RESUMEN
A series of oxime carbamates have been identified as potent inhibitors of fatty acid amide hydrolase (FAAH), an important regulatory enzyme of the endocannabinoid signaling system. Kinetic analysis indicates that they behave as non-competitive, reversible inhibitors, and show remarkable selectivity for FAAH over the other components of the endocannabinoid system.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Carbamatos/química , Inhibidores Enzimáticos/química , Oximas/química , Amidohidrolasas/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Carbamatos/síntesis química , Carbamatos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Relación Estructura-ActividadAsunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Carbamatos/química , Carbamatos/farmacología , Animales , Moduladores de Receptores de Cannabinoides/metabolismo , Carbamatos/administración & dosificación , Carbamatos/metabolismo , Endocannabinoides , Humanos , Ratones , Plasma/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A water soluble derivative (2) of topopyrones was selected for NMR studies directed to elucidate the mode of binding with specific oligonucleotides. Topopyrone 2 can intercalate into the CG base pairs, but the residence time into the double helix is very short and a fast chemical exchange averaging occurs at room temperature between the free and bound species. The equilibria involved become slow below room temperature, thus allowing to measure a mean lifetime of the complex of ca. 7 ms at 15 degrees C. Structural models of the complex with d(CGTACG)(2) were developed on the basis of DOSY, 2D NOESY and (31)P NMR experiments. Topopyrone 2 presents a strong tendency to self-associate. In the presence of oligonucleotide a certain number of ligand molecules are found to externally stack to the double-helix, in addition to a small fraction of the same ligand intercalated. The external binding to the ionic surface of the phosphoribose chains may thus represents the first step of the intercalation process.
Asunto(s)
Antraquinonas/química , ADN/química , Pironas/química , Inhibidores de Topoisomerasa I , Antraquinonas/farmacología , Secuencia de Bases , Sitios de Unión , ADN/metabolismo , Humanos , Sustancias Intercalantes , Espectroscopía de Resonancia Magnética , Conformación de Ácido Nucleico , Pironas/farmacología , SolubilidadRESUMEN
A series of structurally simple analogues of natural topopyrone C were synthesized and tested for cytotoxic and topoisomerase I inhibitory activities. The removal of the hydroxyl groups at the 5 and 9 positions resulted in an increased cytotoxic potency and ability to stabilize topoisomerase-mediated cleavage. In addition, the results suggest that some structural features, such as the pyrone ring and a polar group in position 11, are fundamental for topoisomerase I inhibitory effect. These structural requirements are also consistent with the cytotoxic activity.