RESUMEN
Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of SIRTs catalytic activity was recently reported in the literature as being beneficial in human diseases, with very promising applications in cancer therapy and enzymatic neurodegeneration. By combining a structure-based virtual screening of the Specs database with cell-based assays, we identified the 5-benzylidene-hydantoin as new scaffold for the inhibition of SIRT2 catalytic activity. Compound 97 (Specs ID AH-487/41657829), active in the low µM range against SIRT2, showed the optimal physicochemical properties for passive absorption as well as relatively low cytotoxicity in vitro. Further studies revealed non-competitive and mixed-type kinetics toward acetyl-lysine substrates and NAD(+), respectively, and a non-selective profile for SIRT inhibition. A binding mode consistent with the experimental evidence was proposed by molecular modeling. Additionally, the levels of acetyl-p53 were shown to be increased in HeLa cells treated with 97. Taken together, these results encourage further investigation of 5-benzylidene-hydantoin derivatives for their SIRT-related therapeutic effects.
Asunto(s)
Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Hidantoínas/química , Hidantoínas/farmacología , Sirtuinas/antagonistas & inhibidores , Acetilación/efectos de los fármacos , Células HeLa , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Cinética , Lisina/metabolismoRESUMEN
Over the past decade, human histone deacetylases (HDACs) have become interesting as therapeutic targets because of the benefits that their modulation might provide in aging-related disorders. Recently, studies using crystallography and computational chemistry have provided information on the structure and conformational changes related to HDAC-mediated recognition events. Through the description of the key mass and one-off movements observed in metal-dependent HDACs, here we highlight the impact of flexibility on drug-binding affinity and specificity. The collected information will be useful for not only a better understanding of the biological functions of HDACs, but also the conception of new selective binders.
Asunto(s)
Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Animales , Sitios de Unión , Dominio Catalítico , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/química , Humanos , Isoenzimas , Ligandos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Hemp seed is known for its content of fatty acids, proteins, and fiber, which contribute to its nutritional value. Here we studied the secondary metabolites of hemp seed aiming at identifying bioactive compounds that could contribute to its health benefits. This investigation led to the isolation of 4 new lignanamides, cannabisin M (2), cannabisin N (5), cannabisin O (8), and 3,3'-demethyl-heliotropamide (10), together with 10 known lignanamides, among which 4 was identified for the first time from hemp seed. Structures were established on the basis of NMR, HR-MS, UV, and IR as well as by comparison with the literature data. Lignanamides 2, 7, and 9-14 showed good antioxidant activity, among which 7, 10, and 13 also inhibited acetylcholinesterase in vitro. The newly identified compounds in this study add to the diversity of hemp seed composition, and the bioassays implied that hemp seed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds.
Asunto(s)
Antioxidantes/farmacología , Cannabis/química , Inhibidores de la Colinesterasa/farmacología , Fenoles/química , Fenoles/farmacología , Semillas/química , Etanol , Modelos Moleculares , Estructura Molecular , Extractos Vegetales/química , Pirrolidinas/química , Pirrolidinas/farmacocinéticaRESUMEN
Essential oils from Calyptranthes concinna, C. lucida and C. rubella, collected in Southern Brazil, were analyzed by GC and GC/MS. Sixty-two compounds were identified representing about 98 por cento of the oil contents. All samples were rich in cyclic sesquiterpenes (more then 90 por cento), mainly those from cadinane, bisabolane and germacrane cyclization pathway. The mainly components characterized were byclogermacrene (22.1 por cento in C. concinna; 11.7 por cento in C. rubella), cis-calamenene (10.3 por cento in C.concinna), beta-caryophyllene (16.5 por cento in C. rubella; 9.4 por cento in C. lucida), beta-bisabolene (25.5 por cento in C. lucida), spathulenol (15.4 por cento in C. rubella) and caryophyllene oxide (7.6 por cento in C. concinna)