Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
ChemMedChem ; : e202400234, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38742678

RESUMO

Synthetic nucleoside mimics are re-emerging as crucial contenders for antiviral and anticancer medications. While, Ribavirin stands out for its unique antiviral properties, predominantly associated with its distinctive triazole heterocycle as a nucleobase, the exploration of alternative nitrogen-based aromatic heterocycles hold great promises for the discovery of novel bioactive nucleoside mimics. Although nucleoside derivatives synthesised from hydrazine-ribose units have been in development for many decades, they have been little evaluated biologically and even less for their antiviral properties. With the aim of taking a closer look at these under-explored derivatives and investigating their synthetic pathways, this concise review provides an overview of the molecular design, the chemical synthesis, and the biological activity, when available, of these nucleoside analogues. Overall, the entire body of work already done motivates further exploration of theses analogues and encourages us of formulating structurally novel nucleoside drug candidates featuring innovative mode of action.

2.
Eur J Med Chem ; 258: 115581, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37402342

RESUMO

The nucleotidase ISN1 is a potential therapeutic target of the purine salvage pathway of the malaria parasite Plasmodium falciparum. We identified PfISN1 ligands by in silico screening of a small library of nucleos(t)ide analogues and by thermal shift assays. Starting from a racemic cyclopentyl carbocyclic phosphonate scaffold, we explored the diversity on the nucleobase moiety and also proposed a convenient synthetic pathway to access the pure enantiomers of our initial hit (compound (±)-2). 2,6-Disubstituted purine containing derivatives such as compounds 1, (±)-7e and ß-L-(+)-2 showed the most potent inhibition of the parasite in vitro, with low micromolar IC50 values. These results are remarkable considering the anionic nature of nucleotide analogues, which are known to lack activity in cell culture experiments due to their scarce capacity to cross cell membranes. For the first time, we report the antimalarial activity of a carbocyclic methylphosphonate nucleoside with an L-like configuration.


Assuntos
Antimaláricos , Organofosfonatos , Plasmodium falciparum/metabolismo , Organofosfonatos/farmacologia , Antimaláricos/farmacologia , Antimaláricos/metabolismo , Nucleosídeos , Purinas/metabolismo
3.
ChemMedChem ; 18(7): e202200594, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36700491

RESUMO

Various series of 4,6-biaryl-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6-disubstituted 3-cyano-2-chloro-pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell-based assays, highlighting the difficulty to target protein-protein interface on proteins existing as soluble and membrane-bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6-biaryl-2-thiopyridine core were shown to be able to reverse the adenosine-mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)-N-(isoxazol-3-yl)acetamide (with total reversion at 100 µM) and methyl 2-((3-cyano-4,6-bis(4-morpholinophenyl)pyridin-2-yl)thio)acetate (with partial reversion at 10 µM). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors.


Assuntos
5'-Nucleotidase , Adenosina , Humanos , Adenosina/farmacologia , Piridinas/farmacologia , Proteínas Recombinantes/química
4.
ChemMedChem ; 17(20): e202200377, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36032023

RESUMO

Recently, we reported the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented. The activities against these different strains show that the activities of bis(POM) prodrug (-)-9 are equivalent or even superior to those of (R)-PMPA.


Assuntos
Fármacos Anti-HIV , Organofosfonatos , Pró-Fármacos , Organofosfonatos/farmacologia , Fármacos Anti-HIV/farmacologia , Nucleosídeos/farmacologia , Adenina , Tenofovir , Antivirais
5.
Bioorg Chem ; 107: 104577, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33450542

RESUMO

Three series of nucleotide analogues were synthesized and evaluated as potential CD73 inhibitors. Nucleobase replacement consisted in connecting the appropriate aromatic or purine residues through a triazole moiety that is generated from 1,3-dipolar cycloaddition. The first series is related to 4-substituted-1,2,3-triazolo-ß-hydroxyphosphonate ribonucleosides. Additional analogues were also obtained, in which the phosphonate group was replaced by a bisphosphonate pattern (P-C-P-C, series 2) or the ribose moiety was removed leading to acyclic derivatives (series 3). The ß-hydroxyphosphonylphosphonate ribonucleosides (series 2) were found to be potent inhibitors of CD73 using both purified recombinant protein and cell-based assays. Two compounds (2a and 2b) that contained a bis(trifluoromethyl)phenyl or a naphthyl substituents proved to be the most potent inhibitors, with IC50 values of 4.8 ± 0.8 µM and 0.86 ± 0.2 µM, compared to the standard AOPCP (IC50 value of 3.8 ± 0.9 µM), and were able to reverse the adenosine-mediated immune suppression on human T cells. This series of compounds illustrates a new type of CD73 inhibitors.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Algoritmos , Nucleotídeos/farmacologia , Triazóis/farmacologia , 5'-Nucleotidase/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Cinética , Estrutura Molecular , Nucleotídeos/síntese química , Nucleotídeos/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
6.
J Org Chem ; 85(18): 11778-11793, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32871069

RESUMO

3-Acetoacetyl-4,6-diaryl-2-pyridones are synthesized in three steps from chalcones and then condense with carbon disulfide to afford 8-azachromones containing a methylthio group at C2. This leaving group offers an entry point for the insertion of more complex moieties via nucleophilic substitution. For this purpose, N-nucleophiles are explored according to their positions in the Mayr's nucleophilicity scale (N parameter), and three main classes are distinguished depending on whether the substitution takes place from their neutral forms, from their deprotonated anionic forms, or under nucleophilic catalysis. A broad range of primary and secondary amines may be inserted by this method, including enantiomerically pure amino acids, enabling us to explore structural diversity.

7.
Molecules ; 25(16)2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32823897

RESUMO

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.


Assuntos
Fármacos Anti-HIV/farmacologia , Citosina/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Nucleosídeos/química , Organofosfonatos/farmacologia , Uracila/química , Fármacos Anti-HIV/química , Infecções por HIV/virologia , Humanos , Organofosfonatos/química , Relação Estrutura-Atividade , Replicação Viral
8.
ChemMedChem ; 14(15): 1431-1443, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31264794

RESUMO

Derivatives of 5'-aminoadenosine containing methyl carboxylate, methyl phosphonate, gem-bisphosphonate, bis(methylphosphonate), and α-carboxylmethylphosphonate or phosphonoacetate moieties were synthesized from key intermediate 5'-aminonucleoside. These nucleotide analogues were envisaged as 5'-mono- or diphosphate nucleoside mimics. All compounds were evaluated for CD73 inhibition in a cell-based assay (MDA-MB-231) and toward the purified recombinant protein. Most of them failed to reach significant inhibition of AMP hydrolysis by CD73 at 100 µm. Among the new compounds, the most interesting candidates, 5 (5'-deoxy-5'-N-phosphonomethyladenosine) and 7 (5'-deoxy-5'-N-(ethoxyphosphorylacetate)adenosine), inhibited recombinant CD73 by 36 and 46 % and cellular CD73 by 61 and 45 % at 100 µm, respectively. Molecular modeling partially explains this lack of activity, as the initially predicted docking scores had been encouraging, especially for compound 9.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/síntese química , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Adenosina/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Modelos Moleculares , Estrutura Molecular , Organofosfonatos/química , Compostos Organofosforados/química , Ligação Proteica , Conformação Proteica , Proteínas Recombinantes/química , Relação Estrutura-Atividade
9.
ChemMedChem ; 14(5): 522-526, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30637958

RESUMO

The synthesis and anti-HIV evaluation of hitherto unknown 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine with modifications at the 4' position (ethynyl, vinyl, ethyl, hydroxymethyl) is described. One of the synthesized compounds was found to be an inhibitor of HIV-1 replication, but with moderate efficiency relative to (R)-9-(2-phosphonylmethoxypropyl)adenine ((R)-PMPA, tenofovir), with no concomitant cytotoxicity.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Organofosfonatos/química , Adenina/química , Células Sanguíneas , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tenofovir/farmacologia , Replicação Viral/efeitos dos fármacos
10.
Eur J Med Chem ; 150: 642-654, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29558735

RESUMO

The synthesis and the antiviral evaluation of 3'-halo (iodo and fluoro) 5'-norcarbocyclic nucleoside phosphonates is described. No antiviral activity was observed against Zika virus, Dengue virus 2, HSV-1, HSV-2 and Chikungunya virus. In contrast, some of the synthesized compounds are potent inhibitors of the replication of HIV-1, comparatively to (R)-PMPA, with no concomitant cytotoxicity.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Nucleosídeos/farmacologia , Organofosfonatos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Organofosfonatos/síntese química , Organofosfonatos/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
11.
Org Biomol Chem ; 16(11): 1903-1911, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29484333

RESUMO

We report here the synthetic route of two constrained dinucleotides and the determination of the sugar puckering by NMR analyses of the starting nucleosides. Enzymatic ligation to microhelix-RNAs provide access to tRNA analogues containing a 3' terminal A76 locked in South conformation. Biological evaluation of our tRNA analogues has been performed using amino-acyl tRNA-dependent transferase FemXWv, which mediates non-ribosomal incorporation of amino acids into the bacterial cell wall. We have shown that our tRNA analogues inhibited the aminoacyl transfer reaction catalyzed by FemXWv with IC50s of 10 and 8 µM. These results indicate that FemXWv displays a moderate preference for tRNAs containing a terminal A76 locked in the South conformation and that a South to North switch in the conformation of the terminal ribose might contribute to the release of the uncharged tRNAAla product of the aminoacyl transfer reaction catalyzed by FemXwv.


Assuntos
Técnicas de Química Sintética/métodos , RNA de Transferência/química , Ribonucleotídeos/química , Ribose/análogos & derivados , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/metabolismo , Proteínas de Bactérias/metabolismo , Modelos Moleculares , Conformação de Ácido Nucleico , RNA de Transferência/síntese química , RNA de Transferência/metabolismo , Ribonucleotídeos/síntese química , Ribonucleotídeos/metabolismo , Ribose/síntese química , Ribose/metabolismo , Weissella/enzimologia , Weissella/metabolismo
12.
Beilstein J Org Chem ; 13: 251-256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28326134

RESUMO

The racemic synthesis of new carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity.

13.
Bioorg Med Chem Lett ; 24(17): 4227-30, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25091927

RESUMO

AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior.


Assuntos
Adenina/análogos & derivados , Adenilato Quinase/antagonistas & inibidores , Organofosfonatos/farmacologia , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Adenilato Quinase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 22(1): 513-22, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24280070

RESUMO

An amine group was synthesized starting from an optically active bicyclo[2.2.1]heptane compound, which was then used to build the 5 atoms ring of a key 6-chloropurine intermediate. This was then reacted with ammonia and selected amines obtaining new adenine- and 6-substituted adenine conformationally constrained carbocyclic nucleoside analogues with a bicyclo[2.2.1]heptane skeleton in the sugar moiety. X-ray crystallography confirmed an exo-coupling of base to the ring and a L configuration of the nucleoside analogues. The compounds were tested for anticancer activity.


Assuntos
Antineoplásicos/síntese química , Heptanos/química , Nucleosídeos/química , Antineoplásicos/uso terapêutico , Cristalografia por Raios X , Humanos , Conformação Molecular , Estrutura Molecular , Estereoisomerismo
15.
Bioorg Chem ; 38(6): 275-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20817216

RESUMO

(-)-Neplanocin B, the natural isomer of a component of the neplanocin family was diasteroselectively synthesized from 2,3-O-isopropylidene-D-1,4-ribonolactone. However, when evaluated against several DNA and RNA viruses in cell culture experiments, it did not show any antiviral activity.


Assuntos
Antivirais/síntese química , Actinomycetales/química , Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/farmacologia , Antivirais/farmacologia , Humanos , Estereoisomerismo , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos
16.
Bioorg Chem ; 38(6): 271-4, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20869741

RESUMO

A rapid synthesis of 2',3'-dideoxy-3'-fluoro-ß-D-threo-nucleosides bearing the pyrimidine canonical bases of nucleic acids has been developed in order to discover new nucleoside derivatives as potential antiviral drugs. However, when evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.


Assuntos
Antivirais/síntese química , Nucleosídeos de Pirimidina/síntese química , Antivirais/química , Antivirais/farmacologia , Halogenação , Humanos , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacos
17.
Nucleic Acids Symp Ser (Oxf) ; (52): 545-6, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18776495

RESUMO

(-)-Neplanocin B, the natural isomer of a component of the neplanocin family was enantioselectively synthesized.


Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/química , Estereoisomerismo
18.
Nucleic Acids Symp Ser (Oxf) ; (52): 547-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18776496

RESUMO

Attempts for the synthesis of 2'-deoxy-2'-fluoro nucleoside derivative of 3'-C-methyluridine were reported. The corresponding parent nucleoside was chosen as the starting material. However, the 2'-deoxy-2'-fluoro nucleoside was not obtained. Nevertheless, the new and unexpected nucleoside derivatives obtained as well as some proposals of mechanism regarding their formation will be presented.


Assuntos
Uridina/análogos & derivados , Uridina/síntese química , Uridina/química
19.
Bioorg Med Chem ; 16(15): 7436-42, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18579389

RESUMO

2',3'-Dideoxy-3'-C-methyl nucleosides bearing the five naturally occurring nucleic acid bases were synthesized. Additionally, the 3'-deoxy-3'-C-methyl nucleoside analogues bearing 5-aminoimidazole-4-carboxamide as well as 1,2,4-triazole-3-carboxamide moieties were prepared. The synthesis of the corresponding 2',3'-dideoxy-3'-C-methyl triazole derivative was also accomplished. The dideoxynucleoside derivatives were prepared by radical deoxygenation from their 3'-deoxy-3'-C-methyl parent ribonucleosides. When evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
20.
Artigo em Inglês | MEDLINE | ID: mdl-18058547

RESUMO

The stereospecific synthesis of (-)-neplanocin F was achieved in 15 steps from 2,3-O-isopropylidene-D-1,4-ribonolactone. The synthetic methodology can give an access through appropriate modifications to new series of carbanucleosides.


Assuntos
Adenosina/análogos & derivados , Adenosina/síntese química , Adenosina/química , Métodos , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA