Novel fluorinated curcuminoids and their pyrazole and isoxazole derivatives: Synthesis, structural studies, Computational/Docking and in-vitro bioassay
In a continuing search for “curcuminoid (CUR) inspired” compounds with potential antitumor activity, a series of 21 new CUR-BF2 adducts and CURs bearing fluorine, trifluoromethylthio, trifluoromethoxy, and trifluoromethyl substitutents were synthesized in an effort to improve physicochemical properties such as lipophilicity and metabolic stability. Bulky activating groups namely methoxy, acetoxy, and benzyloxy groups were introduced as a way to tune steric/electronic effects. Multinuclear NMR, X-ray analysis and DFT optimizations confirmed that despite significant differences in their substitution patterns these curcuminoids all exist as enolic tautomers, and their CUR-BF2 adducts are symmetrical with equal B-O bond distances. To gauge the potential role of the enolic moiety in interaction with proteins, a library consisting of 22 aryl-pyrazole and isoxazole derivatives were synthesized. 19F NMR provided a rapid and convenient assay to monitor these transformations. Computational/docking studies were performed to compare binding efficiency to target proteins involved in specific cancers versus known inhibitor drugs. Several CUR pyrazoles and isoxazoles presented very favorable binding affinities, particularly those bearing CF3 groups. Highly favorable docking affinities were observed for the benzyloxy-substituted CURs. Selected compounds were tested by in-vitro bioassay against a panel of 60 cancer cell lines, and more specifically against leukemia cell lines by cell viability assay.
Journal of Fluorine Chemistry
Digital Object Identifier (DOI)
Laali, Greves, W. J., Correa-Smits, S. J., Zwarycz, A. T., Bunge, S. D., Borosky, G. L., Manna, A., Paulus, A., & Chanan-Khan, A. (2018). Novel fluorinated curcuminoids and their pyrazole and isoxazole derivatives: Synthesis, structural studies, Computational/Docking and in-vitro bioassay. Journal of Fluorine Chemistry, 206, 82–98. https://doi.org/10.1016/j.jfluchem.2017.11.013