Microtubule stabilizing agents epothilone

Molnar 1, Schupp T, Ono M, et al. (2000) The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium ceUulosum So ce90. Chem. Biol. 7 97-109. 

Kowalski RJ, Giannakakous P et al (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272 2534-2541... 

Chemical Synthesis and Biological Studies of the Epothilones - Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. 

The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology. 

Peluroside A was the first microtubule stabilizing agent whose conformation has been determined bound to microtubules (those of Paclitaxel and Epothilone were determined in non-microtubular tubulin [5, 12, 38, 91]). In the bound state, the NMR data, assisted by molecular mechanics calculations and docking experiments, indicated that only one (that present in water, B) of the two major conformations existing in water solution is bound to microtubules (a-tubulin). A model of the binding mode to tubulin has also been proposed [27], involving the a-tubulin monomer, in contrast with paclitaxel, which binds to the p-monomcr. 

Chart 9 Schematic representation of the principal microtubule stabilizing agents (MSAA) paclitaxel (10) and docetaxel (11), epothilones A-D (12-15), discodermolide (16), eleutherobin (17) and sarcodictyin (18), laulimalide (19) and peloruside A (20)... 

After the identification of the paclitaxel mechanism of action, several additional microtubule stabilizing agents were discovered from natural sources (Chart 9). Among them, epothilones (12-15) are the most studied and characterized. Epothilones A and B (12,13) were first isolated by Hofle and coworkers [54] from a myxobacterium (Sorangium cellulosum strain 90) in 1993, while their activity in stabilizing microtubule similarly to paclitaxel was reported for the first time by Bollag and co-workers in 1995 [55], Experiments with radio-labeled paclitaxel... 

Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995 55 2325-2333. 

A small, but structurally diverse collection of naturally occurring non-taxane microtubule stabilizing agents (MTS) has been discovered over the last decade. These include the epothilones (EPO), eleutherobin, laulimalide, dicytostatin (Figure 2) and (+)-discodermolide. 

Aza-epothilone 1 (( )-(25,95,7 0f ,77f ,745)-10,14-dihydroxy-9,l 1,13,13-tetramethyl-2-[2-(l,2-dimethyl-benzimidazol-5-yl]-12,16-dioxo-l-oxa-5-aza-cyclo-hexadecane-5-carboxylic acid tert-butylester) and its 7,8-dehydro analogue 2 are potent inhibitors of human cancer cell growth, and represent a structurally new class of natural product-derived microtubule-stabilizing agents. 

---