RESUMO
The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.
Assuntos
Epotilonas/uso terapêutico , Microtúbulos/metabolismo , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Proliferação de Células , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Epotilonas/administração & dosagem , Epotilonas/química , Epotilonas/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinéticaRESUMO
Inhibition of the protein chaperone Hsp90 is a promising new approach to cancer therapy. We describe the preparation of potent non-benzoquinone ansamycins. One of these analogues, generated by feeding 3-amino-5-chlorobenzoic acid to a genetically engineered strain of Streptomyces hygroscopicus, shows high accumulation and long residence time in tumor tissue, is well-tolerated upon intravenous dosing, and is highly efficacious in the COLO205 mouse tumor xenograft model.