2007 Fiscal Year Final Research Report Summary
Dynamic Synthesis of Drug-Candidate Molecules Utilizing Cooperative Effect of Integrated Functional Groups
| Project/Area Number |
18390039
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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 |
Drug development chemistry
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| Research Institution | Nagoya City University |
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Principal Investigator |
HIGUCHI Tsunehiko Nagoya City University, Graduate of Pharmaceutical Sciences, Professor (50173159)
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| Co-Investigator(Kenkyū-buntansha) |
UMEZAWA Naoki Nagoya City University, Graduate of Pharmaceutical Sciences, Associate Professor (40347422)
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| Project Period (FY) |
2006 – 2007
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| Keywords | chemical evolution / equilibrium reaction / self assembly / molecular recognition / active oxveen snecies / auxiliary / drug design / catalvst |
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| Research Abstract |
Dynamic combinatorial chemistry (DCC) is a new approach to integration of combinatorial synthesis and screening based on the shift of chemical equilibrium in a mixture of interconverting components driven by a molecular target. We have designed a new DCC scaffold (BB-4) that has three formyl groups to condense with various amines reversibly at the same side of the benzene ring. N-Ac-L-Ile and N-Ac -Ile-Ala, which are key parts in amyloid β42 for aggregation of amyloid β42 were selected because a good receptors for these compounds can be potential drug for Alzheimer disease.
Equilibration of the scaffold with a mixture of amines was expected to produce imines, the distribution of which would be altered by the addition of N-Ac-L-Ile or N-Ac -Ile-Ala. The imines were then reduced to the secondary amines, the composition of which was analyzed LC/FT-MS. Clearly, addition of the molecular target resulted in dramatic amplification of selected amine peaks. Most amplified compound was 9c of which affinity with N-Ac-L-Ile was relatively high; the binding constant is 0.96 x 10^3 M^<-1>. The present strategy for preparation of low-molecular-weight receptors would be applicable to various molecular targets.
A new Mn (salen) complex bearing an ureido group as an auxiliary that is three-dimensionally fixed by a cyclopentane ring fused to the salen structure was developed. This compound exhibited considerably higher catalase-like activity than the original Mn(salen), i.e., the cyclopentane-fused Mn (salen) without the auxiliary, under near-physiological conditions.
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[Journal Article] A Versatile Strategy for the Synthesis of Crown Ether-Bearing Heterocycles: Discovery of Calcium-Selective Fluoroionophore2007
Author(s)
Yuko, Aoki, Naoki, Umezawa, Yuko, Asano, Keiichiro, Hatano, Yuki, Yano, Nobuki, Kato, Tsunehiko, Higuchi
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Journal Title
Bioorg. Med. Chem 15
Pages: 7108-7115
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Enhanced Catalase-like Activity of Manganese Salen Complexes in Water: Effect of Three-dimensionally Fixed Auxiliary2006
Author(s)
Yoritada, Watanabe, Azusa, Namba, Naoki, Umezawa, Masatoshi, Kawahata, Kentaro, Yamaguchi, Tsunehiko, Higuchi
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Journal Title
Chem. Commun 47
Pages: 4958-4960
Description
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[Presentation] Development of On-chip Fluorescence Assay for Serine/threonine Kinases2007
Author(s)
Akita, S., Umezawa, N., Inamori, K., Kyo, M., Kato, N., Higuchi, T
Organizer
4th International Peptide Symposium
Place of Presentation
Cairns, Queensland, Australia
Year and Date
2007-10-25
Description
「研究成果報告書概要(欧文)」より
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