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Synthesis and its function of novel squaric acid containing amino acids.

新型含氨基酸方酸的合成及其功能。

基本信息

批准号：
15510178
负责人：
SHINADA Tetsuro
金额：
$ 2.37万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15510178/
关键词：
squaric acid amino acid analog peptide enkephalin enolate アミノマロン酸

项目摘要

The carboxyl group in α-amino acids plays an important role as a proton donor and a peptide-bond-forming functional group. α-Amino acid analogs in which the carboxylic acid moiety is replaced with other acidic groups, e.g., phosphonic acid, sulfonic acid, boronic acid, tetrazole are known to be important surrogates of α-amino acid. Squaric acid is an oxocarbon and exhibits several unique physicochemical and chemical properties characterized by strong acidity, aromatic conjugate system, ring strain, electron deficiency, and metal chelating ability. Therefore, 4-hydroxy-2,3-dioxocyclobut-1-enyl (Sq) group has attracted much attention as an isostere of carboxylic acid in medicinal chemistry. In this project, the synthesis of a novel amino acid isostere bearing Sq group as a carboxylate equivalent in α-amino acid (α-Amino Squaric Acid (α-ASqA)) and its incorporation into peptide was implicated. We initially investigated facile and practical carbon-carbon bond-forming reaction to 1'-amino-1-squarylacetate followed by conversion of the resulting alkylated adducts into α-ASqA. Two novel methods involving the use of sq-group incorporating amino malonate equivalent (method A) and addition reaction of dianion enolate (method B) to access α-ASqA were developed. Addition reaction of dianion enolate generated from N-Boc-amino acid ester to squaric acid diisopropyl ester was the key to these methods. Generation efficiency of enolate from N-Boc-Phe-Ot-Bu ester was assessed by deuterium incorporation experiments using various bases. As a result, the use of 2 equiv of sec-BuLi was found to be the most efficient base. This result prompted two new methods A and B to access various α-ASqA possessing natural and unnatural types of α-amino acid side chain. α-ASqA was incorporated into Leu-enkephalin to give three different type of α-ASqA-containing Leu-enkephalin. These biological activities were characterized by receptor binding assay of opioid receptors.

α-氨基酸中的羧基作为质子供体和肽键形成官能团起着重要的作用。α-氨基酸类似物中羧酸部分被其他酸性基团取代，如膦酸、磺酸、硼酸、四氮唑等，是α-氨基酸的重要替代物。方酸是一种氧碳化合物，具有强酸性、芳香共轭体系、环应变、缺电子和金属螯合能力等独特的理化性质。因此，4-羟基-2,3-二氧环丁烯基（Sq）作为羧酸的同分异构体在药物化学中备受关注。在这个项目中，涉及合成一种新的氨基酸等异构体，其中含有α-氨基酸（α-氨基方酸（α-ASqA））的羧酸等同的Sq基团，并将其掺入肽中。我们首先研究了1′-氨基-1-平方乙酸酯的简单和实用的碳-碳成键反应，然后将所得到的烷基化加合物转化为α-ASqA。提出了两种新方法，分别是利用含有氨基丙二酸等价物的sq-基团（方法A）和乙醇酸酯加成反应（方法B）来获得α-ASqA。这些方法的关键是由n - boc -氨基酸酯生成的乙醇酸酯加成成方酸二异丙酯。通过不同碱基的氘掺入实验，评价了n - boc - ph - ot - bu酯生成烯醇酯的效率。因此，使用2等量的sec-BuLi是最有效的基数。这一结果促使A和B两种新方法获得具有天然和非天然类型α-氨基酸侧链的各种α-ASqA。将α-ASqA掺入Leu-enkephalin中，得到三种不同类型的含α-ASqA的Leu-enkephalin。这些生物活性通过阿片受体结合实验进行了表征。