Discodermolide structure

Tubulin Discodermolide (Structure 16.3) Sponge, Discodermia sp. Anticancer14... 

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 natural products eleutherobin (1), epothilone (23), paditaxel (24), nonataxel (25), and discodermolide (26) (Figure 6) show a similar mode of action. Furthermore, competitive inhibition of paditaxel binding to microtubules by epothilone, eleutherobin, and discodermolide is observed, and so a common pharmacophore and the existence of a common tubulin binding site are therefore strongly suggested [15]. The identification of comparable structural characteristics is complicated, since conformations established by NMR spectroscopy or X-ray structure analysis do not necessarily correspond to the binding conformations [16]-... 

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],... 

MS As with different chemical structures have been discovered in different natural sources. Taxanes come from plants, epothilones and cyclostreptin are of microbial origin, whereas discodermolide, dictyostatin, eleutherobin, laulimalide and peloruside were discovered in sea organisms (for a classification and MSA structures see [20]). We do not know of MSAs from a purely synthetic chemistry not related to natural products. 

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. 11 Superimposition of the X-ray structure of discodermolide black) [92], bound to non-assembled tubulin (blue) [91] and bound to microtubules [94]. Minor adjustments are observed...

Canales A, Matesanz R, Gardner NM, Andreu JM, Paterson I, Diaz JF, Jimenez-Barbero J (2008) The bound conformation of microtubule-stabilizing agents (II) NMR insights on the bioactive 3D structure of discodermolide and dictyostatin. Chemistry (DOI 10.1002/chem.200800039)... 

One of these methods is NAMFIS (NMR Analysis of Molecular Flexibility in Solution) [62], which considers all candidate conformations that are theoretically accessible to the molecule and optimizes their mole fractions until their computed variables match the experimental NMR data (usually NOEs and J couplings, in the future potentially also residual dipolar couplings). NAMFIS has been used to analyze the solution structures of several tubulin-binding drugs, such as PTX [63], epothilones [26], discodermolide [60] or laulimalide [64],... 

Fig. 16 Structures of the MT-stabilizing agents Discodermolide (left) and Dictyostatin (right)...

Fig- 17 The X-ray structure and three conformational classes of discodermolide identified by NAMFIS analysis of the NMR spectra in DMSO-d6. a The X-ray conformation, b The corkscrew form, c The sickle motif, d An extended or awl form. (Reprinted with permission from [60]. Copyright 2001 American Chemical Society)... 

Figure 19.11. Structure of discodermolide. The circled biophore is responsible for the inhibition of tubulin polymerization.

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. 

Figure 2 Structures of compounds reported from Caribbean specimens of Discodermia spp. 6 (polydiscamide A), 7 (discobahamin A), 8 (discodermide), 9 (discodermindole), 10 (discodermolide)...

Fig. 2.3 Structures of discodermolide and apoptolidin - two extremely challenging pharmacologically interesting target molecules. 

Figure 7-4 General scheme for natural library creation and screening. The chemical structure of natural product (+)- discodermolide is shown.

ABSTRACT Discodermolide and pironetin are two immunosuppressive agents with antitumor activity. The isolation, structure elucidation, biological activity are reported as well as the synthetic routes to these two compounds. Five syntheses of discodermolide and seven syntheses of pironetin are described. 

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