1998 Fiscal Year Final Research Report Summary
Synthetic Studies on Antitumor Antibiotics Mitomycin C and its Congeners
| Project/Area Number |
08557121
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Chemical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
FUKUYAMA Tohru The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (10272486)
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| Co-Investigator(Kenkyū-buntansha) |
MINAKAMI Tamio Kyowa Hakko Kogyo Co., Ltd., Tokyo Research Center, Senior Researcher, 東京研究所, 主任研究員
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| Project Period (FY) |
1996 – 1998
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| Keywords | mitomycin C / FR900482 / antitumor antibiotics / nitrile oxides / 1,3-dopolar / [3+2] cycloaddition / 8-membered ring |
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| Research Abstract |
Mitomycin C is currently used as chemotherapeutic agent for the treatment of cancer. FR900482 isolated by Fujisawa Pharmaceutical Co., Ltd also possesses parallel antitumore activity as well. We previously achieved total syntheses of both compounds in racemic form. These syntheses, however, is not practical enough to apply these for large-scale production. A main proposes of this research is development of practical and flexible synthetic routes, which would be applicable for mitomycin C, FR900482 and their congeners. After retrosynthetic analysis, we chose 8-membered ring compound as a key intermediate. For the construction of the 8-membered key intermediate, we initially tested intramolecular alkylation reaction between anion and epoxides. Since the intramolecular alkylation approach gave no successful results, we then investigated intramolecular 1,3-dipolar cycloaddition approach using nitrile oxides. Nitrile oxide cycloaddition of the model compounds which is lacking substituents on benzene ring afforded the desired 8-membered ring cycloadducts in reasonable yield. Unexpectedly, however, the substrate for FR900482 bearing appropriate substituents on benzene ring gave an undesired 9-membered ring compound due to changing the regiochemistry of cycloaddition reaction. After further investigations, it was found that cinnamate type substrate afforded the desired 8-membered ring product even with appropriate functionality on benzene ring. Further elaboration from the cycloadduct to FR900482 and its congeners is under investigation.
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