RESUMO
The isolation and characterization is described of four novel cyclic polyethers, bistramides B [2], C [3], D [4], and K [5], which are closely related to the previously reported bistramide A [1] from the New Caledonian urochordata Lissoclinum bistratum. The structures of these metabolites were defined by spectroscopic methods. The four compounds exhibited in vitro cytotoxicity toward six tumor cell lines, including the human non-small cell lung carcinoma (NSCLC-N6) line. Cytofluorimetric analysis with bistramide K showed a complete block of NSCLC-N6 cells in the G1 phase. Bistramide D and particularly bistramide K are less toxic than bistramides A, B, and C and are thereby effective in vivo against NSCLC-N6.
Assuntos
Antineoplásicos/farmacologia , Éteres Cíclicos/farmacologia , Urocordados/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular , Éteres Cíclicos/química , Éteres Cíclicos/isolamento & purificação , Humanos , Neoplasias Pulmonares/patologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Células Tumorais CultivadasRESUMO
The effect of Bistramide A, a toxin isolated from Bistratum lissoclinum Sluiter (Urochordata), on the peak sodium current (INa) of frog skeletal muscle fibres was studied with the double sucrose gap voltage clamp technique. External or internal application of Bistramide A inhibited INa without alteration of the kinetic parameters of the current nor of the apparent reversal potential for Na. The steady-state activation curve of INa was unchanged while the steady-state inactivation curve of INa was shifted towards more negative membrane potentials. Dose-response curves indicated an apparent dissociation constant for Bistramide A of 3.3 microM and a Hill coefficient of 1.2 which suggested a one to one relation between the toxin and Na channel. The inhibition of INa occurred at rest, and was more important at more positive holding potentials. Bistramide A exhibited only a weak frequency-dependent effect. The toxin did not interact with the use-dependent effect of lidocaine. It mainly blocked Na channels at more depolarized holding potentials. The toxin blocked Na channels when it was internally applyed and when the inactivation gating system has been previously destroyed by internal diffusion of iodate. The data suggest that Bistramide A inhibited the Na channel both at rest and in the inactivated state and occupied a site which was not located on the inactivation gate.
