RESUMO
BACKGROUND: Cell permeable ligands of low molecular weight can be used to dissect complex cellular processes. During the past several years this approach has been particularly important in the study of intracellular signal transduction. Discodermolide, a marine natural product, appears to inhibit a signaling pathway in immune cells. The structure of natural discodermolide is known, but its absolute stereochemistry is not. We set out to make both enantiomers and to investigate their biological activity. RESULTS: Both enantiomers of discodermolide were prepared by total synthesis. Surprisingly, both enantiomers have biological activity, and their effects seem to be distinct in that they arrest cells at different stages of the cell cycle. A specific binding activity was identified for (+)-discodermolide but not for (-)-discodermolide, and the binding of the two enantiomers was not competitive. CONCLUSIONS: Both enantiomers of discodermolide have antiproliferative activity, but they act by distinct mechanisms and appear to have distinct cellular targets. The natural product is the (+)-enantiomer, which blocks the cell cycle in the G2 or M phase. The (-)-enantiomer blocks cells in S phase. Both may be useful in studies of the regulation of the cell cycle; we have also identified a specific binding activity for (+)-discodermolide, and have provided evidence that it interacts with a functionally relevant receptor.
Assuntos
Alcanos , Carbamatos , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Lactonas/metabolismo , Lactonas/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Humanos , Camundongos , Pironas , Células Tumorais CultivadasRESUMO
The 4-oxospiro[benzopyran-2,4'-piperidine] ring system is contained within potent class III antiarrhythmic agents. We highlight how these agents can be chemically transformed into a new class of potent (< 1 nM) and selective (> 25-fold) alpha 1a-receptor subtype adrenergic antagonists.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Benzopiranos/farmacologia , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Antiarrítmicos/síntese química , Humanos , Masculino , Hiperplasia Prostática/tratamento farmacológico , RatosRESUMO
Benign prostatic hyperplasia can be managed pharmacologically with alpha-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the alpha-1a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective alpha-1a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo and are devoid of blood pressure side effects.