4836-13-9Relevant academic research and scientific papers
Towards Zwitterionic Oligonucleotides with Improved Properties: the NAA/LNA-Gapmer Approach
Wojtyniak, Melissa,Schmidtgall, Boris,Kirsch, Philine,Ducho, Christian
, p. 3234 - 3243 (2020/09/01)
Oligonucleotides (ON) are promising therapeutic candidates, for instance by blocking endogenous mRNA (antisense mechanism). However, ON usually require structural modifications of the native nucleic acid backbone to ensure satisfying pharmacokinetic properties. One such strategy to design novel antisense oligonucleotides is to replace native phosphate diester units by positively charged artificial linkages, thus leading to (partially) zwitterionic backbone structures. Herein, we report a “gapmer” architecture comprised of one zwitterionic central segment (“gap”) containing nucleosyl amino acid (NAA) modifications and two outer segments of locked nucleic acid (LNA). This NAA/LNA-gapmer approach furnished a partially zwitterionic ON with optimised properties: i) the formation of stable ON-RNA duplexes with base-pairing fidelity and superior target selectivity at 37 °C; and ii) excellent stability in complex biological media. Overall, the NAA/LNA-gapmer approach is thus established as a strategy to design partially zwitterionic ON for the future development of novel antisense agents.
A new and convenient approach for the preparation of β-cyanoethyl protected trinucleotide phosphoramidites
Janczyk, Matthaeus,Appel, Bettina,Springstubbe, Danilo,Fritz, Hans-Joachim,Mueller, Sabine
supporting information; experimental part, p. 1510 - 1513 (2012/03/22)
Herein we report a convenient approach for the preparation of fully protected trinucleotide synthons to be used for the synthesis of gene libraries. The trinucleotide synthons bear β-cyanoethyl groups at the phosphate residues, and thus can be used in standard oligonucleotide synthesis without additional steps for deprotection and work-up.
Pyrimidine-purine and pyrimidine heterodinucleosides synthesis containing a triazole linkage
Lucas,Elchinger,Faugeras,Zerrouki
scheme or table, p. 168 - 177 (2011/08/02)
This article describes a synthetic route to generate two purine-pyrimidine and pyrimidine heterodinucleosides. Both microwave activated regioselective alkylation using hydride and copper-catalyzed-azide-alkyne-cycloaddition (CuAAC) were used in order to perform the synthesis.
Chelation-controlled regioselective alkylation of pyrimidine 2′-deoxynucleosides
Lucas,Teste,Zerrouki,Champavier,Guilloton
scheme or table, p. 199 - 207 (2010/03/23)
Protection-deprotection steps, which are usually needed for regioselective alkylation of pyrimidine deoxynucleosides, can be avoided by choosing the appropriate solvent. The combined effects of low dielectric constant and possible sodium chelation by pyrimidine nucleosides may account for the unexpected regioselectivity observed in THF.
α,β-Difluoromethylene deoxynucleoside 5′-triphosphates: A convenient synthesis of useful probes for DNA polymerase β structure and function
Upton, Thomas G.,Kashemirov, Boris A.,McKenna, Charles E.,Goodman, Myron F.,Prakash, G. K. Surya,Kultyshev, Roman,Batra, Vinod K.,Shock, David D.,Pedersen, Lars C.,Beard, William A.,Wilson, Samuel H.
supporting information; experimental part, p. 1883 - 1886 (2009/10/10)
αβ-Difluoromethylene deoxynucleoside 5′-triphosphates (dNTPs, N = A or C) are advantageously obtained via phosphorylation of corresponding dNDP analogues using catalytic ATP, PEP, nucleoside diphosphate kinase, and pyruvate kinase. DNA pol β Kdd values for the α, β-CF2 and unmodified dNTPs, α, β-NH dUTP, and the α, β-CH2 analogues of dATP and dGTP are discussed in relation to the conformations of α, β-CF2 dTTP versus α, β-NH dUTP bound into the enzyme active site.2009 American Chemical Society.
DNG cytidine: Synthesis and binding properties of octameric guanidinium-linked deoxycytidine oligomer
Szabo, Istvan E.,Bruice, Thomas C.
, p. 4233 - 4244 (2007/10/03)
The synthesis of guanidinium-linked cytidyl oligomer (DNG-C8), a cationic DNA analog, and the corresponding cytidine monomers is described. The DNG monomer synthesis was streamlined to produce a shorter route to the final monomer than previously reported for thymidine and subsequent solid-phase synthesis produced an octameric cytidyl DNG strand. Because octameric deoxyguanosine would be used as the complementary strand in our studies, it was necessary to investigate guanosine self-association. Singular value decomposition was used to mathematically deconvolve the spectral data and confirm the presence of transitions due to DNA-G8 self-association. Job plots show the binding stoichiometry of DNG-C8 with DNA-G 8 to be 1:1. Thermal denaturation studies of the DNG-C 8·DNA-G8 duplex established a T m≥90°C and a ΔG°=-13.3kcalmol-1, indicating the DNG-C8·DNA-G8 duplex is over 1000 times more stable than that of DNA-C8·DNA-G8.
An improved transient method for the synthesis of N-benzoylated nucleosides
Zhu, Xue-Feng,Williams Jr., Howard J.,Scott, A. Ian
, p. 1233 - 1243 (2007/10/03)
The Jones' transient method for the synthesis of N-benzoylated nucleosides is improved by reducing the amounts of chlorotrimethylsilane (TMSCl) and benzoyl chloride to nearly equivalent quantities. The easy work-up and high yields of products are the major advantages of this approach. Jones' method is further simplified by omitting the addition of ammonium hydroxide. The utility of this modification for the preparation of some useful protected nucleosides is also presented.
Selective cleavage of O-(dimethoxytrityl) protecting group with sodium periodate
Rejman, Dominik,Kralikova, Sarka,Tocik, Zdenek,Liboska, Radek,Rosenberg, Ivan
, p. 502 - 508 (2007/10/03)
Sodium periodate in aqueous organic solvents selectively removes, under mild reaction conditions, the O-(dimethoxytrityl) protecting group. Selectivity of the cleavage was studied using the nucleoside derivatives protected by various types of groups commonly used in nucleoside and nucleotide chemistry.
Building blocks for the solution phase synthesis of oligonucleotides: Regioselective hydrolysis of 3′,5′-di-O-levulinylnucleosides using an enzymatic approach
Garcia, Javier,Fernandez, Susana,Ferrero, Miguel,Sanghvi, Yogesh S.,Gotor, Vicente
, p. 4513 - 4519 (2007/10/03)
A short and convenient synthesis of 3′- and 5′-O-levulinyl-2′-deoxynucleosides has been developed from the corresponding 3′,5′-di-O-levulinyl derivatives by regioselective enzymatic hydrolysis, avoiding several tedious chemical protection/deprotection steps. Thus, Candida antartica lipase B (CAL-B) was found to selectively hydrolyze the 5′-levulinate esters, furnishing 3′-O-levulinyl-2′-deoxynucleosides 3 in >80% isolated yields. On the other hand, immobilized Pseudomonas cepacia lipase (PSL-C) and Candida antarctica lipase A (CAL-A) exhibit the opposite selectivity toward the hydrolysis at the 3′-position, affording 5′-O-levulinyl derivatives 4 in >70% yields. A similar hydrolysis procedure was successfully extended to the synthesis of 3′- and 5′-O-levulinyl-protected 2′-O-alkylribonucleosides 7 and 8. This work demonstrates for the first time application of commercial CAL-B and PSL-C toward regioselective hydrolysis of levulinyl esters with excellent selectivity and yields. It is noteworthy that protected cytidine and adenosine base derivatives were not adequate substrates for the enzymatic hydrolysis with CAL-B, whereas PSL-C was able to accommodate protected bases during selective hydrolysis. In addition, we report an improved synthesis of dilevulinyl esters using a polymer-bound carbodiimide as a replacement for dicyclohexylcarbodiimide (DCC), thus considerably simplifying the workup for esterification reactions.
