Structure-activity relationship (SAR) studies on taxoids derived from 14-OH-baccatin III led to the discovery of a highly potent anticancer agent IDN5109. IDN5109 exhibits much superior activity against a variety of drug-resistant cancers as compared to paclitaxel and docetaxel, and is orally active with excellent bioavailability. Human clinical trials began on the basis of highly promising preclinical study results. A series of other "Second Generation Taxoids" that possess 2-3 orders of magnitude higher potencies against drug-resistant human cancer cell lines as compared to paclitaxel have been developed as well. On the basis of SAR results, conformational analyses, and molecular modeling, a common pharmacophore for paclitaxel, epothilones, eleutherobin, and discodermolide, all of which stabilize microtubules, has been proposed. Based on this common pharmacophore, various hybrids that would become significant lead compounds for the next generation de novo microtubule-stabilizing anticancer agents have been synthesized and their activities assayed. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug binding domain of tubulin as well as Pap. Together with the information for microtubule-bound conformation of fluorine-labeled paclitaxel/taxoid obtained by solid state ~(19)F NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge, which is extremely important for the design and development of the next generation anticancer agents targeting microtubules.
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