Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Chou TC,Zhang X,Zhong ZY,Li Y,Feng L,Eng S,Myles DR,Johnson R Jr,Wu N,Yin YI,Wilson RM,Danishefsky SJdoi
10.1073/pnas.0804773105subject
Has Abstractpub_date
2008-09-02 00:00:00pages
13157-62issue
35eissn
0027-8424issn
1091-6490pii
0804773105journal_volume
105pub_type
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