Enantiopure fluorine-containing taxoids: Potent anticancer agents and versatile probes for biomedical problems

Fluorine-containing paclitaxel and docetaxel analogs are reported that are obtained through the coupling of enantiopure (3R,4S)-1-acyl-β-lactams with various baccatins. Some taxoids bearing the trifluoromethyl or difluoromethyl groups at the C-3′ position possessed three orders of magnitude greater potency than either paclitaxel or doxorubicin against both sensitive and drug-resistant human breast cancer cell lines. The incorporation of fluorine in taxoids as a probe has been successfully exploited for the study of their metabolism and structure. Fluorine-containing taxoids are shown to block the metabolic pathways associated with the cytochrome P-450 class of enzymes. Structural studies using ¹⁹F and ¹H NMR techniques on fluorine-containing taxoids in combination with molecular modeling have provided new insights into the biologically relevant conformations of taxoids in solution as well as in the microtubule-bound state.