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.

NORMAN CAMERMAN, ARTHUR CAMERMAN, and BIBUDHENDRA SARKAR. Can. J. Chem. 54, 1309 (1 976).Glycylglycyl-L-histidine-N-methyl amide is a copper-binding tripeptide designed and synthesized to mimic the copper-transport site of human albumin. Reddish-purple crystals of the copper-tripeptide amide complex (Cu-GGHa), erown at physiological pH, are triclinic,

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The tripeptide L-alanyl-L-alanyl-L-alanine has been crystallized from a water/dimethylformamide solution in an unhydrated form, with cell dimensions a = 11.849, b = 10.004, c = 9.862 A, beta = 101.30 degrees, monoclinic space group P21 with 4 molecules per cell (2 independent molecules in the asymmetric unit). The structure was determined by direct methods and refined to a discrepancy index R = 0.057. The tri-L-alanine molecules are packed in a parallel pleated sheet arrangement with unusually long amide nitrogen-carbonyl oxygen contacts within sheets. Comparisons are made with the antiparallel pleated sheet structure of tri-L-alanine hemihydrate, previously crystallized from the same solvent system.

The crystal structure of diazepam has been determined as part of an investigation into relationships between molecular shape and pharmacological activity of anticonvulsant drugs. The compound crystallizes in the monoclinic system with cell dimensions a = 12.928, b = 13.354, c = 7.976 A, /3 = 90.01°, space group P2Ja. The structure was determined by direct centrosymmetric phasing procedures using data collected on a four-circle diffractometer. Refinement was by anisotropic full-matrix least squares to a final R value of 0.039. The two phenyl rings are planar and the obtuse angle between the normals to the two planes is 125°. There are conformational features very similar to certain features found in another anticonvulsant drug, diphenylhydantoin.