR类似物。通过串联N，N′-二环己基碳二亚胺与膦酰基乙酸偶联，描述了两种新颖的膦酰基乙酸酯ADPR类似物的合成。然而，两种类似物均未显示出对TRPM2的显着激动剂或拮抗剂活性，从而强调了完整的焦磷酸盐基序在激活该特定受体中的重要性。

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