Crystal and molecular structure of paclitaxel (taxol).

Abstract

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.

Characterization of the Taxol Binding Site on the Microtubule

“…BzDC-Taxol based on the Taxol x-ray structure (20) places the nitrene on the C-3Ј benzamido moiety close to Val 23 ( Fig. 6B) in good agreement with the photoaffinity labeling result (10), as well as the tubulin crystal structure (12).…”

“…Molecular Modeling-Models for 7-BzDC-Taxol were constructed based on the x-ray crystal structures of Taxotere (19) and Taxol (20) and minimized using the Tripos force field with Gasteiger-Hü ckel charges (Sybyl 6.4). The conformation of the 7-BzDC moiety was selected from among several low energy structures to best illustrate its established interaction with ␤-tubulin Arg 282 .…”

“…The baccatin core of Taxotere included in the tubulin crystal structure (red, A) shows some distortion from that of the energy-minimized 7-BzDC-Taxol. The conformation of the C-13 side chains of Taxol and Taxotere are distinct (20). The position of the conformers in the binding pocket was adjusted within the error of the tubulin crystal structure to accommodate van der Waals contacts.…”

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

“…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. 2b) (27). More recently, during the processing of this manuscript, a pharmacophore model (28) and two studies using This paper was submitted directly (Track II) to the PNAS office.…”

Crystal structure of taxuspinanane A acetonitrile solvate, C47H59NO14 · CH3CN

“…The acid resembles homoisoleucine, an unusual amino acid reported in ergot alkaloid ergogaline and possesses the identical chirality [9]. The conformation of taxuspinanane A backbone is essentially similar to the conformation of baccatin III [10], paclitaxel [4], and some of its semisynthetic derivatives [11][12][13][14]. However, in contrast to all structures reported so far, just 2-hydroxy-3-(4-methyl-hexano-Z.…”