- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
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- 2′-: O -Methyl- and 2′- O -propargyl-5-methylisocytidine: Synthesis, properties and impact on the isoCd-dG and the isoCd-isoGd base pairing in nucleic acids with parallel and antiparallel strand orientation
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Oligonucleotides containing 2′-O-methylated 5-methylisocytidine (3) and 2′-O-propargyl-5-methylisocytidine (4) as well as the non-functionalized 5-methyl-2′-deoxyisocytidine (1b) were synthesized. MALDI-TOF mass spectra of oligonucleotides containing 1b are susceptible to a stepwise depyrimidination. In contrast, oligonucleotides incorporating 2′-O-alkylated nucleosides 3 and 4 are stable. This is supported by acid catalyzed hydrolysis experiments performed on nucleosides in solution. 2′-O-Alkylated nucleoside 3 was synthesized from 2′-O-5-dimethyluridine via tosylation, anhydro nucleoside formation and ring opening. The corresponding 4 was obtained by direct regioselective alkylation of 5-methylisocytidine (1d) with propargyl bromide under phase-transfer conditions. Both compounds were converted to phosphoramidites and employed in solid-phase oligonucleotide synthesis. Hybridization experiments resulted in duplexes with antiparallel or parallel chains. In parallel duplexes, methylation or propargylation of the 2′-hydroxyl group of isocytidine leads to destabilization while in antiparallel DNA this effect is less pronounced. 2′-O-Propargylated 4 was used to cross-link nucleosides and oligonucleotides to homodimers by a stepwise click ligation with a bifunctional azide.
- Jana, Sunit K.,Leonard, Peter,Ingale, Sachin A.,Seela, Frank
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p. 4927 - 4942
(2016/06/13)
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- Sugar conformational effects on the photochemistry of thymidylyl(3′-5′)thymidine
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The synthesis and conformational analysis of 2′-O,5-dimethyluridylyl(3′-5′)-2′-O,5-dimethyluridine (1a), the analogue of thymidylyl(3′-5′)thymidine (TpT; 1b) in which a methoxy group replaces each 2′-α-hydrogen atom, are described. In comparison with TpT, such modification increases the population of the C3′-endo conformer of the sugar ring puckering at the 5′- and 3′-ends from 30 to 75% and from 37 to 66%, respectively. Photolyses of 1a and TpT at 254 nm are qualitatively comparable (the cis-syn cyclobutane pyrimidine dimer and the (6-4) photoproduct are formed), although it is significantly faster in the case of 1a. These results are explained by the increased propensity of the modified dinucleotide to adopt a base-stacked conformation geometry reminiscent of that for TpT.
- Ostrowski, Tomasz,Maurizot, Jean-Claude,Adeline, Marie-Therese,Fourrey, Jean-Louis,Clivio, Pascale
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p. 6502 - 6510
(2007/10/03)
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- Synthesis of amide-linked [(3')CH2CO-NH(5')] nucleoside analogues of small oligonucleotides
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We report syntheses of new amide-linked (di-penta)nucleoside analogues of antisense oligonucleotide components. Solution-phase coupling of 3'- (carboxymethyl)-3'-deoxy- and 5'-amino-5'-deoxynucleoside derivatives provides amide dimers. Activated [3'-(carboxymethyl)-3'-deoxy] units with a 5'-azido-5'-deoxy function provide 'masked' 5'-amino-5'-deoxy residues for chain extension, and a 5'-O-DMT-protected unit provides the 5'-terminus for attachment to a phosphodiester linkage.
- Robins, Morris J.,Doboszewski, Bogdan,Nilsson, Bradley L.,Peterson, Matt A.
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- A novel and economical synthesis of 2′-o-alkyl-uridines
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A highly efficient, two-step method to make 2′-O-methyluridine is described using only inexpensive reagents and no chromatography. The method is applicable for some other alkyls as well as some other pyrimidine derivatives. Copyright
- Ross, Bruce S.,Springer, Robert H.,Tortorici, Zeb,Dimock, Stuart
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p. 1641 - 1643
(2007/10/03)
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- Apparatus and processes for the large scale generation and transfer of diazomethane
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For large scale preparation of pyrimidine ribonucleosides, the intermediate 2-O-methyl-(or ethyl)-1,3,5-tri-O-benzoyl-α-D-ribose can be prepared using a diazomethane (or diazoethane) reaction that is controlled via an inert solvent transferring system. This transfer system allows for large scale preparations of the pyrimidine ribonucleosides.
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- 38. A new access to 2'-O-alkylated ribonucleosides and properties of 2'-O-alkylated oligoribonucleotides
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A general access to 2'-O-alkylated ribonucleosides using the key intermediate 5 is presented. The incorporation of 2'-O-'ethyleneglycol'- and 2'-O-'glycerol'-substituted (i.e., 2'-O-(2-hydroxyethyl)- and 2'-O-(2,3-dihydroxypropyl)-substituted) ribonucleosides into oligonucleotides affords a new generation of oligonucleotides with high affinity for RNA, high specificity, and increased nuclease resistance.
- Martin
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p. 486 - 504
(2007/10/02)
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- General preparative synthesis of 2'-O-methylpyrimidine ribonucleosides
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A convergent and general approach to synthesizing 2'-O-methylpyrimidine ribonucleosides 4a-e-, 6, 7 on a multigram scale is described which begins with an improved procedure for making larger quantities of 2-O-methyl-1,3,5-tri-O-benzoyl-α-D-ribose. The sugar was reacted with the desired silylated pyrimidines at room temperature under Vorbruggen conditions. The crude products contained less than 10% of the α anomers and the desired β anomers were isolated by crystallization. The blocked nucleosides were then deprotected and isolated by standard methods.
- Ross,Springer,Vasquez,Andrews,Cook,Acevedo
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p. 765 - 769
(2007/10/02)
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- 2'-O,5-dimethyluridine: A total synthesis and single crystal X-ray diffraction study
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A new method for the synthesis of 2'-O,5-dimethyluridine (5) has provided the title compound in a higher yield. Application of a one-pot ribosylation methodology resulted in an efficient, high yield synthesis of 5-methyluridine (ribothymine, 3b). An X-ray diffraction analysis of 5 disclosed the conformation of the sugar moiety of this nucleoside as anti, N(3'-endo), g+.
- Lewis,Revankar,Hogan
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p. 1309 - 1316
(2007/10/02)
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