NMR and molecular modeling study of the conformations of taxol and of its side chain methylester in aqueous and non-aqueous solution.

Williams, Howard J.; Scott, A. Ian; Dieden, Reiner; Swindell, Charles S.; Chirlian, Lisa Emily; Francl, Michelle; Heerding, Julia M.; Krauss, Nancy E.

doi:10.1016/s0040-4020(01)81823-8

Cited by 101 publications

(87 citation statements)

References 28 publications

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“…In more polar solvents there is evidence for a change in the C13 side-chain conformation. In both the NMR and molecular modeling study of paclitaxel in aqueous solution by Williams et al (12) and the NMR studies of paclitaxel and docetaxel in mixtures of water and organic solvents by Vander Velde et al (13), it was found that the C3' phenyl group is positioned close to the C2 benzoyl and C4 acetyl groups. The crystal structure conformation of paclitaxel molecule B shows the same clustering of the C2 benzoyl, C4 acetyl, and C3' phenyl groups as suggested by the results of the NMR polar solvent studies.…”

Section: Resultsmentioning

confidence: 99%

Crystal and molecular structure of paclitaxel (taxol).

Mastropaolo

Camerman²,

Luo³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

178

163

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Paclitaxel (formerly called taxol), an important anticancer drug, inhibits cell replication by binding to and stabilizing microtubule polymers. As drug-receptor interactions are governed by the three-dimensional stereochemistries of both participants, we have determined the crystal structure of paclitaxel to identify its conformational preferences that may be related to biological activity. The monoclinic crystals contain two independent paclitaxel molecules in the asymmetric unit plus several water and dioxane solvent molecules. Taxane ring conformation is very similar in both paclitaxel molecules and is similar to the taxane ring conformation found in the crystal structure of the paclitaxel analogue docetaxel (formerly called taxotere). The two paclitaxel molecules have carbon-13 side-chain conformations that differ from each other and from that of the corresponding side chain in the docetaxel crystal structure. The carbon-13 sidechain conformation of one paclitaxel molecule is similar to what was proposed from NMR studies done in polar solvents, while that of the other paclitaxel molecule is different and hitherto unobserved. The paclitaxel molecules interact with each other and with solvent atoms through an extensive network of hydrogen bonds. Analysis of the hydrogen-bonding network together with structure-activity studies may suggest which atoms of paclitaxel are important for binding to microtubule receptors.Since its isolation from the extract of the inner bark of the Pacific Yew tree (1) and the demonstration of its antineoplastic activity against a variety of tumors (2), paclitaxel (formerly called taxol) has become one of the most promising anticancer drugs to appear in decades. Paclitaxel has a complex and novel chemical structure (see Fig. 1) and a unique antitumor mechanism of action. Like the vinca alkaloids vincristine and vinblastine, paclitaxel's site of action is the microtubules. However, unlike the vinca alkaloids, which cause depolymerization of microtubules, paclitaxel promotes microtubule assembly and stabilizes microtubule polymers, thereby blocking cell replication (3).Clinical development of paclitaxel progressed slowly because of the small amounts of drug obtainable from the crude bark extract and its poor water solubility. Adequate supplies can now be synthesized from a precursor found in the needles or leaves of a variety of yew trees (4-6). Paclitaxel has been approved by the U.S. Food and Drug Administration for the treatment of ovarian and breast cancer, and phase II trials are in progress on a wide variety of carcinomas including lung, colon, prostate, head and neck, cervical, and brain. However, along with the tremendous potential that paclitaxel has shown as an antitumor drug, clinical problems with solubility, toxicity, and development of drug resistance are sufficiently severe that the need for paclitaxel analogues with better therapeutic efficacy and less toxicity is clear.

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Section: Resultsmentioning

confidence: 99%

Crystal and molecular structure of paclitaxel (taxol).

Mastropaolo

Camerman²,

Luo³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

178

163

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“…Initially, the nonpolar conformer, with the C-2 and C-3Ј phenyl side chains exhibiting hydrophobic collapse (Fig. 2a), was proposed as the bioactive one (17)(18)(19). Shortly thereafter, however, several laboratories argued in favor of the polar form (20)(21)(22) that juxtaposes the C-2 and C-3Ј benzamido side chains (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Taxol combines a polar and rigid tetracyclic core with an equally polar set of four flexible side chains, containing 10 single bonds that contribute to the conformational flexibility of the molecule. Here we have explicitly considered 26 PTX conformers derived from x-ray crystal structures and from NMR nuclear Overhauser effect data of PTX and its derivatives (15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and a large number of computergenerated conformers. The individual conformers were docked into the experimental density map of the TB-PTX complex.…”

Section: Methodsmentioning

confidence: 99%

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

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The chemotherapeutic drug Taxol is known to interact within a specific site on ␤-tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography, the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the ␤-tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the ␣-tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structureactivity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells.

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“…16 The T-shaped conformers superimpose well with the binding conformation of Taxol inˇ-tubulin. 17,31 The structural information determined by solution NMR in nonpolar organic solvents 18,19 or mixture of polar and organic solvents 15 have significant differences 20,21 and we are thus motivated to investigate the molecular structure of Taxol in solid phase. In this work, we applied 13 C solid-state NMR spectroscopy to characterize the structure of Taxol in powder form.…”

Section: Methodsmentioning

confidence: 99%