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Conformationally Constrained 2‘-N,4‘-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides

Varghese, Oommen P ; Barman, Jharna ; Pathmasiri, Wimal ; Plashkevych, Oleksandr ; Honcharenko, Dmytro ; Chattopadhyaya, Jyoti

Journal of the American Chemical Society, 2006-11, Vol.128 (47), p.15173-15187 [Periódico revisado por pares]

Washington, DC: American Chemical Society

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Título:
Conformationally Constrained 2‘-N,4‘-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
Autor: Varghese, Oommen P ; Barman, Jharna ; Pathmasiri, Wimal ; Plashkevych, Oleksandr ; Honcharenko, Dmytro ; Chattopadhyaya, Jyoti
Assuntos: Base Sequence ; Biochemistry ; Biokemi ; Bridged-Ring Compounds - chemical synthesis ; Bridged-Ring Compounds - chemistry ; Carbohydrates. Nucleosides and nucleotides ; Chemistry ; DNA - blood ; DNA - chemistry ; Drug Stability ; Exact sciences and technology ; General and physical chemistry ; Heterocyclic compounds ; Heterocyclic compounds with only one n hetero atom and condensed derivatives ; Humans ; Kemi ; Kinetics ; Models, Molecular ; NATURAL SCIENCES ; NATURVETENSKAP ; Nuclear Magnetic Resonance, Biomolecular ; Nucleic Acid Conformation ; Nucleosides, nucleotides and oligonucleotides ; Oligonucleotides, Antisense - blood ; Oligonucleotides, Antisense - chemical synthesis ; Oligonucleotides, Antisense - chemistry ; Organic chemistry ; Phosphodiesterase I - chemistry ; Phosphodiesterase I - metabolism ; Preparations and properties ; Stereoisomerism ; Thermodynamics ; Thymidine - analogs & derivatives ; Thymidine - blood ; Thymidine - chemical synthesis ; Thymidine - chemistry
É parte de: Journal of the American Chemical Society, 2006-11, Vol.128 (47), p.15173-15187
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Descrição: The 2‘-deoxy-2‘-N,4‘-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2‘-ara-trifluoromethylsufonyl-4‘-cyanomethylene 11 to give a pair of 3‘,5‘-bis-OBn-protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7° < P < 27°, 44° < φm < 52°). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2‘-nitrogen, which has axial N−H in 12b and equatorial N−H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with E a = 25.4 kcal mol-1, which is thus far the highest observed inversion barrier at pyramidal N−H in the bicyclic amines. The 5‘-O-DMTr-aza-ENA-T-3‘-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a T m increase of 2.5−4 °C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3‘ degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.
Editor: Washington, DC: American Chemical Society
Idioma: Inglês

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Conformationally Constrained 2‘-N,4‘-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides

Varghese, Oommen P ; Barman, Jharna ; Pathmasiri, Wimal ; Plashkevych, Oleksandr ; Honcharenko, Dmytro ; Chattopadhyaya, Jyoti

Washington, DC: American Chemical Society

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