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

• Published in: Bioorganic chemistry 2022-02, Vol.119, p.105578-105578, Article 105578
• Main Authors: Wang, Changwei, Chen, Lei, Sun, Yi, Guo, Wanrong, Taouil, Adam K., Ojima, Iwao
• Format: Article
• Language: English
• Subjects: 3rd-generation taxoid; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Difluoromethoxy; Difluorovinyl; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Fluorine - chemistry; Fluorine - pharmacology; Fluorine-containing; Humans; Molecular docking analysis; Molecular Docking Simulation; Molecular Structure; Multidrug resistance; SAR study; Structure-Activity Relationship; Taxane; Taxoids - chemical synthesis; Taxoids - chemistry; Taxoids - pharmacology; Trifluoromethoxy; Tumor Cells, Cultured
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105578

[Display omitted] •Strategic incorporation of CF2CH, OCF3 and OCHF2 groups to 3rd-generation taxoids.•3rd-generation DFV-taxoids possess remarkable potency against MDR cancer cells.•SAR and kill curve analysis of novel taxoids in various cancer cell lines.•Novel DFV-taxoids bearing 3-OCHF2 at the C2-benzoate exhibit the best potency.•Unique molecular interactions of CF2CH and CF3O/CHF2O groups with β-tubulin. 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 CF3O and CHF2O 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 in 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, pancreatic and prostate cancer cell lines. All of these new DFV-taxoids exhibited subnanomolar IC50 values against drug-sensitive cell lines, A549, HT29, Vcap and PC3, as well as CFPAC-1. All of the novel DFV-taxoids exhibited 2–4 orders of magnitude greater potency against extremely drug-resistant cancer cell lines, LCC6-MDR and DLD-1, 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-CF3O/CHF2O-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 a