Taxol and taxinine are members of the taxane diterpene family, natural substances which are isolated from various Taxus (yew) species. Taxol possesses intriguing activity as a mitotic spindle poison. Unlike classical spindle poisons (e.g. colchicine, vinblastine), taxol is unique in its ability to promote the polymerization of tubulin into microtubular structures in the absence of GTP, and to stabilize microtubules toward de-polymerization in the presence of Ca and at low temperatures. Through this affect, taxol treated cells are blocked in metaphase and cellular replication is inhibited. Undoubtedly, these characteristics underlie the anti-leukemic and anti-tumor activities exhibited by taxol; taxol has shown promising activities against melanoma and ovarian tumors. The broad objectives of this work are to augment through the synthesis of taxinine and taxol existing methodology for the chemical synthesis of functionally and stereochemically complex carbon polycycles possessing unusual skeleta (especially those containing medium rings) which might exhibit interesting biological and medicinal activity. In addition, this work should make available synthetic and semi-synthetic taxol analogues of potential value to clinical and biological investigations. The following are specific goals of this application: 1. Synthesis of Taxinine: This work will continue with special emphasis on the elaboration of the C-ring features. Although taxinine lacks the important biological activity associated with taxol, it shares many structural aspects with taxol and so represents a relevant preliminary target. The synthesis of taxinine will provide a standard by which to judge the success of the overall taxane synthesis strategy. 2. Synthesis of Taxol: One of the routes to taxinine which will receive high priority in the next grant period will provide an intermediate of importance to the taxol plans. Its involvement in a sequence targeted at taxol will be investigated. A homochiral synthesis of the taxol C-13 sidechain has been completed and attempts will be made to attach it to baccatin III, thereby completing a partial synthesis of taxol and making baccatin III a relay target. 3. Preparation of Taxol Analogues of Biological Significance and Related Studies: Work toward the synthesis and partial synthesis of taxol analogues of interest in biological studies will be extended by investigating the preparation of tubulin photoaffinity and fluorescent labels, substrates for the production of antibodies against taxol, analogues for further definition of structure/activity relationships and with potential as more readily accessible drugs and hydrophilic analogues and pro-drugs. In addition, X-ray crystallographic structures for certain key taxanes will be obtained. Several of these avenues of investigation will yield information of interest in total synthesis studies.
| Swindell, C S; Heerding, J M; Krauss, N E et al. (1994) Characterization of two taxol photoaffinity analogues bearing azide and benzophenone-related photoreactive substituents in the A-ring side chain. J Med Chem 37:1446-9 |
| Rao, S; Krauss, N E; Heerding, J M et al. (1994) 3'-(p-azidobenzamido)taxol photolabels the N-terminal 31 amino acids of beta-tubulin. J Biol Chem 269:3132-4 |
| Swindell, C S; Krauss, N E; Horwitz, S B et al. (1991) Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2' configurations. J Med Chem 34:1176-84 |
