RESUMO
The novel bridged nucleic-acid analogue 2',4'-BNA(NC) (2'-O,4'-C-aminomethylene bridged nucleic acid), containing a six-membered bridged structure with an N-O linkage, was designed and synthesized efficiently, demonstrating a one-pot intramolecular NC bond-forming key reaction to construct a perhydro-1,2-oxazine ring (11 and 12). Three monomers of 2',4'-BNA(NC) (2',4'-BNA(NC)[NH], [NMe], and [NBn]) were synthesized and incorporated into oligonucleotides, and their properties were investigated and compared with those of 2',4'-BNA (LNA)-modified oligonucleotides. Compared to 2',4'-BNA (LNA)-modified oligonucleotides, 2',4'-BNA(NC) congeners were found to possess: (i) equal or higher binding affinity against an RNA complement with excellent single-mismatch discriminating power, (ii) much better RNA selective binding, (iii) stronger and more sequence selective triplex-forming characters, and (iv) immensely higher nuclease resistance, even higher than the S(p)-phosphorthioate analogue. 2',4'-BNA(NC)-modified oligonucleotides with these excellent profiles show great promise for applications in antisense and antigene technologies.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Nucleotídeos/síntese química , Oligonucleotídeos/síntese química , Sequência de Bases , Hidrocarbonetos Aromáticos com Pontes/química , Dicroísmo Circular , Cristalografia por Raios X , Desoxirribonucleases/química , Modelos Moleculares , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Nucleotídeos/química , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Espectrofotometria UltravioletaRESUMO
Oligonucleotides modified with 2 ',4 '-BNA(NC) (N-H)/(N-Me) monomers exhibited excellent hybridizing and nuclease resistance properties. Duplex and triplex thermal stabilities were greatly enhanced by incorporating 2',4'-BNA(NC) (N-H) and (N-Me) monomers and nuclease resistance was tremendously higher than that of natural oligonucleotide.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , DNA/química , Hibridização de Ácido Nucleico , Nucleotídeos/química , Oligonucleotídeos/química , Endonucleases/química , Temperatura AltaRESUMO
Oligonucleotides modified with a novel BNA analogue, 2', 4'-BNA(NC)[N-Me], were synthesized, and in comparison to 2',4'-BNA (LNA), have similarly high RNA affinity, better RNA selectivity and much higher resistance to nuclease degradation, suggesting that the novel BNA analogue may be particularly useful for antisense approaches.
Assuntos
Endonucleases/metabolismo , Oligonucleotídeos Antissenso/síntese química , RNA/química , Sequência de Bases , Hibridização de Ácido Nucleico , Oligonucleotídeos Antissenso/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Homologia de Sequência do Ácido NucleicoRESUMO
2',4'-BNA(NC), a bridged nucleic acid analogue, which was designed and synthesized in our laboratory, showed very high binding affinity towards complementary RNA and DNA strands. Its duplex-forming ability towards a single-stranded RNA was similar to or slightly higher than that of 2',4'-BNA and the overall triplex-forming ability against a double-stranded DNA was also better than that of 2',4'-BNA. 2',4'-BNA(NC) exhibited higher RNA selectivity than 2',4'-BNA.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , DNA/química , Nucleotídeos/química , RNA/química , DNA de Cadeia Simples/química , Oligonucleotídeos/química , TemperaturaRESUMO
We have recently designed and synthesized a novel bridged nucleic acid analogue 2',4'-BNA(NC), bearing an N-O bridged structure, which furnished both higher duplex and triplex-forming abilities and sequence selectivity towards complementary RNA and/or DNA, respectively, and showed excellent resistance against nuclease degradation. Duplex and triplex-forming abilities were slightly higher or similar to those of 2',4'-BNA and nuclease resistance was as high as that of S-oligo.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Oligonucleotídeos/química , Timidina Monofosfato/análogos & derivados , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , DNA/química , Hibridização de Ácido Nucleico , Oligonucleotídeos/síntese química , Oligonucleotídeos/metabolismo , Fosfodiesterase I , RNA/química , Timidina Monofosfato/síntese química , Timidina Monofosfato/química , Timidina Monofosfato/metabolismoRESUMO
Based on the 4-hydroxy-1-azabicyclo[3.1.0]hexane structure of azinomycin, a 3,4-epoxypiperidine structure was designed as a novel and simple alkylating molecular unit, and some 3,4-epoxypiperidine derivatives were found to show DNA-cleavage activity, the structural requirements for which were revealed.