81246-79-9Relevant academic research and scientific papers
Synthesis, Structural, and Conformational Analysis of 4′-C-Alkyl-2′-O-Ethyl-Uridine Modified Nucleosides
Nikam, Rahul R.,Harikrishna,Gore, Kiran R.
, p. 924 - 932 (2021/02/01)
Sugar modifications have attracted much attention due to their potential structural and functional influence on therapeutic nucleic acids. Herein, we report the synthesis of dual modified 4′-C-azidomethyl-2′-O-ethyl-uridine (4′-AzM-2′-OEt?U) and 4′-C-aminomethyl-2′-O-ethyl-uridine (4′-AM-2′-OEt?U) nucleosides using linear multi-step synthesis (16 linear steps). Additionally, we report an alternative route for the synthesis of 2′-O-ethyl-uridine nucleoside which has been achieved in three steps with an overall yield of 40 %. X-ray structure of 4′-AzM-2′-OEt?U illustrates that the nucleoside adopts C2′-endo (South) conformation having a DNA-type glycosidic bond (χ) angle of ?116.01°. Computational studies revealed the C2′-endo and C4′-exo conformations for 4′-AzM-2′-OEt?U and 4′-AM-2′-OEt?U free nucleosides, respectively. The C4′-exo conformation in 4′-AM-2′-OEt?U free nucleoside is collectively stabilized by various non-covalent interactions between positively charged aminomethyl and 2′,3′-hydroxyl groups. Insights into the structural and conformational analysis of dual sugar modified nucleosides and oligonucleotides will be helpful in the rational design of modified nucleosides and therapeutic oligonucleotides.
5’-Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A
Berney, Mark,Fay, Ellen M.,Manoj, Manav T,McGouran, Joanna F.
supporting information, (2022/01/13)
Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5’–3’ exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5’-position, as well as zinc-binding groups at the 3’-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5’-phosphate dramatically increased the potency of the inhibitors.
Azido Functionalized Nucleosides Linked to Controlled Pore Glass as Suitable Starting Materials for Oligonucleotide Synthesis by the Phosphoramidite Approach
Müggenburg, Frederik,Biallas, Alexander,Debiais, Mégane,Smietana, Michael,Müller, Sabine
, p. 6408 - 6416 (2021/11/30)
It has long been debated whether easily reducible azide groups can withstand the conditions of oligonucleotide synthesis by phosphoramidite chemistry. We have synthesized various 2′- and 3′-azido modified nucleosides and immobilized them on controlled pore glass (CPG) to be used as starting material for the synthesis of oligonucleotides (ONs) with 3′-terminal azide (attached to C2′ or C3′). In a model study, immobilized 3′-azidoadenosine was used as a starting block for the synthesis of a series of oligodeoxynucleotides (ODNs) of increasing length. Upon synthesis, the ODNs were enzymatically digested into monomers and analyzed by RP-HPLC. A peak corresponding to 3′-azidoadenosine was clearly identified in all samples. Quantitative analysis showed that 3′-azidoadenosine was present in nearly the expected ratio to deoxycytidine, which was used as an internal standard. Most importantly, the ratio remained the same for all three ODNs regardless of their length, demonstrating that a higher number of coupling cycles does not lead to higher degradation of the azide. Thus, 2′- or 3′-azido nucleosides attached to a solid support are excellent starting materials for the synthesis of oligonucleotides with 3′-terminal azide.
Measurement of Angstrom to Nanometer Molecular Distances with 19F Nuclear Spins by EPR/ENDOR Spectroscopy
Meyer, Andreas,Dechert, Sebastian,Dey, Surjendu,H?bartner, Claudia,Bennati, Marina
supporting information, p. 373 - 379 (2019/11/22)
Spectroscopic and biophysical methods for structural determination at atomic resolution are fundamental in studies of biological function. Here we introduce an approach to measure molecular distances in bio-macromolecules using 19F nuclear spins and nitroxide radicals in combination with high-frequency (94 GHz/3.4 T) electron–nuclear double resonance (ENDOR). The small size and large gyromagnetic ratio of the 19F label enables to access distances up to about 1.5 nm with an accuracy of 0.1–1 ?. The experiment is not limited by the size of the bio-macromolecule. Performance is illustrated on synthesized fluorinated model compounds as well as spin-labelled RNA duplexes. The results demonstrate that our simple but strategic spin-labelling procedure combined with state-of-the-art spectroscopy accesses a distance range crucial to elucidate active sites of nucleic acids or proteins in the solution state.
UNA AMIDITES AND USES THEREOF
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Paragraph 0343; 0347, (2020/12/29)
Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a disease which utilize a composition or
Addressing regio- And stereo-specificity challenges in the synthesis of nucleoside 2′,3′-cyclic monophosphate analogs-a rapid and facile synthesis of nucleoside-2′,3′-: O, O -phosphoro-thioate or -selenoate, and elucidation of the origin of the rare specificity
Nassir, Molhm,Balaom, Lara,Fischer, Bilha
supporting information, p. 11633 - 11636 (2020/10/19)
A new facile, rapid, stereo- and regio-selective one-pot synthesis of nucleoside-2′,3′-O,O-phosphorothioate and selenoate analogs has been developed. This method avoids the need for protection strategies and chiral reagents, chiral metal catalysts, or chiral separations. This synthetic method has been applied to all natural nucleosides (U/A/G/C/T). Furthermore, we have deciphered the origin of the stereo- and regio-selectivity of the reaction.
NUCLEIC ACID-POLYPEPTIDE COMPOSITIONS AND USES THEREOF
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Paragraph 0453-0455, (2019/04/27)
Disclosed herein are compositions and pharmaceutical formulations that comprise a binding moiety conjugated to a modified polynucleic acid molecule and a polymer. Also described herein include methods for treating a cancer which utilize a composition or a pharmaceutical formulation comprising a binding moiety conjugated to a polynucleic acid molecule and a polymer.
UDP-GlcNAc Analogues as Inhibitors of O-GlcNAc Transferase (OGT): Spectroscopic, Computational, and Biological Studies
Ghirardello, Mattia,Perrone, Daniela,Chinaglia, Nicola,Sádaba, David,Delso, Ignacio,Tejero, Tomas,Marchesi, Elena,Fogagnolo, Marco,Rafie, Karim,van Aalten, Daan M. F.,Merino, Pedro
supporting information, p. 7264 - 7272 (2018/05/04)
A series of glycomimetics of UDP-GlcNAc, in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring, has been synthesized by the application of different click-chemistry procedures. Their affinities for human O-GlcNAc transferase (hOGT) have been evaluated and studied both spectroscopically and computationally. The binding epitopes of the best ligands have been determined in solution by means of saturation transfer difference (STD) NMR spectroscopy. Experimental, spectroscopic, and computational results are in agreement, pointing out the essential role of the binding of β-phosphate. We have found that the loss of interactions from the β-phosphate can be counterbalanced by the presence of hydrophobic groups at a pyrroline ring acting as a surrogate of the carbohydrate unit. Two of the prepared glycomimetics show inhibition at a micromolar level.
Tricyclanos: Conformationally constrained nucleoside analogues with a new heterotricycle obtained from a d-ribofuranose unit
Kicsák, Máté,Mándi, Attila,Varga, Szabolcs,Herczeg, Mihály,Batta, Gyula,Bényei, Attila,Borbás, Anikó,Herczegh, Pál
supporting information, p. 393 - 401 (2018/02/06)
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.05,11]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl2, Et3SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.
Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism
Downey, A. Michael,Pohl, Radek,Roithová, Jana,Hocek, Michal
supporting information, p. 3910 - 3917 (2017/03/27)
Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed “anhydrose”) under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.
