RESUMEN
The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Oximas/química , Simulación por Computador , Neoplasias Endometriales , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Modelos Moleculares , Oximas/síntesis química , Relación Estructura-Actividad , Activación Transcripcional , Células Tumorales CultivadasRESUMEN
Salicylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERbeta pharmacophore with the pseudocycle A' ring, which has previously been shown to behave as a bioequivalent of phenols in nonselective ER ligands. In this series, small substituents (CH 3, CN, Cl) were introduced into the central phenyl scaffold. An efficient sequential halogen-selective double cross-coupling reaction was developed for the synthesis of the methyl-substituted ER ligand. The measured ERbeta affinity proved to be very sensitive to the effect of central core substituents. The binding affinities of the compounds herein reported were in good agreement with the results of computational docking analysis. The chloro-substituted derivative showed the highest beta affinity and selectivity, and it also proved to be an ERbeta partial agonist with an EC 50 of 11 nM.
Asunto(s)
Receptor beta de Estrógeno/metabolismo , Oximas/síntesis química , Fenoles/síntesis química , Unión Competitiva , Línea Celular , Agonismo Parcial de Drogas , Endometrio/citología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/genética , Femenino , Genes Reporteros , Humanos , Ligandos , Modelos Moleculares , Oximas/química , Oximas/farmacología , Fenoles/química , Fenoles/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Transcripción GenéticaRESUMEN
N-Me-anthranylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A-ring that is characteristic of most estrogen receptor (ER) ligands. We have investigated the role played by substituents introduced into either one or both of the peripheral 3- and 4-phenyl rings in modulating ER binding affinity. An efficient synthetic strategy was employed for the preparation of differentially substituted 3- and 4-aryl derivatives that involved exploiting the different reactivity of bromo- versus chloro-aryl groups in palladium-catalyzed cross-couplings. The binding data showed that ERalpha affinity could be improved by a single p-OH group in the 4-phenyl ring, whereas the same substitution on the 3-phenyl ring caused a dramatic reduction of ERbeta affinity. The most ERalpha-selective compound was the one with two p-OH groups on both phenyl substituents. To rationalize these results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) studies were carried out. These analyses suggested a molecular basis for the interaction of these compounds with the ERs and enabled the development of models able to predict the mode of ligand binding.
Asunto(s)
Derivados del Benceno/síntesis química , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Oximas/síntesis química , Derivados del Benceno/química , Derivados del Benceno/farmacología , Sitios de Unión , Unión Competitiva , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Oximas/química , Oximas/farmacología , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-Actividad , TermodinámicaRESUMEN
Resveratrol, a natural product with a stilbene structure, exerts profound proapoptotic activity in human cancer cells, by triggering the accumulation of ceramide, a bioactive sphingolipid. We studied the biological effects of seven methoxylated and/or naphthalene-based resveratrol analogues and compared these compounds with resveratrol with the objective to identify an analogue with higher ceramide-mediated proapoptotic activity relative to resveratrol. Here we show that the compound with three hydroxyls and a naphthalene ring is the most effective in triggering apoptosis coupled to the induction of endogenous ceramide in human cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Apoptosis , Ceramidas/biosíntesis , Estilbenos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Resveratrol , Estilbenos/química , Estilbenos/farmacología , Relación Estructura-ActividadRESUMEN
Aberrant signalling through the pathways of small GTP-binding proteins, belonging to the Ras superfamily (Ras, Rho, Rac, Cdc42 etc.), occurs in several types of cancer, where mutated Ras accumulates in its GTP-bound active form and causes uncontrolled cell proliferation. For these reasons, molecules able to target the Ras pathway in any of its stages are potentially useful in anti-cancer therapies. Inhibition of farnesyl-protein transferase (FTase), the enzyme that post-translationally activates Ras, has been pursued for the obvious role of the Ras oncoprotein in human malignancies. It was later found that some mutated forms of Ras (K- and N-Ras) can also be geranylgeranylated by geranylgeranyl-protein transferase (GGTase) when FTase is blocked, circumventing the antiproliferative effects of FTase inhibitors. Therefore, a new task has been the search for new GGTase inhibitors, which can also interfere on cell proliferation by blocking the isoprenylation of other Ras superfamily proteins (i.e. Rho, Rac, Cdc42) involved in the regulation of cell cycle progression. We have recently described a series of phosphonoacetamido- and phosphonoacetamidoxy-stable analogues of geranylgeranyl-diphosphate (GGdP) possessing good GGTase inhibitory properties and, some of them, also remarkable GGTase/FTase selectivity levels. We have now extended this series to a larger number of variously substituted phosphonoacetamidoxy-analogues of GGdP in order to establish the effect on GGTase inhibitory activity and selectivity due to the presence of different substituents in the polar portion of these GGdP mimics. We have also measured the cytotoxicity of these compounds on tumour cell lines with the aim of evaluating their potential anti-proliferative effects.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diterpenos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Fosfatos de Poliisoprenilo/química , Acetamidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Compuestos Organofosforados/químicaRESUMEN
Stable analogues of geranylgeranyl diphosphate, possessing 3-(phosphono)propionamido moieties in the place of the metabolically unstable diphosphate portion, were prepared and submitted to prenyltransferase (GGTase and FTase) inhibition assays. In one case, an excellent GGTase inhibitory activity was obtained (IC(50) = 39 nM), accompanied by a certain degree of GGTase vs. FTase selectivity.