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A bridged nucleic acid, 2',4'-BNA COC: synthesis of fully modified oligonucleotides bearing thymine, 5-methylcytosine, adenine and guanine 2',4'-BNA COC monomers and RNA-selective nucleic-acid recognition.

Mitsuoka Y, Kodama T, Ohnishi R, Hari Y, Imanishi T, Obika S - Nucleic Acids Res. (2009)

Bottom Line: Oligonucleotides (BNA(COC)) containing this monomer show high affinity with complementary single-stranded RNA and significant resistance to nuclease degradation.Furthermore, mismatched sequence studies showed that BNA(COC) generally improved the sequence selectivity with Watson-Crick base-pairing compared to the corresponding natural DNA and RNA.A CD spectroscopic analysis indicated that the BNA(COC) formed duplexes with complementary DNA and RNA in a manner similar to natural RNA.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.

ABSTRACT
Recently, we synthesized pyrimidine derivatives of the 2'-O,4'-C-methylenoxymethylene-bridged nucleic-acid (2',4'-BNA(COC)) monomer, the sugar conformation of which is restricted in N-type conformation by a seven-membered bridged structure. Oligonucleotides (BNA(COC)) containing this monomer show high affinity with complementary single-stranded RNA and significant resistance to nuclease degradation. Here, BNA(COC) consisting of 2',4'-BNA(COC) monomers bearing all four bases, namely thymine, 5-methylcytosine, adenine and guanine was efficiently synthesized and properties of duplexes containing the 2',4'-BNA(COC) monomers were investigated by UV melting experiments and circular dichroism (CD) spectroscopy. The UV melting curve analyses showed that the BNA(COC)/BNA(COC) duplex possessed excellent thermal stability and that the BNA(COC) increased thermal stability with a complementary RNA strand. On the other hand, BNA(COC)/DNA heteroduplexes showed almost the same thermal stability as RNA/DNA heteroduplexes. Furthermore, mismatched sequence studies showed that BNA(COC) generally improved the sequence selectivity with Watson-Crick base-pairing compared to the corresponding natural DNA and RNA. A CD spectroscopic analysis indicated that the BNA(COC) formed duplexes with complementary DNA and RNA in a manner similar to natural RNA.

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Reagents and conditions: (a) p-TsOH·H2O, (CH2O)n, DCE, reflux, 3 h, 81%; (b) TBAF, THF, rt, 3 h, 91%; (c) 20% Pd(OH)2-C, cyclohexene, EtOH, reflux, 3 h, 89%.
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Figure 5: Reagents and conditions: (a) p-TsOH·H2O, (CH2O)n, DCE, reflux, 3 h, 81%; (b) TBAF, THF, rt, 3 h, 91%; (c) 20% Pd(OH)2-C, cyclohexene, EtOH, reflux, 3 h, 89%.

Mentions: It is of great interest to synthesize 2′,4′-BNACOC bearing a purine nucleobase for potential use in a wide variety of applications and to investigate the conformations of oligonucleotides containing 2′,4′-BNACOC. Moreover, conformational analysis of duplex, which is formed from fully modified oligonucleotides consisted of 2′,4′-BNACOC, is very fascinating. In general, a purine glycosidic linkage is more acid-labile than a pyrimidine glycosidic linkage (31). Therefore, it is readily expected that the acidic conditions used for the synthesis of 2′,4′-BNACOC with a pyrimidine nucleobase are not suitable for the purine congener (Scheme 1). Here, we report the synthesis of 2′,4′-BNACOC monomers having a purine nucleobase via formation of a COC linkage under mild conditions, and we describe the properties of the corresponding oligonucleotide derivatives.


A bridged nucleic acid, 2',4'-BNA COC: synthesis of fully modified oligonucleotides bearing thymine, 5-methylcytosine, adenine and guanine 2',4'-BNA COC monomers and RNA-selective nucleic-acid recognition.

Mitsuoka Y, Kodama T, Ohnishi R, Hari Y, Imanishi T, Obika S - Nucleic Acids Res. (2009)

Reagents and conditions: (a) p-TsOH·H2O, (CH2O)n, DCE, reflux, 3 h, 81%; (b) TBAF, THF, rt, 3 h, 91%; (c) 20% Pd(OH)2-C, cyclohexene, EtOH, reflux, 3 h, 89%.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651773&req=5

Figure 5: Reagents and conditions: (a) p-TsOH·H2O, (CH2O)n, DCE, reflux, 3 h, 81%; (b) TBAF, THF, rt, 3 h, 91%; (c) 20% Pd(OH)2-C, cyclohexene, EtOH, reflux, 3 h, 89%.
Mentions: It is of great interest to synthesize 2′,4′-BNACOC bearing a purine nucleobase for potential use in a wide variety of applications and to investigate the conformations of oligonucleotides containing 2′,4′-BNACOC. Moreover, conformational analysis of duplex, which is formed from fully modified oligonucleotides consisted of 2′,4′-BNACOC, is very fascinating. In general, a purine glycosidic linkage is more acid-labile than a pyrimidine glycosidic linkage (31). Therefore, it is readily expected that the acidic conditions used for the synthesis of 2′,4′-BNACOC with a pyrimidine nucleobase are not suitable for the purine congener (Scheme 1). Here, we report the synthesis of 2′,4′-BNACOC monomers having a purine nucleobase via formation of a COC linkage under mild conditions, and we describe the properties of the corresponding oligonucleotide derivatives.

Bottom Line: Oligonucleotides (BNA(COC)) containing this monomer show high affinity with complementary single-stranded RNA and significant resistance to nuclease degradation.Furthermore, mismatched sequence studies showed that BNA(COC) generally improved the sequence selectivity with Watson-Crick base-pairing compared to the corresponding natural DNA and RNA.A CD spectroscopic analysis indicated that the BNA(COC) formed duplexes with complementary DNA and RNA in a manner similar to natural RNA.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.

ABSTRACT
Recently, we synthesized pyrimidine derivatives of the 2'-O,4'-C-methylenoxymethylene-bridged nucleic-acid (2',4'-BNA(COC)) monomer, the sugar conformation of which is restricted in N-type conformation by a seven-membered bridged structure. Oligonucleotides (BNA(COC)) containing this monomer show high affinity with complementary single-stranded RNA and significant resistance to nuclease degradation. Here, BNA(COC) consisting of 2',4'-BNA(COC) monomers bearing all four bases, namely thymine, 5-methylcytosine, adenine and guanine was efficiently synthesized and properties of duplexes containing the 2',4'-BNA(COC) monomers were investigated by UV melting experiments and circular dichroism (CD) spectroscopy. The UV melting curve analyses showed that the BNA(COC)/BNA(COC) duplex possessed excellent thermal stability and that the BNA(COC) increased thermal stability with a complementary RNA strand. On the other hand, BNA(COC)/DNA heteroduplexes showed almost the same thermal stability as RNA/DNA heteroduplexes. Furthermore, mismatched sequence studies showed that BNA(COC) generally improved the sequence selectivity with Watson-Crick base-pairing compared to the corresponding natural DNA and RNA. A CD spectroscopic analysis indicated that the BNA(COC) formed duplexes with complementary DNA and RNA in a manner similar to natural RNA.

Show MeSH
Related in: MedlinePlus