2020 Fiscal Year Annual Research Report
光触媒による2-デオキシ糖の立体選択的グリコシル化の開発とミスラマイシンの全合成
Project/Area Number |
19F01098
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Research Institution | Gifu University |
Principal Investigator |
安藤 弘宗 岐阜大学, 糖鎖生命コア研究所, 教授 (20372518)
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Co-Investigator(Kenkyū-buntansha) |
VIBHUTE AMOL 岐阜大学, 糖鎖生命コア研究所, 外国人特別研究員
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Project Period (FY) |
2019-10-11 – 2022-03-31
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Keywords | glycosylation |
Outline of Annual Research Achievements |
In order to accomplish the proposed project entitled as “Photocatalytic stereoselective glycosylation of 2-deoxysugars and synthesis of Mithramycin,” we first synthesized the building blocks in the first year. We then tested the hypothesis by using tribenzyl glucal, triacetyl glucal/galactal as donors and 2,3,4-tri-O-benzyl α-methylglucoside as acceptor. The photocatalyst such as fac-Ir(ppy)3 and Eosin Y. were used along with hexaphenyl disilane as silylating agent in presence of blue LED as light source. Unfortunately, despite many attempts, we could not succeed to generate the silyl radical and therefore the glycosylation reaction did not happen. Since, we were not getting the satisfactory results, we decided to work on the backup project. We thought that instead of our original anticancer agent targeted natural product “mithramycin,” we will carry out the synthesis of another natural product such as core M3 glycan. The M3 glycan is O-mannosyl glycan of α-dystroglycan found in mammals. The complete structure of core M3 glycan is “((3GlcAβ1,3Xylα1)n-3GlcAβ1,4Xylβ1,4RboP-1RboP-3GalNAcβ1,3GlcNAcβ1,4(phospho-6)Manα1)”. Our plan is to synthesize partial trisaccharidic structure with modifications at GalNAc C3 position and the attachment of labelling reagents or affinity probes at Man1 position with linker. For the synthesis of core M3 glycan, the necessary building blocks derived from galactosamine, glucosamine and mannose are synthesized with appropriate protecting groups.
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Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
While submitting the progress report last year, we have set the milestones to be achieved in the following year. We planned to use various light sources such as LED, mercury lamp and UV lamp for the radical generation. Also, we planned to use various polar and non-polar solvents and different silylating reagents to carry out the proposed glycosylation reaction. In this year we have tried all these possibilities to find out the feasible reaction condition. However, unfortunately we were not successful to arrive at the positive results. Alongside with this work, we started synthesizing similar natural product such as core M3 glycan. Since, we have synthesized all the building blocks required for its synthesis, the final product will be synthesized quickly in recent future.
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Strategy for Future Research Activity |
In future, the synthesized building blocks will be tested for their glycosylation reactions. Once the glycosylation reactions worked successfully, the scale up synthesis will be undertaken to generate good amount of material to carry out the further reactions. Upon good quantity of trisaccharide in hand, our aim will be to successfully carry out the incorporation of phosphate group at C6 position of mannose. Then, in order to synthesize the core M3 glycan, the complete deprotection will be carried out. The biotin will be conjugated to the amine moiety installed on the mannose sugar. The GalNAc C3 modified analogs will then be synthesized by slightly changing the deprotection strategies. The glycerol phosphate group will be one of the modification performed on the Gal3 position of the biotinylated core M3 glycan. Further, we will collaborate with expert biologist to carry out cell incorporation, labeling and physiological studies on our synthesized core M3 glycan and the glycan modified with labeling and affinity probes. The results of the synthetic studies of M3 glycan will be published as soon as synthesis is finished and then the results obtained from the biologist will be published separately at the end of the fellowship.
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