Stereochemical Studies of Nucleosides and Nucleotides

核苷和核苷酸的立体化学研究

• 批准号: 59470117
• 负责人: TOHRU Ueda
• 金额: $ 4.86万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1984
• 资助国家: 日本
• 起止时间: 1984 至 1986
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-59470117/
• 关键词: Nucleosides; Nucleotides; Stereochemistry; Cyclonucleosides; Nucleoside conformation; Ribonuclease; アデノシンデアミナーゼ

It has been generally recognized that the syn-anti conformation around the glycosylic linkages of nucleosides is one of the important determinants in the interaction of nucleosides and nucleotides with various enzymes utilizing them. To elucidate the stereochemistry of such interactions, the cyclonucleosides would be useful. In this respect, cyclonucleosides where the glycosyl torsion angle is fixed in an appropriate degree by the carbon bridge is regarded as useful model. This report summarized the result of synthesis of C-cyclonucleosides of pyrimidines and purines. Synthesis of some their phosphates and certain biological properties are also described.1. Synthesis of carbon-bridged pyrimidine cyclonucleosides.The following new compounds have been prepared: 5'-deoxy-6,5'-methanouridine; 2'-deoxy-6,2'-ethanouridine; 2'-deoxy-6,2'-methanouridine; 6,2'-methanouridine; 6,3'-methanouridine; 6,3'-methanocytidine; 6,3'-methanothymidine; 6,5'-cyclo-2',5'-di-deoxyuridine 6,5'-cyclo5'-deoxythymidine; 6,5'-cyclo-5'-deoxy-5'-hydroxyethyluridine, and related intermediates.2. The 2',3'-cyclic phosphates of 5'-deoxy-6,5'-cyclouridines were the substrates of pancreatic ribonuclease (RNase). The 3'-phosphates were strong inhibitors. This means that the RNase recognizes the anti form of the pyrimidine nucleosides.3. Synthesis of carbon-bridged purine cyclonucleosides.The following compounds were newly synthesized: 2'-deoxy-8,2'-ethanoadenosine; 3'-deoxy-8,3'-ethanoadenosine; 8,2'-ethanoadenosine; 2'-deoxy-8,2'-methanoadenosine; 8,2'-methanoadenosine; 8,2'-methanoguanosine and its alpha anomer. The 8,2'-cyclo-adenosines were the substrates of adenosine deaminase whereas the 8,3'-compound was not. The conformation of the 5'-hydroxyl group may also be important for the binding of the substrate to the enzyme.4. Some of the cyclonucleosides were tested for the antitumor (L1210) and antiviral (HSV-I) properties. None of them showed distinct activities to a level of 100 <micro> g/ml.

人们普遍认为，核苷糖键周围的正反构象是核苷和核苷酸与利用它们的各种酶相互作用的重要决定因素之一。为了阐明这种相互作用的立体化学，环核苷将是有用的。在这方面，通过碳桥将糖基扭转角固定在适当程度的环核苷被认为是有用的模型。本文综述了嘧啶类和嘌呤类C-环核苷的合成结果。还描述了它们的一些磷酸盐的合成和某些生物学性质。合成了如下新化合物：5‘-脱氧-6，5’-甲基尿苷；2‘-脱氧-6，2’-乙基尿苷；2‘-脱氧-6，2’-甲基尿苷；6，2‘-甲基尿苷；6，3’-甲基尿苷；6，3‘-甲基胞苷；6，3’-甲硫嘧啶；6，5‘-环-2’，5‘-二脱氧尿苷6，5’-环5‘-脱氧胸苷；6，5’-环-5‘-脱氧-5’-羟乙基尿苷及相关中间体2。胰腺核糖核酸酶(RNase)的底物为5‘-脱氧-6，5’-环状磷酸。3‘-磷酸盐类是很强的抑制剂。这意味着核糖核酸酶识别的是嘧啶核苷的反形式。新合成的化合物：2‘-脱氧-8，2’-乙基腺苷；3‘-脱氧-8，3’-乙基腺苷；8，2‘-乙基腺苷；2’-脱氧-8，2‘-甲基腺苷；8，2’-甲基腺苷；8，2‘-甲鸟苷及其α-异构体。8，2‘-环腺苷是腺苷脱氨酶的底物，而8，3’-化合物不是。5‘-羟基的构象对于底物与酶的结合也可能是重要的。对部分环核苷进行了抗肿瘤(L1210)和抗病毒(HSV-I)性能测试。它们的活性均未达到100微克/毫升的水平。

项目成果

Hiroyuki Usui: Chem.Pharm.Bull.34(4). 1518-1523 (1986)

臼井宏之：Chem.Pharm.Bull.34(4)。

Yukari Suzuki: "Synthesis of 6,5'-cyclo-5'-deoxy-5'(R and S)-(2-hydroxyethyl)-uridines (Nucleosides and Nucleotides LXXIII)" Chem. Pharm. Bull.35. in press (1987)

Yukari Suzuki：“6,5-环-5-脱氧-5（R和S）-（2-羟乙基）-尿苷（核苷和核苷酸LXXIII）的合成”化学。

Hiroyuki Usui: "Synthesis of 2'-deoxy-8,2'-ethanoadenosine and 3'-deoxy-8,3'-ethanoadenosine (Nucleosides and Nucleotides LXIV)" Chem. Pharm. Bull.34(1). 15-23 (1986)

Hiroyuki Usui：“2-脱氧-8,2-乙醇腺苷和3-脱氧-8,3-乙醇腺苷（核苷和核苷酸LXIV）的合成”化学。

Jerzy Boryski: Nucleosides and Nucleotides. 4(4). 477-486 (1985)

Jerzy Boryski：核苷和核苷酸。

Akira Matsuda: Tetrahedron. 41(24). 6013-6017 (1985)

松田晃：四面体。