DESCRIPTION: (Verbatim from the Applicant's Abstract) Paclitaxel is a novel diterpenoid which is now well established as a clinically active anticancer agent. Due to the complexity of the molecule, attempts to create paclitaxel analogs to obtain mechanistic information have been limited. Thus, there is relatively little information on the biochemical basis of this natural agonist at the tubulin binding site. Using crystal structure and NMR data, we have (along with several other groups) successfully computer-modeled the paclitaxel molecule in an aqueous environment. Contrary to other structures that have been modeled, for the most part in organic solvent, we have found that in water the paclitaxel molecule, to some degree, collapses upon itself. In this collapsed form, several functionalities, which are not likely neighbors in the traditional non-aqueous models, become extremely close to each other in space. Since in the body's aqueous environment, the paclitaxel molecule is most likely found in some form of the collapsed structure, we have postulated that the collapsed paclitaxel structure is likely to be an excellent model for the pharmacologically active shape. Thus, we are proposing the synthesis of several paclitaxel congeners that are "tied down" to mimic various stages of molecular collapse. Base on our computer-modeling data, we would expect these derivatives to show a high degree of binding specificity to the tubulin binding site.