RESUMO
Supramolecular construction of a targeted and stimuli-responsive drug delivery system is still a challenging task. Herein, GSH-responsive supramolecular prodrug nanoparticles were constructed by the host-guest complexation between a ß-d-galactose-functionalized water-soluble pillar[5]arene (GalP5) and a disulfide bond containing camptothecin prodrug (G). The obtained prodrug nanoparticles were stable under physiological conditions, whereas efficient drug release was triggered in a simulated tumor environment with high GSH concentration. In vitro studies revealed that these prodrug nanoparticles preferentially entered asialoglycoprotein receptor-overexpressing HepG2 cells due to the active targeting effect of galactose units. This active targeting effect resulted in the maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells.
Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Compostos Macrocíclicos/farmacologia , Nanopartículas/química , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Receptor de Asialoglicoproteína/metabolismo , Camptotecina/síntese química , Camptotecina/toxicidade , Bovinos , Linhagem Celular Tumoral , Reação de Cicloadição , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Galactosídeos/síntese química , Galactosídeos/química , Galactosídeos/farmacologia , Galactosídeos/toxicidade , Glutationa , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/toxicidade , Nanopartículas/toxicidade , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/toxicidadeRESUMO
Two fluorescent galactofuranosides were synthesized and their biological activities evaluated on non-infected and Leishmania infected macrophages. Both tagged scaffolds were able to penetrate macrophages. Compared to the activity of the parent octyl galactofuranoside used as a reference, the fluorescein-conjugate showed altered biological properties while the rhodamine 6G one synergistically acted with the lipid chain to significantly increase antiparasitic activity.
Assuntos
Antiprotozoários/farmacologia , Fluoresceínas/farmacologia , Corantes Fluorescentes/farmacologia , Galactosídeos/farmacologia , Rodaminas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/toxicidade , Fluoresceínas/síntese química , Fluoresceínas/toxicidade , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Galactosídeos/síntese química , Galactosídeos/toxicidade , Humanos , Leishmania donovani/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Rodaminas/síntese química , Rodaminas/toxicidadeRESUMO
A facile, convenient and high yielding synthesis of novel S-glycosides and N-glycosides incorporating 1,2,3,4-tetrahydronaphthalene and or 1,2-dihydropyridines moieties has been described. The aglycons 2, 4, and 7 were coupled with different activated halosugars in the presence of basic and acidic medium. The preliminary in-vitro cytotoxic evaluation revealed that compounds 3c, 3f, 5c and 7b show promising activity. A molecular docking study was performed against tyrosine kinase (TK) (PDB code: 1t46) by Autodock Vina. The docking output was analyzed and some compounds have shown hydrogen bond (H-B) formation with reasonable distances ranged from 2.06 A° to 3.06 A° with Thr 670 and Cys 673 residues found in the specified pocket. No hydrogen bond was observed with either Glu 640 nor Asp 810 residues, as was expected from pdbsum.
Assuntos
Galactosídeos/química , Galactosídeos/toxicidade , Simulação de Dinâmica Molecular , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Ligação de Hidrogênio , CamundongosRESUMO
Anthracycline antibiotics, particularly doxorubicin (DOX) and daunorubicin, have been used extensively in the treatment of human malignancies. However, cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. The DOX prodrug N-(beta-D-glucopyranosylbenzyloxycarbonyl)-doxorubicin (prodrug 1) was synthesized for specific activation by beta-galactosidase, which is expected to release in necrotic areas of tumor lesions. Described here is the safety, pharmacokinetics, and biodistribution studies of a beta-galactoside prodrug of DOX. In vivo safety evaluation was done in the Ehrlich Ascites Carcinoma (EAC) tumor model. The dose of DOX was 8 mg/kg and the dose of prodrug was 8 mg/kg and 24 mg/kg of DOX equivalents. Our results on cytotoxicity, which demonstrated compression in the number of EAC cells and their viability, substantiate these data. Prodrug 1 was safe up to a dose of 24 mg/kg of DOX equivalents in EAC mice. The pharmacokinetics and biodistribution of prodrug (300 mg/kg) in normal mice were determined and compared with DOX (20 mg/kg). Administration of DOX in normal mice resulted in a peak plasma concentration of 19.45 microM (t = 30 minutes). Prodrug injection resulted in 3- to 16-fold lower concentrations in the tissues of normal mice. As it is more polar, lower levels were observed in tissues and plasma in contrast to the parent compound DOX. In vivo safety studies have shown that prodrug 1 had a maximum tolerated dose compared with DOX and led to improved pharmacokinetics in normal mice.
Assuntos
Antineoplásicos/farmacocinética , Doxorrubicina/análogos & derivados , Galactosídeos/farmacocinética , Pró-Fármacos/farmacocinética , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Área Sob a Curva , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/metabolismo , Doxorrubicina/farmacocinética , Doxorrubicina/toxicidade , Feminino , Galactosídeos/uso terapêutico , Galactosídeos/toxicidade , Meia-Vida , Taxa de Depuração Metabólica , Camundongos , Pró-Fármacos/uso terapêutico , Pró-Fármacos/toxicidade , Distribuição TecidualRESUMO
We have reported the synthesis of a series of anthracycline analog prodrugs that give rise to intensely cytotoxic metabolites in the presence of carboxylate esterases and beta-glucuronidases. We now report structurally related prodrugs that are converted to similar potent metabolites in the presence of beta-galactosidases. The prototypical compound, N-[(4"RS)-4"-ethoxy-4"(1'"-O-beta-D-galactopyranosyl)butyl]daunorubicin, 8a, was prepared by reductive condensation of daunomycin with 1-O-[(1'RS)-1'-ethoxy-4'-oxobutyl]-2, 3, 4, 6-tetra-O-acetyl-beta-D-galactopyranoside in the presence of sodium cyanoborohydride, followed by deacetylation of the galactoside moiety with sodium methoxide. A related prodrug (8b) with enhanced lipophilicity (the 4'-hexoxy analog of 8a) and 8c (the propyldaunomycin analog of 8a) were prepared for comparative studies. 8a and 8b were isolated after chromatography on silica as a mixture of 4'R and 4'S diastereomers; 8c, on the other hand, was resolved into its component 3' diastereomers, 8c(R) and 8c(S). 8a, 8c(R) and 8c(S) showed no evidence of decomposition when incubated at 37 degrees C in 0.05 M phosphate buffer, pH 7.4, for 2 weeks; 8b, under the same conditions, was degraded with a half-life of 49 h. In the presence of two units of Escherichia coli beta-galactosidase per pmol of substrate, the half-lives of 8a, 8b, 8c(R) and 8c(S) were 1.98, 1.06, 3.5 and 2.4 h, respectively. HPLC analysis of the incubation mixtures showed that 8a and 8b gave rise to a single, chromatographically identical metabolite. 8c(R) and 8c(S) also gave rise to a single, identical metabolite. 8a and 8b were nearly one million-fold more toxic to human A375 melanoma cells in culture in the presence of E. coli beta-galactosidase than in the absence of the enzyme. The activation products of 8c(R) and 8c(S) were approximately 1000-fold less potent. These beta-galactoside prodrugs have chemotherapeutic potential for use in conjunction with tissue-targeting strategies such as antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT).