RESUMO
A series of novel functionalized mono-, bis- and tris-(S)-{[(2S,4R,8R)-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl)}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60), human neuroblastoma (SH-SY5Y), human hepatoma (HepG2) and human breast cancer (MCF-7) cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay and the 50% inhibitory concentration (IC(50)) values were determined. Our data indicate that the precursor amine has no antitumor activity in vitro, but the bis-methanamines with ureido-, thioureido and amide-type linkers display attractive in vitro cytotoxicity and cytostatic effects on HL-60, HepG2, MCF-7 and SH-SY5Y cells. Besides 1H- and 13C-NMR methods the structures of the new model compounds were also studied by DFT calculations.
Assuntos
Aminas/síntese química , Antineoplásicos/síntese química , Compostos Ferrosos/síntese química , Quinina/análogos & derivados , Quinina/síntese química , Acilação , Aminas/química , Aminas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Humanos , Concentração Inibidora 50 , Metalocenos , Modelos Químicos , Conformação Molecular , Quinina/química , Quinina/farmacologiaRESUMO
all-endo-3-amino-5-hydroxybicyclo[2.2.2]octane-2-carboxylic acid (13) and all-endo-5-amino-6-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol (10) were prepared via dihydro-1,3-oxazine or g-lactone intermediates by the stereoselective functionalization of an N-protected derivative of endo-3-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acid (2). Ring closure of b-amino ester 4 resulted in tricyclic pyrimidinones 15 and 16. The structures, stereochemistry and relative configurations of the synthesized compounds were determined by IR and NMR.
Assuntos
Aminoácidos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Pirimidinonas/síntese química , Aminoácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclização , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Pirimidinonas/química , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of 3-methoxyestrane 17α- and 17ß-azide epimers (3 and 5) with different terminal alkynes afforded novel 1,4-substituted triazolyl derivatives (8a-f and 11a-f). If the Ph3P in the classical CuAAC process was replaced by Et3N, the formation of small quantities of 5-iodotriazoles (9a-f and 11a-f) was observed. For the preparation of 5-iodo-1,2,3-triazoles (9a-f and 11a-f), an improved method was developed, directly from steroidal azides and terminal alkynes, in reactions mediated by CuI and ICl as iodinating agents. The antiproliferative activities of the structurally related triazoles were determined in vitro with the microculture tetrazolium assay on six malignant human cell lines of gynecological origin (HeLa, A2780, MCF7, MDA-MB-231, MDA-MB-361 and T47D). X-ray analysis revealed the presence of the iodo substituent on the 1,2,3-triazole ring.
Assuntos
Antineoplásicos , Cobre/química , Citotoxinas , Estranos , Hidrocarbonetos Iodados , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Catálise , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estranos/síntese química , Estranos/química , Estranos/farmacologia , Células HeLa , Humanos , Hidrocarbonetos Iodados/síntese química , Hidrocarbonetos Iodados/química , Hidrocarbonetos Iodados/farmacologia , Células MCF-7RESUMO
During the alkaline methanolysis of 3beta-acetoxy-21-chloromethyl-pregn-5-ene-20beta-N-phenylurethane, and its p-substituted phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)tetrahydrooxazin-2-on-6-yl]androst-5-en-3beta-ol and its p-substituted phenyl derivatives are formed. The cyclization takes place with (N(-)-6) neighboring group participation. Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding delta4-3-ketosteroids. The structures of the new compounds were proved by IR, 1H and 13C NMR spectroscopy, using up-to-date measuring techniques such as 2D-COSY, HMQC, and HMBC. The inhibitory effects (CI50) of the delta4-3-ketosteroids on 5alpha-reductase were studied.
Assuntos
Inibidores de 5-alfa Redutase , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Oxazinas/síntese química , Esteroides/síntese química , Esteroides/farmacologia , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/química , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Conformação Molecular , Oxazinas/química , Oxazinas/farmacologia , Estereoisomerismo , Esteroides/química , Relação Estrutura-AtividadeRESUMO
New Mannich ketones of fused bicyclic ketones as 1-indanones and 1-tetralones were prepared using the classical acid-catalysed Mannich reaction. Known members of this family were used in comparative biological tests. Antibacterial activity of these new water-soluble compounds was reported against Pseudomonas aeruginosa, Escherichia coli, E. coli ReD31m4, Salmonella minnesota Re595, Shigella sonnei Re4350, Staphylococcus aureus, Staphylococcus saprophyticus, Micrococcus luteus and Bacillus subtilis standard strains. Human cytotoxicity of our new compounds was evaluated against HeLa cell line. Some compounds showed low cytotoxicity (56.738 nM mL(-1) for 24, 47.497 nM mL(-1) for 31 and 48.379 nM mL(-1) for 26) and proved to be efficient antibacterial agents against the Gram-positive and partly against E. coli strains. Minimum inhibitory concentrations (MIC) changed in the range of 1.56->200 microg mL(-1). The deep rough mutants showed (generally eight times) higher sensitivity toward the compounds than the smooth E. coli. Hence, the permeability of Gram-negative outer membrane can influence the MIC values of our compounds. A preliminary quantitative structure-activity relationship (QSAR) study indicated the maximum positive charge (MaxQ(+)) as the parameter that most significantly affected antibacterial activity against E. coli. In B. subtilis, the influence of a topological descriptor (first-order valence-connectivity index, XV1) was also revealed; however, other strains did not yield meaningful QSAR with the set of descriptors employed.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Bases de Mannich/química , Bases de Mannich/farmacologia , Células HeLa , Humanos , Concentração Inibidora 50 , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana/métodos , Relação Quantitativa Estrutura-Atividade , Espectrofotometria Infravermelho , Compostos de Sulfidrila/análiseRESUMO
Pentacyclic isoxazolines were obtained by the cycloaddition of benzonitrile oxide to norbornene-azetidinone-fused 3,1-oxazines. The constitutions of two of the isomers obtained, and the configurations and conformations of all products, were determined by means of 1 H and 13 C NMR spectroscopy and DNOE experiments.
RESUMO
A series of novel 3(5)-aryl/ferrocenyl-5(3)-phenothiazinylpyrazoles and pyrazolines were obtained by substituent-dependent regioselective condensation of the corresponding (E)-3-(2-alkyl-10H-phenothiazin-3-yl)-1-aryl/ferrocenylprop-2-en-1-one with hydrazine or methylhydrazine in acetic acid. The different propensity of the primary formed beta-hydrazino adducts to undergo competitive retro-Mannich reaction was interpreted in terms of tautomerisation equilibrium constants calculated by DFT using a solvent model. The regioselectivity of the cyclisation reactions with methylhydrazine and the substituent-dependent redox properties of pyrazolines were also rationalized by comparative DFT calculations performed for simplified model molecules. On the effect of ultrasound-promoted oxidation with copper(II)nitrate phenothiazine-containing pyrazolines, enones and oxo-compounds were selectively transformed into sulfoxides. Only one sulfoxide enone was partially converted into an oxirane derivative. The structure of the novel products was determined by IR and NMR spectroscopy including COSY, HSQC, HMBC and DNOE measurements.
Assuntos
Cobre/química , Hidrazinas/química , Nitratos/química , Fenotiazinas/química , Ciclização , Espectroscopia de Ressonância Magnética , Oxirredução , Fenotiazinas/síntese química , Pirazolonas/química , Sonicação , Espectrofotometria InfravermelhoRESUMO
Some new glycosides of 3-ferrocenyl-1-(4'-hydroxyphenyl)-prop-2-en-1-one were prepared and transformed into the corresponding pyrazoline and pyrazole derivatives. Using methyl-hydrazine, formation of regioisomers was observed. DDQ was found to be a mild and efficient reagent for the pyrazoline-pyrazole dehydroaromatization process. The structure of the new compounds was proved by IR and NMR spectroscopy. The in vitro antitumor activity of the substances was investigated against human leukemia (HL-60) cells by the MTT method. Among these new compounds some chalcone derivatives (3 a, 3 b, 5 a, and 5 b) showed attractive in vitro antitumor effects on human leukemia cells. These molecules contained ferrocenyl moieties and a p-hydroxy-phenolic ring or a size-independent apolar substitution of that.