It has been shown that the incorporation of fluorine or organofluorine groups into pharmaceutical and agricultural drugs often induces desirable pharmacological properties through unique protein-drug interactions, involving fluorine. We have reported separately remarkable effects of the 2,2-difluorovinyl (DFV) group at the C3’ position, as well as those of the OCF3 and OCHF2 groups at the 3-position of the C2-benzoyl moiety of the 2nd- and 3rd-generation taxoids on their potency and pharmacological properties. Thus, it was very natural for us to investigate the combination of these two modifications in the 3rd-generation taxoids and to find out whether these two modifications are cooperative at the binding site in the β-tubulin or not, as well as to see how these effects are reflected to the biological activities of the new 3rd-generation DFV-taxoids. Accordingly, we designed, synthesized and fully characterized 14 new 3rd-generation DFV-taxoids. These new DFV-taxoids exhibited remarkable cytotoxicity against human breast, lung, colon, pancreactic and prostate cancer cell lines. All these new DFV-taxoids exhibited subnanomolar IC50 values against drug-sensitive cell lines. Furthermore, all these new DFV-taxoids exhibited 2-4 orders of magnitude greater potency against extremely drug-resistant cancer cell lines as compared to paclitaxel, indicating that these new DFV-taxoids can overcome MDR caused by the overexpression of Pgp and other ABC cassette transporters. Dose-response (kill) curve analysis of the new DFV-taxoids in LCC6-MDR and DLD-1 cell lines revealed highly impressive profiles of several new DFV-taxoids. The cooperative effects of the combination of the 3’-DFV group and 3-OCF3/OCHF2-benzoyl moiety at the C2 position were investigated in detail by molecular docking analysis. We found that both the 3’-DFV moiety and the 3-CF3O/3-CHF2O group of the C2-benzoate moiety are nicely accommodated to the deep hydrophobic pocket of the paclitaxel/taxoid binding site in the β-tubulin, enabling an enhanced binding mode through unique attractive interactions between fluorine/CF3O/CHF2O and the protein beyond those of paclitaxel and new-generation taxoids without bearing organofluorine groups, which are reflected to the remarkable potency of the new 3rd-generation DFV-taxoids.

Design, synthesis and SAR study of fluorine-containing 3rd-generation taxoids

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.