Zwitterionic oligodeoxyribonucleotide N3'->P5' phosphoramidates: Synthesis and properties (original) (raw)
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Synthesis and properties of RNA analogs-oligoribonucleotide N3'-->P5' phosphoramidates
Nucleic Acids Research, 1999
The synthesis and characterization of RNA mimetics, uniformly modified oligoribonucleotide N3′→ ′→ ′→ ′→P5′ ′ ′ ′ phosphoramidates containing all four natural bases (uracil, cytosine, adenine and guanine) as well as thymidine and 2,6-diaminopurine, are described. These RNA analogs contain N3′→ ′→ ′→ ′→P5′ ′ ′ ′ phosphoramidate internucleotide linkages which replaced natural RNA O3′→ ′→ ′→ ′→P5′ ′ ′ ′ phosphodiester groups. These oligonucleotides were constructed from novel monomeric units
Tetrahedron Letters, 2000
A novel 2 H -modi®cation, 2 H -O- [3-(N,N-dimethylamino)propyl] or 2 H -O-DMAP, has been incorporated into oligonucleotides and compared to the known 2 H -O-(3-aminopropyl) or 2 H -O-AP modi®cation for antisense properties. The 2 H -O-DMAP modi®ed oligonucleotides exhibit very high nuclease resistance like the 2 H -O-AP modi®cation due to the`charge eect' and maintain high binding anity to target RNA relative to known modi®cations when a few 2 H -O-DMAP residues are dispersed throughout the oligonucleotide. #
alpha-Oligodeoxyribonucleotide N3'-->P5' phosphoramidates: synthesis and duplex formation
Nucleic Acids Research, 1998
The synthesis and hybridization properties of novel nucleic acid analogs, α-anomeric oligodeoxyribonucleotide N3′→P5′ phosphoramidates, are described. The α-3′-aminonucleoside building blocks used for oligonucleotide synthesis were synthesized from 3′-azido-3′-deoxythymidine or 3′-azido-2′,3′-dideoxyuridine via acid catalyzed anomerization or transglycosylation reactions. The base-protected α-5′-O-DMT-3′-aminonucleosides were assembled into dimers and oligonucleotides on a solid support using the oxidative phosphorylation method. 1 H NMR analysis of the α-N3′→P5′ phosphoramidate dimer structures indicates significant differences in the sugar puckering of these compounds relative to the β-N3′→P5′ phosphoramidates and to the α-phosphodiester counterparts. Additionally, the ability of the α-oligonucleotide N3′→P5′ phosphoramidates to form duplexes was studied using thermal denaturation experiments. Thus the N3′→P5′ phosphoramidate decamer containing only α-thymidine residues did not bind to poly(A) and exhibited lower duplex thermal stability with poly(dA) than that for the corresponding β-anomeric phosphoramidate counterpart. A mixed base decamer α-CTTCTTCCTT formed duplexes with the RNA and DNA complementary strands only in a parallel orientation. Melting temperatures of these complexes were significantly lower, by 34-47 or 15-25_C, than for the duplexes formed by the isosequential β-phosphoramidates in antiparallel and parallel orientations respectively. In contrast, the α-decaadenylic N3′→P5′ phosphoramidate formed duplexes with both RNA and DNA complementary strands with a stability similar to that of the corresponding β-anomeric phosphoramidate. Moreover, the self-complementary oligonucleotide α-ATATATATAT did not form an α:α homoduplex. These results demonstrate the effects of 3′-aminonucleoside anomeric configuration on sugar puckering and consequently on stability of the duplexes.
Nucleic Acids Research, 1996
Pyrimidine oligonucleotides containing alternating anionic and stereo-uniform cationic N-(dimethylaminopropyl)phosphoramidate linkages [e.g. d(T+T-) 7 T, d(T+T-) 2 (T+C-) 5 T and (U′+U′-) 7 dT, where U′ is 2′-Omethyluridine)] are shown to bind to complementary double-stranded DNA segments in 0.1 M NaCl at pH 7 to form triple-stranded complexes with the pyrimidine.purine.pyrimidine motif. For each of the sequences investigated, one stereoisomer bound with higher affinity, and the other stereoisomer with lower affinity, than the corresponding all-phosphodiester oligonucleotide. The stereoisomer of d(T+T-) 7 T that interacted weakly with a dT.dA target in 0.1 M NaCl formed a novel dA.dA.dT triple-stranded complex with poly(dA) or d(A 15 C 4 A 15) in 1 M NaCl; in contrast, the stereoisomer that bound strongly to the dT.dA target failed to form a dA.dA.dT triple-stranded complex.
Russian Journal of Bioorganic Chemistry, 2017
⎯N-Sulfonyl phosphoramidate derivatives of oligodeoxyribonucleotides containing N-tosyl phosphoramidate groups are first reported. The synthesis is based on Staudinger reaction between tosyl azide and 3',5'-dinucleoside β-cyanoethyl phosphite comprising the immobilized oligonucleotide, which is obtained by the phosphoramidite coupling during the solid-phase oligonucleotide synthesis. The N-tosyl phosphoramidate group was stable under conditions of the oligonucleotide synthesis, in particular, upon acidic detritylation followed by the removal of protective groups and cleavage from the polymer support by the treatment with concentrated aqueous ammonia at 55°C. The stability of DNA and RNA duplexes of the model oligonucleotides containing N-tosyl phosphoramidate groups was only slightly lower than that of native DNA:DNA and DNA:RNA duplexes, respectively.
Oligonucleotide N3'-->P5' phosphoramidates
Proceedings of the National Academy of Sciences, 1995
Synthetic oligonucleotides and their analogs have attracted considerable interest recently. These compounds may lead to highly specific therapeutic agents, as well as to powerful diagnostic tools. Here, we present the synthesis of uniformly modified oligodeoxyribonucleotide N3' -> P5' phosphoramidates containing 3'-NHP(O)(0-)0-5' internucleoside linkages and the study of their hybridization properties. Thermal dissociation experiments show that these compounds form very stable duplexes with single-stranded DNA, RNA, and with themselves following Watson-Crick base pairing. The duplex thermal stability was enhanced by 2.2-2.60C per modified linkage compared with phosphodiesters. The structure of complexes formed by phosphoramidates closely resembles that of RNA oligomers and corresponds to an A form, as judged by CD spectroscopy. N3' -> P5' phosphoramidates also form stable triplexes with doublestranded DNA under near-physiological conditions when natural phosphodiesters fail to do so. Physicochemical characteristics of the amidates are similar to those ofRNA oligomers, even though they are composed of 2'-deoxyfuranose-based nucleosides.
Hydration effects on the duplex stability of phosphoramidate DNA-RNA oligomers
Nucleic acids research, 1997
Recent studies on uniformly modified oligonucleotides containing 3'-NHP(O)(O-)O-5'internucleoside linkages (3'amidate) and alternatively modified oligonucleotides containing 3'-O(O-)(O)PNH-5'internucleoside linkages (5'amidate) have shown that 3'amidate duplexes, formed with DNA or RNA complementary strands, are more stable in water than those of the corresponding phosphodiesters. In contrast, 5'amidates do not form duplexes at all. There is no steric reason that the 5'amidate duplex should not form. We demonstrate that these differences arise from differential solvation of the sugar-phosphate backbones. By molecular dynamics calculations on models of 10mer single-stranded DNA and double-stranded DNA-RNA molecules, both with and without the phosphoramidate backbone modifications, we show that the single-stranded 3'amidate and 5'amidate backbones are equally well solvated, but the 5'amidate backbone is not adequately solvated in an A-fo...
Tetrahedron Letters, 1999
Two oligonucleotidcs, partially modified with N,N-dimethylaminoethyl phosphoramidate groups, were obtained by an optimized solid-phase synthesis cycle based on H-phosphonate chemistry. Their use as third strands in parallel triple helices was shown to produce a decrease in stability with respect to all-phosphodiester otigonucleotide complexes, most probably due to unfavourable steric cftizcts. Phosphoramidate-modified oligonucleotides were shown to be notably stable to exonucleases.
Synthesis of oligodeoxyribonucleotide N3′→P5′ phosphoramidates
Nucleic Acids Research, 1995
An efficient synthesis of the novel nucleic acid analogs oligodeoxyribonucleotide N3'-4P5' phosphoramidates, where the 3'-oxygen is substituted by a 3'-nitrogen, is described. Synthesis of the title compounds was accomplished by the following synthetic steps. First, 5'-ODMT base-protected-3'-amino-2',3'-dideoxynucleosides were prepared. The 3'-aminopyrimidines were obtained via the corresponding 2,3'-anhydronucleosides, whereas 3'-aminopurines were derived via 2'-deoxyxylo precursors. Second, using the prepared 3'-aminonucleosides, oligonucleotide N3'-1P5' phosphoramidates were synthesized on a solid support.
Synthesis and Properties of Oligodeoxynucleotides Possessing N-Phosphoryl Groups
European Journal of Organic Chemistry, 2003
A 2'-O-methyluridylic acid derivative 3 having a cyclic structure linked between the 5-position of the uracil residue and the 5'-phosphate group was synthesized. The NMR analysis suggests that this cyclouridylic acid derivative has exclusively the C3'-endo conformation that is in favor of duplex formation with RNA. Two oligonucleotides ¿pc3Um(pT)(9) and pc3Um(pU)(9) incorporating this cyclouridylic acid unit at the 5'-terminal site were synthesized by using the fully protected cyclouridylic acid 3'-phosphoramidite derivative 11 in the solid-phase synthesis. To examine the actual effect of this cyclic structure on the thermal stability of duplexes between the modified oligonucleotides and their complementary oligonucleotides, two oligonucleotides ¿pUm(pT)(9) and pUm(pU)(9) having an acyclic structure were also synthesized. As the complementary oligonucleotides, dA(pdA)(9) and A(pA)(9) were used for T(m) experiments with these 5'-terminal modified oligonucleotides. The T(m) values of all the possible duplexes were measured. These results clearly show that the duplex of pc3Um(pT)(9)-A(pA)(9) has a higher T(m) value by 5.5 degrees C than that of A(pA)(9)-T(pT)(9). This is rather significant compared with all other cases. Moreover, the T(m) value of pc3Um(pT)(9)-A(pA)(9) is 4.5 degrees C higher than that of pUm(pT)(9)-A(pA)(9). This result suggests that the cyclic structure can considerably contribute to stabilization of the duplex only in the case of the modified oligomer (DNA) and decaadenylate (RNA).