| Project/Area Number |
17380070
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioproduction chemistry/Bioorganic chemistry
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| Research Institution | Yokohama College of Pharmacy (2006)
Tohoku University (2005) |
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Principal Investigator |
OHRUI Hiroshi Yokohama College of Pharmacy, School of Pharmacy, Professor, 薬学部, 教授 (20100050)
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| Co-Investigator(Kenkyū-buntansha) |
KUWAHARA Shigefumi Tohoku University, Graduate School of Agricultural Science, Division of Life Science, Professor, 大学院・農学研究科, 教授 (30170145)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2005: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | nucleic acid / virus / AIDS / Organic synthesis / bioactivity / nucleoside / ヌクレオシド系逆転写酵素阻害薬 / 薬剤耐性HIV / 4'-C-置換-2'-デオキシヌクレオシド / 血漿半減期 / DNAポリメラーゼγ / 4'-エチニ-2'-デオキシ-2-フルオロアデノシン |
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| Research Abstract |
4'-Ethynyl-2'-deoxy-2-fluoroadenosine (1) was found to be a promising drug for treatment of AIDS since it was shown to have potent anti-HIV activity against all types of HIV including resistant viruses such as MDR with no acute toxicity in mice, and furthermore its triphosphate derivative was much more stable than the corresponding AZT triphosphate derivative, and showed low inhibitory activity toward mitochondrial DNA polymerase γ. To provide a sufficient amount of 1 for clinical trial, an efficient synthetic route to 1 (9 steps in total) involving a stereoselective nucleophilic addition of a hydroxymethyl unit to an optically active α-siloxy acetylenic ketone was designed and the synthetic pathway leading to a penultimate intermediate has been accomplished. Syntheses of carbocyclic analogs of 4'-ethynyl-2'deoxynuclesides bearing uracil, thymine, cytosine, and adenine as nucleobase, which were aimed to reduce the toxicity and increase the stability of the nucleosides, were also achieved. Furthermore, a new efficient synthesis of the carbocyclic analog of 1 was addressed, which culminated in a short-step synthesis of the carbocyclic sugar-like moiety of 1.
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