Epothilone semisynthetic derivatives

The most recent additions to the portfolio of epothilone-type clinical development compounds are the semisynthetic derivatives BMS-310705 (23), which differs from Epo B by the presence of a primary amino group at C21, and C20-desmethyl-C20-methylsulfanyl-Epo B (32, ABJ879). As indicated above, BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), thus allowing the use of clinical formulations not containing Cremophor-EL. Accordingly, no hypersensitivity reactions were observed in phase I studies with BMS-310705 (23) in contrast to BMS-247550 (1) (in the absence of premedication). 

Figure 12.5 Structures of epothilone B in comparison to its semisynthetic derivative ixabepilone and the effect of both compounds on eukaryotic cells (nuclei were stained blue, microtubules were labeled with green).

Ixabepilone is a semisynthetic derivative of epothilone B. It has been approved by the US FDA, for use as monotherapy or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer that is resistant or refractory to standard chemotherapy options (anthracyclines, tax-anes, capecitabine) [l J. It also has activity in prostate, renal, and pancreatic cancers and in non-small cell lung cancer. 

Another epothilone derivative BMS-310705 146 developed by BMS is a semisynthetic analog of epothilone B. A microbial hydroxylation process was developed for converting epothilone B 144 to epothilone F 147 by Amycolatopsis orientalis SC 15847. Epothilone F is a key intermediate for the synthesis of an anticancer drug 146. A bioconversion yield of 37-47% was obtained when the process was scaled up to 100-2501. The epothilone B hydroxylase along with the ferredoxin gene has been cloned and expressed in Streptomyces rimosus from A. orientalis SC 15847. Variants of this cloned enz3une have been used in the hydroxylation of epothilone B, providing 80% )delds of epothilone F [188,189]. 

---