RESUMO
Novel L- and D-configuration 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine and their 5-fluoro analogues have been synthesized from 1-benzyloxy-2-propanone and L-ascorbic acid in eight steps and evaluated for biological activity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Animais , Antineoplásicos/síntese química , Antivirais/síntese química , Citidina/química , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia L1210 , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Various 2-halogen-substituted analogues (38, 39, 43 and 44), 3-halogen-substituted analogues (51 and 52), and 2',3'-dihalogen-substituted analogues (57-60) of 3-deazaadenosine and 3-halogen-substituted analogues (61 and 62) of 3-deazaguanosine have been synthesized as potential anticancer and/or antiviral agents. Among these compounds, 3-deaza-3-bromoguanosine (62) showed significant cytotoxicity against L1210, P388, CCRF-CEM and B16F10 cell lines in vitro, producing IC50 values of 3, 7, 9 and 7 microM, respectively. Several 3-deazaadenosine analogues (38, 51, 57 and 59) showed moderate to weak activity against hepatitis B virus.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Guanosina/análogos & derivados , Guanosina/síntese química , Guanosina/farmacologia , Animais , Antineoplásicos/química , Bioquímica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Guanosina/química , HIV-1/efeitos dos fármacos , Halogênios/química , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia L1210 , Testes de Sensibilidade Microbiana , Células Tumorais CultivadasRESUMO
A nonnaturally occurring L-configuration nucleoside analog, L-beta-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (L-BVOddU) selectively inhibited varicella-zoster virus growth in human embryonic lung (HEL) 299 cell culture with an EC(50) of 0.055 microM, whereas no inhibition of CEM and HEL 299 cell growth or mitochondrial DNA synthesis was observed at concentrations up to 200 microM. L-BVOddU was phosphorylated by viral thymidine kinase but not by human cytosolic thymidine kinase, and the antiviral activity of this compound is dependent on the viral thymidine kinase. Unlike other D-configuration bromovinyl deoxyuridine analogs, such as E-5-(2-bromovinyl)-2'-deoxyuridine and 1-beta-arabinofuranosyl-E-5-(2-bromovinyl)uracil, this compound was metabolized only to its monophosphate metabolite. The di- or triphosphate metabolites were not detected. This suggested that the inhibitory mechanism may be unique and different from other anti-herpesvirus nucleoside analogs.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 3/efeitos dos fármacos , Nucleosídeos/farmacologia , Pró-Fármacos/metabolismo , Timidina Quinase/metabolismo , Uracila/farmacologia , Aciclovir/metabolismo , Aciclovir/farmacologia , Antivirais/metabolismo , Células Cultivadas , Herpesvirus Humano 3/enzimologia , Humanos , Cinética , Nucleosídeos/metabolismo , Fosforilação , Uracila/análogos & derivados , Uracila/metabolismoRESUMO
Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.
Assuntos
Citosina/análogos & derivados , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Timina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Divisão Celular/efeitos dos fármacos , Citosina/síntese química , Citosina/farmacologia , Dioxolanos/síntese química , Dioxolanos/farmacologia , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Timina/síntese química , Timina/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Compostos Aza/síntese química , Compostos Heterocíclicos/química , Nucleosídeos de Pirimidina/síntese química , Tiofenos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Azauridina/química , Glicosilação , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Células Tumorais CultivadasAssuntos
Antivirais/síntese química , Antivirais/farmacologia , Didesoxinucleosídeos/síntese química , Didesoxinucleosídeos/farmacologia , Flúor/química , Antivirais/química , Linhagem Celular , Didesoxinucleosídeos/química , HIV/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , HumanosRESUMO
The synthesis of beta-D-Fd4C was achieved in a stereoselective fashion from D-xylose. The antiviral activity and cytotoxicity of beta-D-Fd4C was compared with that of beta-L-Fd4C and 3TC (Lamivudine). Of the three agents compared, beta-L-Fd4C was found to be the most potent antiviral agent.
Assuntos
Antivirais/síntese química , Zalcitabina/análogos & derivados , Animais , Antivirais/farmacologia , HIV/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Camundongos , Ratos , Estereoisomerismo , Zalcitabina/síntese química , Zalcitabina/farmacologiaRESUMO
The combination of L(-)-2',3'-dideoxy-3'-thiacytidine (L(-)SddC, 3TC), L(-)-2',3'-dideoxy-5-fluorocytidine (L(-)FddC), or L(-)-2',3'-dideoxy-5-fluoro-3'-thiacytidine (L(-)(FTC) with 3'-azido-3'-deoxythymidine (AZT) synergistically inhibited replication of human immunodeficiency virus (HIV) in vitro. Similar synergistic activity was also obtained when these compounds were used in combination with 2',3'-didehyro-2',3'-dideoxythymidine (D4T). In terms of 2',3'- dideoxyinosime (ddI) and 2',3'-dideoxycytidine (ddC), only additive anti-HIV activity was observed. None of the beta-L(-) nucleoside analogues had additive toxicity in cell culture, and they could protect against the delayed mitochondrial toxicity associated with AZT, D4T, ddC, and ddI in drug-treated cells. Thus, combinations of beta-L(-) nucleoside analogues with any of the approved anti-HIV drugs could have a potentially beneficial outcome.