2003 Fiscal Year Final Research Report Summary
Synthesis and properties of novel artificial nucleic acid analogs having chiral backbones
| Project/Area Number |
14580607
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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 |
Bioorganic chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
WADA Takeshi The University of Tokyo, Graduate School of Frontier Sciences, Associate Professor, 大学院・新領域創成科学研究科, 助教授 (90240548)
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| Project Period (FY) |
2002 – 2003
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| Keywords | nucleic acid analog / artificial nucleic acid / polyester / solid-phase synthesis / L-serine / peptide nucleic acid / PNA / condensing reagent |
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| Research Abstract |
Peptide nucleic acid(PNA), an oligonucleotide mimic, has an achiral polyamide backbone, to which nucleobases are attached. Since PNA binds to single stranded DNA and RNA as well as to double stranded DNA, it is regarded as a potentially useful molecule for antisense strategy. It is well known that the PNA-DNA and PNA-RNA duplexes are more stable than the corresponding DNA-DNA and DNA-RNA duplexes. However, the recent structural studies on PNA-DNA and PNA-RNA duplexes by NMR indicated that the conformation of PNA in such complexes was not optimal RNA because the helical pitch of PNA is much larger than that of DNA and RNA. In this study, I tried to synthesize a new type of DNA analog derived from L-serine with ester linkages, serine-based nucleobase-linked polyester (SNE). The present DNA analog bearing a polyester backbone is expected to have a shorter helical pitch compared with that of PNA, which is identical for the hybridization with complementary nucleic acids. I developed a new strategy for the synthesis of a polyester-type nucleic acid analog consist of N-(thymin-1-yl)acetyl L-serine. The monomer unit bearing thymine base was synthesized from L-serine ethyl ester by a three-step reaction in good yield without racemization. 3-Nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) was found to be highly effective for the rapid ester bond formation without racemization. 2-Phenyl-2-(trimethylsilyl)ethyl group was successfully employed as a carboxyl protecting group in solution-phase synthesis. Solid-phase synthesis of SNE was achieved by using a novel type of linker and amino-protecting groups that can be removed under mild neutral conditions.
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