Synthesis of branched sugar nucleosides based on epoxy structure in the sugar portion

基于糖部分环氧结构的支链糖核苷的合成

• 批准号: 15590020
• 负责人: TANAKA Hiromichi
• 金额: $ 2.3万
• 依托单位: School of Pharmaceutical Sciences, Showa 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-15590020/
• 关键词: uncleoside; antiviral activity; reverse transcriptase inhibito; branched sugar nucleoside; epoxid e; organoaluminum reagent; HIV; unsaturated sugar nucleoside; アルミニウム試薬; 抗ウイルス; 抗HIV; 有機アルミニウム試剤; 立体選択的; 合成; 生理活性

Oxidation of unsaturated sugar nucleosides with an acetone solution of dimethyldioxirane allowed isolation of the corresponding 1',2'- and 4',5'-epoxides for the first time, This enabled us to carry out the reaction of these epoxides with organoaluminum and organosilicon regants. As a result, a new access to 1'-and 4'-branched nucleosides has been disclosed The branched nucleosides thus synthesized were evaluated their antiviral activity.Among these nucleoside analogues, 4'-ethynylstavudine was found to show higher anti-HIV activity than the parent compound stavudine which is under clinical use. Additional appeals of 4'-ethynylstavudine are listed below:1) This compound is much less cytotoxic than stavudine,2) to contrast to stavudine, this compound does not inhibit mitochondrial DNA synthesis,3) This compound acts synergistically with lamivudine, elvucitabine, didanosine, and zidovudine against HIV,4) This compound is phosphorylated by purified human thymidine kinase 1(TK-1) from CEM … More cells with a faster relative V_<mm> and a lower K_m value than stavudine, and efficiency of TK-1 in the phosphorylation of this compound is fourfold better than stavudine.5) While stave dine is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of this compound is below detection.These characteristics of 4'-ethynylstavudine led us to carry out further investigation, especially its large scale preparation that is necessary when developing this compound as an HIV agent. The above synthetic method utilizing dimethyldioxirane is not suitable for this purpose, because a 4 concentrated acetone solution of dimethyldioxirane cannot be prepared. We, therefore, decided to apply nucleophilic substitution at the 4'-position. The substrate for this reaction was prepared again from 4',5'-unsaturated thymine derivative by reacting with lead tetrabenzoate. The resulting 4'-benzoyloxy derivative, upon reacting with an ethynylaluminum reagent, gave the 4'-ethynylated product with the desired stereochemistry in 62% yield. Precise examination of this reaction revealed that chlorination at the 4'-position is the initial step for the ethynylation. Although actual reaction mechanism remains to be investigated and also the yield has to be improve, it is to be mentioned that this ethnylation gave none of the product having opposite 4'-stereochemstry.Other studies carried out in this project are 1) the synthesis of 5'-aldehyde derivative of 4'-ethynylstavudine : this compound is to be used for the preparation oftritium labeled compound, 2) structure-activity relationships of 4'-ethynylstavudine. For the latter purpose, analogues with CH_2 and sulfur instead of furanose oxygen were synthesized each as a racemate. As a result of antiviral evaluation of these analogues, the sulfur-replaced analogue was found to be as active as stavudine. Optical resolution of this sulfur analogue is now under way to find out which enantiomer is actual anti-HIV active compound. Less

用二甲基二环氧乙烷的丙酮溶液氧化不饱和糖核苷，首次分离出相应的1 ′，2 ′-和4 ′，5 ′-环氧化物，这使我们能够进行这些环氧化物与有机铝和有机硅试剂的反应。结果，公开了1 ′-和4 ′-支链核苷的新途径。由此合成的支链核苷被评价了它们的抗病毒活性。在这些核苷类似物中，发现4 ′-乙炔基司他夫定显示出比临床使用的母体化合物司他夫定更高的抗HIV活性。4 '-乙炔基司他夫定的其他吸引力如下：1）该化合物的细胞毒性比司他夫定小得多，2）与司他夫定相反，该化合物不抑制线粒体DNA合成，3）该化合物与拉米夫定、艾夫他滨、去羟肌苷和齐多夫定协同作用对抗HIV，4）该化合物被来自CEM的纯化的人胸苷激酶1（TK-1）磷酸化 ...更多信息 TK<mm>-1对该化合物的磷酸化效率是司他夫定的四倍。5）当司他夫定被分解代谢酶胸苷磷酸化酶分解时，该化合物的分解水平低于检测水平。4 '-乙炔基司他夫定的这些特性使我们进行了进一步的研究，尤其是在开发这种化合物作为HIV试剂时所必需的大规模制备。上述使用二甲基二环氧乙烷的合成方法不适合于此目的，因为不能制备二甲基二环氧乙烷的4-浓丙酮溶液。因此，我们决定在4 '-位上进行亲核取代。通过与四苯甲酸铅反应，从4 ′，5 ′-不饱和胸腺嘧啶衍生物再次制备该反应的底物。所得4 ′-苯甲酰氧基衍生物与乙炔基铝试剂反应，得到具有所需立体化学的4 ′-乙炔化产物，产率为62%。对该反应的精确检测表明，在4 '-位的氯化是乙炔化的初始步骤。尽管实际的反应机理仍有待研究，产率也有待提高，但值得一提的是，这种乙基化反应没有得到具有相反4 ′-立体化学的产物。该化合物可用于制备氚标记化合物; 2）4’-乙炔基司他夫定的构效关系。为了后者的目的，合成了以CH_2和硫取代呋喃糖氧的类似物，每个都是外消旋体。作为这些类似物的抗病毒评价的结果，发现硫取代的类似物与司他夫定一样具有活性。目前正在对这种硫类似物进行光学拆分，以确定哪种对映体是真正的抗艾滋病毒活性化合物。少

项目成果

Ring opening of nucleoside 1',2'-epoxides with organoaluminum reagents : stereoselective entry to ribonucleosides branched at the anomeric position

用有机铝试剂对核苷 1,2-环氧化物进行开环：立体选择性进入异头位置支化的核糖核苷

• 发表时间: 2004
• 期刊: Journal of Organic Chemistry 69巻
• 作者: Kazuhiro Haraguchi et al.

Synthesis of (+/-)-4'-ethynyl and 4'-cyano carbocyclic analogues of stavudine (d4T).

司他夫定 (d4T) 的 (l-)-4-乙炔基和 4-氰基碳环类似物的合成。

• DOI: 10.1081/ncn-51900
• 发表时间: 2005
• 期刊: Nucleosides, nucleotides & nucleic acids.
• 作者: Kumamoto,Hiroki;Haraguchi,Kazuhiro;Tanaka,Hiromichi;Nitanda,Takao;Baba,Masanori;Dutschman,GingerE;Cheng,Yung-Chi;Kato,Keisuke
• 通讯作者: Kato,Keisuke

Novel 4'-substituted stavudine analog with improved anti-HIV activity and decreased cytotoxicity

新型 4-取代司他夫定类似物，具有改善的抗 HIV 活性和降低的细胞毒性

• 发表时间: 2004
• 期刊: Antimicrobial Agents and Chemotherapy 48巻
• 作者: Nozomi Aaito;et al.;Yosuke Matsumura;H.Kisyuku;Ginger E.Dutschman et al.
• 通讯作者: Ginger E.Dutschman et al.

Kazuhiro Haraguchi: "Ring Opening of 1',2'-Epoxynucleosides with Aluminum Reagents Stereoselective Entry to Ribonucleosides Substituted at the Anomeric Position"Journal of Organic Chemistry. 2004(印刷中).

Kazuhiro Haraguchi：“1,2-环氧核苷与铝试剂立体选择性进入异头位置取代的核糖核苷”有机化学杂志 2004 年（出版中）。

Synthesis and anti-HIV activity of 4'-eyano-2',3'-di-dehydro-3'-deoxythymidine

4-eyano-2,3-二-脱氢-3-脱氧胸苷的合成及抗HIV活性

• 发表时间: 2004
• 期刊: Nucleosides, Nucleotides, and Nucleic Acids 23
• 作者: K.Haraguchi;Y.Itoh;S.Takeda;Y.Honma;H.Tanaka;T.Nitanda;M.Baba;G.B.Dutschamn;Y.-C.Cheng
• 通讯作者: Y.-C.Cheng