Recent strategies in the development of taxane anticancer drugs

Paclitaxel (Taxol®, Bristol-Myers Squibb) and docetaxel (Taxtere®, Rhone-Poulenc Rorer SA - now Aventis), complex polyoxygenated taxane diterpenoids bearing phenylisoserine moieties currently in extensive clinical use for the treatment of breast, ovarian and other cancers, are considered to be two of the most important drugs in cancer chemotherapy. However, low solubility, multi-drug resistance (MDR), dose-limiting toxicity as well as other adverse effects associated with these drugs present significant drawbacks. Accordingly, seeking the solutions to these problems of taxane anticancer drugs has been the main focus of both academic and industrial research activities for the period of 1997-1999. New taxoids (i.e., Taxol®-like compounds) with various modifications at the baccatin skeleton and the phenylisoserine side chain have been developed, which possess improved potency, especially against cancers expressing P-glycoprotein (P-gp)-based MDR. A number of prodrugs of paclitaxel and taxoids have been designed and synthesised to tackle the solubility problem, mainly by attacking water-soluble subunit(s) to the C-2 and/or C-7 hydroxyl groups. Novel tumour-recognising taxoids and taxane-based MDR modulators have also been developed, showing considerable promise. Recently, the improvement in drug formulation and delivery of taxane anticancer agents has been receiving increasing attention.