Fluoro-curcuminoids and curcuminoid-BF2 adducts: synthesis, x-ray structures, bioassay, and computational/docking study.

LAALI, KENNETH K.; QI, X.; BUNGE, S.; RATHMAN, B.; BOROSKY, GABRIELA L.

JOURNAL OF FLUORINE CHEMISTRY

ELSEVIER SCIENCE SA

Lugar: Amsterdam; Año: 2016 vol. 191 p. 29 - 41

0022-1139

A series of alpha-carbonyl fluorinated curcuminoids were synthesized by direct mono- and difluorination with Selectfluor (F-TEDA-BF4) at r.t. without using a base or additive. Ring fluorinated/trifluoromethy-lated curcuminoid-BF2 adducts were synthesized by reaction of the corresponding benzaldehydes with acetylacetone-BF2. Decomplexation of CUR-BF2 adducts under microwave irradiation gave the corresponding curcuminoids. Multinuclear NMR and X-ray analysis confirm that curcuminoids bearing fluorines or trifluoromethyl groups in the aryl rings as well as those that are monofluorinated at the active methylene position all exist as enol tautomers. The alpha,alpha-difluorination brings about significant conformational change as these curcuminoids become fixed in the 1,3-diketone configuration. The X-ray structures of CUR-BF2 complexes are consistent with the formation of symmetrical adducts with equal B-O bond distances. The anti-proliferative activity of these compounds were tested by in-vitro bioassay against several different cancer cell lines. The corresponding CUR-BF2 adducts exhibited exceptionally high activities at micromolar and in some cases nanomolar concentrations that greatly surpass the activity of parent curcumin. Computational docking calculations were performed to gauge bindingenergies of these compounds in HER2 protein, and in 20S proteasome, for comparison with the bioassay-derived activity data.