Chemistry and Biology of Epothilones

Photoswitchable epothilone-based microtubule stabilisers allow GFP-imaging-compatible, optical control over the microtubule cytoskeleton

“…26,27 Epothilones have proven particularly useful as research reagents, in that their greater solubility, bioavailability, and ability to cross the blood-brain barrier, allow applications inaccessible to taxanes: such as systemic (rather than local) administration for stabilising axons, to regenerate the central nervous system after injury. 28 The synthetic tractability of the epothilones has enabled extensive drug analogue campaigns ( Fig 1d ), clarifying structure-activity relationship (SAR) features; 29,30 and a range of epothilone derivatives have undergone advanced clinical trials, with ixabepilone being FDA-approved for treatment of metastatic breast cancer. A further advantage of the chemically simpler epothilone is that late-stage modifications that preserve binding activity while altering chemically or biologically problematic groups are known; in our case, this would later prove to be removal of the C12/C13 epoxide of epothilone B, to give the Z- alkene epothilone D. The SAR of epothilones suggests that while aryl-aryl substituents are not tolerated around C12/C13, 31 even relatively large heterocycles can be tolerated in place of the thiazole, with potent thiazole, purine, quinoline and benzothiazole derivatives all being known, and larger rings particularly tolerated in epothilone D derivatives.…”

“…A further advantage of the chemically simpler epothilone is that late-stage modifications that preserve binding activity while altering chemically or biologically problematic groups are known; in our case, this would later prove to be removal of the C12/C13 epoxide of epothilone B, to give the Z- alkene epothilone D. The SAR of epothilones suggests that while aryl-aryl substituents are not tolerated around C12/C13, 31 even relatively large heterocycles can be tolerated in place of the thiazole, with potent thiazole, purine, quinoline and benzothiazole derivatives all being known, and larger rings particularly tolerated in epothilone D derivatives. 29…”

12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

“…Inspired by the required presence of a basic nitrogen atom in a certain position in highly active epothilones and motivated by the necessity for suitable functional groups as points of attachment for conjugation studies, , we decided to focus on epothilone analogues in which the epoxide moiety of epothilone B is replaced with an aziridine moiety. Given that most synthetic routes to epothilones proceed through the corresponding C12–C13 olefin and mindful of the power of the recently disclosed Ess–Kürti–Falck aziridination, we initiated an exploration to test whether epothilones C and D ( 3 and 4 , Figure ) could serve as substrates for this reaction.…”

“…The epothilone class of natural products, represented by epothilones A, B, C, and D ( 1 – 4 , Figure ), enjoys a rich history of synthetic studies stemming from total synthesis and semisynthesis expeditions . These investigations led to several drug candidates with one receiving approval as a clinical agent for the treatment of metastatic or locally advanced breast cancer ( 5 , ixabepilone, marketed as Ixempra, Figure ).…”

A Highly Stereoselective, Efficient, and Scalable Synthesis of the C(1)–C(9) Fragment of the Epothilones

“…1 Epothilone B (epo B) in particular possesses sub-nanomolar potencies against a variety of cell lines, and in 2007 the FDA approved ixabepilone (the lactam analog of epo B) for use in the treatment of particularly aggressive and otherwise unresponsive forms of metastatic breast cancer. 2 Extensive SAR studies have been carried out in numerous laboratories, 3 and this has led to several analogs being advanced into clinical trials, most notably sagopilone, 4 whose development has been halted for unspecified reasons despite demonstrating efficacy in several Phase II trials, and iso-fludelone, 5 Danishefsky’s designed analog that has exhibited a remarkably favorable pharmacokinetic profile in an extensive pre-clinical evaluation and that is currently being evaluated in a Phase I trial. As a prelude to launching our own program in the design, synthesis, and evaluation of epothilone analogs possessing novel functionality, we targeted the development of an efficient, step-economical, and scalable synthesis 6,7 of the C(1)–C(9) fragment that is conserved in every important epothilone derivative save sagopilone.…”