Molecular Design and Synthesis of Novel 6-Carbon-Substituted Cytokinin Analogs

新型 6-碳取代细胞分裂素类似物的分子设计与合成

• 批准号: 13660106
• 负责人: NISHIKAWA Shiro
• 金额: $ 2.18万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13660106/
• 关键词: cytokinin; carbon-substituted analog; 1-dezapurine; Tobacco culls; Amaranthus seedling; Pd coupling; betacyanin; structure-activity-relationship; サイトカイン; 1-デアザプリン; ヒモゲイトウ試験; ノーデアザプリン; 炭素置換デアザプリン

As novel candidates of highly active cytokinins, 1-deazapurine derivatives were designed carefully and synthesized in preparative scale. To compare with the derivatives which have been prepared, some 7-arylethynyl- and 7-alkylethynyl-substituted 1-deazapurines were designed and synthesized. The important intermediate, 7-iodo-l-imidazo[4,5-b]pyrimidine-triacetyl riboside vas subjected to the Sonogashira Coupling with terminal alkynes with various substituents using Pd and Cu as catalysts to yield 7-alkynyl triacetyl-riboside derivatives of 1-deazapurines. The obtained 7-alkynyl triacetyl-ribosides were deprotected by hydrolysis with methanolic ammonia to remove acetyl protective groups. The deprotected ribosides were further hydrolyzed with 1NHC1 to obtain free bases of 7-alkynyl-l-deazapurine derivatives. Six ribosides, and six free bases were finally prepared as novel cytokinin analogs. The obtained 7-alkynykl-riboseides were also subjected to the reaction with sodium methylmercaptane … More to yield the Z and E geometrical isomers of 7-alkenyl-l-deazapurine ribosides. Four of five cases of this addition, Z isomers were predominant to the corresponding E isomer; the 1-Naphthyl derivative of alkenyl-ribosides gave an only Z isomer because of the bulkiness of naphthyl substituent. Nine novel derivatives were prepared for this type of 7-alkenyl-derivatives.The biological activities of the obtained cytokinin analogs were estimated by Tobacco Culls propagation test and Betacyanine formation test with Seedling of Amaranthus Among the compounds with aliphatic substituents on 7-position of 1-deazapurine, the 4-methylpentinyl derivative showed a moderate cytokinin activity. On the other hand, compounds with aromatic substituents showed strong activity in case of 3-methothypenylethynyl and 3-fluorophenylethynyl derivatives. The 3-methothyphenylethynyl derivative was one of the most effective cytokinin analogs, and was almost equivalent and/or more better than the traditional N^6substituted cytokinin, Benzyladenine (BA). Therefore, the introduction of 3-methoxyphenylethynyl substituent at the 7-position of 1-deazapurine ring was revealed as quite effective drug-design for strong cytokinin analogs. Moreover, because the compound has a moderate fluorescence activity, the 3-methoxyphenyleth.tnyl derivative will be useful for mechanistic studies for the incorporation, distribution and degradation of cytokinin within the living plant cell. Less

作为新的高活性细胞分裂素候选化合物，1-去氮嘌呤类化合物经过精心设计和规模化合成。为了与已有的衍生物进行比较，设计并合成了7-芳乙炔和7-烷基乙炔取代的1-去氮嘌呤类化合物。重要的中间体7-碘-L-咪唑并[4，5-b]嘧啶-三乙酰核苷在钯和铜的催化下，与末端具有不同取代基的烯烃发生Sonogashira偶联反应，合成了1-去氮尿嘧啶的7-炔基三乙酰基核苷衍生物。得到的7-炔基三乙酰核苷用甲醇氨水解脱保护，去掉乙酰基保护基团。脱保护的核苷用1NHCl进一步水解，得到7-炔基-L-去氮嘌呤衍生物的游离碱。最终合成了6个核苷和6个游离碱，作为新的细胞分裂素类似物。得到的7-炔基-核糖还与甲硫醇钠…反应进一步得到7-烯基-L-去氮嘌呤核苷的Z和E几何异构体。这种加成的5种情况中，有4种是Z异构体优于相应的E异构体；1-萘基的烯基核糖苷的衍生物由于其取代基的体积大而只有一个Z异构体。合成了9个新的7-烯基7-烯基衍生物，并对所得的细胞分裂素类似物进行了细胞分裂素活性测定，其中4-甲基戊基取代物具有中等的细胞分裂素活性。另一方面，含芳香族取代基的化合物在3-甲硫基苯乙炔和3-氟苯乙炔衍生物中表现出较强的活性。3-甲基苯乙炔是最有效的细胞分裂素类似物之一，与传统的N^6取代的细胞分裂素--苯基腺嘌呤(BA)几乎相当和/或更好。因此，在1-去氮嘌呤环的7-位引入3-甲氧基苯乙炔取代基是一种非常有效的强细胞分裂素类似物的药物设计。此外，由于该化合物具有中等的荧光活性，3-甲氧基苯乙基衍生物将用于研究细胞分裂素在活植物细胞内的掺入、分布和降解的机理。较少