RESUMEN
Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases.
Asunto(s)
Alquenos/síntesis química , Alquenos/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Transducción de Señal , Tocoferoles/síntesis química , Tocoferoles/farmacología , Alquenos/química , Animales , Antiinflamatorios/química , Cromanos/síntesis química , Cromanos/química , Cromanos/farmacología , Cinética , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Micelas , Infiltración Neutrófila/efectos de los fármacos , Células RAW 264.7 , Tocoferoles/química , Pez CebraRESUMEN
A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI50 values between 1 and 5 µM. A structure-activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.
Asunto(s)
Antineoplásicos/farmacología , Tocoferoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , 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 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tocoferoles/síntesis química , Tocoferoles/químicaRESUMEN
Natural tocopherols are one of the main types of antioxidants found in living creatures, but they also have other critical biological functions. The biopotency of natural (+)-alpha-tocopherol (RRR) is 36% higher than that of the synthetic racemic mixture and 300% higher than the SRR stereoisomer. Vegetable oil deodorizer distillates (DD) are an excellent source of natural tocopherols. Catalytic hydrogenation of DD preconcentrates has been suggested as a feasible route for recovery of tocopherols in high yield. However, it is important to know whether the hydrogenation operation, as applied to these tocopherol-rich mixtures, is capable of preserving the chiral (RRR) character, which is critical to its biopotency. Fortified (i.e., (+)-alpha-tocopherol enriched) sunflower oil and methyl stearate, as well as sunflower oil DD, were fully hydrogenated using commercial Ni and Pd catalysts (120-180 degrees C; 20-60 psig). Products were analyzed by chiral HPLC. Results show that the desired chiral configuration (RRR) is fully retained. Thus, the hydrogenation route can be safely considered as a valid alternative for increasing the efficiency of tocopherol recovery processes from DDs while preserving their natural characteristics.
Asunto(s)
Antioxidantes/síntesis química , Destilación/métodos , Odorantes/análisis , Aceites de Plantas/química , Tocoferoles/síntesis química , Adsorción , Catálisis , Cromatografía Líquida de Alta Presión , Hidrogenación , Isomerismo , Aceites de Plantas/metabolismo , Estearatos , Aceite de Girasol , Propiedades de Superficie , Temperatura , Tocoferoles/análisis , Tocoferoles/químicaRESUMEN
Synthesis and biological characterization of a series of alpha-tocopherol analogs with NO-releasing capacity are reported. The selected NO-donor moieties were nitrooxy and furoxan. All products were tested for their in vitro NO-releasing capacities, vasodilating properties, and antiplatelet activity. They were also capable of preventing LDL oxidation.