| Project/Area Number |
16590007
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
MURAKAMI Nobutoshi Osaka University, Graduate School of pharmaceutical sciences, Professor, 薬学研究科, 教授 (00210013)
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| Co-Investigator(Kenkyū-buntansha) |
TAMURA Satoru Osaka University, Graduate school of pharmaceutical science, Research associate, 薬学研究科, 助手 (30362619)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | nuclear export signal (NES) / 1'-acetoxychavicol acetate / inhibitor for nuclear export / medicinal leads / anti-HIV agents / anti-tumor agents / CRM1 / molecular orbital calculation / 1)-acetoxychavicol acetate |
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| Research Abstract |
1'-Acetoxychavicol acetate (ACA), a NES-antagonistic inhibitor against nuclear export of NES containing protein, was suggested to be readily hydrolyzed in vivo because of its two acetyl moieties. Thus, some carbamate and carbonate analogs were prepared to be analyzed for its activity and stability in the medium containing serum. This analysis clarified that the functional group, which is difficult to be hydrolyzed, on phenolic hydroxyl portion extremely reduced the inhibitory activity for nuclear export of NES containing protein. Additionally, reactants of ACA and N-acetyl-L-cyctein methyl ester established 1-acetoxy-2-ene moiety as the binding site of cystein-529 in CRM1 and presumed the hydrolysis of ester linkage at 4-OH followed by formation of p-quininemethide intermediate to be essential for potent activity. Under this circumstance, molecular orbital calculation for each energy barrier based on the plausible mechanism of action of ACA disclosed the hydrolysis energy of acetyl group at 4-OH in ACA to be a rate-determining step. Furthermore, 2,3-difluoro-ACA analog with lower E1 was shown to exhibit 50 fold more potent activity than that of ACA. On the other hand, homology model of human CRM1 was built by means of a fold recognition method. Through the docking study of the analogs and the constructed homology model, the correlation between interaction energy and biological activity was obserbed.
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