Epothilone

Epothilones A (R = H) and B (R = CH3)A: C26H39NO6SB: C27H41NO6SA: 493.66 g/molB: 507.68 g/molA: 152044-53-6B: 152044-54-7A: 448799B: 448013Epothilones C (R = H) and D (R = CH3)C: C26H39NO5SD: C27H41NO5SC: 477.66 g/molD: 491.68 g/molD: 189453-10-9C: 9891226D: 447865Epothilones E (R = H) and F (R = CH3)E: C26H39NO7SF: C27H41NO7SE: 509.66 g/molF: 523.68 g/molThe epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epothilones have better efficacy and milder adverse effects than taxanes. The epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epothilones have better efficacy and milder adverse effects than taxanes. As of September 2008, epothilones A to F have been identified and characterised.Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed. Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B. Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. The structure of epothilone A was determined in 1996 using x-ray crystallography. The principal mechanism of the epothilone class is inhibition of microtubule function. Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Epothilone B possess the same biological effects as paclitaxel both in vitro and in cultured cells. This is because they share the same binding site, as well as binding affinity to the microtubule. Like paclitaxel, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. Furthermore, epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by formation of microtubule bundles throughout the cytoplasm. Finally, epothilone B also causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis. The ability of epothilone to inhibit spindle function is generally attributed to its suppression of microtubule dynamics; but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher antimitotic concentrations, paclitaxel appears to act by suppressing microtubule detachment from centrosomes, a process that is normally activated during mitosis. It is quite possible that epothilone can also act though similar mechanism. One analog, ixabepilone, was approved in October 2007 by the United States Food and Drug Administration for use in the treatment of aggressive metastatic or locally advanced breast cancer no longer responding to currently available chemotherapies. In November 2008, the EMEA refused a marketing authorisation for Ixabepilone. Several synthetic epothilone analogs are currently undergoing clinical development for treatment of various cancers. Epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models. As a result, epothilone B (patupilone) and various analogues are As of 2001 undergoing various clinical phases: patupilone and the fully synthetic sagopilone are in phase II trials; BMS-310705 and BMS-247550 in phase I trials). Results of a phase III trial with ixabepilone (BMS-247550) in combination with capecitabine in metastatic breast cancer have been announced (2007 – leading to FDA approval).