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1.
Bioorg Chem ; 140: 106806, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37660625

RESUMO

Solid-phase synthesis is, to date, the preferred method for the manufacture of oligonucleotides, in quantities ranging from a few micrograms for research purposes to several kilograms for therapeutic or commercial use. But for large-scale oligonucleotide manufacture, scaling up and hazardous waste production pose challenges that necessitate the investigation of alternate synthetic techniques. Despite the disadvantages of glass supports, using soluble supports as a substitute presents difficulties because of their high overall yield and complex purification steps. To address these challenges, various independent approaches have been developed; however, other problems such as insufficient cycle efficiency and synthesis of oligonucleotide chains of desired length continue to exist. In this study, we present a review of the current developments, advantages, and difficulties of recently reported alternatives to supports based on controlled pore glass, and discuss the importance of a support choice to resolve issues arising during oligonucleotide synthesis.


Assuntos
Ácidos Nucleicos , Oligonucleotídeos
2.
J Org Chem ; 84(21): 13447-13456, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31580069

RESUMO

The generation of unique thermosensitive fluorescent dyes via heteroaromatic Heck cross-coupling and N-pyridin-2-yl nucleophilic substitution was described. To demonstrate thermosensitive properties, the precursor was converted into carbonates or phosphates and heated at various temperatures and for various time periods. Significant changes in the fluorescence intensity and emission wavelengths, between carbonates and the cyclic product, were observed, and it was proved that the dyes may serve as removable fluorescent labels with large Stokes shifts (>80 nm). The application of thermosensitive fluorescent dyes in oligonucleotide labeling has been demonstrated.

3.
PLoS One ; 13(9): e0203604, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235232

RESUMO

1D and 2D NMR investigations as well as computational studies, including static quantum-mechanics calculations, density function theory formalism, and classical molecular dynamics, were applied to determine the protonation sites in the thermolabile protecting group (TPG) containing a 2-pyridynyl moiety within its structure. This protecting group has three possible sites for protonation: an azomethine (pyridinic) atom (N1), 2-aminoethanol residue (N2), and 4-amino substituent (N4). Our investigations showed that the protonation mainly occurs on the N1 atom. Such protonation seems to be a major inhibitory factor in the thermal removal of 2-pyridynyl TPG by the "chemical switch" approach and decreases the aromaticity of the pyridine ring. We also discussed possible participation of N2 nitrogen in irreversible intramolecular cyclization under acidic conditions.


Assuntos
Compostos Azo/química , Etanolamina/química , Tiossemicarbazonas/química , Espectroscopia de Ressonância Magnética , Nitrogênio/química
4.
Curr Protoc Nucleic Acid Chem ; 68: 2.20.1-2.20.25, 2017 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-28252183

RESUMO

Application of 2-pyridinyl thermolabile protecting groups (2-PyTPGs) for protection of hydroxyl, phosphate, and carboxyl functions is presented in this unit. Their characteristic feature is a unique removal process following the intramolecular cyclization mechanism and induced only by temperature rise. Deprotection rate of 2-PyTPGs is dependent on certain parameters, such as solvent (aqueous or non-aqueous medium), pH values, and electron distribution in a pyridine ring. The presented approach pertains not only to protecting groups but also to an advanced system of controlling certain properties of 2-pyridinyl derivatives. We improved the "chemical switch" method, allowing us to regulate the protecting group stability by inversing the electron distribution in 2-PyTPG. Together with pH values manipulation, this allows us to regulate the protecting group stability. Moreover, phosphite cyclization to oxazaphospholidine provides a very stable but easily reversible tool for phosphate protection/modifications. For all TPGs we confirmed their utility in a system of protecting groups. This concept can contribute to designing the general protecting group that could be useful in bioorganic chemistry. © 2017 by John Wiley & Sons, Inc.


Assuntos
Bioquímica/métodos , Carbonatos/síntese química , Piridinas/química , Ciclização , Radical Hidroxila , Nucleosídeos/química , Fosfatos/química
5.
Org Lett ; 18(13): 3230-3, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27336291

RESUMO

A thermolabile protecting group strategy for carboxylic acids is expanded. Thermosensitive esters are readily prepared using a known procedure, and their stability under neutral condition is investigated. Effective thermolytic deprotection initiated only by temperature for different carboxylic acids is demonstrated, and the compatibility of a thermolytic protecting group with acidic and basic protecting groups in an orthogonal protection strategy is also presented. This study showed interesting correlations between the pKa of acids and the deprotection rate of their well-protected moieties.

6.
J Org Chem ; 80(24): 12129-36, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26544024

RESUMO

A novel and effective method is presented for modulating the stability of 2-Pyridinyl Thermolabile Protecting Groups (2-Py TPGs) in the "chemical switch" approach. The main advantage of the discussed approach is the possibility of changing the nucleophilic character of pyridine nitrogen using different switchable factors, which results in an increase or decrease in the thermal deprotection rate. One of the factors is transformation of a nitro into an amine group via reduction with a low-valent titanium in mild conditions. The usefulness of our approach is corroborated using 3'-O-acetyl nucleosides as model compounds. Their stability in various solvents and temperatures before and after reduction is also examined. Pyridine N-oxide and pH are other factors responsible for the nucleophilicity and stability of 2-Pyridinyl Thermolabile Protecting Groups in thermal deprotection. Protonation of 4-amino 2-Pyridinyl Thermolabile Protecting Groups is demonstrated by (1)H-(15)N HMBC and HSQC NMR analysis.

7.
Molecules ; 20(7): 12652-69, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26184145

RESUMO

The rationale for the synthesis of cationic modified nucleosides is higher expected nuclease resistance and potentially better cellular uptake due to an overall reduced negative charge based on internal charge compensation. Due to the ideal distance between cationic groups, polyamines are perfect counterions for oligodeoxyribonucleotides. We have synthesized non-nucleosidic analogues built from units that carry different diol structures instead of sugar residues and functionalized with polyamines. The non-nucleosidic analogues were attached as internal or 5'-terminal modifications in oligodeoxyribonucleotide strands. The thermodynamic studies of these polyaminooligonucleotide analogues revealed stabilizing or destabilizing effects that depend on the linker or polyamine used.


Assuntos
DNA/química , Oligodesoxirribonucleotídeos/química , Putrescina/química , Espermina/química , Cátions , Técnicas de Química Sintética , Mimetismo Molecular , Nucleosídeos/química , Compostos Organofosforados/química , Termodinâmica
8.
Biochim Biophys Acta ; 1840(3): 1163-70, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24361616

RESUMO

BACKGROUND: The nature of the polyamine-DNA interactions at a molecular level is not clearly understood. METHODS: In order to shed light on the binding preferences of polyamine with nucleic acids, the NMR solution structure of the DNA duplex containing covalently bound spermine was determined. RESULTS: The structure of 4-N-[4,9,13-triazatridecan-1-yl]-2'-deoxycytidine (dCSp) modified duplex was compared to the structure of the reference duplex. Both duplexes are regular right-handed helices with all attributes of the B-DNA form. The spermine chain which is located in a major groove and points toward the 3' end of the modified strand does not perturb the DNA structure. CONCLUSION: In our study the charged polyamine alkyl chain was found to interact with the DNA surface. In the majority of converged structures we identified the presumed hydrogen bonding interactions between O6 and N7 atoms of G4 and the first internal -NH2(+)- amino group. Additional interaction was found between the second internal -NH2(+)- amino group and the oxygen atom of the phosphate of C3 residue. GENERAL SIGNIFICANCE: The knowledge of the location and nature of a structure-specific binding site for spermine in DNA should be valuable in understanding gene expression and in the design of new therapeutic drugs.


Assuntos
DNA/química , Desoxicitidina/análogos & derivados , Espectroscopia de Ressonância Magnética/métodos , Oligonucleotídeos/química , Espermina/química , Desoxicitidina/química
9.
Bioorg Med Chem ; 20(4): 1594-606, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22264759

RESUMO

Synthetic RNAi activators have shown considerable potential for therapeutic application to silencing of pathology-causing genes. Typically these exogenous RNAi activators comprise duplex RNA of approximately 21 bp with 2 nt overhangs at the 3' ends. To improve efficacy of siRNAs, chemical modification at the 2'-OH group of ribose has been employed. Enhanced stability, gene silencing and attenuated immunostimulation have been demonstrated using this approach. Although promising, efficient and controlled delivery of highly negatively charged nucleic acid gene silencers remains problematic. To assess the potential utility of introducing positively charged groups at the 2' position, our investigations aimed at assessing efficacy of novel siRNAs containing 2'-O-guanidinopropyl (GP) moieties. We describe the formation of all four GP-modified nucleosides using the synthesis sequence of Michael addition with acrylonitrile followed by Raney-Ni reduction and guanidinylation. These precursors were used successfully to generate antihepatitis B virus (HBV) siRNAs. Testing in a cell culture model of viral replication demonstrated that the GP modifications improved silencing. Moreover, thermodynamic stability was not affected by the GP moieties and their introduction into each position of the seed region of the siRNA guide strand did not alter the silencing efficacy of the intended HBV target. These results demonstrate that modification of siRNAs with GP groups confers properties that may be useful for advancing therapeutic application of synthetic RNAi activators.


Assuntos
Sistemas de Liberação de Medicamentos , Compostos Organofosforados/síntese química , RNA Interferente Pequeno/química , Succinatos/química , Estabilidade de Medicamentos , Inativação Gênica/efeitos dos fármacos , Células HEK293 , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Oligonucleotídeos/síntese química , Oligonucleotídeos/genética , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , RNA Interferente Pequeno/síntese química , RNA Interferente Pequeno/farmacologia , Succinatos/síntese química , Succinatos/farmacologia
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