Fluorine containing chalcones as anticancer agents: Solvent-free synthesis and cytotoxicity against HepG2 cancer cells

Abstract

Introduction: Chalcone analogs are commonly synthesized by the base-catalyzed Claisen-Schmidt condensation reaction of acetophenones and aromatic benzaldehydes. The shortcomings of the traditional protocols are side-products. Grinding and microwave-assisted methods under solvent-free conditions are green approaches for the preparation of chalcones. Herein, we focused on the synthesis of chalcone-based analogs bearing –F/-OCH₃/-OH groups on both A and B rings using grinding and microwave irradiation procedures. In our efforts to search for anticancer agents, fluoro-containing chalcones were subsequently assayed for cytotoxic activities against HepG2 cells.

Method: The fluorinated chalcones were synthesized using cross-aldol reactions between fluoro acetophenones and benzaldehyde analogs. Fluorinated chalcones bearing –OCH₃ at positions of the ring B were prepared by grinding reagents with solid NaOH under solvent-free condition, while fluoro-containing chalcones bearing –OH substituents in the B ring were obtained from the clay-catalyzed microwave irradiation in the absence of solvent. Chemical structures of fluorinated chalcones were elucidated by NMR and MS spectra. The inhibitory activity against HepG2 cells was evaluated through the half-maximal inhibitory concentration (IC₅₀, µM).

Results: Twelve fluorinated chalcones (1a-1c, 2a-2c, 3a-3c, 4a-4c) were successfully synthesized in 33-49% yields. Compounds 3a, 3b, 3c and 4c are novel fluoro-containing chalcones. Except for compounds 1a-1c, fluorinated chalconoids exhibited cytotoxic activities against HepG2 cancer cells with IC₅₀ values in the range 67.51-108.20 µM. Chalconoid 2a showed a highest inhibitory activity with an IC₅₀ value of 67.51±2.26 µM.

Conclusions: The grinding of reagents together prior to adding solid NaOH resulted in desired products. The clay-catalyzed microwave irradiation in the absence of solvent is effective to prepare hydroxy chalcones.  Among synthesized structures by eco-friendly approaches, four fluorinated chalcones 3a-3c and 4c are novel compounds. The scaffold of 4¢-F-3-OCH₃ might contribute to the cytotoxicity against HepG2 cells.