RESUMEN
Pyridinium-containing polyheterocycles exhibit distinctive biological properties and interesting electrochemical and optical properties and thus are widely used as drugs, functional materials, and photocatalysts. Here, we describe a unified two-step strategy by merging Rh-catalyzed C-H vinylation with two switchable electrocyclizations, including aza-6π-electrocyclization and all-carbon-6π-electrocyclization, for rapid and divergent access to dihydropyridoisoquinoliniums and dihydrobenzoquinolines. Through computation, the high selectivity of aza-electrocyclization in the presence of an appropriate "HCl" source under either thermal conditions or photochemical conditions is shown to result from the favorable kinetics and symmetries of frontier orbitals. We further demonstrated the value of this protocol by the synthesis of several complex pyridinium-containing polyheterocycles, including the two alkaloids berberine and chelerythrine.
RESUMEN
The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two-step process, thereby providing a highly effective approach to 5-unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3-dipolar cycloaddition of α-iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five-step total synthesis of the pyrrolizidine natural product isoretronecanol.
Asunto(s)
Compuestos Azo/química , Productos Biológicos/síntesis química , Alcaloides de Pirrolicidina/síntesis química , Tiosemicarbazonas/química , Compuestos Azo/síntesis química , Productos Biológicos/química , Reacción de Cicloadición , Alcaloides de Pirrolicidina/química , Estereoisomerismo , Tiosemicarbazonas/síntesis químicaRESUMEN
We reported recently that berberine (Ber), a traditional oriental medicine to treat gastroenteritis, binds and activates retinoid X receptor α (RXRα) for suppressing the growth of colon cancer cells. Here, we extended our studies based on the binding mode of Ber with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel Ber analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently than Ber, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing the Wnt/ß-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved Ber's tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 did not show obvious side effects including hypertriglyceridemia as other RXRα agonists or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of Ber-derived RXRα activators as novel effective antineoplastic agents for colon cancer.
Asunto(s)
Antineoplásicos/química , Berberina/análogos & derivados , Receptor alfa X Retinoide/agonistas , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Berberina/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Ratas , Receptor alfa X Retinoide/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A concise, asymmetric total synthesis of (+)-fusarisetin A, a hybrid natural product, has been achieved. A one-pot four-reaction process efficiently delivered the tetracycle 2 which served as a key intermediate for the synthesis of the title natural product and its analogues through amino acid incorporation.