New Fluorescent Water-Soluble Taxol Derivatives

摘要

Paclitaxel (taxol, 1), a natural diterpenoid found in the stem bark of the pacific yew Taxus brevifolia, is one of the most promising anticancer agents for a variety of tumors, due to its unique ability to inhibit cell division as well as other interphase processes by stabilizing microtubules. This has stimulated an intense and detailed study in many laboratories of the chemistry and the biochemistry of this exciting antitumor agent. Reports describing the total synthesis of taxol, its chemical modifica-tion and structural analysis, and the search Tor new taxoids with improved pharmacological-properties have been published. The basic mechanism of the biological action of taxol is also a research topic of relevance for the development of practicaltherapies with this drug. We have described the low-resolution solution structures of taxoid-induced microtubules, the assembly of purified GDP-tubulin in the presence of taxoids, and the link between the taxoid binding and microtubule assembly reactions.In the course of these investigations we realized that a fluorescent and water-soluble taxol derivative would be an enormous help, because a) it would allow the direct in vivo study of the target microtubules in tumour cell cultures by fluorescence microscopy, and b) it would provide an extremely useful tool for the study of the molecular mechanisms of taxoid-induced microtubule assembly, as well as for the discovery of other putative taxol targets and clinical diagnostic assays.