RESUMEN
New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.
RESUMEN
A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Azepinas/química , Azepinas/farmacología , Compuestos Heterocíclicos de Anillo en Puente/química , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Lactonas/química , Lactonas/farmacología , Piperidinas/química , Piperidinas/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Azepinas/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Euphorbiaceae/química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Humanos , Lactonas/síntesis química , Neoplasias/tratamiento farmacológico , Piperidinas/síntesis químicaRESUMEN
DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Metilasas de Modificación del ADN/química , Metilasas de Modificación del ADN/metabolismo , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Moleculares , Terapia Molecular Dirigida/métodos , Neoplasias/enzimología , Neoplasias/genética , Nucleósidos/química , Nucleósidos/farmacologíaRESUMEN
INTRODUCTION: DNA methylation is an epigenetic modification that modulates gene expression without altering the DNA base sequence. It plays a crucial role in cancer by silencing tumor suppressor genes (TSG). The DNA methyltransferases (DNMT) are the enzymes that catalyze DNA methylation and they are interesting therapeutical targets since DNA methylation is reversible such that an aberrant hypermethylation of DNA can be reverted by inhibition of DNMTs. Today, two drugs are on the market for the treatment of myelodysplastic syndrome, azacitidine and decitabine. AREAS COVERED: Here, we present a review of the patents describing the chemistry and biological activities of novel DNMT inhibitors and discuss select clinical studies. EXPERT OPINION: DNMT inhibitors have shown efficacy in clinics. However, highly efficient and specific DNMT inhibitors have not yet been identified. Improving methods will certainly lead to the prediction of novel directly binding inhibitors in the future.
Asunto(s)
Antineoplásicos/farmacología , Metilasas de Modificación del ADN/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Patentes como Asunto , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular , Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Conformación Proteica , Relación Estructura-Actividad , TransfecciónRESUMEN
This review presents the different human DNA methyltransferases (DNMTs), their biological roles, their mechanisms of action and their role in cancer. The description of assays for detecting DNMT inhibitors (DNMTi) follows. The different known DNMTi are reported along with their advantages, drawbacks and clinical trials. A discussion on the features of the future DNMT inhibitors will conclude this review.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Neoplasias/genética , Animales , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimologíaRESUMEN
The anaplastic lymphoma kinase (ALK) is a validated target for the therapy of different malignancies. Aberrant expression of constitutively active ALK chimeric proteins has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL) and has been detected in other cancers such as inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, certain non-small-cell lung cancers, rhabdomyosarcomas, neuroblastomas and glioblastomas. In the course of a screening program aimed at identifying kinase inhibitors with novel scaffolds, the two pyridoisoquinoline derivatives F91873 and F91874, were identified as multikinase inhibitors with activity against ALK in a biochemical screen. F91873 and F91874 also inhibited nucleophosmin-ALK and signal transducer and activator of transcription 3 phosphorylation in the ALCL cell line COST with the same potency. Both F91873 and F91874 behaved as ATP noncompetitive inhibitors and inhibited cell proliferation of the ALK(+) ALCL cell lines COST, PIO, and Karpas299 ALCL. This growth inhibition effect was associated with a G1-phase cell cycle arrest. Furthermore, administration of F91874 to severe combined immunodeficient mice bearing COST tumor xenografts resulted in a significant antitumor efficacy at 15 mg/kg/day, illustrating the potential utility of such compounds in the treatment of ALK-related pathologies.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinolizinas/uso terapéutico , Tiazoles/uso terapéutico , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/síntesis química , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/enzimología , Femenino , Fase G1/efectos de los fármacos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/patología , Ratones , Ratones Endogámicos ICR , Ratones SCID , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Quinolizinas/síntesis química , Proteínas Tirosina Quinasas Receptoras , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Tiazoles/síntesis química , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Antineoplásicos Fitogénicos/química , Microtúbulos/efectos de los fármacos , Vinblastina/análogos & derivados , Antineoplásicos Fitogénicos/síntesis química , Ensayos Clínicos como Asunto , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Humanos , Vinblastina/síntesis química , Vinblastina/químicaRESUMEN
Vinca alkaloids vinblastine and vincristine and some of their derivatives such as vinorelbine are widely used in therapy of leukemia and several solid tumors. Their action is associated with alterations of the mitotic spindle functions that prevent the cell cycle progression and lead to mitotic block. A number of studies show that some Vinca alkaloids inhibit CaM-target interaction. The newest microtubule inhibitor, vinflunine (Javlor), currently in clinical trials, is remarkably more active than vinblastine against a number of tumors. Moreover, vinflunine is significantly less toxic than other Vinca alkaloids. The high antitumor activity of this molecule is not well understood since it binds to tubulin with an overall affinity several-fold lower than that of vinblastine or vincristine. In this study, we examined the interaction of Ca2+-CaM with vinflunine, vinblastine, and stable tubule only polypeptide (STOP) by using a combination of thermodynamic and mass spectrometric approaches. We characterized the influence of Vinca alkaloids on Ca2+-CaM-STOP complex formation. Our results revealed different binding modes to Ca2+-CaM for vinflunine and vinblastine, highlighting that adding fluorine atoms on the cleavamine moiety of the Vinca alkaloid molecule is critical for the localization of the drug on calmodulin. We demonstrate that vinflunine is a better inhibitor for STOP binding to calmodulin than vinblastine. We suggest that vinflunine action on calmodulin can have an effect on microtubule dynamics. These data may contribute to a better understanding of the superior antitumor efficiency and lower toxicity of vinflunine.
Asunto(s)
Calmodulina/metabolismo , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Vinblastina/análogos & derivados , Animales , Calmodulina/química , Calorimetría , Modelos Moleculares , Estructura Molecular , Péptidos/metabolismo , Unión Proteica , Desnaturalización Proteica , Espectrometría de Masa por Ionización de Electrospray , Temperatura , Termodinámica , Vinblastina/química , Vinblastina/farmacologíaRESUMEN
A rapid method for the determination of Vinca alkaloids by nonaqueous capillary electrophoresis with diode array detection has been developed. A group of 11 alkaloids (catharanthine, vinorelbine, anhydrovinblastine, vinflunine, vindoline, 4-O-deacetylvinorelbine, 4-O-deacetylvinflunine, vindesine, vinblastine, 4'-deoxy-20',20'-difluorovinblastine, vincristine) could be readily separated within 10 min. The compounds were separated using a capillary of 38 cm effective length, a running buffer composed of 50 mM ammonium acetate and 0.6 M acetic acid in a methanol-acetonitrile (75:25, v/v) mixture. A constant voltage of 25 kV with a ramp time of 1 min and a 344.7 x 10(3) Pa pressure, applied simultaneously to inlet and outlet buffer vials, were used during sample analysis. Five of these alkaloids were selected for optimization of the separation and for validation studies with respect to specificity, linearity, range, limits of quantification and detection and then accuracy. The feasibility of the assay was demonstrated by analyzing a commercial sample of vinorelbine (Navelbine, ampoule at 10 mg/ml of vinorelbine base). The results were compared with a high-performance liquid chromatography method.
Asunto(s)
Alcaloides de la Vinca/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Electroforesis Capilar , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The binding of two antitumour alkaloids, vinorelbine and vinflunine, to the alpha/beta-tubulin dimer has been investigated at equilibrium by nuclear magnetic resonance (NMR) spectroscopy. Tubulin stability and assembly induced by these drugs has been checked under NMR experimental conditions, and tubulin spirals were found in majority. Then, using increasing ligand concentrations, the alkaloids were titrated against tubulin. A non-specific binding of both compounds to tubulin (K(d)>10(-5)M) was characterised by broad NMR ligand signal at 4 and 30 degrees. The tubulin dimer exhibited also 2.7 (sigma: 0.3) and 2.6 (sigma: 0.6) binding sites with a K(d)<10(-5)M for vinorelbine at 4 and 30 degrees, respectively. In contrast, if the tubulin dimer exhibited 2.7 (sigma: 0.2) binding sites for vinflunine at 4 degrees, these sites were not detected at 30 degrees. This NMR study revealed for the first time the presence of specific binding sites and a clear differential affinity of vinorelbine and vinflunine to the tubulin dimer at physiological temperatures which could possibly account for their differential cytotoxicity.
Asunto(s)
Tubulina (Proteína)/metabolismo , Vinblastina/análogos & derivados , Vinblastina/metabolismo , Animales , Antineoplásicos Fitogénicos/metabolismo , Antineoplásicos Fitogénicos/farmacología , Sitios de Unión , Dimerización , Espectroscopía de Resonancia Magnética , Conformación Molecular , Peso Molecular , Ovinos , Vinblastina/farmacología , VinorelbinaRESUMEN
Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids.