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1.
ACS Med Chem Lett ; 12(4): 510-517, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33854700

RESUMO

Great pioneers of nucleic acid chemistry had elucidated nucleic acid functions and structures and developed various antiviral modified nucleoside drugs. It is possible in theory that antiviral modified nucleosides prevent viral replication by inhibiting viral polymerases. However, biological phenomena far exceed our predictions at times. We describe the characteristics of the approved antiviral modified nucleosides from an organic chemistry perspective. Also, based on our experiences and findings through the development of the HIV-1 reverse-transcriptase inhibitor "Islatravir", we provide the practical and approximate guidelines for the drug development of antiviral modified nucleosides against COVID-19.

2.
Biosci Biotechnol Biochem ; 84(2): 217-227, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31589093

RESUMO

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) and 4'-ethynyl-2'-deoxyadenosine (EdA) are nucleoside analogues which inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. EdAP, a cyclosaligenyl (cycloSal) phosphate derivative of EdA, inhibits the replication of the influenza A virus. The common structural feature of these compounds is the ethynyl group at the 4'-position. In this study, these nucleoside analogues were prepared by a common synthetic strategy starting from the known 1,2-di-O-acetyl-D-ribofuranose. Biological evaluation of EdAP revealed that this compound reduced hepatitis B virus (HBV) replication dose-dependently without cytotoxicity against host cells tested in this study.


Assuntos
Antivirais/síntese química , Nucleotídeos de Desoxiadenina/síntese química , Desoxiadenosinas/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Linhagem Celular , Nucleotídeos de Desoxiadenina/farmacologia , Desoxiadenosinas/farmacologia , Vírus da Hepatite B/fisiologia , Humanos
3.
Molecules ; 24(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319565

RESUMO

Influenza A viruses leading to infectious respiratory diseases cause seasonal epidemics and sometimes periodic global pandemics. Viral polymerase is an attractive target in inhibiting viral replication, and 4'-ethynyladenosine, which has been reported as a highly potent anti-human immunodeficiency virus (HIV) nucleoside derivative, can work as an anti-influenza agent. Herein, we designed and synthesized a 4'-ethynyl-2'-deoxyadenosine 5'-monophosphate analog called EdAP (5). EdAP exhibited potent inhibition against influenza virus multiplication in Madin-Darby canine kidney (MDCK) cells transfected with human α2-6-sialyltransferase (SIAT1) cDNA and did not show any toxicity toward the cells. Surprisingly, this DNA-type nucleic acid analog (5) inhibited the multiplication of influenza A virus, although influenza virus is an RNA virus that does not generate DNA.


Assuntos
Antivirais/farmacologia , Nucleotídeos de Desoxiadenina/farmacologia , Desoxiadenosinas/síntese química , Influenza Humana/tratamento farmacológico , Animais , Antivirais/síntese química , Antivirais/química , Nucleotídeos de Desoxiadenina/síntese química , Nucleotídeos de Desoxiadenina/química , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Cães , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Replicação Viral/efeitos dos fármacos
4.
Sci Rep ; 7(1): 8239, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28811524

RESUMO

The design, synthesis and application of N-acetylneuraminic acid-derived compounds bearing anomeric sulfo functional groups are described. These novel compounds, which we refer to as sulfo-sialic acid analogues, include 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid and its 4-deoxy-3,4-dehydrogenated pseudoglycal. While 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid contains no further modifications of the 2-deoxy-pyranose ring, it is still a more potent inhibitor of avian-origin H5N1 neuraminidase (NA) and drug-resistant His275Tyr NA as compared to the oxocarbenium ion transition state analogue 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. The sulfo-sialic acid analogues described in this report are also more potent inhibitors of influenza NA (up to 40-fold) and bacterial NA (up to 8.5-fold) relative to the corresponding anomeric phosphonic acids. These results confirm that this novel anomeric sulfo modification offers great potential to improve the potency of next-generation NA inhibitors including covalent inhibitors.


Assuntos
Inibidores Enzimáticos/síntese química , Ácidos Siálicos/síntese química , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Ligação Proteica , Ácidos Siálicos/farmacologia , Relação Estrutura-Atividade
5.
Org Lett ; 17(4): 828-31, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25642994

RESUMO

An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-D-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4' position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2'-deoxygenation of a ribonucleoside intermediate.


Assuntos
Aldeídos/química , Desoxiadenosinas/síntese química , Cetoses/química , Ribonucleosídeos/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Desoxiadenosinas/química , Estrutura Molecular , Estereoisomerismo
6.
J Virol ; 87(18): 10016-24, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23824808

RESUMO

The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 (H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Neuraminidase/química , Neuraminidase/metabolismo , Oseltamivir/farmacologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Substituição de Aminoácidos , Cristalografia por Raios X , Humanos , Mutação de Sentido Incorreto , Neuraminidase/genética , Conformação Proteica , Proteínas Virais/genética
7.
Biosci Biotechnol Biochem ; 76(6): 1219-25, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22790950

RESUMO

EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), a nucleoside reverse transcriptase inhibitor with extremely potent anti-HIV activity, was concisely synthesized from (R)-glyceraldehyde acetonide in an 18% overall yield by a 12-step sequence involving highly diastereoselective ethynylation of an α-alkoxy ketone intermediate. The present synthesis is superior, both in overall yield and in the number of steps, to the previous one which required 18 steps from an expensive starting material and resulted in a modest overall yield of 2.5%.


Assuntos
Fármacos Anti-HIV/síntese química , Desoxiadenosinas/síntese química , Gliceraldeído/análogos & derivados , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Gliceraldeído/química , HIV/enzimologia , Transcriptase Reversa do HIV/química , Humanos , Espectroscopia de Ressonância Magnética , Estereoisomerismo
8.
Org Lett ; 13(19): 5264-6, 2011 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-21888325

RESUMO

A concise enantioselective total synthesis of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), an extremely potent anti-HIV agent, has been accomplished from (R)-glyceraldehyde acetonide in 18% overall yield by a 12-step sequence involving a highly diastereoselective ethynylation of an α-alkoxy ketone intermediate.


Assuntos
Fármacos Anti-HIV/síntese química , Desoxiadenosinas/síntese química , Estrutura Molecular , Estereoisomerismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-21422739

RESUMO

An idea to use 4'-C-substituted-2'-deoxynucleoside derivatives was proposed based on a working hypothesis to solve the problems of existing acquired immune deficiency syndrome chemotherapy (highly active antiretroviral therapy). Subsequent studies have successfully proved the validity of the idea and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine and 2'-deoxy-4'-C-ethynyl-2-chloroadenosine, nucleoside reverse transcriptase inhibitors, which have supremely high activity against all human immunodeficiency viruses including multidrug-resistant HIV and low toxicity.


Assuntos
Descoberta de Drogas/métodos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , HIV/efeitos dos fármacos , Mutação/efeitos dos fármacos , Nucleosídeos/farmacologia , Nucleosídeos/toxicidade , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , HIV/genética , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Camundongos , Inibidores da Síntese de Ácido Nucleico , Nucleosídeos/efeitos adversos , Nucleosídeos/química , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
11.
Nucleic Acids Symp Ser (Oxf) ; (52): 631-2, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18776538

RESUMO

The structure of modified nucleosides expected to be highly anti-viral active and lowly toxic is proposed.


Assuntos
Antivirais/química , Nucleosídeos/química , Nucleosídeos/farmacologia , Antivirais/farmacologia , Antivirais/toxicidade , Nucleosídeos/toxicidade
12.
Chem Pharm Bull (Tokyo) ; 56(6): 861-3, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18520097

RESUMO

A new unsaturated fatty acid with unique vicinal dimethyl branches was isolated from the Okinawan soft coral of the genus Sinularia. The structure of the compound was determined based on the results of spectroscopic analysis and chemical conversion. The absolute configuration was deduced by applying the Ohrui-Akasaka method.


Assuntos
Antozoários/química , Ácidos Graxos Insaturados/química , Animais , Cromatografia Líquida de Alta Pressão , Ácidos Graxos Insaturados/isolamento & purificação , Hidrazonas/química , Espectroscopia de Ressonância Magnética , Metanol , Conformação Molecular , Solventes , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho
13.
Anal Sci ; 24(1): 31-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18187847

RESUMO

The development of highly potent chiral discrimination methods that solve the problems of the diastereomer method is described. Explaining the significant results of separations of diastereomers having chiral centers separated by 13 - 27 bonds with reversed-phase HPLC was hitherto impossible. To attract more scientific interest toward the mechanism of the separation, the author proposes a hypothesis, Induced Chiral Fields, that the achiral reversed phases can provide chiral fields depending on the structures of the substrates.


Assuntos
Estereoisomerismo , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Corantes Fluorescentes , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Conformação Molecular
14.
Nucleosides Nucleotides Nucleic Acids ; 26(10-12): 1543-6, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18066823

RESUMO

Working hypotheses to solve the critical problems of the existing highly active anti-retroviral therapy were proposed. The study based on the hypotheses proved the validity of the hypotheses and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, with highly potent activity against all HIV-1, very favorable toxic profiles, and stability in plasma. The nucleoside will prevent or delay the emergence of drug-resistant HIV-1 variants and be an ideal therapeutic agent for both HIV-1 and HBV infections.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Animais , Fármacos Anti-HIV/farmacocinética , Desoxiadenosinas/farmacocinética , Humanos , Camundongos , Relação Estrutura-Atividade
15.
Anal Sci ; 23(3): 311-5, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17372374

RESUMO

2-(2,3-anthracenedicarboximido)cyclohexane derivatives (AC) have been known as the evolutionary diastereomerizing reagents for enantiomer discrimination in HPLC with ODS. However, a substantial separation of diastereomers can be observed only at lower temperatures, such as -40 degrees C. Therefore, in this work, poly(octadecyl acrylate)-grafted silica, ODAn was applied as an alternative stationary phase to ODS for the separation of AC-derived diastereomers. As a result, complete separation was achieved even under the conventional condition: for example, methanol as the mobile phase and 0 degrees C as the column temperature. An investigation on the temperature dependency of the selectivity demonstrated that ODAn shows a remarkable increase in selectivity at temperatures below 30 degrees C, which almost agreed with the peak-top temperature of the endothermic peak in a DSC thermogram for ODA35 immersed in a mobile phase. The better separation would be derived from a highly ordered structure of ODAn and a carbonyl-pi interaction with AC-derived diastereomers.

16.
Proc Jpn Acad Ser B Phys Biol Sci ; 83(5): 127-35, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24019591

RESUMO

The development of highly potent chiral discrimination methods that solve the problems of the diastereomer method, in which it is impossible to discriminate the diastereomers having chiral centers separated by more than four bonds, is described. On the basis of the results obtained, a new hypothesis, Induced Chiral Fields that the achiral reversed phase can provide chiral fields depending on the structures of the eluents, is proposed to explain the significant results of separation of the diastereomers derived from newly developed chiral and fluorescent labeling reagents and optical isomers by reversed-phase HPLC, which was hitherto impossible.

17.
Artigo em Inglês | MEDLINE | ID: mdl-17150787

RESUMO

A working hypothesis to solve the critical problems of existing HAART was proposed. The study based on the hypothesis proved the validity of the hypothesis and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoro-adenosine (4'Ed2FA), a nucleoside reverse transcriptase inhibitor (NRTI) with highly potent activity against all HIV-1 strains, very favourable toxic profiles, and stability in plasma.


Assuntos
Fármacos Anti-HIV/farmacologia , Desoxiadenosinas/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/toxicidade , Desoxiadenosinas/sangue , Desoxiadenosinas/toxicidade , Estabilidade de Medicamentos , Camundongos , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/toxicidade
18.
J Sep Sci ; 29(10): 1390-8, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16894783

RESUMO

Enantiomeric discrimination of chiral primary amines was performed by both reversed-phase HPLC and normal-phase HPLC after labeling with a chiral fluorescent derivatization reagent, (1R,2R)- and (1S,2S)-trans-2-(2,3-anthracenedicarboximido)cyclohexanecarbonyl chloride. Use of HPLC permits separation of diastereomeric derivatives of amines up to C30 which have a primary amino group at the middle of the alkyl chain. The derivatives of primary amines having an anteiso alkyl chain, which has a chiral branched-methyl at the n-3 position of the alkyl chain, were also separated by HPLC, and it was also possible to separate niphatesine D by reversed-phase HPLC after derivatization.


Assuntos
Aminas/química , Antracenos/química , Cloretos/química , Cromatografia Líquida de Alta Pressão/métodos , Cicloexanos/química , Estereoisomerismo , Alcanos/química , Cromatografia Líquida de Alta Pressão/instrumentação , Conformação Molecular , Estrutura Molecular , Piridinas/química
19.
Biosci Biotechnol Biochem ; 70(6): 1517-20, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16794339

RESUMO

The chemiluminescence of gallic acid by hydrogen peroxide had completely inhibited by the presence of ascorbate. After ascorbate had disappeared by oxidation, chemiluminescence returned. The concentration of gallic acid was virtually unchanged by presence of ascorbate, but started to decrease after the disappearance of ascorbate. This might be attributable to the rapid reduction of quinone, which was the first product of the chemiluminescence reactions, to gallic acid by ascorbate or the donation of proton to the phenoxy radical from ascorbate to stop the chemiluminescence reaction at the first stage. The effects of ascorbate on the chemiluminescence of other polyphenols depended on their oxidation rate.


Assuntos
Ácido Ascórbico/farmacologia , Flavonoides/química , Fenóis/química , Ácido Gálico/farmacologia , Medições Luminescentes , Polifenóis
20.
Chem Rec ; 6(3): 133-43, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16795005

RESUMO

An idea to use 4'-C-substituted-2'-deoxynucleoside derivatives was proposed based on a working hypothesis to solve the problems of existing acquired immune deficiency syndrome chemotherapy (highly active antiretroviral therapy). Subsequent studies have successfully proved the validity of the idea and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, which is highly potent to all human immunodeficiency viruses type 1 (HIV-1s) including multidrug-resistant HIV-1 and has a low toxicity.


Assuntos
Desoxiadenosinas/farmacologia , Desoxiadenosinas/toxicidade , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/toxicidade , Animais , Desoxiadenosinas/química , Farmacorresistência Viral , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Testes de Toxicidade Aguda
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