RESUMEN
Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 µM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both c-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue 22 exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue 22 is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Familia-src Quinasas/metabolismo , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proteína Tirosina Quinasa CSK , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Mesilato de Imatinib/farmacología , Indoles/química , Indoles/farmacología , Estructura Molecular , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacologíaRESUMEN
The phytochemical analysis of Staehelina fruticosa led to the isolation of four germacranolide-type sesquiterpene lactones (1- 4), including two new glycosides. The structures of these sesquiterpene lactones were elucidated using spectroscopic techniques, and enzymatic hydrolysis was carried out to confirm the nature of the two glycoside derivatives. Molecular modeling was incorporated to substantiate their relative configuration.