2006 Fiscal Year Final Research Report Summary
Design of Peptide-based Reaction Field and Molecular Recognition Site and Their Synthesis
| Project/Area Number |
16350051
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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 |
Synthetic chemistry
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| Research Institution | Tokyo Insitute of Technology |
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Principal Investigator |
DOI Takayuki Tokyo Institute of Technology, Department of Applied Chemistry, Associate Professor, 大学院理工学研究科, 助教授 (90212076)
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| Project Period (FY) |
2004 – 2006
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| Keywords | combinatorial synthesis / theoretical calculation / solid phase synthesis / intramolecular Diels-Alder reaction / cyclic amines / cyclic peptides / polyazamacrocycles |
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| Research Abstract |
An unprecedented Asp-Thr tethered Diels-Alder reaction was designed based on quantitative predictions by ab initio calculation of the favored transition state structures. Since the molecule is so flexible, we utilized MM2 transition state models for generating possible transition state structures and their energies were estimated by single point energy calculation by a DFT method. The models obtained were optimized by a semi-empirical method, PM3 and were further optimized by a DFT method. In fact, the intramolecular Diels-Alder reaction was accomplished in high regio- and stereoselective manner as expected by above calculations.
Design and synthesis of artificial receptors for selective recognition of bioactive substrates have received considerable interests. Receptor molecules with pre-organized ligands are useful for the effective binding of the guest molecules. A suitable pre-organization of functional groups and conformational constraint can be achieved by controlling the stereoche
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mistry through steric hindrance of the substituents around a rigid platform. We designed the synthesis of chiral polyazamacrocycles as pre-organized ligands. Initial studies focused on the regioselectivity of the ring-opening reaction of N-substituted aziridines with a benzyl secondary amine. It was found that an N-nosyl aziridine derivative induced high regioselectivity in good to excellent yields. We repeatedly utilized this method in the preparation of the cyclization precursors. Finally, intramolecular N-alkylation of the N-nosyl amides was achieved to provide 9-memebred, 12-memebred, and 15-membered polyazamacrocycles.
The solid-phase synthesis of peptide and peptide mimetic libraries has been well developed. We are interested in the synthesis of a variety of cyclic peptide analogues that can be useful for a 3D template for drug discovery and molecular recognition. Mimetics of RGD are of interest as antithrombotics because of their ability to inhibit the aggregation of platelets. We designed cyclic peptides, which contain an aromatic ring, RGD sequence and a spacer. These cyclic peptides should be conformationally restricted and their conformations can be controlled by the positions of the substituents on an aromatic ring and length of the spacer. The o^-; m^-; p-iodobenzylamines were respectively attached to the aldehyde resin by reductive amination. Peptide elongation with four Fmoc-protected amino acids, palladium-catalyzed carbonylative macrocyclization, and acid cleavage provided a combinatorial library of 48-member cyclic peptides. Less
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