2004 Fiscal Year Final Research Report Summary
Design of functional molecules for selective recognition and reaction to the duplex DNA
| Project/Area Number |
15390007
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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 |
Chemical pharmacy
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
SASAKI Shigeki Kyushu University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究院, 教授 (10170672)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Genome-targeting / molecular recognition / reactive molecule / duplex DNA / nitrosyl transfer / triplex DNA / minor-groove binder / artificial nucleoside analog |
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| Research Abstract |
Molecules that can target DNA or RNA with high efficiency and specificity are of great interest because of potential applications to modulation of gene expression at a specific site. Our approach in genome-targeting chemistry has been focused on development of reactive molecules with high base- as well as sequence selectivity. In this study, three contents. In this study, three methods have been investigated, which include (1) DNA/RNA hybridization, (2) triplex DNA formation, (3) DNA minor-groove binding.
In the approach with DNA/RNA hybridization, we investigated the new reactive molecules that can discriminate a single nucleoside difference. We have already developed new cross-linking agents with high selectivity. In this study, the same design concept has been applied to develop a reactive molecule for nitrosyl group transfer. As a result, it has been revealed that S-nitroso thioguanosine can transfer its nitroso group to the amino group of cytosine and 5-methylcytosine selectively,
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and that the nitroso-transferred amino group suffers easy deamination to give uracil or thymine.
In the project for new nucleoside analogs for the formation of stable triplexes having interrupting base pairs, we have continued searching new nucleoside analogs having the WNA (W-shaped nucleoside analog) skeleton. The WNA analogs contain a benzene ring and a heterocyle as a recognition part on the bicyclo[3.3.0]octane skeleton. In this study, a variety of heterocyclic parts have been introduced to the bicyclo[3.3.0]octane skeleton and their triplex-forming ability has been tested. As a result, in addition to the previous WNA analog (WNA-βT) that is selective to a TA interrupting site, the new analog WNA-βC has been identified as a selective base for a CG interrupting site.
In this study, new DNA-binding ligands were designed to mimic Chromomycin A3 (CRA3) which contains a hydroxylated tetrahydroanthracene chromophore substituted with di- and tri-saccharides. The trisaccharide part of CRA3 that is supposed to contribute to form the Mg^<2+>-coordinated dimer was expected to be mimicked by a simple alkyl group attached to the chromophore part as new model compounds. The present study has successfully demonstrated that the new ligands form Mg^<2+>-coordinated dimer complexes to exhibit DNA-binding affinity. Less
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