RESUMEN
Steroidal bivalent ligands were designed on the basis of the described closer proximity of the ATP-site and the putative steroid-binding site of P-glycoprotein (ABCB1). The syntheses of seven progesterone-adenine hybrids were described. Their abilities to inhibit P-glycoprotein-mediated daunorubicin efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein were evaluated versus progesterone.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Adenina/química , Antineoplásicos/síntesis química , Progesterona/química , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Daunorrubicina/farmacología , Diseño de Fármacos , HumanosRESUMEN
This data article is related to a research paper entitled "Solvent- and metal-free hydroboration of alkynes under microwave irradiation" (Gioia et al. TETL-D-19-01698) [1]. Herein we present the spectral data acquired from the synthesis of (E)-alkenyl boronic acid pinacol esters. The data include the general information and the synthetic procedure affording the target derivatives, which were fully characterized by Nuclear Magnetic Resonance (1H and 13C NMR) and, for the most part, by Electrospray Ionization High Resolution Mass (ESI-MS). Proton and carbon NMR spectra and ESI-MS spectra were provided which will be useful for further organic chemists if they are interested in the synthesis of these building blocks.
RESUMEN
The success of the chemotherapeutic treatment of hydatid disease is based upon the drug ability to operate on the germinal layer and on the protoscolices of the hydatid cyst interior at adequate concentrations for sufficient periods. The goal of this study was to evaluate the ability of the drug diffusion through the cyst membrane from sheep hydatid cysts and the increase of drug concentration in the cyst environment. In the first part of this work, the permeation behaviour through the hydatid cyst membrane was studied with five model molecules, having different molecular descriptors (logP, molecular weight, polar surface area ...) onto static Franz glass diffusion cells. A good correlation has been observed between the permeation coefficient and the partition coefficient, log P (r=0.951). In the second part, albendazole-loaded nanoparticles (about 300 nm) prepared by the emulsion solvent evaporation method have shown a sufficient entrapment efficiency (36.4 +/- 6.4%) to raise the apparent solubility of albendazole. The diffusion of drug from the nanoparticles across the hydatid cyst membrane was also improved compare to albendazole suspension. These results have shown the interest of the albendazole-loaded nanoparticles for the treatment of hydatid cysts in the future.
Asunto(s)
Albendazol/farmacocinética , Equinococosis/metabolismo , Nanopartículas , Albendazol/administración & dosificación , Difusión , PermeabilidadRESUMEN
A multi-step procedure has been described which afforded satisfactory yields of N,N'-disubstituted cinnamamides derived from N-Boc-protected amino acids (Boc-Gly, Boc-Val, Boc-Phe). The key step of this synthesis was a regioselective RedAl reduction of an amide function in presence of a carbamate group. Next, these cinnamamides were evaluated in co-admnistration with ciprofloxacin as efflux pump inhibitors against two S. aureus strains, NorA overexpressing SA1199B and wild type SA1199. In parallel, their intrinsic toxicity was appreciated on human lung fibroblast MRC5 cells. Therefore, the cinnamamide combining both carbamate and indol-3-yl groups, was found to be the most active and one of the less toxic EPI and constituted a promising hit.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Cinamatos/farmacología , Ciprofloxacina/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cinamatos/síntesis química , Cinamatos/química , Ciprofloxacina/síntesis química , Ciprofloxacina/química , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Its natural resistance to antiprotozoal chemotherapy characterizes the intestinal protozoan parasite Cryptosporidium parvum and the P-glycoprotein-related multidrug resistance proteins such as CpABC3 could be involved. In order to design and study specific inhibitors of the CpABC3 nucleotide-binding domain, a hexahistidine-tagged recombinant protein encompassing the N-terminal cytosolic NBD1 domain was overexpressed in E. coli and purified. The 45 kDa H6-NBD1 displayed intrinsic fluorescent properties consistent with the presence of two Trp residues in a hydrophobic environment. The binding of ATP and the fluorescent analogue TNP-ATP produced a dose-dependent quenching as well as progesterone and the flavone quercetin. The extrinsic fluorescence of TNP-ATP was enhanced upon binding to H6-NBD1, which was only partially displaced by the natural substrate ATP. The recombinant protein hydrolyzed ATP (K(m)=145.4+/-18.2 microM), but ADP (K(m)=4.3+/-0.6mM) and AMP (K(m)=5.4+/-1.5 microM) were also substrates. TNP-ATP is a competitive inhibitor of the catalytic activity (K(i)=36.6+/-4.5 microM), but quercetin and progesterone were not inhibitors, evidencing different binding sites. The recombinant C. parvum H6-NBD1 should be a valuable tool for rational drug design and will allow the discrimination between specific inhibitors of the catalytic site and molecules binding to other sites.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/aislamiento & purificación , Cryptosporidium parvum/enzimología , Cryptosporidium parvum/genética , Proteínas Protozoarias/genética , Proteínas Protozoarias/aislamiento & purificación , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Clonación Molecular , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Escherichia coli/genética , Expresión Génica , Datos de Secuencia Molecular , Progesterona/farmacología , Estructura Terciaria de Proteína , Proteínas Protozoarias/química , Quercetina/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Especificidad por SustratoRESUMEN
Deoxycholic acid derivatives were designed as P-glycoprotein (Pgp, ABCB1) inhibitors. Thus the synthesis and the biological activity of methyl deoxycholate derivatives 5-10 and their ether analogs 15-20 have been reported. The potency of these compounds to modulate Pgp-mediated MDR was evaluated through daunorubicin accumulation and potentiation of doxorubicin cytotoxicity in K562/R7 multidrug resistant cells overexpressing Pgp. In parallel, their intrinsic toxicity was appreciated on K562 sensitive cells. Methyl 12α-[(2R or 2S) tetrahydro-2H-pyran-2-yloxy]-3-oxo-5ß-cholan-24-oate 9b has shown a good efficiency as a Pgp inhibitor and a low intrinsic toxicity. Therefore, this derivative constitutes a new lead compound which can be used as a starting point to improve the design of non-toxic Pgp modulators.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Daunorrubicina/metabolismo , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/farmacología , Doxorrubicina/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Ácido Desoxicólico/química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Células K562RESUMEN
A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/ß-pregnane-3,20-dione or 5ß-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/ß-pregnane-3,20-dione, among which the 5ß-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 µM versus 1.2 and 10.6 µM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5ß-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 µM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Eritroblástica Aguda/metabolismo , Progesterona/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Células K562 , Leucemia Eritroblástica Aguda/patología , Modelos Moleculares , Conformación Molecular , Progesterona/síntesis química , Progesterona/química , Células Tumorales CultivadasRESUMEN
We previously reported that RSV-transformed quail neuroretina cells (QNR-ts68) were highly resistant to apoptosis provoked by serum withdrawal, and that this property was due to v-Src kinase activity. The present study investigates the cytotoxic effect and the functional mechanism of carbazolequinone-mediated cell death in this system. QNR-ts68 cells were subjected to carbazolequinone treatment and both growth inhibition and cell death induction were examined using formazan assays. Cell death mechanism (both apoptosis and necrosis) was confirmed through phosphatidyl serine exposure and propidium iodide incorporation. Furthermore, the effect of active carbazolequinone was inhibited by a pan caspase inhibitor. Cytofluorimetric and immunofluorescence data demonstrated the activation of caspase-3 and the involvement of mitochondria. Therefore, this study clearly indicates that carbazolequinones could induce cell death in transformed cells displaying high levels of antiapoptotic tyrosine kinase activity. Further investigations would be necessary to elucidate the mechanisms by which these carbazolequinones act as antitumor agents.
Asunto(s)
Apoptosis , Proteínas Bacterianas/biosíntesis , Carbazoles/farmacología , Caspasas/metabolismo , Proteínas de Unión al ADN/biosíntesis , Quinonas/farmacología , Factores de Transcripción , Clorometilcetonas de Aminoácidos/farmacología , Animales , Proteínas Bacterianas/fisiología , Carbazoles/química , Caspasa 3 , Inhibidores de Caspasas , División Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de Cisteína Proteinasa/farmacología , Proteínas de Unión al ADN/fisiología , Interacciones Farmacológicas , Activación Enzimática , Canales Iónicos/metabolismo , L-Lactato Deshidrogenasa/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Proteínas de Transporte de Membrana Mitocondrial , Poro de Transición de la Permeabilidad Mitocondrial , Necrosis , Codorniz , Quinonas/química , Relación Estructura-ActividadRESUMEN
Bivalent ligands were designed on the basis of the described close proximity of the ATP-site and the putative steroid-binding site of P-glycoprotein (ABCB1). The syntheses of 19 progesterone-adenine hybrids are described. Their abilities to inhibit P-glycoprotein-mediated daunorubicin efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein were evaluated versus progesterone. The hybrid with a hexamethylene linker chain showed the best inhibitory potency. The efficiency of these progesterone-adenine hybrids depends on two main factors: (i) the nature of the linker and (ii) its attachment point on the steroid skeleton.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenina/química , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Progesterona/química , Progesterona/farmacología , Línea Celular Tumoral , Técnicas de Química Sintética , Daunorrubicina/farmacología , Humanos , Progesterona/síntesis químicaRESUMEN
The synthesis, structure elucidation and antitumoral activity of novel heterocyclic compounds containing a carbazole nucleus are reported. Oxazinocarbazoles were synthesized by application of the Mannich reaction to the corresponding hydroxylated derivatives leading to 41 new molecules. Their cytotoxic activity was evaluated against various human tumor cell lines including three leukemic cell lines: CEM and Jurkat (type T), Raji (type B); breast cancer cell line (MCF-7); colorectal cancer cell line (Caco-2). A primary screening at 100 microM allowed the selection of the 10 most active compounds, which showed an antiproliferative activity on all the cell lines. A dose-effect study between 12.5 and 100 microM sorted two compounds with a significant activity: 5t and 7e against leukemic cell lines CEM, Jurkat and Raji with IC50 values around 12 microM.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Carbazoles/síntesis química , Carbazoles/farmacología , Oxazinas/síntesis química , Oxazinas/farmacología , Aminas/química , Antineoplásicos/química , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dimerización , Relación Dosis-Respuesta a Droga , Humanos , Bases de Mannich/química , Oxazinas/químicaRESUMEN
The syntheses of new N-polysubstituted imidazo[4,5-b]pyridine-7-one (IP, 5 and 8a-8f) and indazole-4,7-dione (ID, 9 and 10) derivatives are described. The binding affinity of IP and ID towards the recombinant Nucleotide Binding Domain NBD1 of Cryptosporidium parvum CpABC3 was evaluated by intrinsic fluorescence quenching. IP induced a moderate quenching of the intrinsic fluorescence of H6-NBD1 whereas IDs 9 and 10 showed a binding affinity comparable to the ATP analogue TNP-ATP. In addition, 8d, 8e and 10 were shown to be competitive inhibitors of the ATPase activity, but with low affinity. These compounds could thus act like some flavonoid derivatives, which can partly overlap both the nucleotide-binding site and the adjacent hydrophobic steroid-binding region of mammalian P-glycoproteins.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Cryptosporidium parvum , Imidazoles/síntesis química , Imidazoles/metabolismo , Indazoles/síntesis química , Indazoles/metabolismo , Proteínas Protozoarias/metabolismo , Piridinas/síntesis química , Piridinas/metabolismo , Piridonas/síntesis química , Piridonas/metabolismo , Transportadoras de Casetes de Unión a ATP/química , Imidazoles/química , Indazoles/química , Ligandos , Nucleótidos/metabolismo , Unión Proteica , Proteínas Protozoarias/química , Piridinas/química , Piridonas/química , Espectrometría de FluorescenciaRESUMEN
Oxidation of 2- and 3-hydroxycarbazoles with Frémy's salt gave the corresponding ortho-carbazolequinones. These molecules react as carbodienophiles in Diels-Alder reaction with 1-acetoxy-1,3-butadiene and 1,3-cyclopentadiene to provide the novel benzocarbazolequinone structures 15, 16, 18 and 19.
Asunto(s)
Carbazoles/síntesis química , Quinonas/síntesis química , Carbazoles/química , Modelos Químicos , Conformación Molecular , Estructura Molecular , Quinonas/químicaRESUMEN
Benzimidazole-4,7-diones derivatives substituted at 1- and/or 2-position have been synthetized and tested as inhibitors of purine nucleoside phosphorylase (PNP), isolated from two strains of Toxoplasma gondii (RH and ME 49). They were identified as inhibitors of both enzymes.
Asunto(s)
Antiprotozoarios/síntesis química , Bencimidazoles/farmacología , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Toxoplasma/enzimología , Animales , Antiprotozoarios/farmacología , Bencimidazoles/síntesis química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Relación Estructura-ActividadRESUMEN
Quinonic derivatives were tested against a virulent RH strain of Toxoplasma gondii maintained in cell culture in THP-1, a human myelomonocytic cell line. The derivatives were tested at various doses (0.5-4 microg/ml) and compared with the reference molecules clindamycine, sulfadiazine, pyrimethamine and atovaquone. The percentage of parasite growth inhibition was observed after 72 h of incubation. The tested derivatives are bicyclic, tricyclic or tetracyclic quinones. Eight of these compounds exhibit over 70% inhibition of parasite growth; and two were nearly equipotent to pyrimethamine. These data indicate that the most active compounds against the RH strain of T. gondii are bis-heterocyclic quinones.
Asunto(s)
Antiprotozoarios/química , Antiprotozoarios/farmacología , Quinonas/química , Quinonas/farmacología , Toxoplasma/efectos de los fármacos , Animales , Línea Celular , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria/métodos , Relación Estructura-Actividad , Toxoplasma/crecimiento & desarrolloRESUMEN
Boc-aminoethylindoloquinone 8, a key intermediate for the building of pentacyclic quinoneimines, analogues of kuanoniamine A, was synthesized by alkylation of 4,7-dimethoxyindole 3 with 1,2-dibromoethane followed by transformation into azide, reduction of the latter with trimethylphosphine in the presence of 2-(tert-butoxycarbonyloximino)-2-phenylacetonitrile and oxydative demethylation of the Boc-amine 6 with silver(II) oxide. Quinone 8 was then treated in situ with the thiazole o-quinodimethane 10 to afford a regioisomeric mixture of the tetracyclic quinones 11. Treatment of the mixture with trifluoroacetic acid and molecular sieves 4-A provided the corresponding quinoneimines 12. Separation of the regioisomers was performed by preparative thin-layer chromatography on silica gel. The structural assignment was made by 2D 1H-13C HMBC correlations performed on the less polar regioisomer 12b. In vitro anti-leishmanial assays showed that the tested compounds possess a good potency towards two Leishmania sp. as well as against a virulent strain of Toxoplasma gondii and without any cytotoxicity against THP-1 cells.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Alcaloides/química , Alcaloides/toxicidad , Animales , Antiprotozoarios/química , Antiprotozoarios/toxicidad , Línea Celular , Humanos , Concentración 50 Inhibidora , Leishmania/efectos de los fármacos , Estructura Molecular , Toxoplasma/efectos de los fármacosRESUMEN
The synthesis of tetracyclic quinones 10a,b, 14a,b, 19a,b and 20a,b is described. The preparations involve regioselective Diels-Alder reactions via trapping the thiazole o-quinodimethane 9 with several benzofuranquinones and benzothiophenequinones. The structure of the regioisomers was assigned through 2D NMR 1H-13C HMBC experiments performed on 10a and 14a. Compounds 10a,b, 14a as well as phenol 1 and the starting quinones 2, 5, 7 and 15 are evaluated against Leishmania sp., Toxoplasma gondii and THP-1 cells. Almost all the tested compounds exhibit significant antiprotozoal activities with lower cytotoxicities than the reference compounds. Among them, quinones 2 and 14a possess the best activities towards L. donovani and T. gondii with the lowest toxicities.