RESUMEN
Gastric cancer represents a diffuse and aggressive neoplasm, whose mortality index is among the highest in the world. Predisposing factors are E-cadherin mutations, Helicobacter pylori infection, and a diet rich in salted and smoked food, with a low intake of fresh fruits and vegetables. Here, we analyzed the effect of total lipophilic extracts of two Southern Italy tomato varieties, San Marzano and Corbarino, on an in vitro model of gastric cancer, YCC-1, YCC-2 and YCC-3 cell lines, characterized by different aggressiveness. Our results showed a possible role of these two varieties of tomatoes against typical neoplastic features. The treatment with tomato extracts affected cancer cell ability to grow both in adherence and in semisolid medium, reducing also cell migration ability. No toxic effects were observed on non-tumoral cells. We found, on gastric cancer cell lines, effects on both cell cycle progression and apoptosis modulation. The extent of antineoplastic effects, however, did not seem to correlate with the carotenoid content and antioxidant activity of the two tomato varieties. Our data indicate that San Marzano and Corbarino intake might be further considered as nutritional support not only in cancer prevention, but also for cancer patient diet.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antioxidantes/farmacología , Carotenoides/farmacología , Solanum lycopersicum/química , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Apoptosis/efectos de los fármacos , Carotenoides/aislamiento & purificación , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frutas/química , Humanos , Italia , Invasividad Neoplásica , Fitoterapia , Plantas Medicinales , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factores de TiempoRESUMEN
In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.
Asunto(s)
Cromonas/farmacología , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Modelos Moleculares , Compuestos de Espiro/farmacología , Cromonas/síntesis química , Cromonas/química , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/química , Humanos , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
Asunto(s)
1-Naftilamina/análogos & derivados , Acrilamidas/química , Anilidas/química , Cinamatos/química , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Daño por Reperfusión Miocárdica/tratamiento farmacológico , 1-Naftilamina/síntesis química , 1-Naftilamina/química , 1-Naftilamina/farmacología , Acrilamidas/síntesis química , Acrilamidas/farmacología , Anilidas/síntesis química , Anilidas/farmacología , Animales , Calcio/metabolismo , Cinamatos/síntesis química , Cinamatos/farmacología , Femenino , Masculino , Ratones Endogámicos C57BL , Mitocondrias Cardíacas/metabolismo , Mitocondrias Hepáticas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Dilatación Mitocondrial/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Conejos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Cyclin-dependent kinases (CDKs) are the key drivers of cell cycle progression and are often deregulated in cancer, therefore, targeting CDKs has long been pursued as a therapeutic strategy to tackle cancer. Unfortunately, however, none of the first-generation CDK inhibitors has yielded the expected efficacy to be successfully translated to the clinic mostly because, by targeting the very conserved kinase ATP-binding site resulted to be poorly specific and quite toxic. AREAS COVERED: Here, the authors review recent approaches aimed at developing more specific CDK inhibitors mostly through the aid of computational drug design studies and report various small molecules and peptides, which resulted in promising CDK ATP-noncompetitive inhibitors. EXPERT OPINION: Despite few successes, these new approaches still need additional considerations to generate effective antitumoral agents. The authors discuss some of the hurdles to overcome for a successful clinical translation.
Asunto(s)
Adenosina Trifosfato/metabolismo , Antineoplásicos/uso terapéutico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Unión Competitiva , Ciclo Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Quinasas Ciclina-Dependientes/genética , Descubrimiento de Drogas , Humanos , Estructura Molecular , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.
Asunto(s)
Antineoplásicos/farmacología , Benzoxazinas/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzoxazinas/síntesis química , Benzoxazinas/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HeLa , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Células K562 , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/patología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.
Asunto(s)
Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Piperidinas/química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Proteínas Sanguíneas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450 , Evaluación Preclínica de Medicamentos , Semivida , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacocinética , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Ratones , Ratones Desnudos , Estructura Molecular , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.
Asunto(s)
Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Ácidos Hidroxámicos/síntesis química , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
All four stereoisomers of the fragrance Jasmal of structure 3,4,5,6-tetrahydro-3-pentyl-2H-pyran-4-yl acetate were prepared by enzymatic resolutions of the corresponding alcohols. The absolute configurations were unambiguously determined by comparison with the enantiomer (3R,4S)-1 prepared from L-tartaric acid. The four stereoisomers of the fragrance Jessemal of structure 3-butyl-5-methyl-3,4,5,6-tetrahydro-2H-pyran-4-yl acetate were obtained starting from the epoxy alcohol 10, which was obtained in an optically pure state by enzymatic resolution of the racemic mixture. The olfactory evaluations of all stereoisomers are reported. (1)H-NMR Conformational analysis of diastereoisomers (3RS,4RS,5RS)-2 and (3RS,4SR,5RS)-2 is also reported.
Asunto(s)
Acetatos/química , Enzimas/metabolismo , Hidrógeno/química , Odorantes/análisis , Piranos/metabolismo , Olfato/fisiología , Acetatos/metabolismo , Humanos , Estructura Molecular , Piranos/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Enantiomerically pure 1,3-diols 1-3 were obtained by a chemoenzymatic approach (lipase PS from Burkholderia cepacia). These diols were converted into useful chiral synthons, which could be considered homologues of glyceraldehyde and glyceric acid acetonides. Applications of these synthons to the de novo synthesis of sugars and preparation of conagenin carboxylic moiety were shown. Hydroxy ketone 4 was chosen as a model system for another synthetic evolution: it was obtained in enantiomerically pure form by enzymatic resolution and converted into chiral tetrahydropyranes, such as the stereoisomers of the commercial fragrance Gyrane.
Asunto(s)
Alcoholes/química , Alcoholes/síntesis química , Ésteres/síntesis química , Gliceraldehído/síntesis química , Cetonas/química , Lipasa/química , Burkholderia cepacia/enzimología , Cristalografía por Rayos X , Ésteres/química , Gliceraldehído/química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
[structure: see text] The work describes the enzyme-mediated preparation and the odor evaluation of the single stereoisomers of the commercial odorants Muguesia and Pamplefleur. The synthetic approach to Muguesia stereoisomers helped to clear the assignment of the relative configuration of intermediate diols 5. The odor response of Pamplefleur isomers was found to be rather unusual. No stereoisomer prevailed, but each one played a definite role in establishing the odor sensation of the final blend.
Asunto(s)
Butanoles/síntesis química , Odorantes , Butanoles/farmacología , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Olfato/efectos de los fármacos , EstereoisomerismoRESUMEN
Our sense of smell is enantioselective. This review reports interesting examples of single stereoisomers of natural and synthetic odorants, prepared via bioorganic routes, that support this statement. This article is the summary of a talk given at the Flavours & Fragrances 2004 conference in Manchester at the MCC/UMIST, 12-14 May, 2004.