Recent advances in the strategic incorporation of fluorine into new-generation taxoid anticancer agents.

This account describes our recent progress on the strategic incorporation of fluorine and organofluorine moieties into new-generation taxoid anticancer agents for medicinal chemistry and chemical biology studies. In the case study 1, novel 3rd-generation fluorotaxoids bearing 3-OCF or 3-OCFH group in the C2-benzoate moiety were designed, synthesized and examined for their anticancer activities. The potency of novel taxoids against drug-resistant cancer cell lines was 2-3 orders of magnitude higher than that of paclitaxel (PTX). Molecular modeling analysis indicated the favorable van der Waals interactions of OCF and OCHF groups in the binding site. Overall, taxoids bearing a OCHF group at the C2 benzoate position exhibited the highest potencies against multidrug-resistant (MDR) cancer cell lines and cancer stem cell (CSC)-enriched cell lines, indicating that the new 3rd-generation fluorotaxoids are promising candidates as chemotherapeutic agents. In the case study 2, novel 3rd-generation 3'-difluorovinyl (DFV)-taxoids, bearing 3-CFO or 3-CHFO group in the C2-benzoyl moiety, were designed, synthesized, and evaluated for their potencies and pharmacological properties. These new DFV-taxoids exhibited remarkable cytotoxicity against extremely drug-resistant cancer cell lines with subnanomolar IC values, indicating that these new DFV-taxoids can overcome MDR caused by the overexpression of Pgp and other ABC cassette transporters. The molecular docking analysis of new DFV-taxoids revealed that the 3'-DFV moiety and the 3-CFO/3-CHFO group of the C2-benzoate moiety are nicely accommodated to the deep hydrophobic pocket of the PTX/taxoid binding site in the β-tubulin, enabling an enhanced binding through unique attractive interactions between F/OCF/OCHF and the protein. This enhancement in binding is reflected in the remarkable high potency of new 3rd-generation DFV-taxoids. In the case study 3.1, the therapeutic potential of new 3rd-generation DFV-taxoids in anaplastic thyroid cancer (ATC) cells was evaluated and . This study demonstrated that these new DFV-taxoids were more efficacious than PTX against ATC cell lines and tumor xenografts, as demonstrated by the efficient inhibition of cell proliferation and colony formation, induction of apoptosis via the mitotic arrest at the G2/M phase, as well as the suppression of tumorigenic potential in nude mice. Furthermore, tubulin polymerization assay and molecular docking analysis confirmed that these new DFV-taxoids promoted far more rapid polymerization of β-tubulin than PTX through stronger binding to tubulin/microtubules. Taken together, this study has indicated a promising therapeutic potential of these new DFV-taxoids against ATC. In the case study 3.2, DFV-OTX displayed potent cytotoxicity and effective induction of β-tubulin polymerization, as well as the G2/M phase arrest, leading to apoptosis in PTX-sensitive and PTX-resistant breast cancer cells. Furthermore, DFV-OTX clearly exhibited efficacy against MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Thus, DFV-OTX effectively overcame PTX-resistance in MDA-MB-231R cells and tumor xenografts, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation. DFV-OTX was also effective against MCF-7R cells and tumor xenografts, which are PTX-resistant due to different MOA. Accordingly, DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers. Overall, these next-generation fluorotaxoids are promising candidates for highly potent chemotherapeutic agents, as well as payloads for tumor-targeting drug conjugates such as antibody-drug conjugates (ADCs).