CRYSTAL AND MOLECULAR-STRUCTURE OF PACLITAXEL (TAXOL)

Paclitaxel (formerly called taxol), an important anticancer drug, inhi bits cell replication by binding to and stabilizing microtubule polyme rs, As drug-receptor interactions are governed by the three-dimensiona l stereochemistries of both participants, we have determined the cryst al structure of paclitaxel to identify its conformational preferences that may be related to biological activity, The monoclinic crystals co ntain 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 ta xane ring conformation found in the crystal structure of the paclitaxe l analogue docetaxel (formerly called taxotere). The two paclitaxel mo lecules have carbon-13 side-chain conformations that differ from each other and from that of the corresponding side chain in the docetaxel c rystal structure, The carbon-13 sidechain conformation of one paclitax el molecule is similar to what was proposed from NMR studies done in p olar solvents, while that of the other paclitaxel molecule is differen t 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 structu re-activity studies may suggest which atoms of paclitaxel are importan t for binding to microtubule receptors.