The Epothilones Home UW Madisn Department of Chemistry埃博霉素家威斯康星大学麦迪逊分校化学系.pptVIP

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The Epothilones Home UW Madisn Department of Chemistry埃博霉素家威斯康星大学麦迪逊分校化学系.ppt

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The Epothilones Home UW Madisn Department of Chemistry埃博霉素家威斯康星大学麦迪逊分校化学系

The Epothilones Epothiwhat? Overview The epothilones are extremely cytotoxic agents with a similar mode of action to Taxol? Epo B is more active than Taxol (in vitro) Comparatively simple in structure Overview The epothilones are active against Taxol resistant cancer cell lines The epothilone scaffold is easier to derivatize than Taxol The epothilones are more water soluble than Taxol Outline Discovery and Background Mode of Action Biosynthesis Initial Synthetic Efforts Selected Total Syntheses Structure Activity Relationships (SAR) In vivo Studies and Phase I/II Clinical Results Discovery First isolated from the common soil bacteria Sorangium cellulosum as early as 1987 by H?fle and Reichenbach (GBF) Exhibited a narrow antifungal spectrum (against Mucor hiemalis only) Found to be too toxic for use as an antifungal Cytotoxicity Bollag (Merck) discovered taxol-like cytotoxicity Epo A and B were competitive inhibitors of taxol binding IC50 values comparable (Epo A) or better (Epo B) than Taxol Active against Pgp MDR (“Taxol refractory”) cells Comparison of IC50 Values [nM] Mode of Action Like Taxol, the epothilones are microtubule stabilizers Both bind to β tubulin Competitive binding suggests same binding site Epo B efficacy against tubulin-mutated cell lines suggests different interactions Epothilone B / Taxol Mode I Epothilone B / Taxol Mode II Formation of Microtubules Stabilized Microtubules BlockMitosis Epothilone Biosynthesis Biosynthesis Produced by the myxobacterium Sorangium cellulosum So Ce90 ~20 mg/L 2:1 Epo A : Epo B The So Ce90 genome sequenced: Nine modules of polyketide synthase (PKS) One nonribosomal peptide synthetase (NRPS) Cytochrome P450 monooxygenase (epoxidation) Epothilone Gene Cluster Post Assembly Line Epoxidation Cloning and Heterologous Expression The epothilone gene cluster has been expressed in Streptomyces coelicolor CH999. Doubling time of 2h vs. 16h Expression in Myxococcus xanthus 1:10 Epo A: Epo B “Large Scal