Paclitaxel , discodermolide

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

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 study of the tubulin-bound conformation of paclitaxel has resulted in a number of protein-ligand models, partially or fully based on the electron diffraction structure of aP-tubulin in paclitaxel-stabilized Zn2+-induced sheets [5, 12], Obviously, the nature of the paclitaxel binding site and the paclitaxel conformation in the binding site have key implications for the design of new MSA. A deep knowledge of the bioactive conformation would also help to explain how compounds as structurally diverse as the epothilones [48], discodermolide [49], and eleutherobin [50] have very similar mechanisms of action. 

Fig. 12 a Superimposition of the bound conformers of discodermolide and dictyostatin bound to assembled microtubules [94], b AUTODOCK solution of discodermolide and dictyostatin (blue) bound to tubulin (1JFF), also compared with bound paclitaxel (green)... 

We have found that nearly all of the compounds that stabilize MTs also stabilize the 2-D crystals. Compounds that have been used include paclitaxel, epothilone-A and B, discodermolide and eleutherobin. Laulimalide, however, disrupts the sheets and causes them to reform into MTs. Microtubule destabilizing compounds have also been found to disrupt the crystals. 

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)... 

Chart 21 The common pharmacophoric regions proposed by Ojima et al. for paclitaxel and discodermolide... 

The two benzoyl moieties of paclitaxel were compared to two unsaturated hydrophobic regions of discodermolide (regions A and B), while the 10-acetyl group superposed the oxygen-rich region of the 5-lactone (region C). 

Several natural products, such as epothilones, discodermolide, and eleutherobin, were found to have a similar mechanism of action as paclitaxel. A recent review outlined many tubulin stabilization natural products and their analogs as anticancer... 

The similarity in the mechanisms of action of paclitaxel (Section 1.1), the epothilones (Section 1.3), discodermolide and eleutherobin (section 1.2) has led to proposals that these structurally dissimilar substances possess common pharmacophores which could lead to the design and synthesis of analogs having substantially different structures and superior activities. 

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. 

Balachandran, R., Terhaar, E., Welsh, M.J., Grant, S.G., and Day, B.W (1998) The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells preliminary comparisons to paclitaxel. Anti-Cancer Drugs, 9, 67-76. 

Kowalski, R.J., Giannakakou, P., Gunasekera, S.P., Longley, R.E., Day, B.W., and Hamel, E. (1997) The microtubule-stabillizing agent discodermolide competitively inhibits the binding of paditaxd (Taxol) to tubulin polymers, enhances tubulin nudeation reactions more potently than paclitaxel, and inhibits the growth of paditaxel-resistant cells. Mol. Pharmacol. 52,613-622. 

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