2018 Fiscal Year Research-status Report
Development of Sulfo-Sialic Acids into Next-Generation Antimicrobial Agents
| Project/Area Number |
18K06577
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| Research Institution | Kobe University |
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Principal Investigator |
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)
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| Co-Investigator(Kenkyū-buntansha) |
清田 洋正 岡山大学, 環境生命科学研究科, 教授 (30234397)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | Neuraminidase / Sialic acid / Covalent inhibitors / Synthetic biology / Microwave reaction / Decarboxylation / Fluoro sugars / Synthetic biology |
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| Outline of Annual Research Achievements |
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.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
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.
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| Strategy for Future Research Activity |
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.
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| Causes of Carryover |
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.
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[Journal Article] Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids2019
Author(s)
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
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Journal Title
Nature Communications
Volume: 10
Pages: 2015
DOI
Peer Reviewed
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