Recent advances in the medicinal chemistry of taxoid anticancer agents

Taxol^® (paclitaxel) and Taxotère^® (docetaxel) are currently considered to be the most promising leads in cancer chemotherapy. Both paciltaxel and docetaxel exhibit significant antitumor activity against various cancers, especially breast and ovarian cancers, which have not been effectively treated by existing chemotherapeutic drugs. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e. causing mitotic arrest in cancer cells leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesired side effects as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against various classes of tumors. This chapter describes the accounts of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface including: (i) the development of a highly efficient method for the semisynthesis of paclitaxel and a variety of taxoids by means of the β-Lactam Synthon Method (β-LSM), (ii) the structure-activity relationship (SAR) study of taxoids for their activities against human cancer cell lines, (iii) the discovery and development of "second-generation" taxoid anticancer agents that possess exceptional activities against drug-resistant cancer cells expressing the MDR phenotype as well as solid tumors (human cancer xenografts in mice), (iv) the development of fluorine-containing taxoids as a series of the second-generation taxoid anticancer agents and as excellent probes for the identification of bioactive conformation(s) of paclitaxel and taxoids by means of ¹⁹F NMR in solution as well as in solid state for the microtubule-taxoid complex, (v) the development of radiolabeled photoreactive analogues of paclitaxel for photoaffinity labeling and mapping of the drug-binding domain on microtubules as well as P-glycoprotein that is responsible for MDR, and (vi) an SAR study of taxoids on their activities for inducing NO and tumor necrosis factor (TNF) through macrophage activation, which may be operative as an alternative mechanism of action. Thus, this chapter covers a wide range of issues associated with these powerful taxoid anticancer agents, discussing current status and future prospects.