Taxoids structure

Kingston, D.G.I. Natural Taxoids Structure and Chemistry. In Paclitaxel Science and Application , Suffness, M., Ed. CRC Press Boca Raton, 1995 287-315. 

Kingston D. Natural taxoids Structure and chemistry. In Taxol Science and Application, Ed. Suffness M. CRC Press, New York, 1995, p. 287. 

Ojima I, Slater JC, Kuduk SD, Takeuchi CS, Gimi RH, Sun CM, Park YH, Pera P, Veith JM, Bemacki RJ. (1997) Syntheses and structure-activity relationships of taxoids derived from 14 betahydroxy-lO-deacetylbaccatin III. 

D. Nor-Seco Taxoids Probing the Minimum Structural Requirements... 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

It is worthy of note that the activity against MCF7-R expressing MDR phenotype is very sensitive to the structure of the C-10 modifier, while this structural variation generally has little effect on the activity against the normal cancer cell lines. The fact clearly indicates that there is no apparent correlation between the activities of the taxoids against the normal cancer cell lines and the drug-resistant cell line. 

B. The Fluorine Probe Approach Solution-Phase Structure and Dynamics of Taxoids... 

The use of 19F NMR for a variable temperature (VT) NMR study of fluorinated taxoids is obviously advantageous over the use of H NMR because of the wide dispersion of the l9F chemical shifts that allows fast dynamic processes to be frozen out. Accordingly, F2-paclitaxel 65 and F-docetaxel 66 were selected as probes for the study of the solution structures and dynamic behavior of paclitaxel and docetaxel, respectively, in protic and aprotic solvent systems.77 The inactive 2, 10-diacetyldocetaxel (73) was also prepared to investigate the role of the 2 -hydroxyl moiety in the conformational dynamics.89 While molecular modeling and NMR analyses (at room temperature) of 73 indicate that there is no significant conformational changes as compared to paclitaxel, the 19F NMR VT study clearly indicates that this modification exerts marked effects on the dynamic behavior of the molecule.77... 

Thus, the fluorine probe approach has proved useful for the conformational analysis of paclitaxel and taxoids in connection with the determination of possible bioactive conformations.77 The previously unrecognized conformer C might be the molecular structure first recognized by the P-tubulin binding site on microtubules. 

P-Hydroxy-10-deacetylbaccatin III (75, 14P-OH-DAB) was first isolated from the needles of the Himalayan yew tree (Taxus wallichiana Zucc.) and its structure was determined by X-ray crystallographic analysis in 1992.93 Because of an extra hydroxyl group at the C-14 position, 14P-OH-DAB (75) has much higher water solubility than DAB (3), the key precursor of paclitaxel and docetaxel. We envisaged that new taxoids derived from 75 would improve water solubility and bioavailability, and also reduce hydrophobicity-related drug resistance. These improved... 

VI. NOR-SECO TAXOIDS PROBING THE MINIMUM STRUCTURAL REQUIREMENTS FOR ANTICANCER ACTIVITY... 

It is very important to clarify the minimum structural requirements for paclitaxel and taxoids to exhibit anticancer activity by looking at simplified structure analogues. Along this line, we have investigated the role of the A ring by synthesizing novel nor-seco analogues of paclitaxel and docetaxel.37,96... 

The results obtained clearly indicate the importance of the A ring for the strong cytotoxicity of taxoids.19 However, the fact that the reduced-structure analogues, 104a and 104b, retain a certain level of cytotoxicity and their potency against... 

A series of taxoids modified at the C-3 and the C3 -N position (Figure 9) was synthesized and assayed for their ability to induce NO or TNF production by murine C3H/HeN (LPS-responsive) and C3H/HeJ (LPS-hyporesponsive) M< ) and for inhibition of the growth of M(j)-like cell lines, as well as that of LPS-responsive J774.1 and its LPS-hyporesponsive mutant J7.DEF3 cell lines.109 The SAR study revealed the structural requirements to be entirely different from those for strong cytotoxicity. 

Our SAR study of paclitaxel analogues on their ability to activate macrophage, inducing the production of NO and TNF, has revealed stark differences in the structural requirements for cytotoxicity vs. macrophage activation. The results warrant a great deal of further study on the possible alternative or auxiliary mechanism of action for paclitaxel and taxoids, which might lead to the discovery of a new series of taxoid anticancer agents with unique mechanism of action. 

The second chapter addresses new facets of the medicinal chemistry of the important anticancer drug Taxol (paclitaxel). Ojima and coworkers explore, in particular, the structure-activity relationship associated with the 3-phenylisoserine side chain, synthetically exploiting their P-Lactam Synthon Method . Their research has led to, among other things, a series of noteworthy second-generation taxoid anticancer agents. 

For building up a library around a given core structure many examples have been given, e.g. an Indolactam library by Waldmann et al. [11], a Sarcodictyin-based library by Nicoloau et al. [12] and a Taxoid library by Xiao et al. [13]... 

It has been noted that the global shape of other taxoid site ligands, such as PTX, DTX or epothilones, can be described as consisting of a cyclic core and a side-chain tail [124], Although DDM structure is not cyclic and hence its conformation is less restricted, it seems that DDM folds in such a way to resemble the shape of the other drugs. 

Fig. 30 Taxoid site on (3-tubulin and predicted peloruside site on a-tubulin. a Surface representation (view from the inner side of the microtubule) of a tubulin dimer with FIX (red) bound to P-tubulin (green) and peloruside A (orange) bound to the predicted site in a-tubulin (blue), b View of the peloruside binding site. Hydrogen bonds are represented as yellow dashed lines, and the residues involved in these bonds are labeled. Some secondary structure elements are also labeled, c View of the taxol binding site. Some secondary structure elements are labeled. In panels b and c, H7 is colored in orange, and the N-terminal and intermediate domains are colored in green and blue, respectively. (Reprinted with permission from [17]. Copyright 2006 American Chemical Society)...

The attainment of this pocket by quite different structural motifs indicates that the pocket on (3-tubulin may be malleable and its moulding by natural product ligands may be the key to unravelling the mechanisms of tubulin assembly.61 As taxoids and epothilones have proven successful in the clinic,62,63 advancing the understanding as to the mechanisms involved in regulating... 

Peloruside A 14 (Scheme 6.1 Part 2) was isolated from a New Zealand Mycale hentschei marine sponge and initially showed activity against P388 murine leukaemia cells at 10 ng/mL.98 Peloruside s cytotoxicity profile and structural similarity to bryostatin led to the examination of protein kinase C (PKC) as a possible mode of action.242 This was determined to be incorrect and it was soon established that the remarkable activity of peloruside was through the stabilisation of microtubules at a site distinct from the taxoid site.243... 

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