Probing the Paclitaxel-microtubule Binding Site and Interactions: Design, Synthesis and Evaluation of New Photoaffinity Taxoids

摘要

Paclitaxel (taxol), a structurally complex diterpenoid1 has been developed as a potent drug.against a variety of cancers including breast cancer, ovarian cancer, Kaposi's sarcoma and advanced lung cancer. It possesses unique mechanism of action by binding microtubule and disrupting the microtubule network during cell division. However, the exact paclitaxel binding site on tubulin still remains unclear at the molecular level, and it is essential to understand the interactions of paclitaxel with tubulin and to identify the paclitaxel-tubulin binding interactions on the tubulin peptide in order to design and synthesize more potent analogs of paclitaxel. The photoaffinity labeling approach is a very powerful method to identify the paclitaxel binding site and to study the interactions with tubulin. By attaching various photoaffinity labels to the paclitaxel molecule, the photolabeled analogues can be used as probes to map the paclitaxel binding site on tubulin. Based on the proposal, I have successfully designed and prepared some of the photoaffinity analogs modified at c10, c7. The radioactive analogs modified at C7 were also completed. Biological evaluation of these analogs indicated that they possess good microtubule assembly activity and useful for probing paclitaxel binding site studies.