Epothilone derivatives applications

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. 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

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