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TOTAL CHEMICAL SYNTHESIS OF CADPR AND CADPR ANALOGS

CADPR 和 CADPR 类似物的全化学合成

基本信息

批准号：
2868063
负责人：
STEVEN McGrath GRAHAM
金额：
$ 3.15万
依托单位：
ST. JOHN'S UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 1999-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2868063
关键词：
NAD(H) analog adenosine diphosphate biomimetics calcium flux carbene chemical synthesis cyclic compound nicotinamide adenine dinucleotide ribose phosphate sea urchins second messengers

项目摘要

Cyclic adenosine diphosphate ribose (cADPR) appears to be a new and important second messenger that mediates Ca2+ release. The large majority of cADPR preparations in the literature are enzymatic syntheses. in vivo and in vitro, ADP-ribosyl cyclase catalyzes the conversion of nAD+ to cADPR. A biomimetic chemical synthesis of cADPR from NAD+ has recently been reported. Herein the first non-enzymatic total chemical synthesis of cADPR is proposed. Such a synthesis is a prerequisite to the eventual total chemical synthesis of cADPR photoaffinity labels (PALs) because it is unlikely that the available methods for the synthesis of cADPR can be sufficiently modified. cADPR acyclic precursors will be prepared from nucleotide and glycoside building blocks. These acyclic precursors can be "armed" and activated towards oxocarbenium ion formation and ring closure using the methodology of Fraser-Reid. This analysis is based on the common intermediacy of oxocarbenium ions intermediates in the biomimetic and enzymatic cyclizations of NAD+ and in Fraser-Reid's work. The proposed synthesis has the advantage that it is easily adapted to construct cADPR analogues, including cADPR PALs and cADPR affinity chromatography (AC) ligands. With a method for the chemical synthesis of cADPR and analogues in hand we will turn our attention to the biochemical evaluation of the cADPR analogues. Specifically constructed cADPR PALs and AC ligands are expected to be invaluable tools for identifying, purifying, and isolating cADPR receptor, effector, and binding proteins. Assays for biological activity and photoaffinity labeling experiments will use the original sea urchin egg systems, with the long term goal being the development of a set of general tools to study this new Ca2+-mediated second messenger system. The knowledge and methodology gained in the course of this work are expected to make important contributions to our understanding of this and potentially other second messenger pathways. Should the proposed experiments prove successful we would then be equipped to significantly expand the scope of the project to include systems more complex than the sea urchin.

环腺苷二磷酸核糖(CADPR)是一种新型的重要的第二信使，调节钙的释放。绝大多数人文献中的cADPR制剂多为酶促合成。体内在体外，ADP-核糖环化酶催化NAD+转化为 Cadpr.从NAD+仿生化学合成cADPR最近已经上报了。在此首次进行了非酶全化学合成。提出了cadpr的概念。这样的综合是最终实现全化学合成cADPR光亲和标记(PAL)，因为它是合成cADPR的现有方法不太可能是经过了充分的修改。CADPR无环前驱体将从核苷酸和糖苷构建块。这些非循环前体可以是 “武装”，并朝着氧碳正离子的形成和环的闭合而被激活使用弗雷泽-里德的方法论。这一分析是基于共同的氧碳正离子中间体在仿生和生物合成中的中间体 NAD+的酶催化环化和弗雷泽-里德的工作。建议数合成的优点是很容易被用来构建cadpr。类似物，包括cADPR PALS和cADPR亲和层析(AC) 配基。有了化学合成cADPR及其类似物的方法，我们我们将把注意力转向cadpr的生化评价。类似物。预计将有专门构建的cADPR PAL和AC配体是鉴定、提纯和分离cADPR的无价工具受体、效应器和结合蛋白。生物活性测定而光亲和标记实验将使用原始的海胆卵系统，长期目标是开发一套通用的研究这一新的钙离子介导的第二信使系统的工具。这个在这项工作过程中获得的知识和方法可望对我们理解这一点并可能做出重要贡献其他第二信使途径。如果提议的实验证明如果成功，我们将有能力显著扩大该项目将包括比海胆更复杂的系统。