RESUMO
With the aim to discover orally active small molecules that stimulate glucose uptake, high throughput screening of a library of 5000 drug-like compounds was conducted in differentiated skeletal muscle cells in presence of insulin. N-Substituted phthalazinone acetamide was identified as a potential glucose uptake modulator. Several novel derivatives were synthesized to establish structure activity relationships. Identified lead thiazolyl-phthalazinone acetamide (7114863) increased glucose uptake (EC50 of 0.07±0.02 µM) in differentiated skeletal muscle cells in presence of insulin. Furthermore, 7114863 was superior to rosiglitazone under similar experimental conditions without inducing PPAR-γ agonist activity thus making it a very interesting scaffold.
Assuntos
Acetamidas/química , Ftalazinas/química , Tiazóis/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes , Insulina/farmacologia , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Ftalazinas/síntese química , Ftalazinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
A new hexacyclic pyridoacridine alkaloid, nordehydrocyclodercitin (1), from an ascidian, Aplidium sp., cf. Aplidium cratiferum collected at Arab Reef, Great Barrier Reef, Australia is reported. Nordehydrocyclodercitin is structurally related to stellettamine (2) and cyclodercitin (3), which are sponge metabolites, and cycloshermilamine D (4) which was isolated from the marine tunicate Cystodytes violatinctus. The structure of nordehydrocyclodercitin was determined by interpretation of spectroscopic data, particularly those obtained from HMBC correlations, and by comparison with reported data for known related pyridoacridine alkaloids.
