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Establishment of systematic chemical synthetic method of element substitution type nucleic acid oligomer which becomes the next generation nucleic acid drug candidate

建立元素取代型核酸寡聚物的系统化学合成方法，成为下一代核酸候选药物

基本信息

批准号：
19H00930
负责人：
千葉一裕
金额：
$ 27.12万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2019
资助国家：
日本
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

项目摘要

一般の化学合成法だけでは達成することが困難な, 次世代核酸医薬であるアザヌクレオチドオリゴマーを高純度品として大量供給できる新たな化学反応法に関する学術基盤を確立し，医薬品，農薬としての実用化開発に対応できる構造の多様化，機能拡張に展開することを目的とする．核酸医薬は低分子医薬，抗体医薬に続く次世代の革新的医薬品として期待されているが，その中でも第四世代の核酸医薬の一つに位置づけられているアザヌクレオシドは，天然型核酸構造の一部の酸素原子を窒素原子に置換した基本骨格を有し，従前の核酸医薬候補物質を凌ぐ優れた機能や活性が確認されている．しかし，その化学合成法は多段階を要し，必要量を得るためには大きな困難を伴う．本研究では申請者がこれまでに独自に開発した有機電解反応法および，逆ミセル液相反応を基軸とした中分子の化学合成法を進展させることにより，従来法では達成困難な各種アザヌクレオシド誘導体の体系的合成法を拓く．すなわち，アザヌクレオシドを構成ユニットとするアザヌクレオチドオリゴマーを極めて短工程で効率的に得ることによって，次世代核酸医薬開発の飛躍的進展に寄与する．本研究では研究代表者が実証してきた低電位電解カチオン発生法（Redox タグ法）を導入することを特徴とする．この方法は核酸塩基導入前に電子供与基を有する芳香環などのRedox タグを導入する．これは隣接する窒素上に任意の置換基が導入されていても分解しない．さらに，その後で穏やかな電解酸化条件でタグを外すと同時に，望みの核酸塩基を導入するものである．本研究では，この方法を立体選択的な核酸塩基の導入法と併せて実施することに成功した．RNA型およびDNA型Ｎ-αアザヌクレオシドの合成法として一般化できるものと期待される．

In general, the chemical synthesis method is very difficult, and the next-generation nucleic acid medicine is used in the second generation of nucleic acid medicine. There is a large supply of high-quality products to the new chemical reaction method. The basic science of science is established, medical products, agricultural products, pharmaceutical products, agricultural products, medical products, agricultural products, pharmaceutical products, medical products, agricultural products, medical products, medical products, agricultural products, The machine can be used to develop the low molecular weight medicine of nucleic acid medicine, antibody medicine of the next generation, the innovative medical products of the next generation, the fourth generation of nucleic acid medicine, the location of the fourth generation of nucleic acid medicine, the location of the fourth generation of nucleic acid medicine, the location of the fourth generation of nucleic acid medicine, the location of the fourth generation of nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the location of the fourth generation nucleic acid medicine, the natural nucleic acid The former nucleic acid medicine candidate was able to confirm the activity of the chemical synthesis method, and the chemical synthesis method was used for multi-stage screening, and it was necessary to obtain the necessary amount of equipment. In this study, the applicants who applied for this study were unable to open an electronic counter-response test alone. In the reverse phase, the chemical synthesis of molecules in the basic chemical method has been developed, and the method has been developed in order to develop the synthesis of all kinds of molecular chemical synthesis systems. in the reverse phase, the chemical synthesis method of molecules in the molecular chemical synthesis method has been developed in the opposite way. in the reverse phase, the chemical synthesis method of molecular chemical synthesis has been developed by the chemical synthesis method of molecules. The next generation of nucleic acid medicine has been launched in recent years. In this study, the representative of this study was involved in this study. The representative of this study was involved in the low-potential electrolysis (Redox) method. The nucleic acid radical was introduced into the front end of the battery for the transfer of aromatic compounds to the Redox in the base metal. Set the base to enter the database and decompose the data. In the future, the conditions of electrolysis acidification are different in the same time, and we hope that the nucleic acid radical will be introduced into the enzyme chain. In this study, the nucleic acid radical selected by this method has been successfully applied in this study. RNAi DNA type DNA type N-α DNA complex synthesis method has been widely used in this study.