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1.
Nat Commun ; 11(1): 469, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980608

RESUMO

The selective transport of ions across cell membranes, controlled by membrane proteins, is critical for a living organism. DNA-based systems have emerged as promising artificial ion transporters. However, the development of stable and selective artificial ion transporters remains a formidable task. We herein delineate the construction of an artificial ionophore using a telomeric DNA G-quadruplex (h-TELO) and a lipophilic guanosine (MG). MG stabilizes h-TELO by non-covalent interactions and, along with the lipophilic side chain, promotes the insertion of h-TELO within the hydrophobic lipid membrane. Fluorescence assays, electrophysiology measurements and molecular dynamics simulations reveal that MG/h-TELO preferentially transports K+-ions in a stimuli-responsive manner. The preferential K+-ion transport is presumably due to conformational changes of the ionophore in response to different ions. Moreover, the ionophore transports K+-ions across CHO and K-562 cell membranes. This study may serve as a design principle to generate selective DNA-based artificial transporters for therapeutic applications.


Assuntos
Quadruplex G , Transporte de Íons , Nucleosídeos/química , Ionóforos de Potássio/química , Animais , Células CHO , Cricetulus , Humanos , Células K562 , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Simulação de Dinâmica Molecular , Estrutura Molecular , Nucleosídeos/síntese química , Ionóforos de Potássio/síntese química , Espectrometria de Fluorescência
2.
Nat Commun ; 11(1): 405, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964883

RESUMO

Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes. Chemical synthesis is an efficient and scalable method to produce well-defined and pure carbohydrate-containing molecules for deciphering their functions and developing therapeutic agents. However, the development of glycosylation methods for efficient synthesis of both O-glycosides and nucleosides is one of the long-standing challenges in chemistry. Here, we report a highly efficient and versatile glycosylation method for efficient synthesis of both O-glycosides and nucleosides, which uses glycosyl ortho-(1-phenylvinyl)benzoates as donors. This glycosylation protocol enjoys the various features, including readily prepared and stable donors, cheap and readily available promoters, mild reaction conditions, good to excellent yields, and broad substrate scopes. In particular, the applications of the current glycosylation protocol are demonstrated by one-pot synthesis of several bioactive oligosaccharides and highly efficient synthesis of nucleosides drugs capecitabine, galocitabine and doxifluridine.


Assuntos
Benzoatos/química , Técnicas de Química Sintética/métodos , Química Farmacêutica/métodos , Glicosídeos/síntese química , Nucleosídeos/síntese química , Produtos Biológicos/síntese química , Capecitabina/síntese química , Floxuridina/síntese química , Glicosilação , Estrutura Molecular
3.
Chem Pharm Bull (Tokyo) ; 68(1): 1-33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902899

RESUMO

Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates, in which the following items are covered. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation under neutral condition from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel ß-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.


Assuntos
Produtos Biológicos/química , Metais/química , Animais , Produtos Biológicos/síntese química , Proliferação de Células/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/química , Metano/metabolismo , Nitrilos/química , Nucleosídeos/síntese química , Nucleosídeos/química
4.
Curr Protoc Nucleic Acid Chem ; 80(1): e103, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31985895

RESUMO

This article describes chemical synthesis of 2'-fluorinated Northern methanocarbacyclic (2'-F-NMC) nucleosides and phosphoramidites, based on a bicyclo[3.1.0]hexane scaffold bearing all four natural nucleobases (U, C, A, and G), and their incorporation into oligonucleotides by solid-supported synthesis. This synthesis starts from commercially available cyclopent-2-en-1-one to obtain the fluorinated carbocyclic pseudosugar intermediate (S.13), which can be converted to the uridine intermediate by condensation with isocyanate, followed by cyclization, and to adenine and guanine precursors by microwave-assisted reactions. All four 2'-F-NMC phosphoramidites are synthesized from S.13 in a convergent approach, and the monomers are used for synthesis of 2'-F-NMC-modified oligonucleotides. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Preparation of fluorinated carbocyclic pseudosugar intermediate Basic Protocol 2: Preparation of 2'-F-NMC uridine and cytidine phosphoramidites Basic Protocol 3: Preparation of 2'-F-NMC adenosine phosphoramidite Basic Protocol 4: Preparation of 2'-F-NMC guanosine phosphoramidite Basic Protocol 5: Synthesis of oligonucleotides containing 2'-F-NMC.


Assuntos
Flúor/química , Nucleosídeos/síntese química , Oligonucleotídeos/química , Nucleosídeos/química , Compostos Organofosforados/química
5.
Chemistry ; 26(12): 2597-2601, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31860145

RESUMO

A highly regio- and stereoselective route to d- and l-cyclohexenyl nucleosides has been devised, using the Tsuji-Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.


Assuntos
Nucleosídeos/síntese química , Carbonatos/química , Catálise , Teoria da Densidade Funcional , Estrutura Molecular , Estereoisomerismo , Termodinâmica
6.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861655

RESUMO

Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure-activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2'-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.


Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Nucleosídeos/síntese química , Transferases/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Proteínas de Bactérias/química , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/farmacologia , Relação Estrutura-Atividade , Timidina/química , Transferases/química , Uridina/análogos & derivados , Uridina/química
7.
Chemistry ; 25(67): 15419-15423, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31609050

RESUMO

Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4'-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4'-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4'-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3'-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4'-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4'-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.


Assuntos
Adenosina/química , Nucleosídeos/análogos & derivados , Nucleosídeos/síntese química , Carboidratos/química , Reação de Cicloadição , Teoria da Densidade Funcional , Dicloroetilenos/química , Glicosilação , Metais/química , Estrutura Molecular , Oxirredução , Estereoisomerismo , Termodinâmica
8.
Chem Commun (Camb) ; 55(81): 12216-12218, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31552932

RESUMO

acp3U is a hypermodified base that is found in the tRNAs of prokaryotes and eukaryotes and also in the ribosomal RNA of mammals. Its function has so far been unknown but it is speculated that acp3U complexes Mg ions, which may contribute to the stabilization of the RNA structure. As a hypermodified base in which a nucleoside is covalently connected to an amino acid, acp3U is a natural nucleoside between genotype and phenotype and hence is also of particular importance for theories about the origin of life. Herein, we report the development of a phosphoramidite building block and of a solid phase protocol that allows synthesis of RNA containing acp3U.


Assuntos
Nucleosídeos/síntese química , Aminoácidos/química , Sequência de Bases , Ciclização , Isomerismo , Estrutura Molecular , Oligonucleotídeos/química , RNA de Transferência/síntese química , Técnicas de Síntese em Fase Sólida/métodos
9.
Eur J Med Chem ; 183: 111667, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536893

RESUMO

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the Ki values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a Ki value of 0.2 µM for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4-6 µM range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads.


Assuntos
Antimaláricos/síntese química , Nucleosídeos/síntese química , Organofosfonatos/síntese química , Pentosiltransferases/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Sulfetos/química , Sulfonas/química , Sulfóxidos/química , Antimaláricos/farmacologia , Humanos , Estrutura Molecular , Nucleosídeos/farmacologia , Organofosfonatos/farmacologia , Oxirredução , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Termodinâmica
10.
Nucleosides Nucleotides Nucleic Acids ; 38(12): 980-1005, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380708

RESUMO

Two series of novel fluorinated nucleosides dimers with an unnatural 1,2,3-triazole linkage were synthesized. The obtained molecules were prepared using "click" chemistry approach based on copper(I) catalyzed Huisgen azide-alkyne cycloaddition. It was performed between 3'- and 5'-azido-nucleosides as the azide components, and the 3'-O- and 5'-O-propargyl-nucleosides as the alkyne components. Based on analysis of the 3 JHH, 3 JH1'C2 and 3 JH1'C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. All described nucleosides dimers analogs were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7).


Assuntos
Antineoplásicos/síntese química , Floxuridina/química , Nucleosídeos/síntese química , Timidina/química , Triazóis/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Click/métodos , Reação de Cicloadição/métodos , Dimerização , Células HeLa , Humanos , Células KB , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nucleosídeos/farmacologia
11.
Chem Pharm Bull (Tokyo) ; 67(8): 877-883, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366836

RESUMO

The 4-vinylpyrimidin-2-one nucleoside (T-vinyl) forms a cross-link with the RNA containing uracil at the complementary site at a high reaction rate. To obtain the stable T-vinyl derivative so that its reactivity is protected until it access to the target site, several derivatives were investigated, and the 2-thiopyridinyl- and 2-thiopyrimidinyl T-vinyl derivatives were determined to be good candidates. The 2-thiopyrimidinyl T-vinyl derivative was found to more efficiently cross-link with mRNA albeit having a better stability than the 2-thiopyridinyl T-vinyl derivative. The investigation using the luciferase (Luc) mRNA, the synthetic mRNA and non-cellular translation system revealed that the translation is terminated at the end of the cross-linked duplex between the mRNA and the oligoribonucleotide (ORN). Thus, the 2-thiopyrimidinyl T-vinyl derivative has successfully demonstrated both a good stability and high efficiency for the cross-linking reaction, and expanded its applicability in biological applications.


Assuntos
Reagentes para Ligações Cruzadas/química , Nucleosídeos/química , Oligorribonucleotídeos/química , RNA Mensageiro/química , Compostos de Vinila/química , Reagentes para Ligações Cruzadas/síntese química , Estrutura Molecular , Nucleosídeos/síntese química , Compostos de Vinila/síntese química
12.
Photochem Photobiol Sci ; 18(10): 2449-2460, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31407765

RESUMO

Glycol nucleic acids (GNA) are synthetic genetic-like polymers with an acyclic three-carbon propylene glycol phosphodiester backbone. Here, synthesis, luminescence properties, circular dichroism (CD) spectra, and confocal microscopy speciation studies of (R,S) and (S,R) pyrenyl-GNA (pyr-GNA) nucleosides are reported in HeLa cells. Enantiomerically pure nucleosides were obtained by a Sharpless asymmetric dihydroxylation reaction followed by semi-preparative high-performance liquid chromatography (HPLC) separation using Amylose-2 as the chiral stationary phase. The enantiomeric relationship between stereoisomers was confirmed by CD spectra, and the absolute configurations were assigned based on experimental and theoretical CD spectra comparisons. The pyr-GNA nucleosides were not cytotoxic against human cervical (HeLa) cancer cells and thus were utilized as luminescent probes in the imaging of these cells with confocal microscopy. Cellular staining patterns were identical for both enantiomers in HeLa cells. Compounds showed no photocytotoxic effect and were localized in the lipid membranes of the mitochondria, in cellular vesicles and in other lipid cellular compartments. The overall distribution of the pyrene and pyrenyl-GNA nucleosides inside the living HeLa cells differed, since the former compound gives a more granular staining pattern and the latter a more diffuse one.


Assuntos
Corantes Fluorescentes/química , Microscopia Confocal , Ácidos Nucleicos/química , Nucleosídeos/síntese química , Pirenos/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Cristalografia por Raios X , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Glicóis/química , Células HeLa , Humanos , Conformação Molecular , Nucleosídeos/química , Nucleosídeos/farmacologia , Estereoisomerismo
13.
ACS Chem Biol ; 14(8): 1698-1707, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310712

RESUMO

Optimized and stringent chemical methods to profile nascent RNA expression are still in demand. Herein, we expand the toolkit for metabolic labeling of RNA through application of inverse electron demand Diels-Alder (IEDDA) chemistry. Structural examination of metabolic enzymes guided the design and synthesis of vinyl-modified nucleosides, which we systematically tested for their ability to be installed through cellular machinery. Further, we tested these nucleosides against a panel of tetrazines to identify those which are able to react with a terminal alkene, but are stable enough for selective conjugation. The selected pairings then facilitated RNA functionalization with biotin and fluorophores. We found that this chemistry not only is amenable to preserving RNA integrity but also endows the ability to both tag and image RNA in cells. These key findings represent a significant advancement in methods to profile the nascent transcriptome using chemical approaches.


Assuntos
Nucleosídeos/metabolismo , RNA/metabolismo , Compostos de Vinila/metabolismo , Reação de Cicloadição , Células HEK293 , Compostos Heterocíclicos com 1 Anel/química , Humanos , Cinética , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Nucleosídeos/síntese química , Teoria Quântica , RNA/química , Compostos de Vinila/síntese química
14.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185601

RESUMO

A small library of 3'-deoxy-C3'-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3'-exomethylene derivatives of 2',5'-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.


Assuntos
Citostáticos/síntese química , Citostáticos/farmacologia , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Xilose/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Sulfidrila/química
15.
Artigo em Inglês | MEDLINE | ID: mdl-31187692

RESUMO

Due to the unique rigid and small steric feature of cyclopropane, cyclopropane nucleosides (CPNs) in which the ribose (deoxyribose) of nucleosides are replaced by a hydroxy-substituted cyclopropane, are of great biological interest. Novel 1,1,2-trisubstituted cyclopropane nucleosides were synthesized in enantiomerically pure forms as potential antiviral agents. In the synthesis, two cyclopropane tosylates, which were prepared from chiral cyclopropane lactones previously reported by us, were used effectively as common intermediates for the CPNs. These CPNs are also potentially useful as nucleoside units to incorporate into oligonucleotides in nucleic acids chemotherapy studies.


Assuntos
Antivirais/síntese química , Ciclopropanos/síntese química , Nucleosídeos/síntese química , Ciclização , Desenho de Fármacos , Estrutura Molecular , Oxirredução , Estereoisomerismo , Relação Estrutura-Atividade
16.
Curr Protoc Nucleic Acid Chem ; 77(1): e86, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31125509

RESUMO

This unit describes the detailed preparation of 5-alkynyl-2'-halogenated arabinosyl uridine nucleosides (2'-halo-ara-EdU) from uridine. These compounds were synthesized as prospective chemical probes for the detection of DNA synthesis in proliferating cells. Currently, this is the only synthetic methodology reported to access these compounds. The key to success of the synthetic approach was to employ a 3-N-nitro-protecting group to stabilize the required 2'-triflate nucleoside precursor toward nucleophilic substitution. Several synthetic challenges were overcome to accommodate the combination of a 5-alkyne and 3-N-nitro functional group, including facile introduction and removal of the N-nitro group, and removal of the sugar acetyl groups under acidic conditions. © 2019 by John Wiley & Sons, Inc.


Assuntos
Alquinos/química , Halogênios/química , Nucleosídeos/síntese química , Uridina/química , Sondas Moleculares , Nucleosídeos/química , Análise Espectral/métodos
17.
Eur J Med Chem ; 173: 154-166, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995568

RESUMO

Aminoacyl-tRNA synthetases (aaRSs) catalyse the ATP-dependent coupling of an amino acid to its cognate tRNA. Being vital for protein translation aaRSs are considered a promising target for the development of novel antimicrobial agents. 5'-O-(N-aminoacyl)-sulfamoyl adenosine (aaSA) is a non-hydrolysable analogue of the aaRS reaction intermediate that has been shown to be a potent inhibitor of this enzyme family but is prone to chemical instability and enzymatic modification. In an attempt to improve the molecular properties of this scaffold we synthesized a series of base substituted aaSA analogues comprising cytosine, uracil and N3-methyluracil targeting leucyl-, tyrosyl- and isoleucyl-tRNA synthetases. In in vitro assays seven out of the nine inhibitors demonstrated Kiapp values in the low nanomolar range. To complement the biochemical studies, X-ray crystallographic structures of Neisseria gonorrhoeae leucyl-tRNA synthetase and Escherichia coli tyrosyl-tRNA synthetase in complex with the newly synthesized compounds were determined. These highlighted a subtle interplay between the base moiety and the target enzyme in defining relative inhibitory activity. Encouraged by this data we investigated if the pyrimidine congeners could escape a natural resistance mechanism, involving acetylation of the amine of the aminoacyl group by the bacterial N-acetyltransferases RimL and YhhY. With RimL the pyrimidine congeners were less susceptible to inactivation compared to the equivalent aaSA, whereas with YhhY the converse was true. Combined the various insights resulting from this study will pave the way for the further rational design of aaRS inhibitors.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Nucleosídeos/farmacologia , Pirimidinas/farmacologia , Aminoacil-tRNA Sintetases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/síntese química , Escherichia coli/citologia , Escherichia coli/enzimologia , Estrutura Molecular , Nucleosídeos/análise , Nucleosídeos/síntese química , Pirimidinas/análise , Pirimidinas/síntese química , Relação Estrutura-Atividade
18.
Carbohydr Res ; 477: 39-50, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959446

RESUMO

A general synthesis of hetaryl and aryl C-4(5) linked imidazole C-nucleoside analogues has been developed by the reaction of sugar alkynes with het(aryl) iodides, KMnO4/TBAB oxidation and CoFe2O4 NPs catalyzed muti-component coupling of the corresponding diketones, NH4OAc and aromatic aldehydes in one-pot. The sugar alkynes include pyranosides and furanosides with acid sensitive protecting groups. The het(aryl) iodides comprise iodoaromatics, iodoheterocycles, and sterically hindered iodoheteroaromatics.


Assuntos
Cobalto/química , Compostos Férricos/química , Imidazóis/síntese química , Nanopartículas/química , Nucleosídeos/síntese química , Catálise , Imidazóis/química , Estrutura Molecular , Nucleosídeos/química
19.
PLoS Biol ; 17(4): e3000204, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951520

RESUMO

Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2'-deoxyriboside 5'-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activity. The crystal structure of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical interaction, in which the nucleobase is flipped in the active site. In this orientation, the methoxy group of 5-MeCITP extends out of the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs 1 and 2 in the fingers domain and T-motif in the RNA-binding domain of the telomerase reverse transcriptase. In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically administered nucleoside analog reverse transcriptase inhibitor azidothymidine (AZT). In addition, cell-based studies show that treatment with the cell-permeable nucleoside counterpart of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT treatment.


Assuntos
Nucleosídeos/metabolismo , Telomerase/antagonistas & inibidores , Telomerase/fisiologia , Animais , Domínio Catalítico/efeitos dos fármacos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Nucleosídeos/síntese química , Nucleosídeos/fisiologia , Nucleotídeos/síntese química , Nucleotídeos/metabolismo , RNA/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Telômero , Tribolium/genética , Tribolium/metabolismo , Zidovudina/metabolismo , Zidovudina/farmacologia
20.
Org Lett ; 21(9): 2998-3002, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30939024

RESUMO

An asymmetric transfer hydrogenation via dynamic kinetic resolution of a broad range of rac- α-(purin-9-yl)cyclopentones was first developed. A series of cis-ß-(purin-9-yl)cyclopentanols were obtained with up to 97% yield, >20/1 dr, and >99% ee. This also provides an efficient synthetic route to a variety of chiral carbocyclic nucleosides.


Assuntos
Cetonas/química , Nucleosídeos/síntese química , Purinas/química , Catálise , Complexos de Coordenação/química , Hidrogenação , Cinética , Rutênio/química , Estereoisomerismo
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