Fluorinated and N-Acryloyl-Modified 3,5-Di[(E)-benzylidene]piperidin-4-one Curcuminoids for the Treatment of Pancreatic Carcinoma

Abstract

Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…In most cases, the resulting solid is separated from the reaction mixture by vacuum filtration and washed with ice water to remove the excess base. Finally, the solid product is dried and recrystallized from hexane/ethyl acetate or EtOH to obtain pure crystals [18,[23][24][25][26].…”

“…Homogeneous basic catalysts allow the CSC reaction to be conducted at lower temperatures in a shorter time. Protocols based on catalysts like NaOH/EtOH [18,23,27] and NaOH/MeOH [24,[28][29][30] have been reported. Nevertheless, these methods have certain limitations, such as the following: excess or stoichiometric amounts of reactants are employed, and the reactants can be corrosive and may not be recoverable.…”

“…Additionally, the authors found that the pro-apoptotic activity of compound 207 in pancreatic cancer cells surpasses the apoptosis induction properties of compound 171, and that compound 207 activates caspase-3, suppresses antiapoptotic BCL2 and BCL-XL expression, and increases PARP cleavage in pancreatic cancer cells. They concluded that the anti-pancreatic cancer activity is favored by the N-acryloyl-piperidin-4-one moiety combined with 3,4-difluoro-or 3-fluoro-4-methoxy-substituted phenyl rings [24].…”

Monoketone Curcuminoids: An Updated Review of Their Synthesis and Biological Activities

“…In some methodologies, at the end of the reaction, the reaction mixture is neutralized by adding a hydrochloric acid (HCl) solution to the vessel [21] In most cases, the resulting solid is separated from the reaction mixture by vacuum filtration and washed with ice water, to remove excess base. Finally, the solid product is dried and recrystallized from hexane/ethyl acetate, EtOH, or EtOH/ to obtain pure crystals [16,[21][22][23][24]. Besides NaOH, calcium hydroxide (Ca(OH)2) has been used as a basic catalyst in CSC to obtain MKCs.…”

“…Additionally, the authors found that the proapoptotic activity of compound 207 in pancreatic cancer cells surpasses the apoptosis induction properties of compound 171, and that compound 207 activates caspase-3, suppresses the antiapoptotic BCL2 and BCL-XL expression, and increase PARP cleavage in pancreatic cancer cells. They concluded that the antipancreatic cancer activity is favored by the N-acryloyl-piperidin-4-one moiety combined with 3,4-difluoro-or 3-fluoro-4-methoxy-substituted phenyl rings [22]. Curcumin A (10) inhibits human gastric cancer cells with no observable toxicity to normal cells [64].…”