Complex Target-Oriented Synthesis in the Drug Discovery Process:  A Case History in the dEpoB Series

and, Christina R. Harris†; Danishefsky, Samuel J.

doi:10.1021/jo991006d

Cited by 120 publications

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References 118 publications

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“…[16][17][18][19][20][21][22]). At the same time, the methodology developed in the course of those studies has been exploited for the synthesis of a host of synthetic analogs for SAR studies (reviewed in [16,17,20,[23][24][25][26][27]), which highlights the difference in structural complexity (and, consequently, in synthetic accessibility) between epothilone-type structures and taxol. Beyond the investigation of fully synthetic analogs, however, important aspects of the epothilone SAR (structure-activity relationship) have also been derived from numerous semisynthetic epothilone analogs and ixabepilone ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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

2011

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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.

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