RESUMEN
BACKGROUND: Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic ß-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest. METHODS: In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives. RESULTS: We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards µ-amyloid aggregation. CONCLUSION: Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Amiloidosis/tratamiento farmacológico , Antioxidantes/química , Antioxidantes/uso terapéutico , Azepinas/química , Azepinas/uso terapéutico , Compuestos Heterocíclicos de Anillo en Puente/química , Compuestos Heterocíclicos de Anillo en Puente/uso terapéutico , Lactonas/química , Lactonas/uso terapéutico , Piperidinas/química , Piperidinas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Masculino , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , RatasRESUMEN
Oxidative stress and mitochondrial disturbances are the common and important causative factors of aging, and play an important role in the late onset of sporadic neurodegenerative diseases, including Alzheimer disease (AD). Furthermore, emerging evidence from in vitro and in vivo disease models suggests that oxidative stress and increased vulnerability to induction of mitochondrial permeability transition leads to the pathogenesis of the neurological disorders. Towards the goals of developing effective neuroprotectors, this article describes the synthesis and neuroprotective studies of various derivatives of the naturally occurring alkaloid securinine, based on which a lead compound, allomargaritarine (a diastereomer of margaritarine), was identified as an effective therapeutic for neuroprotection. Allomargaritarine exhibits high antioxidant activity, and has significant mitoprotective effect on cellular models of neurodegeneration.