Cell discodermolide

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 Schreiber synthesis is particularly noteworthy in that the absolute configuration of discodermolide was assigned unambiguously, and through the preparation of numerous analogues the first structure-activity relationship study was possible [35,44], Their synthesis of the unnatural antipode (ent-1) also led to the unexpected discovery that it causes cell cycle arrest in the S-phase [107],... 

Discodermolide (DDM, Fig. 16) is a marine natural product that promotes MT assembly more potently than PTX and is active against some PTX-resistant cell lines [118-120], The photoaffmity analogue C19-BPC-DDM labels (3-tubulin in close proximity to the taxol binding site [121] and DDM itself is a competitive inhibitor of PTX binding to MT [120], suggesting that DDM also binds to the PTX binding site on P-tubulin. 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

Honore S, Kamath K, Braguer D, Wilson L, Briand C, Jordan MA. Suppression of microtubule dynamics by discodermolide by a novel mechanism is associated with mitotic arrest and inhibition of tumor cell proliferation. Mol. Cancer Ther. 2003 2 1303-1311. 

Discodermolide (88) was isolated from Discodermia disso-luta by using a P388 cell line toxicity bioassay later it was... 

On the other hand, virtually all target molecules can be synthesized by chemists, using nonenzymatic and/or biocatalytic methods. However, the scale up is still not an easy task, especially in the case of nonenzymatic methods. Discodermolide, for instance, a potent inhibitor of tumor cell growth, has been synthesized on a 60 g scale. However, the 39-step synthesis is the result of the work of 43 industrial chemists and was build on the preparatory work of two leading academic groups (Scheme 4.21) [83]. 

Hydrosilylation-protodesilylation sequence has also been used in several natural product syntheses. The platinum-catalyzed intramolecular hydrosilylation-protodesilylation protocol has been successfully applied in the synthesis of C27-C33 segment of immunosuppressant drug rapamycin C1-C15 fragment of the marine macrolide leucascandrolide A and C17-C24 terminus of discodermolide—a potent inhibitor of tumor cell growth (4). 

Discodermolide (36) is a cytotoxic polyketide isolated in low yield from the Caribbean sponge Discodermia dissoluta 44), The recent discovery that discodermolide shares the same microtubule-stabilising mechanism of antimitotic action as the clinically important anticancer drug, Taxol (paclitaxel), and retains activity against Taxol -resistant cancer cells has stimulated considerable interest (45,46). Due to the scarce supply of the natural material, the development of an efficient total synthesis (47-52) of (+)-discodermolide is needed to provide useful quantities for further testing, as well as enabling access to structurally simplified analogues. 

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