Epothilone derivatives

Patupilone (epothilone B, EPO906) 29 (Novartis) is being evaluated in a Phase III trial for the treatment of patients with ovarian, primary fallopian or peritoneal cancer.191,196,197 Patupilone (then called epothilone B) 29 was first reported by Hofle and co-workers198 200 31 from the myxobacterium Sorangium cellulosum in a 1991 patent application and epothilones were shown by workers at Merck in 1995 to have tubulin-stabilising activity similar to that of paclitaxel 60.31 Ixabepilone 28, which is the semi-synthetic lactam derivative of patupilone 29, was the first epothilone derivative approved (October 2007) for the treatment of breast cancer. 

Structure-activity relationships of published epothilone derivatives have been included in the review article and publications of Nicolaou et al. [57, 58] and Danishefsky et al. [2, 59, 60]. 

As described above, although module 4 determines the structure at positions 12 and 13 of epothilone, the 12,13-cu double bond in epothilones C and D, the products of the PKS, must be introduced by a function outside of this module. In a recent paper (15), we reported that replacement of the complete set of reduction domains in module S of the epothilone PKS resulted in the production of an epothilone derivative that had lost the 12,13-cu double bond and carried an OH group at C-13, as predicted from the domain organization of module 4 (Fig. 4). This structure led us to propose that the DH domain of module 5 acted on the nascent chain produced by the upstream module to insert a cis double bond. The presence of the 10,1 trans double bond in the resulting compound was puzzling in that it would normally originate from the action of the DH domain of module 5, which was absent from the modified PKS. We... 

An example of particular interest is epothilone from Sorangium cellulosum So ce90, which has recentiy been approved for the treatment of breast cancer. Epothilone inhibits microtubule depolymerization and is active against multidrug-resistant cancer cell lines and paclitaxel-resistant tumors. The most comprehensively characterized and so far only epothilone derivative, which received FDA approval for clinical use, is ixabepi-lone. The compound is marketed in the US by Bristol-Myers Squibb (BMS) under the trade name Ixembra . 

Figure 19 Epothilone biosynthesis and novel derivatives generated by genetic engineering. Domains with an asterisk are assumed to be inactive. The hydroxyl group formed by the KR domain in module 4 is dehydrated by the DH domain found in module 5. Module 4 incorporates either malonyl-CoA or methylmalonyl-CoA extender units (the figure only shows the incorporation of malonyl-CoA). Epothilone derivatives generated by genetic engineering are shown in boxes (see text) and the sites of mutagenesis are indicated.

A9, A431 and A549 cell lines, 3478 12a,13a-Aziridinyl epothilone derivatives, 990 Aaptos ciliata, 1292 AATs. See Anthocyanin acyltransferases (AATs)... 

Ixabepilone 114, a novel epothilone derivative was prepared from epothiolne B by Bristol-Myers Squibb Company (BMS), was approved by FDA for the treatment of patients with malignant tumors [212,213j. 

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]. 

At this point in time, nine epothilone-derived structures are known to have been advanced to clinical trials in humans one of these, ixabepilone, has received FDA approval in 2007, which has provided final validation of the lead potential of epothilones for anticancer drug discoveiy. On the other hand, and with the exception of UTDl and iso-fludelone, the development of all other candidate drugs in cancer is either uncertain (patupilone, sagopi-lone) or seems to have been terminated. However, Epo D is now in clinical trials for neurodegenerative diseases. Clearly, there are still numerous interesting preclinical candidates to be explored further, but it remains to be seen whether any of these will be taken into the clinic (either in cancer, or, perhaps, for neurodegenerative diseases) and, if so, whether any can be developed into a clinical drug. 

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