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2018 年度 実施状況報告書

Development of Sulfo-Sialic Acids into Next-Generation Antimicrobial Agents

研究課題

研究課題/領域番号 18K06577
研究機関神戸大学

研究代表者

ヴァヴリッカ クリストファー  神戸大学, 科学技術イノベーション研究科, 特命助教 (20809199)

研究分担者 清田 洋正  岡山大学, 環境生命科学研究科, 教授 (30234397)
研究期間 (年度) 2018-04-01 – 2021-03-31
キーワードNeuraminidase / Sialic acid / Covalent inhibitors / Synthetic biology / Microwave reaction / Decarboxylation / Fluoro sugars / Synthetic biology
研究実績の概要

Our previously developed sulfosialic acids are stable and difficult to convert to dehydrogenated and halogenated products. Therefore, to produce our target compound 2,3-difluoro-sulfosialic acid, we now start with 3-fluoro-sialic acid (3F-SA) to produce a 3-fluoro-sulfosialic acid intermediate. We developed a synthetic biology enzyme-mediated strategy to produce 3F-SA. We also succeeded with the key step of decarboxylating 3F-SA in a microwave-assisted reaction, resulting in an unreported key intermediate. This represents completion of about half of our proposed synthesis (3 of 6 steps). To prevent formation of a difficult 1,7-lactone by-product, a 7-O-acetyltransferase enzyme was also identified with M-path enzyme prediction software developed at Kobe University.

現在までの達成度 (区分)
現在までの達成度 (区分)

2: おおむね順調に進展している

理由

The planned synthesis involves 3F-SA production (1), protection/deprotection (2), decarboxylation (3), anomeric sulfur addition (4), oxidation (5), and anomeric fluorine addition (6). Steps 3 and 6 were predicted to be the most difficult and we were able to complete step 3. Therefore we are satisfied with the current progress.

In addition, this grant has already been acknowledged in one review article in press, and in one Nature Communications article that was published online on May 1st.

今後の研究の推進方策

Protection/deprotection and microwave decarboxylation are now being optimized. After scaling up production of decarboxylated intermediate, anomeric addition of thiobenzoic acid will be performed according to our previous methods. Use of thiobenzoic acid instead of thioacetic acid will help with separation of resulting products by allowing for use of less polar mobile phases for chromatography.

Anomeric thiol compounds will be oxidized to sulfonates with oxone or H2O2. An anomeric fluorine will be added using selectfluor or other electrophilic fluorination reagents. Fluorination may be tested before, during, or after thiol oxidation.

Mass analysis systems are readily available to rapidly screen reactions for both expected products and unexpected products that might also be useful.

次年度使用額が生じた理由

The laboratory at Kobe University is well established and large infrastructure expenditures were not necessary to get started. Furthermore, the first year of experiments involved many small scale tests of new reactions to avoid waste. Now that key reactions are established, we will scale up the experiments will require use of more laboratory supplies.

  • 研究成果

    (3件)

すべて 2020 2019 2018

すべて 雑誌論文 (2件) (うち査読あり 2件) 学会発表 (1件)

  • [雑誌論文] Towards improvement of covalent NA inhibitors with anomeric substitution2020

    • 著者名/発表者名
      Christopher J. Vavricka, Tatsuma Matsumoto, Hiromasa Kiyota
    • 雑誌名

      Trends in Glycoscience and Glycotechnology

      巻: 32 ページ: E1-E5

    • DOI

      doi: 10.4052/tigg.1801.1E

    • 査読あり
  • [雑誌論文] Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids2019

    • 著者名/発表者名
      Christopher J. Vavricka, Takanobu Yoshida, Yuki Kuriya, Shunsuke Takahashi, Teppei Ogawa, Fumie Ono, Kazuko Agari, Hiromasa Kiyota, Jianyong Li, Jun Ishii, Kenji Tsuge, Hiromichi Minami, Michihiro Araki, Tomohisa Hasunuma, Akihiko Kondo
    • 雑誌名

      Nature Communications

      巻: 10 ページ: 2015

    • DOI

      https://doi.org/10.1038/s41467-019-09610-2

    • 査読あり
  • [学会発表] シアル酸1位置換誘導体の合成研究2018

    • 著者名/発表者名
      松本達磨、武藤千明、森さおり、Christopher J. Vavricka、蓮沼誠久、泉実、清田洋正
    • 学会等名
      農芸化学会中四国支部大会

URL: 

公開日: 2019-12-27  

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