Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Nucleosides Nucleotides Nucleic Acids ; 20(4-7): 1299-302, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11563008

RESUMO

Chlorotrimethylsilane completely dealkylates phosphonate esters at elevated temperature in a sealed reaction vessel. These conditions are tolerated by a variety of functional groups and lead to high conversions of dimethyl, diethyl and diisopropyl phosphonates to their corresponding phosphonic acids.


Assuntos
Organofosfonatos/química , Fosfitos/química , Compostos de Trimetilsilil/química , Remoção de Radical Alquila
2.
J Med Chem ; 39(6): 1321-30, 1996 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-8632439

RESUMO

Pyranosyl nucleotide analogues have been designed so that the intramolecular base to phosphorus distance closely approximates that of natural nucleotides. This was achieved by attaching the phosphorus directly at the anomeric position and the base at the 4-position of the carbohydrate. A series of compounds incorporating natural bases and having this novel structure were made via a short synthesis starting from commercially available glycals. Addition of triisopropyl phosphite to the glycals furnished alpha- and beta-2-enopyranosylphosphonates which were then substituted with the heterocycle using Mitsunobu chemistry. Deprotection afforded the 2',3'-unsaturated isonucleotide analogue. In some cases the deprotection sequence induced double-bond migration leading to the 1',2'-unsaturated derivative. NMR spectroscopic structural analysis established an axial preference for the base and an equatorial preference for the beta-phosphorus which results in intramolecular base to phosphorus distances within 1 A of that of natural nucleotides. All of the deprotected compounds were screened for inhibition of HCMV, HSV-2, and HIV replication. Several compounds inhibited HCMV and HSV-2, the most potent of which was the unsaturated cytosine analogue 18 (HCMV IC50 = 10 microM, HSV-2 IC50 = 85 microM). None of the compounds were cytotoxic at the highest dose (1 mM) tested. None of the compounds were inhibitory to HIV.


Assuntos
Antivirais/síntese química , Nucleotídeos/síntese química , Antivirais/química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Nucleotídeos/farmacologia
4.
J Med Chem ; 37(4): 431-8, 1994 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-8120862

RESUMO

The three-dimensional structure of 4'-azidothymidine has been determined for the solid state and in solution. X-ray crystal analysis indicates the presence of two independent molecules (A and B) having the following conformational parameters: Phase angles, PA = 13.7 degrees, PB = 12.6 degrees (C3'-endo envelope); puckering amplitude psi mA = 32.4 degrees, psi mB = 37.2 degrees; glycosyl torsion angle chi A = -88.2 degrees, chi B = -71.2 degrees; 4'-5' torsion angle gamma A = 58.5 degrees, gamma B = 36.0 degrees. The solution conformation was determined from NMR coupling constants in D2O. Analysis using the computer programs PSEUROT and DAERM yielded phase angles (P) of 53.2 degrees (C4'-exo envelope) (major conformer) and 63 degrees (C4'-exo envelope), respectively, with corresponding puckering amplitudes (psi m) of 34.9 degrees and 45.8 degrees. A gated 13C NMR experiment was used to determine the 1H-13C vicinal coupling constants used to calculate the solution glycosyl torsion angle (chi) to be either -80 degrees or -160 degrees and a 4'-5' torsion angle, gamma, of ca. 180 degrees. These studies show that 4'-azidothymidine is conformationally exceptional among the antiretroviral nucleosides both as a solid and in solution. The C3'-endo (northern) conformation determined by X-ray crystallography is rare among HIV-inhibitory nucleosides which usually exist in the solid state in a southern conformation. The solution structure is even more peculiar in that it exists in the extremely rare 4'-exo envelope conformation.


Assuntos
Antivirais/química , Zidovudina/análogos & derivados , Antivirais/farmacologia , Cristalografia por Raios X , HIV/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estereoisomerismo , Zidovudina/química , Zidovudina/farmacologia
5.
J Med Chem ; 35(8): 1440-51, 1992 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-1573638

RESUMO

A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4'-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in suit epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoxy-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80 microM for 4'-azido-2'-deoxyuridine (6c) to 0.003 microM for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoxy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.


Assuntos
Antivirais/síntese química , HIV/efeitos dos fármacos , Nucleosídeos/síntese química , Linhagem Celular , Nucleosídeos/farmacologia , Relação Estrutura-Atividade
6.
J Biol Chem ; 267(1): 257-60, 1992 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-1730594

RESUMO

4'-Azidothymidine (ADRT) is a novel nucleoside analog, that selectively inhibits human immunodeficiency virus replication in human lymphocytes. Unlike the dideoxyribonucleoside analogs and 3'-azido-2',3'-dideoxythymidine (AZT), ADRT retains the 3'-hydroxy group. The pathways of ADRT metabolism were elucidated by determining: (i) the kinetics of the interactions of ADRT and its metabolites with enzymes of thymidine metabolic pathways, (ii) the pool sizes of phosphorylated metabolites, and (iii) the nature of ADRT incorporation into human DNA. ADRT is not a substrate for thymidine phosphorylase, but is metabolized by kinases. Thymidine kinase phosphorylates ADRT to ADRT monophosphate (ADRT-MP). For this enzyme, ADRT has a Ki value of 5.2 microM, in comparison to a Km value of 0.7 microM for thymidine. The Km value of ADRT toward thymidine kinase is 8.3 microM and the rate of ADRT phosphorylation is 1.4% that of thymidine phosphorylation. ADRT-MP has a low affinity toward thymidylate kinase (a Ki value of 28.9 microM versus a Km value of 0.56 microM for thymidylate), and toward thymidylate synthase (a Ki value of 180 microM versus a Km value of 8 microM for deoxyuridylate). The results suggest that ADRT can be activated effectively by cellular kinases without significant interference of normal thymidine metabolism. In cultured human lymphocytes (A3.01, H9, and U937 cells), ADRT was phosphorylated efficiently to ADRT 5'-triphosphate (ADRT-TP), which is the major metabolite of ADRT. The intracellular concentrations of ADRT-TP ranged from 1 to 3.3 microM after 24 h of incubation with 2 microM of ADRT and the half-life of ADRT-TP varied from 3 to 6 h. Although ADRT-TP is a poor competitive inhibitor against dTTP toward DNA polymerases alpha and beta with Ki values of 62.5 and 150 microM, respectively. ADRT-MP was found to be internally incorporated into cellular DNA. The extent of ADRT-MP substitution for dTMP in DNA was 1 in 6979 for A3.01 cells incubated with 2.9 microM ADRT for 24 h. Internal incorporation of ADRT-MP contrasts with the mechanism of other 2',3'-dideoxynucleoside analogs (i.e. AZT, ddC, ddI, d4T...), which are DNA chain terminators. This finding indicates that a 3'-deoxy structure in a nucleoside analog is not a prerequisite for anti-human immunodeficiency virus activity.


Assuntos
HIV/efeitos dos fármacos , Zidovudina/análogos & derivados , Linhagem Celular , DNA/metabolismo , HIV/fisiologia , Humanos , Cinética , Fosforilação , Especificidade por Substrato , Linfócitos T/microbiologia , Timidina/metabolismo , Timidina Quinase/metabolismo , Timidina Fosforilase/metabolismo , Replicação Viral/efeitos dos fármacos , Zidovudina/metabolismo , Zidovudina/farmacologia
7.
Antimicrob Agents Chemother ; 32(12): 1887-90, 1988 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2469388

RESUMO

Reverse transcriptase from the simian immunodeficiency virus (SIV) was found to have kinetic behavior similar to that of enzyme from the human immunodeficiency virus (HIV). Michaelis constants for the substrates TTP and dGTP and inhibition constants for the inhibitors 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2'-3'-dideoxyguanosine 5'-triphosphate were obtained for SIV reverse transcriptase and were found to be similar to the corresponding values for HIV reverse transcriptase. Thus, the interaction of SIV reverse transcriptase with nucleotide analogs appears to be indistinguishable from that of the HIV enzyme, suggesting that SIV/simian acquired immunodeficiency syndrome (SAIDS) is a potentially good model of AIDS.


Assuntos
HIV/enzimologia , Inibidores da Transcriptase Reversa , Vírus da Imunodeficiência Símia/enzimologia , Nucleotídeos de Desoxiguanina/farmacologia , Didesoxinucleotídeos , Humanos , Cinética , Nucleotídeos de Timina/farmacologia , Zidovudina/análogos & derivados , Zidovudina/farmacologia
8.
J Med Chem ; 31(9): 1798-804, 1988 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-2842505

RESUMO

New carbocyclic adenosine analogues substituted at the 6'-position with fluorine, hydroxyl, methylene, or hydroxymethyl have been synthesized as potential mechanism-based inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. The synthetic routes began with a functionalized (+/-)-azidocyclopentane 2, which was elaborated to the adenosine analogue, or with functionalized cyclopentane epoxides 11, 20, and 27, which were opened directly with adenine in the presence of base. The 6' alpha-fluoro, 6' beta-fluoro, and 6'-methylene carbocyclic adenosine analogues were potent inhibitors of AdoHcy hydrolase. None of the compounds displayed significant activity against herpes simplex virus type 1 or type 2, but several demonstrated potent inhibition of vaccinia virus replication.


Assuntos
Adenosina/análogos & derivados , Hidrolases/antagonistas & inibidores , Simplexvirus/efeitos dos fármacos , Vaccinia virus/efeitos dos fármacos , Adenosina/síntese química , Adenosina/farmacologia , Adenosil-Homocisteinase , Animais , Antivirais , Fenômenos Químicos , Química , Coelhos , Relação Estrutura-Atividade , Vaccinia virus/fisiologia , Replicação Viral/efeitos dos fármacos
9.
J Med Chem ; 29(12): 2445-50, 1986 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3023613

RESUMO

Since biologically active nucleoside 2',3'-dialdehydes exist as six-membered cyclic acetals (1) in solution, we have investigated the antiviral activity of some structurally similar 1,4-dioxane nucleoside analogues. By reacting 2',3'-seconucleoside tosylates with base, the guanine (10) and adenine (18) substituted (hydroxymethyl)dioxanes have been constructed. In addition, an unusual adenine-substituted divinyl ether (22) was synthesized via a base-catalyzed, double elimination of a 2',3'-di-O-tosyl-2',3'-secoadenosine. None of these compounds showed significant antiviral activity.


Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Divisão Celular , Linhagem Celular , Dioxanos/síntese química , Dioxanos/farmacologia , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Nucleosídeos/farmacologia , Vírus da Parainfluenza 3 Humana/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , Relação Estrutura-Atividade , Vaccinia virus/efeitos dos fármacos
10.
J Med Chem ; 29(5): 671-5, 1986 May.
Artigo em Inglês | MEDLINE | ID: mdl-3009811

RESUMO

A series of phosphate esters of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1) were synthesized and evaluated for antiherpes virus activity. The cyclic phosphate esters were made by a new, efficient method utilizing stannic chloride as a solubilizing agent. Monophosphate 2 and bisphosphate 4 showed comparable activity to DHPG and probably acted as prodrugs of DHPG. On the other hand, the cyclic phosphate of DHPG 3 was taken up by cells and bypassed the virus-specified thymidine kinase. As a result, 3 was active against DHPG-resistant HSV mutants that lacked the viral-specified thymidine kinase and was more toxic than DHPG to uninfected cells. The phosphonate 5, the least toxic of the derivatives tested, was only marginally active against HSV but showed substantial activity against human cytomegalovirus in vitro.


Assuntos
Aciclovir/análogos & derivados , Ganciclovir/análogos & derivados , Organofosfonatos , Fosfatos , Simplexvirus/efeitos dos fármacos , Aciclovir/administração & dosagem , Aciclovir/síntese química , Aciclovir/farmacologia , Administração Oral , Animais , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Feminino , Haplorrinos , Humanos , Técnicas In Vitro , Injeções Subcutâneas , Espectroscopia de Ressonância Magnética , Camundongos , Testes de Sensibilidade Microbiana , Simplexvirus/enzimologia , Timidina Quinase/metabolismo
11.
J Med Chem ; 29(2): 239-44, 1986 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-3950906

RESUMO

The syntheses of the title compounds were accomplished by Koenig-Knorr condensation of acylated furanoses with digitoxigenin followed by basic hydrolysis of protecting groups. In this manner the riboside, 5-amino-5-deoxyriboside, 3,6-anhydroglucoside, and 3,6-dideoxy-3,6-iminoglucoside of digitoxigenin were prepared. These compounds as well as several of the synthetic intermediates showed weak to moderate cardiotonic activity.


Assuntos
Glicosídeos Cardíacos/síntese química , Digitoxigenina/síntese química , Animais , Glicosídeos Cardíacos/farmacologia , Digitoxigenina/análogos & derivados , Digitoxigenina/farmacologia , Cobaias , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Relação Estrutura-Atividade
12.
J Biol Chem ; 257(22): 13390-7, 1982 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-7142154

RESUMO

Analogs of (A2'p)2A core and ppp(A2'p)2A were chemically synthesized and their susceptibility to phosphodiesterase degradation and ability to either activate an endonuclease or to inhibit cell growth were determined. The absence of the internal 3'-OH groups ((3'dA2'p)2A) resulted in a 5-fold increase in stability, but also in a 10-fold decrease in activity, as measured by (a) activation of an endonuclease in cell-free extracts and inhibition of protein synthesis in intact cells by the 5'-triphosphate species and (b) inhibition of DNA synthesis in synchronized cells by the core analogs. An uncharged derivative of this analog containing two methylphosphotriesters, although significantly more stable, was even less active. Additional deletion of the terminal 3'-OH ((3'd A2'p)23'dA) resulted in a further 6-fold increase in stability (30-fold overall increase in stability), as well as approximately a 2-fold increase in ability to inhibit cell growth, as compared to the natural 2'5' A core. The analog lacking a terminal 2'-OH as well as lacking the internal 3'-OH group ((3'dA2'p)22'dA) showed an overall 15-fold increased stability, yet showed very little activity in inhibiting cell growth. The most stable (120-fold increased overall stability) as well as most active analog was a xyloadenosine analog of 2'5' A core, (xyloA2'p)2xyloA. These results show that modification of the 3'-terminal OH appears to be most important in increasing 2'-5' A core stability as well as biological activity. However, the mechanism of cell growth inhibition by these 2'-5' A core analogs may involve pathways different from those utilized by the 2'-5' A-dependent endonuclease.


Assuntos
Nucleotídeos de Adenina/farmacologia , Oligonucleotídeos/farmacologia , Oligorribonucleotídeos/farmacologia , Nucleotídeos de Adenina/biossíntese , Animais , Bioensaio , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Estabilidade de Medicamentos , Células L/efeitos dos fármacos , Células L/metabolismo , Camundongos , Oligorribonucleotídeos/biossíntese , Biossíntese de Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA