RESUMO
The enantioselective total synthesis of (-)-tetrodotoxin [(-)-TTX] and 4,9-anhydrotetrodotoxin, which are selective blockers of voltage-gated sodium channels, was accomplished from the commercially available p-benzoquinone. This synthesis was based on efficient stereocontrol of the six contiguous stereogenic centers on the core cyclohexane ring through Ogasawara's method, [3,3]-sigmatropic rearrangement of an allylic cyanate, and intramolecular 1,3-dipolar cycloaddition of a nitrile oxide. Our synthetic route was applied to the synthesis of the tetrodotoxin congeners 11-norTTX-6(R)-ol and 4,9-anhydro-11-norTTX-6(R)-ol through late-stage modification of the common intermediate. Neutral deprotection at the final step enabled easy purification of tetrodotoxin and 11-norTTX-6(R)-ol without competing dehydration to their 4,9-anhydro forms.
Assuntos
Bloqueadores dos Canais de Sódio/síntese química , Tetrodotoxina/análogos & derivados , Tetrodotoxina/síntese química , Benzoquinonas/síntese química , Benzoquinonas/química , Técnicas de Química Sintética , Bloqueadores dos Canais de Sódio/química , Estereoisomerismo , Tetrodotoxina/químicaRESUMO
BIN1 is a genetic risk factor of late-onset Alzheimer disease (AD), which was identified in multiple genome-wide association studies. BIN1 is a member of the amphiphysin family of proteins, and contains N-terminal Bin-Amphiphysin-Rvs and C-terminal Src homology 3 domains. BIN1 is widely expressed in the mouse and human brains, and has been reported to function in the endocytosis and the endosomal sorting of membrane proteins. BACE1 is a type 1 transmembrane aspartyl protease expressed predominantly in neurons of the brain and responsible for the production of amyloid-ß peptide (Aß). Here we report that the depletion of BIN1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces BACE1 lysosomal degradation, resulting in increased Aß production. Our findings provide a mechanistic role of BIN1 in the pathogenesis of AD as a novel genetic regulator of BACE1 levels and Aß production.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Ácido Aspártico Endopeptidases/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/biossíntese , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Endocitose/genética , Endossomos/metabolismo , Humanos , Lisossomos/metabolismo , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/metabolismo , Transporte Proteico , Proteólise , Proteínas Supressoras de Tumor/metabolismoRESUMO
A novel method for the preparation of N-acylpyrrole is described. The method involves condensation of carboxylic acids with 2,4,4-trimethoxybutan-1-amine, followed by acid-mediated cyclization to form the pyrrole ring. The preparative procedure is highly tolerant of a variety of functional groups.
