RESUMEN
A phenylpropanoid 1, a slovenolide 2, and two germacranes bearing a methylthiopropenoate moiety, 3 and 4, along with twenty known metabolites have been isolated from the roots of Thapsia villosa var. villosa L. The structures of two known phenylpropanoids 5 and 6 have been corrected. Compounds 7 and 8 showed activity as potential inhibitors of the sarco- and endoplasmic Ca(2+)-dependent ATPases (SERCA) pump. Compounds 9, 10 and 11 increased significantly the cytoplasmic free calcium concentration ([Ca(2+)](c)) in human platelets in a concentration-dependent manner.
Asunto(s)
Plaquetas/metabolismo , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Calcio/sangre , Inhibidores Enzimáticos/farmacología , Extractos Vegetales/farmacología , Thapsia/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/aislamiento & purificación , Compuestos Heterocíclicos con 3 Anillos/aislamiento & purificación , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Lactonas/aislamiento & purificación , Lactonas/farmacología , Estructura Molecular , Extractos Vegetales/química , Raíces de Plantas , Propanoles/química , Propanoles/aislamiento & purificación , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/aislamiento & purificación , Sesquiterpenos de Germacrano/farmacología , Sesquiterpenos de Guayano/aislamiento & purificación , Sesquiterpenos de Guayano/farmacología , Compuestos de Sulfhidrilo/aislamiento & purificación , AzufreRESUMEN
Four phenylpropanoids and a thapsigargin analogue have been isolated from the fruits of Thapsia garganica. A spectroscopic method for elucidating the relative stereochemistry at the two pairs of stereogenic centers in the phenylpropanoids has been developed. The phenylpropanoids were found to be potent cytotoxins.
Asunto(s)
Fenilpropionatos/aislamiento & purificación , Thapsia/química , Tapsigargina/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Fenilpropionatos/química , Fenilpropionatos/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Conejos , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/antagonistas & inhibidores , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Tapsigargina/aislamiento & purificación , Tapsigargina/farmacologíaRESUMEN
An analysis of the binding of the 8-O-N-tert-butoxycarbonyl-12-aminododecanoyl derivative of 8-O-debutanoylthapsigargin to the target molecule, the SERCA pump, has revealed the importance of the length and flexibility of the side chain attached to O-8. Based on the analysis a series of analogues to the 2-unsubstituted analogue trilobolide has been constructed and shown to be equipotent with thapsigargin as SERCA inhibitors. Only the 12-Boc-aminododecaonoyl derivative, however, was found to be apoptotic.
Asunto(s)
ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Neoplasias de la Próstata/patología , Animales , Línea Celular Tumoral , Humanos , Masculino , Espectrometría de Masas , Modelos Moleculares , Neoplasias de la Próstata/enzimología , Conejos , ATPasas Transportadoras de Calcio del Retículo SarcoplásmicoRESUMEN
Analysis of molecular interaction fields based on the published crystal structure of thapsigargin bound to the sarco/endoplasmatic reticulum Ca(2+)-ATPase and analysis of the volume and shape of the ligand binding site and of the SERCA-thapsigargin interactions have enabled design of two new compounds inhibiting SERCA in the subpicomolar range. The two inhibitors were synthesized using (S)-carvone as starting material and found to be 3 and 10 times more potent than thapsigargin.