Strategic Incorporation of Fluorine into Taxoid Anticancer Agents for Medicinal Chemistry and Chemical Biology Studies.

This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chemistry and chemical biology studies. Novel 3'-difluorovinyltaxoids were strategically designed to block the metabolism by cytochrome P-450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3'-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3'-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymerization assay, morphology analysis by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR analysis. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other analytical methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical solution to this problem.