Eleutherobin

Dess-Martin period. jgso J.OTES NaHC03, Py h iOTES 

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For a tandem Diels-Alder/fragmentation approach to the eleutherobin aglycone, Winkler et al. used Marshall s protocol in an early step of the synthesis. The building block 95 was prepared in that way (Scheme 15.24) [56]. 

Scheme 19.17 A tandem Diels-Alder approach to eleutherobin.

Fig. 2.1 Structures of the naturally occurring mictrotubule stabilizing compounds paclitaxel, epothilones A and B, discodermolide, and eleutherobin.

Several natural products and pharmaceuticals have been made in which a TPAP-catalysed oxidation of a primary alcohol to aldehyde step occurs, and these are listed in 2.1.3. They include agardhilactone, (-)-ceratopicanol, eleutherobin, (-)-eriolangin, (-)-eriolanin, okadaic acid, QS-21A p, cis- rapamycin, solamin and taxol syntheses. 

Cinel, B. Patrick, B.O. Roberge, M. Andersen, R.J. (2000) Solid-state and solution conformations of eleutherobin from X-ray diffraction analysis and solution NOE data. Tetrahedron Lett., 41, 2811-5. 

Hamel, E., Sackett, D. L., Vourloumis, D., and Nicolaou, K. C. (1999). The coral-derived natural products eleutherobin and sarcodictyins A and B Effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry 38, 3490-3498. 

Eleutherobin, via ring-closing diene metathesis, 11, 229 Eleven-membered rings with G-G bonds, 3, 706-707 via ring-closing diene metathesis, 11, 227 Eleven-vertex carboranes, preparation, 3, 63, 3, 97 Elimination reactions... 

Eleutherobin Synthesis, Structure/Activity Relationship, and Pharmacophore... 

The natural product eleutherobin (1) was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [1]. Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 3]. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. 

The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. 

Fig. 1. Molecular structures of eleutherobin, eleuthosides, sarcodictyins, and valdivone.

Both total syntheses of eleutherobin (1) are completed by the introduction of the methyl-urocanic acid moiety through acylation of the C8 hydroxyl group. Finally, the natural product is obtained by removal of protecting groups. 

From an additional study, modification or removal of the sugar moiety also has a substantial influence on the cytotoxic potency of eleutherobin and its cross-resistance in Taxol-resistant cells [14]. These structure/activity profiles should be usable for future design of more potent eleutherobin derivatives. 

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