RESUMO
The identification and optimization of a series of acylguanidine-based melanocortin-4 receptor antagonists is discussed.
Assuntos
Guanidina/química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Compostos de Sulfidrila/química , Animais , Sítios de Ligação , Encéfalo/metabolismo , Guanidina/análogos & derivados , Guanidina/farmacologia , Concentração Inibidora 50 , Camundongos , Plasma/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Fatores de TempoRESUMO
Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.
Assuntos
Alcaloides/síntese química , Isoquinolinas/síntese química , Catálise , Técnicas de Química Combinatória , Cristalografia por Raios X , Ciclização , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] The first total synthesis of (+/-)-jamtine (4), a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties, is described. The key step involves a tandem thionium/N-acyliminium ion cyclization from enamido sulfoxide 13. The cascade process takes place with high diastereoselectivity and in excellent yield.
Assuntos
Alcaloides/síntese química , Anti-Infecciosos/síntese química , Isoquinolinas/síntese química , Caproatos/química , Lactonas/química , Plantas Medicinais , Compostos de Amônio Quaternário/químicaRESUMO
The suppression of chaos in an one-dimensional model of malignant tumor growth is presented. As a result, a steady-state and differentperiodic motions, embedded in the chaotic attractor, arestabilized.
RESUMO
A model of competition between populations of two species, describedby a two dimensional map, is analytically and numerically studied. A rich dynamics is observed.