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
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
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
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
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.