RESUMO
We have synthesized a range of gelators based on the nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and transmission electron microscopy. Growth inhibition studies of gemcitabine derivatives confirmed the feasibility of these compounds as novel treatments, indicating the potential of nucleoside-based gelators for localized drug delivery.
Assuntos
Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos , Géis/farmacologia , Lamivudina/farmacologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/síntese química , Desoxicitidina/química , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Géis/síntese química , Géis/química , Humanos , Lamivudina/administração & dosagem , Lamivudina/síntese química , Lamivudina/química , Microscopia Eletrônica de Transmissão , Reologia , Substâncias Viscoelásticas/síntese química , Substâncias Viscoelásticas/química , Substâncias Viscoelásticas/farmacologia , GencitabinaRESUMO
We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from l-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the novel catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process.
Assuntos
Lamivudina/química , Lamivudina/síntese química , Boroidretos/química , Técnicas de Química Sintética , Glicosilação , Tiofenos/químicaRESUMO
BACKGROUND: Antiretroviral drug discovery and formulation design will facilitate viral clearance in infectious reservoirs. Although progress has been realized for selected hydrophobic integrase and nonnucleoside reverse transcriptase inhibitors, limited success has been seen to date with hydrophilic nucleosides. To overcome these limitations, hydrophobic long-acting drug nanoparticles were created for the commonly used nucleoside reverse transcriptase inhibitor, lamivudine (2',3'-dideoxy-3'-thiacytidine, 3TC). METHODS: A 2-step synthesis created a slow-release long-acting hydrophobic 3TC. Conjugation of 3TC to a fatty acid created a myristoylated prodrug which was encased into a folate-decorated poloxamer 407. Both in vitro antiretroviral efficacy in human monocyte-derived macrophages and pharmacokinetic profiles in mice were evaluated for the decorated nanoformulated drug. RESULTS: A stable drug formulation was produced by poloxamer encasement that improved monocyte-macrophage uptake, antiretroviral activities, and drug pharmacokinetic profiles over native drug formulations. CONCLUSIONS: Sustained release of long-acting antiretroviral therapy is a new therapeutic frontier for HIV/AIDS. 3TC depot formation in monocyte-derived macrophages can be facilitated through stable subcellular internalization and slow drug release.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/farmacocinética , Lamivudina/farmacologia , Lamivudina/farmacocinética , Poloxâmero/síntese química , Animais , Fármacos Anti-HIV/síntese química , Preparações de Ação Retardada/síntese química , Portadores de Fármacos/síntese química , Humanos , Lamivudina/síntese química , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB CRESUMO
The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).
Assuntos
Antivirais/química , Antivirais/síntese química , Radioisótopos do Iodo/química , Lamivudina/química , Lamivudina/síntese química , Ácido Ursodesoxicólico/química , Técnicas de Química Sintética , RadioquímicaRESUMO
The origin of enantioenrichment in enzyme-catalyzed dynamic kinetic resolution of 1,3-oxathiolane derivatives, key intermediates for asymmetric lamivudine synthesis, was elucidated. The chirality control could be determined by chiral HPLC and NOE NMR spectroscopy using a modified 1,3-oxathiolane compound obtained through enzyme-catalyzed selective hydrolysis. Solvent-dependent stereoselectivity was observed under biphasic conditions using different organic solvents with phosphate buffer.
Assuntos
Lamivudina/síntese química , Tiofenos/química , Catálise , Cromatografia Líquida de Alta Pressão , Cinética , Lamivudina/química , Espectroscopia de Ressonância Magnética , Fenômenos de Química Orgânica , Solventes/química , EstereoisomerismoRESUMO
The combined use of silanes (Et3SiH or PMHS) and I2 as novel N-glycosidation reagents for the synthesis of bioactive oxathiolane nucleosides 3TC and FTC is reported. Both systems (working as anhydrous HI sources) were devised to act as substrate activators and N-glycosidation promoters. Excellent results in terms of chemical efficiency and stereoselectivity of the reactions were obtained; surprisingly, the nature of the protective group at the N4 position of (fluoro)cytosine additionally influenced the stereochemical reaction outcome.
Assuntos
Desoxicitidina/análogos & derivados , Lamivudina/síntese química , Desoxicitidina/síntese química , Desoxicitidina/química , Emtricitabina , Glicosilação , Lamivudina/química , Estrutura Molecular , EstereoisomerismoRESUMO
[Formula: see text]New phosphonate homodimers of 3'-azido-3'-deoxythymidine (AZT) and a phosphonate heterodimer of ß-L-2',3'-dideoxy-3'-thiacytidine (3TC) and AZT were synthesized. The compounds demonstrated moderate anti-HIV activity. Stability of the compounds in human blood serum was studied. A correlation between anti-HIV activity and stability was defined.
Assuntos
Lamivudina/análogos & derivados , Lamivudina/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Estabilidade de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Hidrólise , Lamivudina/farmacocinética , Lamivudina/farmacologia , Testes de Sensibilidade Microbiana , Ressonância Magnética Nuclear Biomolecular , Pró-Fármacos/farmacologia , Zidovudina/farmacocinética , Zidovudina/farmacologiaRESUMO
The anti-HIV nucleoside lamivudine was asymmetrically synthesized in only three steps via a novel surfactant-treated subtilisin Carlsberg-catalyzed dynamic kinetic resolution protocol. The enantiomer of lamivudine could also be accessed using the same protocol catalyzed by Candida antarctica lipase B.
Assuntos
Fármacos Anti-HIV/síntese química , Proteínas Fúngicas/metabolismo , Lamivudina/síntese química , Lipase/metabolismo , Fármacos Anti-HIV/química , Técnicas de Química Sintética , Enzimas , Cinética , Lamivudina/química , EstereoisomerismoRESUMO
A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 µM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29.4 µM) and 5'-O-N(4)-disubstituted (EC(50) = 72.6 to >154.0 µM) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC(50) = 0.2-0.9 µM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC(50) = 11.4-32.7 µM). The EC(90) values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.
Assuntos
Fármacos Anti-HIV/síntese química , Azidas/síntese química , Citidina/análogos & derivados , Ácidos Graxos/síntese química , HIV-1/efeitos dos fármacos , Lamivudina/análogos & derivados , Lamivudina/síntese química , Fármacos Anti-HIV/farmacologia , Azidas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citidina/síntese química , Citidina/farmacologia , Farmacorresistência Viral Múltipla , Ésteres , Ácidos Graxos/farmacologia , HIV-1/isolamento & purificação , Humanos , Hidrólise , Lamivudina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2',3'-dideoxycytidine (ddC; zalcitabine), 2',3'-dideoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Ensaios Clínicos como Assunto , Desoxicitidina/síntese química , Desoxicitidina/química , Emtricitabina , Infecções por HIV/virologia , Humanos , Lamivudina/síntese química , Lamivudina/química , Lamivudina/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Resultado do Tratamento , Zalcitabina/síntese química , Zalcitabina/química , Zalcitabina/farmacologiaRESUMO
In order to find antiviral compounds with novel structures, geldanamycin and lamivudine with different antiviral mechanisms were conjunctively synthesized to acquire a new compound TC-GM, and the antiviral activity of TC-GM was measured. The antiviral activity against HIV-1 was examined by p24 antigen ELISA kit. The activity against HBV was examined by dotblot. The activity against HSV and CoxB virus was examined by CPE. TC-GM exhibited broad-spectrum antiviral activities similarly like geldanamycin. TC-GM inhibited the replication of different viruses, including HIV-1, HBV, HSV 1 and 2, CoxB6. TC-GM showed more potent inhibitory activity against HIV-1 and HBV than other detected virus.
Assuntos
Fármacos Anti-HIV/síntese química , Antivirais/síntese química , Benzoquinonas/síntese química , Lactamas Macrocíclicas/síntese química , Lamivudina/síntese química , Replicação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Antivirais/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Enterovirus Humano B/efeitos dos fármacos , Enterovirus Humano B/fisiologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/fisiologia , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Lamivudina/química , Lamivudina/farmacologia , Células Madin Darby de Rim Canino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Células VeroRESUMO
The objective of this study was to determine the in vitro transdermal permeation through the human stratum corneum (SC) of the antiretroviral (ARV) drug lamivudine (3TC) (1) and its synthesised methoxypoly(ethylene glycol) (MPEG) carbamates and carbonates in phosphate buffer solution and with the use of Pheroid as delivery system and to establish a relationship, if any, with selected physicochemical properties. The synthesis and in vitro human skin permeation flux of three N4-methoxypoly(ethylene glycol) carbamates (3)-(5) and three 6'-O-methoxypoly(ethylene glycol) carbonates (6)-(8) of lamivudine are reported. The derivatives were synthesised in a two-step process by coupling activated MPEG oligomers of various chain lengths to either the 4-amino or 6'-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increases as the MPEG chain lengthens while the solubility in octanol (lipophilicity) remained almost constant. Regardless of the mechanism of diffusion viz. passive (in PBS) or use of enhancer (Pheroid), no derivative penetrate the skin better than the parent drug itself. The use of Pheroid even appeared to significantly retard the skin permeation.
Assuntos
Carbamatos/química , Carbonatos/química , Lamivudina/síntese química , Lamivudina/farmacocinética , Polietilenoglicóis/química , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Feminino , Humanos , Lamivudina/análogos & derivados , Estrutura Molecular , Pele/química , Pele/efeitos dos fármacos , Testes Cutâneos , Solubilidade , Estereoisomerismo , Distribuição TecidualRESUMO
We report here the synthesis of a novel series of 5'-O-carbonates of 3TC, using different aliphatic alcohols and N,N-carbonyldiimidazol. Its antiviral activity was determined in peripheral blood mononuclear cells (PBMCs) showing some carbonate derivatives with an activity similar to or better than 3TC, except 3TC-Metha and 3TC-2Pro with less activity. In vitro assays in PBMCs have demonstrated that cytotoxicity increases as the carbon chain length of the alcohol moiety increases, showing compounds with a normal chain length of n=2-5 good selective index, compared to the parent drug. Thus, this work is an important contribution leading to the suppression of HIV replication.
Assuntos
Fármacos Anti-HIV/síntese química , Lamivudina/análogos & derivados , Pró-Fármacos/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/toxicidade , Células Sanguíneas/efeitos dos fármacos , Carbonatos/química , Humanos , Lamivudina/síntese química , Lamivudina/toxicidade , Pró-Fármacos/química , Pró-Fármacos/toxicidade , Replicação Viral/efeitos dos fármacosRESUMO
Novel iso D-2',3'-dideoxythianucleoside derivatives 1-3 were designed and asymmetrically synthesized to search for new anti-HIV agents. Final compounds 1-3 were evaluated against a variety of viruses including HIV-1 and 2. Only cytosine analog 3 showed a potent anti-VSV activity (EC(50) = 9.43 microg/mL). This result implies that iso 2',3'-dideoxy sugar templates might play a role of a sugar surrogate of nucleosides for the development of anti-RNA virus agent.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Lamivudina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Células HeLa , Humanos , Lamivudina/síntese química , Lamivudina/química , Lamivudina/farmacologia , Testes de Sensibilidade Microbiana , Estereoisomerismo , Células Vero , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacosRESUMO
Homo- and heterodimers of nucleoside/nucleotide analogues as reverse transcriptase inhibitors are effective on HIV-1-infected human monocyte-derived macrophages (M/M) compared to the single drugs or their combination. Since the combined treatment of lamivudine (3TC) and tenofovir ((R)PMPA) has an antiretroviral efficacy and a synergic effect respect to separate drugs, the heterodinucleotide 3TCpPMPA was synthesized. A single administration of the dimer as free drug or 3TCpPMPA-loaded RBC selectively targeted to M/M was able to almost completely protect macrophages from "de novo" infection.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Lamivudina/análogos & derivados , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adenina/síntese química , Adenina/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Eritrócitos/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Técnicas In Vitro , Lamivudina/administração & dosagem , Lamivudina/síntese química , Lamivudina/química , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Organofosfonatos/síntese química , Organofosfonatos/química , Tenofovir , Replicação Viral/efeitos dos fármacosRESUMO
The synthesis of a novel series of lamivudine prodrugs involving N4-substitution with isatin derivatives is described. The in-vitro antiretroviral activities indicated that compound 3b was found to be equipotent to lamivudine with EC50 of 0.0742+/-0.04 microM. Lamivudine prodrugs bearing fluoroquinoles antibacterial showed 92-100% inhibition against Mycobacterium tuberculosis strain H37Rv at 6.25 microg ml(-1). At pH 7.4, 37 degrees C, the hydrolytic t(1/2) ranged between 120 and 240 min.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Lamivudina/síntese química , Lamivudina/farmacologia , Fármacos Anti-HIV/química , Antituberculosos/química , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/análogos & derivados , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-AtividadeRESUMO
New formamidine-3TC (3TC = 2',3'-dideoxy-3'-thiacytidine) analogues have been synthesized through various methods, and their antiviral activities (HIV, HBV) have been evaluated in vitro. Anti-HIV-1 in acutely infected MT-4 cells and peripheral blood monocellular cells (PBMCs) showed that compounds substituted by N,N-diarylformamidine side chains at the 4-N nucleic base position (compounds 3 and 8-11) had at least equivalent anti-HIV activity as 3TC (EC50 = 0.5 and 11.6 microM, respectively). Moreover, the newly synthesized compounds demonstrated higher anti-HBV activity (EC50 ranging from 0.01 to 0.05 microM) compared to the parent nucleoside 3TC (EC50 = 0.2 microM). It should be underlined that these new promising derivatives inhibited HIV in cells of a macrophage lineage, which are known to be cellular reservoir for HIV. These results were particularly of interest, since the antiviral activities appeared not to be mediated through the formamidine bond hydrolysis and consequently the release of free 3TC. These new analogue series were found to be highly stable to hydrolysis even after prolonged incubation in different biological media (t(1/2) ranged from 48 to 120 h). This enzymatic stability, coupled to the fact that no delay in the antiviral response was observed compared to the free 3TC antiviral response, suggest that this new N,N-diarylformamidine nucleoside series should not be considered as classical prodrugs.
Assuntos
Amidinas/síntese química , Antivirais/síntese química , Lamivudina/análogos & derivados , Lamivudina/síntese química , Amidinas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/farmacologia , Extratos Celulares , Linhagem Celular , Meios de Cultura , Estabilidade de Medicamentos , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Hidrólise , Técnicas In Vitro , Lamivudina/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/virologia , Relação Estrutura-AtividadeRESUMO
A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.
Assuntos
Fármacos Anti-HIV/síntese química , Lamivudina/análogos & derivados , Lamivudina/síntese química , Pró-Fármacos/síntese química , Fármacos Anti-HIV/farmacologia , Diaminas/química , Humanos , Lamivudina/farmacologia , Macrófagos/metabolismo , Espectrometria de Massas , Pró-Fármacos/farmacologia , Células Tumorais CultivadasRESUMO
The syntheses and biological evaluation of polyaminated 2',3'-dideoxy-3'-thiacytidine have been performed. A new lead was found to increase the in vitro antiviral potency (syncitia formation on MT-4 cell line) of two order magnitude greater than the parent nucleoside drug. Moreover, the in vitro activity on HIV macrophages was found to be more than 3 log greater than the activity of the parent drug 1.