Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives

Abstract

Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabilization of cellular microtubules (i.e., a "taxol-like" mechanism of action). They have proven to be highly productive lead structures for anticancer drug discovery, with at least seven epothilone-type agents having entered clinical trials in humans over the last several years. SAR studies on epothilones have included a large number of fully synthetic analogs and semisynthetic derivatives. Previous reviews on the chemistry and biology of epothilones have mostly focused on analogs that were obtained by de novo chemical synthesis. In contrast, the current review provides a comprehensive overview on the chemical transformations that have been investigated for the major epothilones A and B as starting materials, and it discusses the biological activity of the resulting products. Many semisynthetic epothilone derivatives have been found to exhibit potent effects on human cancer cell growth and several of these have been advanced to the stage of clinical development. This includes the epothilone B lactam ixabepilone (Ixempra(®), which has been approved by the FDA for the treatment of advanced and metastatic breast cancer.

Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides

“…5). The pH values of the culture media were measured after cultivation of A. oryzae (OE::pksCH-2), [11][12][13][14][15] . c, Diversity-oriented semi-synthetic process that combines heterologous biosynthesis and artificial diversification (this work).…”

“…To conduct a successful screening of promising drug leads and biological probes, a compound library should be developed that is diverse with regard to the molecular framework. One strategy for expanding the diversity of natural-product-related scaffolds is to make good use of readily available natural products as starting points [11][12][13][14][15] . Although this semi-synthetic approach has great potential to expand the chemical space of natural products, the limited number of natural products that fulfil the availability and reactivity requirements has hindered the emergence of successful examples.…”

Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities

“…Epothilone A was dropped from clinical development due to structural instability in animal plasma. 99 An excellent, comprehensive review of the chemistry and biology of semi-synthetic epothilones was published in 2011 by Prof. Altmann and colleagues 100 and only a few new studies are described here. Lin and co-workers 101 demonstrated the efficient and total synthesis of epothilone B that resulted in an 8% yield in 10–11 steps.…”

Seek and Destroy: The Use of Natural Compounds for Targeting the Molecular Roots of Cancer

“…In contrast to taxol, cytotoxicity of epothilones was not affected in this situation [46]. Currently, the epothilone B lactam ixabepilone is the sole drug to reach the market for cancer treatment [46,50]. These characteristics, coupled with their greater potency and broader activity compared with taxanes, stimulated the development of new synthetic epothilone analogues [49].…”