Science and Technology Development Journal

An official journal of Viet Nam National University Ho Chi Minh City, Viet Nam since 1997

Skip to main content Skip to main navigation menu Skip to site footer

 Section: NATURAL SCIENCES

HTML

0

Total

0

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






 Open Access  

Downloads

Download data is not yet available.

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.

Keywords: Fluorinated chalcones, anticancer activity, HepG2 cells, Claisen-Schmidt condensation, grinding, microwave-assisted synthesis.

INTRODUCTION

Chalconoids are a common group of natural products. Chemically, chalcones are composed of two aromatic rings attached at the two ends of a three-carbon α,β-unsaturated carbonyl linker 1 . In view of this, chalconoids have been commonly synthesized from aryl methyl ketones with benzaldehydes via a base-catalyzed Claisen-Schmidt condensation reaction in the liquid phase for several hours 2 , 3 . However, this procedure has several drawbacks, such as long reaction times with probabilities of byproducts (Cannizaro and/or Michael addition products) 3 , 4 . To limit disadvantages, the condensation of acetophenones and aromatic benzaldehydes was carried out in the solid phase in good yields 5 , 6 , 7 . A series of chalconoids were previously prepared via solvent-free grinding and microwave-assisted methods 6 , 7 , 8 .

From a biological point of view, chalcones exhibit diverse properties, including antioxidant 9 , anti-inflammatory 10 , antidiabetic 11 and anticancer 12 activities. In particular, the different functional groups on both aromatic rings of chalcones are responsible for their anticancer properties 13 . Interestingly, the substitution of hydrogen with fluorine in chalcone molecules has improved anticancer activity 14 , 15 . The potent activities can be attributed to the stereochemical changes in the C‒F bond, which modulate the reactivity and stability of overall molecules in metabolic transformations in biological systems 16 , 17 . The antiproliferative activities of fluorinated chalcones against HepG2 cells have been reported. Considering their cytotoxicity against HepG2 cells, Burmaoglu et al. reported that fluoro-substituted chalcones were more effective than nonfluorinated compounds were 18 . The bioisosteric substitution of fluorine instead of hydrogen resulted in increased activities of fluoro-containing chalcones. The in vitro and in silico studies on fluoro-substituted chalcones indicated that the anticancer properties of fluorinated chalcones toward HepG2 cells are dependent on the position, number and size of the substituents. The methoxy (-OCH 3 ) and fluoro (-F) groups contributed to the potent anticancer activity 19 .

Figure 1 . General synthetic procedures for producing fluorinated chalcones by grinding at room temperature (RT) (Method A) and microwave irradiation at 150 °C with montmorillonite K10 (MK10) clay as a catalyst (Method B).

Figure 1 General synthetic procedures for producing fluorinated chalcones by grinding at room temperature (RT) (Method A) and microwave irradiation at 150 °C with montmorillonite K10 (MK10) clay as a catalyst (Method B).

[Download figure]

Motivated by these findings, we synthesized chalcones with the -F group at various positions of ring A and –OCH 3 /-OH at positions of ring B via microwave-assisted, MK10-catalyzed and grinding procedures under solvent-free conditions. In continuation of our studies on anticancer agents, we evaluated their cytotoxicity against HepG2 cells.

MATERIALS AND METHODS

Chemicals

All chemicals and solvents used for synthesis and purification were purchased from suppliers without further purification. 4'-Fluoroacetophenone (99%, Acros Organics), 3'-fluoroacetophenone (99%, Acros Organics), 3',4'-difluoroacetophenone (96%, Fisher), 4-methoxybenzaldehyde (98%, Acros Organics), 3-methoxybenzaldehyde (99%, Acros Organics), 2,3-dihydroxybenzaldehyde (98%, Acros Organics), and 4-hydroxybenzaldehyde (98%, Acros Organics) were selected as starting materials for the synthesis of fluorinated chalconoids in the present work. Sodium hydroxide (NaOH, 99%, China) and montmorillonite K10 (surface area 220–270 m 2 /g, Sigma‒Aldrich) were used as catalysts for grinding and microwave-assisted methods. n -Hexane (HEX, > 99%, J. T. Baker), dichloromethane (DCM, > 99%, J. T. Baker) and ethyl acetate (EA, > 99%, J. T. Baker) as solvents were stored in 4.0 L glass bottles.

Analytical methods

Nuclear magnetic resonance-NMR spectra were recorded on a Bruker Avance (600 MHz ( 1 H), 150 MHz ( 13 C)). Chemical shifts δ [ppm] were referenced to residual protonated solvent signals of: CDCl 3 : δ = 7.26 ppm ( 1 H); 77.16 ppm ( 13 C), DMSO- d 6 : δ = 2.50 ppm ( 1 H); 39.52 ppm ( 13 C). The proton and carbon signals are abbreviated as s (singlet), brs (broad singlet), d (doublet), dd (doublet of doublet), td (triplet of doublet), t (triplet), and m (multiplet). Mass spectrometry-MS measurements were performed on an AGILENT 1200 series LC‒MSD. The intermediates and products were monitored and purified via thin layer chromatography-TLC (silica gel 60 F 254 , Merck) and flash column chromatography-CC (silica gel 0.035–0.070 mm, Merck). UV–detection was carried out at λ = 254 and 365 nm to visualize spots via TLC.

Synthesis of fluorinated chalcones (1a-1c; 2a-2c) via a solvent-free grinding method (Method A)

A mixture including benzaldehydes (5.0 mmol, 1.0 equiv) and fluorinated methyl ketones (5.0 mmol, 1.0 equiv) was ground in an open mortar for 10 min at room temperature using a pestle. Sodium hydroxide (5.0 mmol, 1.0 equiv.) catalyst was added sequentially, and the mixture was ground for 20 min. The progress of the synthetic reactions was monitored by TLC. The reaction mixture was then added to distilled water (15 mL) and transferred completely to a separatory funnel (125 mL). The crude product was extracted with dichloromethane (DCM, 3x15 mL). The combined organic layer was separated, dried over Na 2 SO 4 and evaporated via a rotary evaporator. The residue was chromatographed by CC over silica gel and eluted successively with n -hexane (HEX)/ethyl acetate (EtOAc) (98/2 90/10, v/v ) to afford fluorinated chalcones 1a - 1c ; 2a - 2c .

Synthesis of fluorinated chalcones (3a-3c; 4a-4c) via a solvent-free, MK10 grinding, microwave-assisted method (Method B)

Starting materials of hydroxy-substituted benzaldehydes (5.0 mmol, 1.0 equiv) and fluorinated acetophenones (5.0 mmol, 1.0 equiv) and montmorillonite K10 clay catalyst (1.0 g, 0.2 g/mmol) were first ground using an open mortar with a pestle at room temperature for 20 min. Consequently, the mixture was transferred to a 10 mL vial sealed with a 10 mL cap and heated at 150 o C under microwave irradiation (Microwave Reactor Discover 2.0, CEM, USA). The “standard” method (vessel type: Pyrex; control type: standard; temperature: 150 o C; time: 1.5 h) was selected to perform the reactions. After irradiation for 1.5 h, the mixture was cooled and diluted with 45 mL EtOAc. The solution was filtered through a Büchner funnel to remove the catalyst. The organic phase was dried over Na 2 SO 4 and filtered, and the solvent was removed under reduced pressure. The crude product was purified via CC (eluent: HEX/EtOAc = 95/5→ 80/20).

Assays for HepG2 cells

Fluorinated chalcones were assayed for their cytotoxic activities against human hepatocellular carcinoma (HepG2) cells in vitro via the modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma‒Aldrich, USA) method 20 . Doxorubicin (0.01 mM) was used as a positive control to assess validity. The HepG2 (ATCC, HB-8065TM, USA) cell line was seeded in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and other components. The cells (3×10 5 ) were grown in a 37 o C humidified incubator with 5% CO 2 . Fluorinated chalconoids were dissolved in 10% dimethylsulfoxide in medium (DMSO, Aldrich 99.9%) at a concentration of 20 mg/mL. The final concentrations of the samples in the wells were 128, 32, 8, and 2 µg/mL. Each concentration was tested in four separate wells per 96-well plate and in duplicate (4×2). The concentration of DMSO in the test wells was 0.5%. The growing cells were inoculated at the appropriate concentration (190 µL volume) into each well of a 96-well plate. Sample solutions were applied (10 µL volume) to the culture wells, and the cultures were incubated for 72 hours at 37 o C. MTT was prepared at 5 mg/mL, and 10 µL was added to the microculture wells. After 4 hours of incubation at 37 o C, 210 µL of culture medium was removed from each well, and the formazan product was dissolved in 100 µL of DMSO. The optical density (OD) at 540 nm was measured with a BioTek microplate reader. The percent inhibition I (%) of HepG2 inhibitory activity was calculated via the following equation:

I (%) = [(OD Culture medium with cells – OD Sample )/(OD Culture medium with cells - OD Culture medium without cells )] × 100%

The half-maximal inhibitory concentration (IC 50 ) was determined from the I% values at various inhibitor concentrations.

RESULTS

Solvent-free synthesis of fluorinated chalconoids

Among the twelve fluorinated compounds synthesized in our present work, four fluorinated chalcones, 3a , 3b , 3c and 4c , were synthesized for the first time. The commercial fluoro-substituted acetophenones were coupled with benzaldehydes via a grinding method under solvent-free and NaOH-catalyzed conditions to afford chalcones 1a - 1c and 2a - 2c ( Figure 2 ) in 41-49% yields ( Table 1 ).

Figure 2 . Chemical structures of fluorinated chalconoids.

Figure 2 Chemical structures of fluorinated chalconoids.

[Download figure]

In addition, with the MK10 catalyst in hand, we applied the solvent-free, microwave-assisted method for the synthesis of chalcones bearing hydroxy groups in ring B. After 1.5 h of irradiation at 150 o C, work-up followed by CC resulted in the purification of 3a - 3c ; 4a - 4c in 33-44% yields ( Figure 2 and Table 1 ). The desired products were isolated by silica gel CC using gradients of n -hexane/EtOAc as eluents. The chemical structures were subsequently elucidated via NMR and MS data analysis. According to the NMR spectra, the geometries of the synthetic chalcones were assigned as trans configurations.

( E )-1-(4'-Fluorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1a): Yield 42%, white solid, C 16 H 13 FO 2 [256.09 g/mol]; R f = 0.53 (HEX/EtOAc = 95/5); m.p. 104.7 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.86 (s, 3 H, -OCH 3 ), 6.94 (d, 3 J = 9.0 Hz, 2 H, H3,5), 7.17 (dd, 3 J H,F = 9.0 Hz, 3 J = 8.4 Hz, 2 H, H3',5'), 7.37 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.60 (d, 3 J = 8.4 Hz, 2 H, H2,6), 7.78 (d, 3 J = 15.6 Hz, 1 H, H ), 8.04 (dd, 3 J = 9.0 Hz, 4 J H,F = 5.4 Hz, 2 H, H2',6') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 55.5 (-OCH 3 ), 114.5 (C3,5), 115.6 (d, 2 J C,F = 21.0 Hz, C3',5'), 119.4 (Cα), 127.6 (C1), 130.3 (C2,6), 131.0 (d, 3 J C,F = 9.0 Hz, C2',6'), 134.9 (C1'), 144.9 (C ), 161.8 (C4), 165.5 (d, 1 J C,F = 253.5 Hz, C4'), 188.9 (>C=O) ppm. ESI-MS calcd for [M] - : 256.09; found: m/z 255.60 [M] - .

( E )-1-(3'-Fluorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1b): Yield: 41%, white solid, C 16 H 13 FO 2 ; R f = 0.41 (HEX/EtOAc = 95/5); m.p: 52.6 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.86 (s, 3 H, -OCH 3 ), 6.94 (d, 3 J = 8.4 Hz, 2 H, H3,5), 7.28 (m, 1 H, H4'), 7.35 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.47 (m, 1 H, H5′), 7.61 (d, 3 J = 9.0 Hz, 2 H, H2,6), 7.69 (m, 1 H, H2'), 7.79 (d, 3 J = 7.2 Hz, 1 H, H6'), 7.80 (d, 3 J = 15.6 Hz, 1 H, Hβ) ppm 13 C-NMR (150 MHz, CDCl 3 ): δ = 55.5 (-OCH 3 ), 114.5 (C3,5), 115.2 (d, 2 J C,F = 22.5 Hz, C2'), 119.3 (Cα), 119.5 (d, 2 J C,F = 22.5 Hz, C4'), 124.1 (C6'), 127.5 (C1), 130.2 (d, 3 J C,F = 7.5 Hz, C5'), 130.4 (C2,6), 140.7 (C1'), 145.5 (Cβ), 161.9 (C4), 162.9 ( 1 J C,F = 246.0 Hz, C3'), 189.2 (>C=O) ppm. ESI–MS calcd for [M+H] + : 257.10; found: m/z 256.90 [M+H] + .

( E )-1-(3',4'-Difluorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1c): Yield: 43%, white solid, C 16 H 12 F 2 O 2 ; R f = 0.31 (HEX/EtOAc = 9/1); m.p: 116.7 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.87 (s, 3 H, -OCH 3 ), 6.95 (d, 3 J = 9.0 Hz, 2 H, H3,5), 7.29 (m, 1 H, H5′), 7.33 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.61 (d, 3 J = 9.0 Hz, 2 H, H2,6), 7.80 (m, 1 H, H6'), 7.81 (d, 3 J = 15.6 Hz, 1 H, Hβ), 7.86 (m, 1 H, H2') ppm. 13 C-NMR (150 MHz, CDCl 3 ): δ = 55.5 (-OCH 3 ), 114.6 (C3,5), 117.6 (d, 2 J C,F = 49.5 Hz, C5'), 117.7 (d, 2 J C,F = 49.5 Hz, C2'), 118.6 (Cα), 125.2 (dd, 3 J C,F = 6.0 Hz, 4 J C,F = 3.0 Hz, C6'), 127.3 (C1), 130.4 (C2,6), 135.5 (C1'), 145.7 (Cβ), 162.0 (C4), 187.7 (>C=O) ppm. ESI–MS calcd for [M+H] + : 275.09; found: m/z 275.00 [M+H] + .

( E )-1-(4'-Fluorophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (2a): Yield 49%, white solid, C 16 H 13 FO 2 [256.09 g/mol]; R f = 0.48 (HEX/EtOAc = 9/1); m.p. 66.8 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.86 (s, 3 H, -OCH 3 ), 6.98 (dd, 3 J = 7.8 Hz, 4 J = 1.8 Hz, 1 H, H4), 7.15 (dd, 4 J = 2.4 Hz, 4 J = 1.8 Hz, 1 H, H2), 7.18 (dd, 3 J H,F = 9.0 Hz, 3 J = 8.4 Hz, 2 H, H3',5'), 7.23 (d, 3 J = 7.8 Hz, 1 H, H6), 7.34 (dd, 3 J = 8.4 Hz, 3 J = 7.8 Hz, 1 H, H5), 7.47 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.77 (d, 3 J = 15.6 Hz, 1 H, H ), 8.05 (dd, 3 J = 9.0 Hz, 4 J H,F = 5.4 Hz, 2 H, H2',6') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 55.4 (-OCH 3 ), 113.6 (C2), 115.7 (d, 2 J C,F = 21.0 Hz, C3',5'), 116.4 (C4), 121.1 (C6), 122.0 (Cα), 130.0 (C5), 131.1 (d, 3 J C,F = 9.0 Hz, C2',6'), 134.6 (d, 4 J C,F = 3.0 Hz, C1'), 136.2 (C1), 145.0 (C ), 160.0 (C3), 165.7 (d, 2 J C,F = 252.0 Hz, C4'), 188.9 (>C=O) ppm. ESI-MS calcd for [M-HF] - : 236.09; found: m/z 235.90 [M-HF] - .

( E )-1-(3'-Fluorophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (2b): Yield 42%, yellow solid, C 16 H 13 FO 2 [256.09 g/mol]; R f = 0.46 (HEX/EtOAc = 9/1); m.p. 62.4 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.87 (s, 3 H, -OCH 3 ), 6.98 (dd, 3 J = 8.4 Hz, 4 J = 2.4 Hz, 1 H, H4), 7.16 (brs, 1 H, H2), 7.25 (d, 3 J = 8.4 Hz, 1 H, H6), 7.29 (m, 1 H, H4'), 7.35 (t, 3 J = 7.8 Hz, 1 H, H5), 7.45 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.50 (m, 1 H, H5'), 7.70 (m, 1 H, H2'), 7.78 (d, 3 J = 9.6 Hz, 1 H, H6'), 7.79 (d, 3 J = 15.6 Hz, 1 H, H ) ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 55.4 (-OCH 3 ), 113.6 (C2), 115.3 (d, 2 J C,F = 22.5 Hz, C2'), 116.6 (C4), 119.8 (d, 2 J C,F = 22.5 Hz, C4'), 121.2 (C6), 121.9 (Cα), 124.2 (C6'), 130.0 (C5), 130.3 (d, 3 J C,F = 7.5 Hz, C5'), 134.5 (C1'), 136.1 (C1), 145.5 (C ), 160.1 (C3), 161.1 (d, 1 J C,F = 309 Hz, C3'), 189.6 (>C=O) ppm. ESI-MS calcd for [M+H] + : 257.10; found: m/z 257.00 [M+H] + .

( E )-1-(3',4'-Difluorophenyl)-3-(3-methoxyphenyl)prop-2-en-1-one (2c): Yield 45%, yellow solid, C 16 H 12 F 2 O 2 [274.08 g/mol]; R f = 0.44 (HEX/EtOAc = 9/1); m.p. 81.4 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 3.87 (s, 3 H, -OCH 3 ), 6.98 (dd, 3 J = 8.4 Hz, 4 J = 2.1 Hz, 1 H, H4), 7.15 (brs, 1 H, H2), 7.24 (d, 3 J = 7.8 Hz, 1 H, H6), 7.28 (m, 1 H, H5'), 7.35 (t, 3 J = 7.8 Hz, 1 H, H5), 7.42 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.78 (d, 3 J = 15.6 Hz, 1 H, H ), 7.81 (m, 1 H, H6'), 7.88 (m, 1 H, H2') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 55.4 (-OCH 3 ), 113.6 (C2), 116.6 (C4), 117.6 (d, 2 J C,F = 18.0 Hz, C5'), 117.9 (d, 2 J C,F = 18.0 Hz, C2'), 121.2 (C6), 121.3 (Cα), 125.3 (m, C6'), 130.0 (C5), 135.3 (C1'), 135.9 (C1), 145.7 (C ), 160.0 (C3), 187.7 (>C=O) ppm. ESI-MS calcd for [M+H] + : 275.09; found: m/z 274.90 [M+H] + .

( E )-1-(4'-Fluorophenyl)-3-(2,3-dihydroxyphenyl)prop-2-en-1-one (3a): Yield 38%, yellow solid, C 15 H 11 FO 3 [258.07 g/mol]; R f = 0.38 (HEX/EtOAc = 7/3); m.p. 132.3 °C; 1 H-NMR (600 MHz, CD 3 OD): δ = 6.75 (t, 3 J = 7.4 Hz, 1 H, H5), 6.87 (dd, 3 J = 7.8 Hz, 4 J = 1.2 Hz, 1 H, H4), 7.19 (dd, 3 J = 7.8 Hz, 4 J = 1.2 Hz, 1 H, H6), 7.28 (dd, 3 J H,F = 9.0 Hz, 3 J = 8.4 Hz, 2 H, H3',5'), 7.79 (d, 3 J = 15.6 Hz, 1 H, Hα), 8.14 (dd, 3 J = 9.0 Hz, 4 J H,F = 5.4 Hz, 2 H, H2',6'), 8.15 (d, 3 J = 15.6 Hz, 1 H, H ) ppm 13 C-NMR (150 MHz, CD 3 OD): d = 116.6 (d, 2 J C,F = 21.0 Hz, C3',5'), 118.0 (C4), 120.6 (C5), 121.0 (C6), 122.4 (Cα), 123.2 (C1), 132.4 (d, 3 J C,F = 9.0 Hz, C2',6'), 136.2 (C1'), 142.8 (C ), 146.8 (C3), 147.7 (C2), 166.1 (d, 2 J C,F = 264.0 Hz, C4'), 191.6 (>C=O) ppm. ESI-MS calcd for [M+H] + : 259.08; found: m/z 258.90 [M+H] + .

( E )-1-(3'-Fluorophenyl)-3-(2,3-dihydroxyphenyl)prop-2-en-1-one (3b): Yield 35%, yellow solid, C 15 H 11 FO 3 [258.07 g/mol]; R f = 0.28 (HEX/EtOAc = 8/2); m.p. 122.8 °C; 1 H-NMR (600 MHz, CD 3 OD): δ = 6.75 (dd, 3 J = 8.4 Hz, 3 J = 7.8 Hz, 1 H, H5), 6.87 (dd, 3 J = 7.8 Hz, 4 J = 1.2 Hz, 1 H, H4), 7.20 (dd, 3 J = 8.4 Hz, 4 J = 1.2 Hz, 1 H, H6), 7.39 (m, 1 H, H4'), 7.59 (m, 1 H, H5'), 7.75 (m, 1 H, H2'), 7.78 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.89 (m, 1 H, H6'), 8.15 (d, 3 J = 15.6 Hz, 1 H, H ) ppm 13 C-NMR (150 MHz, CD 3 OD): d = 115.9 (d, 2 J C,F = 22.5 Hz, C2'), 118.1 (C4), 120.6 (C5), 120.7 (d, 2 J C,F = 18.0 Hz, C4'), 121.1 (C6), 122.4 (Cα), 123.1 (C1), 125.5 (d, 4 J C,F = 3.0 Hz, C6'), 131.7 (d, 3 J C,F = 9.0 Hz, C5'), 142.1 (d, 3 J C,F = 6.0 Hz, C1'), 143.4 (C ), 146.8 (C3), 147.8 (C2), 163.6 (d, 2 J C,F = 301.5.0 Hz, C3'), 191.7 (>C=O) ppm. ESI-MS calcd for [M+H] + : 259.08; found: m/z 258.80 [M+H] + .

( E )-1-(3',4'-Difluorophenyl)-3-(2,3-dihydroxyphenyl)prop-2-en-1-one (3c): Yield 44%, yellow solid, C 15 H 10 F 2 O 3 [276.06 g/mol]; R f = 0.22 (HEX/EtOAc = 8/2); m.p. 144.2 °C; 1 H-NMR (600 MHz, CD 3 OD): δ = 6.75 (dd, 3 J = 8.4 Hz, 3 J = 7.8 Hz, 1 H, H5), 6.88 (dd, 3 J = 7.8 Hz, 4 J = 1.8 Hz, 1 H, H4), 7.20 (dd, 3 J = 8.4 Hz, 4 J = 1.2 Hz, 1 H, H6), 7.46 (m, 1 H, H5'), 7.79 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.95 (m, 1 H, H6'), 7.97 (m, 1 H, H2'), 8.17 (d, 3 J = 15.6 Hz, 1 H, H ) ppm 13 C-NMR (150 MHz, CD 3 OD): d = 118.1 (C4), 118.6 (d, 2 J C,F = 22.5 Hz, C5'), 118.7 (d, 2 J C,F = 21.0 Hz, C2'), 120.6 (C5), 121.1 (C6), 121.8 (Cα), 123.1 (C1), 126.9 (d, 3 J C,F = 9.0 Hz, C6'), 137.2 (C1'), 143.4 (C ), 146.8 (C3), 147.8 (C2), 150.8 (C3',4'), and 190.2 (>C=O) ppm. ESI-MS calcd for [M+H] + : 277.07; found: m/z 276.80 [M+H] + .

( E )-1-(4'-Fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (4a): Yield 38%, yellow solid, C 15 H 11 FO 2 [242.07 g/mol]; R f = 0.51 (HEX/EtOAc = 9/1); m.p. 187.4 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 5.64 (1 H, -OH), 6.89 (d, 3 J = 8.4 Hz, 2 H, H3,5), 7.17 (dd, 2 J H,F = 9.0 Hz, 3 J = 8.4 Hz, 2 H, H3',5'), 7.38 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.56 (d, 3 J = 8.4 Hz, 2 H, H2,6), 7.78 (d, 3 J = 15.6 Hz, 1 H, H ), 8.05 (dd, 3 J = 9.0 Hz, 4 J H,F = 5.4 Hz, 2 H, H2',6') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 115.7 (d, 2 J C,F = 27.0 Hz, C3',5'), 116.1 (C3,5), 119.3 (Cα), 127.6 (C1), 130.5 (C2,6), 131.0 (d, 3 J C,F = 10.5 Hz, C2',6'), 134.8 (C1'), 145.1 (C ), 158.2 (C4), 189.2 (>C=O) ppm. ESI-MS calcd for [M-H] - : 241.06; found: m/z 240.80 [M-H] - .

( E )-1-(3'-Fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (4b): Yield 44%, yellow solid, C 15 H 11 FO 2 [242.07 g/mol]; R f = 0.60 (HEX/EtOAc = 8/2); m.p. 63.7 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 6.90 (d, 3 J = 9.0 Hz, 2 H, H3,5), 7.29 (m, 1 H, H4'), 7.34 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.48 (m, 1 H, H5'), 7.56 (d, 3 J = 8.4 Hz, 2 H, H2,6), 7.68 (d, 3 J H,F = 9.6 Hz, 1 H, H2'), 7.79 (d, 3 J = 15.0 Hz, 1 H, H ), 7.80 (d, 3 J = 6.0 Hz, 1 H, H6') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 115.2 (d, 2 J C,F = 21.0 Hz, C2'), 116.1 (C3,5), 119.3 (Cα), 119.6 (d, 2 J C,F = 21.0 Hz, C4'), 124.1 (d, 4 J C,F = 3.0 Hz, C6'), 127.5 (C1), 130.2 (d, 3 J C,F = 7.5 Hz, C5'), 130.7 (C2,6), 140.6 (d, 3 J C,F = 6.0 Hz, C1'), 145.6 (C ), 158.4 (C4), 162.5 (d, 1 J C,F = 246.0 Hz, C3'), 189.5 (>C=O) ppm. ESI-MS calcd for [M-H] - : 241.06; found: m/z 240.80 [M-H] - .

( E )-1-(3',4'-Difluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (4c): Yield 33%, yellow solid, C 15 H 10 F 2 O 2 [260.06 g/mol]; R f = 0.48 (HEX/EtOAc = 7/3); m.p. 176.8 °C; 1 H-NMR (600 MHz, CDCl 3 ): δ = 5.60 (1 H, -OH), 6.90 (d, 3 J = 8.4 Hz, 2 H, H3,5), 7.29 (m, 1 H, H5'), 7.32 (d, 3 J = 15.6 Hz, 1 H, Hα), 7.57 (d, 3 J = 8.4 Hz, 2 H, H2,6), 7.79 (m, 1 H, H6'), 7.80 (d, 3 J = 15.6 Hz, 1 H, H ), 7.86 (m, 1 H, H2') ppm 13 C-NMR (150 MHz, CDCl 3 ): d = 116.1 (C3,5), 117.4 (d, 2 J C,F = 21.0 Hz, C5'), 117.7 (d, 2 J C,F = 22.5 Hz, C2'), 118.6 (Cα), 125.2 (d, 3 J C,F = 9.0 Hz, C6'), 127.5 (C1), 130.7 (C2,6), 135.5 (C1'), 145.7 (C ), 158.4 (C4), and 187.9 (>C=O) ppm. ESI-MS calcd for [M+H] + : 261.07; found: m/z 260.90 [M+H] + .

In vitro cytotoxicity of fluorinated chalcones against HepG2 cells

The in vitro cytotoxic activity of the fluorinated chalcones was assessed against HepG2 cancer cells by determining their half-maximal inhibitory concentration (IC 50 , µM). Doxorubicin was used as a positive control for the MTT assay. To determine the IC 50 values, the percent inhibition of chalconoids was evaluated at final concentrations of 2, 8, 32, and 128 µg/mL in the wells. As summarized in Table 1 , with the exception of chalconoids ( 1a - 1c ), which presented lower cytotoxicities (IC 50 > 128 µg/mL), the other compounds displayed cytotoxic activities against HepG2 cells, with IC 50 values in the micromolar range of 67.51--108.20 µM in our assay. Compounds 2a - 2c exhibited more potent anticancer HepG2 activity than structures 3a - 3c and 4a - 4c did in the present study.

Table 1 Isolated yields of fluorinated chalconoids synthesized by grinding and microwave-assisted procedures and their cytotoxic activity against HepG2 cells

DISCUSSION

Chemistry

Fluorinated chalcones were successfully synthesized via a cross-aldol condensation reaction between benzaldehydes and fluorinated acetophenones in the presence of sodium hydroxide or montmorillonite K10 as catalysts. Starting with the grinding method under solvent-free conditions, an equimolecular mixture of starting materials was ground for 10 min at room temperature before solid NaOH was added. The mixture was further ground for 20 min to afford the expected chalcones 1a - 1c and 2a - 2c in moderate yields of 41-49%. As reported in our previous results, the isolated yields of chalcones synthesized by a base-catalyzed Claisen-Schmidt condensation reaction of aromatic benzaldehydes with acetophenones were dependent on the substituents in the aromatic rings 8 . Under basic conditions, the C‒C bond was formed by nucleophilic attack from the enolate anion to the aldehyde group. Therefore, the presence of electron-donating groups on the benzaldehyde ring was unfavorable for the C‒C coupling reaction. Herein, the moderate conversions of chalcones can be attributed to the effects of the substituents on the aromatic rings. In addition, the yields of the desired chalcones were found to be affected by the synthetic procedure, which led to low yields of the desired chalcones. We found that the majority of the Michael addition product formed by the condensation of the expected chalcone with a second enolate form of acetophenone was observed when the reagents and solid NaOH were ground together. The Michael products were isolated as the main products, and their NMR data are not shown in the present results.

Our target focused on the synthesis of chalcones bearing –F groups in ring A, while the –OCH 3 and –OH groups were substituted in the B ring moiety. In accordance with our previous results of the synthesis of hydroxy chalcones by the grinding method, the C‒C coupling reaction under NaOH-catalyzed conditions was inefficient because of the effects of hydroxy groups 8 . This observation was attributed to the formation of a phenoxide anion, which significantly decreased the reactivity of the carbonyl group via resonance effects. Indeed, our efforts failed to prepare hydroxy chalcones under basic conditions. Clearly, the need for the synthesis of hydroxy chalcones without the protection of hydroxy functional groups becomes apparent. The available protocol for the preparation of the required chalcones under microwave irradiation uses montmorillonite K10 clay as a solid catalyst 7 . Regardless of the absence of hydroxy chalcones in a series of synthesized chalcones, we decided to apply this procedure to synthesize hydroxy chalcones. Surprisingly, except for 4-hydroxy/2,3-dihydroxybenzaldehydes, when a mixture including 2-hydroxy/3-hydroxy/3,4-dihydroxybenzaldehydes and fluorinated acetophenones as starting materials was irradiated at 150 °C for 1.5 h, the expected chalcones were not isolated regardless of the coupling reactions being repeated. We also tested different synthetic conditions for Claisen-Schmidt condensation (irradiation time: 2.0 h; temperature: 170 o C) but obtained disappointing results after purification.

Clay-based catalysts for C‒C bond formation have been widely utilized in organic synthesis 21 , 22 , 23 . The metal ions (M n+ ) present in the MK10 catalyst function as Lewis acids, increasing the electrophilicity of the carbonyl group via coordination 7 . As a result, the attack of the aldehyde group by the enol form of acetophenone becomes favorable for the formation of the desired chalcones. After our attempts, fluorinated chalcones ( 3a - 3c , 4a - 4c ) were obtained in yields not exceeding 44%.

The chemical structures of the fluorinated chalcones were identified via 1 H NMR, 13 C NMR and MS analyses. The 1 H-NMR spectra revealed doublet signals between 7.3 and 7.8 ppm with coupling constants of approximately 15 Hz, indicating the trans-configuration of the chalcones.

Cytotoxicity to HepG2 cells

To evaluate the anticancer activities of the fluorinated chalconoids, we tested the effects of the synthesized compounds on the growth of HepG2 cancer cells. Concentration‒response experiments were carried out to obtain IC 50 (µM) values. As shown in Table 1 , in addition to compounds 1a - 1c , the other fluorinated chalcones induced the death of HepG2 cancer cells, with IC 50 values ranging from 67.51--108.20 µM. Doxorubicin was used as a positive control in the MTT assay. In our study, doxorubicin exhibited cytotoxic activity against HepG2 cancer cells, with an IC 50 value of 28.70 µM, which is higher than that reported in other studies (IC 50 ~ 2-21 µM) 24 , 25 , 26 , 27 , 28 , 29 , 30 .

In general, the biological responses of chalcones are attributed to the presence of the α, -unsaturated carbonyl scaffold as a Michael acceptor. Biologically, the formation of covalent bonds between the α, -unsaturated carbonyl group and nucleophiles such as the sulfhydryl of cysteine or other thiols (-SH) in biological systems to obtain the Michael adduct plays a crucial role in the inhibitory activities 31 , 32 , 33 , 34 , 35 . Indeed, structure‒activity relationship (SAR) analysis of a series of chalcone-based compounds indicated that saturation of the alkene moiety in the chalcone skeleton completely abolished the anticancer activity 33 . In other words, the cytotoxic activities of chalcones toward cancer cells may be due to the Michael acceptor mechanism ( Figure 3 ).

Figure 3 . Michael addition of a chalcone with thiol nucleophiles in biological systems. The picture was taken from Ref. 35.

Figure 3 Michael addition of a chalcone with thiol nucleophiles in biological systems. The picture was taken from Ref. 35.

[Download figure]

A comparison of the chemical structures of all the fluorinated chalcones revealed that the presence of fluoro groups in the A ring and the 4-OCH 3 substitution in the B ring quenched the anticancer activities of compounds 1a - 1c , whereas the remaining candidates presented antiproliferative activities. The effects of fluoro-containing molecules on biological activities remain a trial-and-error process. SAR analysis is relatively simple for interpreting the influence of the fluorine substituent 14 , 15 , 36 . In this study, the motif of chalcones 1a - 1c abolished the cytotoxic effects on HepG2 cells. In our synthetic strategy, the A ring of chalcones is substituted with fluoro groups, while methoxy/hydroxy groups are introduced to the B ring. Considering the contribution of fluoro groups in the A ring to the anticancer activity, compound 2a (IC 50 = 67.51±2.26 µM) displayed a slight increase in activity compared with that of 2b (IC 50 = 72.51±1.79 µM), suggesting that the 4'-F scaffold might contribute to the inhibition of HepG2. The IC 50 values of compounds 3a (IC 50 = 87.22±8.52 µM) and 3c (IC 50 = 79.22±5.03 µM) also suggested the effect of the 4'-F motif on anticancer activity. In our current work, fluorinated chalcones ( 2a - 2c ) bearing a 3-OCH 3 group in the B ring demonstrated higher activities than 3a - 3c did . The 3-hydroxy group and/or increased hydroxylation of the B ring had no apparent effect on the activity against HepG2 cells. 4-Hydroxy chalcone analogs ( 4a - 4c ) exhibited lower activities, suggesting the importance of the 3-OCH 3 /OH position in the inhibitory activity against HepG2 cells.

CONCLUSIONS

In summary, twelve fluoro-containing chalcones were synthesized in 33--49% yields via Claisen-Schmidt condensation by grinding and microwave-assisted methods in a solvent-free environment. Among the structures synthesized via eco-friendly approaches, four fluorinated chalcones, 3a-3c and 4c , are novel compounds. The chemical structures of chalcones were elucidated via NMR and MS analyses. All the compounds were assessed for their anticancer activity against HepG2 cancer cells. Most fluorinated chalcones, with IC 50 values in the range of 67.51--108.20 µM, showed anticancer activity, except for 1a - 1c . The scaffold of 4'-F-3-OCH 3 might contribute to the cytotoxicity against HepG2 cells and warrants further investigation.

LIST OF ABBREVIATIONS

brs: Broad singlet

CC: Column chromatography

DCM: dichloromethane

d: Doublet

dd: Doublet of doublets

DMSO- d 6 : Dimethyl sulfoxide- d 6

equiv: Equivalent

EtOAc: Ethyl acetate

ESI: Electrospray ionization

HEX: n -Hexane

HepG2: Human hepatocarcinoma cell line

IC 50 : Half-maximal inhibitory concentration

MK10: Montmorillonite K10

NMR: Nuclear magnetic resonance

MS: Mass spectrometry

m: Multiplet

RT: Room temperature

SAR: Structure-Activity Relationship

s: Singlet

t: Triplet

TLC: Thin layer chromatography

td: triplet of doublets,

UV: Ultraviolet

AUTHOR CONTRIBUTIONS

Conceptualization: Hoang Minh Hao; development of the synthetic methods: Ho Phuong and Hoang Minh Hao; synthesis of fluorinated chalcones: Ho Phuong, Nguyen Thi Ngoc Anh and Hoang Minh Hao; structural assignment via NMR, MS spectra: Ho Phuong and Hoang Minh Hao; HepG2 assay: Than Quoc An Ha; analysis of cytotoxicity basing on structure: Hoang Minh Hao, Nguyen Thi Loan and Than Quoc An Ha; writing original draft preparation: Ho Phuong and Hoang Minh Hao; writing-review and editing: Hoang Minh Hao. All authors have read and agreed to the published version of the manuscript.

COMPETING INTERESTS

The authors declare that they have no competing interests.

SUPPORTING INFORMATION

The NMR and MS spectra of all the fluorinated chalcones can be found in the Supporting Information.

ACKNOWLEDGMENT

This work belongs to the project grant No: T2024-168 funded by Ho Chi Minh City University of Technology and Education, Vietnam.

References

  1. Rammohan A, Reddy JS, Sravya G, Rao CN, Zyryanov GV. Chalcone synthesis, properties and medicinal applications: a review. Environ Chem Lett [Internet]. 2020 Mar [cited 2024 Jul 21];18(2):433–58. . ;:. Google Scholar
  2. Smith HE, Paulson MC. The Preparation of Chalcones from Hydroxy and Methoxy Aldehydes and Ketones 1. J Am Chem Soc [Internet]. 1954 Sep [cited 2024 Jul 21];76(17):4486–7. . ;:. Google Scholar
  3. Narender T, Papi Reddy K. A simple and highly efficient method for the synthesis of chalcones by using borontrifluoride-etherate. Tetrahedron Lett [Internet]. 2007 Apr [cited 2024 Jul 21];48(18):3177–80. . ;:. Google Scholar
  4. Gaonkar SL, Vignesh UN. Synthesis and pharmacological properties of chalcones: a review. Res Chem Intermed [Internet]. 2017 Nov [cited 2024 Jul 21];43(11):6043–77. . ;:. Google Scholar
  5. Adnan D, Singh B, Mehta SK, Kumar V, Kataria R. Simple and solvent free practical procedure for chalcones: An expeditious, mild and greener approach. Curr Res Green Sustain Chem [Internet]. 2020 Jun [cited 2024 Jul 21]; 3:100041. . ;:. Google Scholar
  6. Rateb NM, Zohdi HF. Atom-Efficient, Solvent-Free, Green Synthesis of Chalcones by Grinding. Synth Commun [Internet]. 2009 Jul 7 [cited 2024 Jun 7];39(15):2789–94. . ;:. Google Scholar
  7. Rocchi D, González J, Menéndez J. Montmorillonite Clay-Promoted, Solvent-Free Cross-Aldol Condensations under Focused Microwave Irradiation. Molecules [Internet]. 2014 Jun 4 [cited 2024 Feb 3];19(6):7317–26. . ;:. Google Scholar
  8. Van PTB, Huy LT, Thuy NTB, Nga VT, Tam LM, Phuong H, et al. Solvent‐free, microwave‐assisted, solid‐catalyzed synthesis and Α‐GLUCOSIDASE inhibition of chalcones. Vietnam J Chem [Internet]. 2023 Jun [cited 2024 Jun 7];61(3):325–32. . ;:. Google Scholar
  9. Cioffi G, Escobar LM, Braca A, De Tommasi N. Antioxidant Chalcone Glycosides and Flavanones from Maclura (Chlorophora) t inctoria. J Nat Prod [Internet]. 2003 Aug 1 [cited 2024 Jul 21];66(8):1061–4. . ;:. Google Scholar
  10. Ur Rashid H, Xu Y, Ahmad N, Muhammad Y, Wang L. Promising anti-inflammatory effects of chalcones via inhibition of cyclooxygenase, prostaglandin E2, inducible NO synthase and nuclear factor κb activities. Bioorganic Chem [Internet]. 2019 Jun [cited 2024 Jul 21]; 87:335–65. . ;:. Google Scholar
  11. Mahapatra DK, Asati V, Bharti SK. Chalcones and their therapeutic targets for the management of diabetes: Structural and pharmacological perspectives. Eur J Med Chem [Internet]. 2015 Mar [cited 2024 Jul 21]; 92:839–65. . ;:. Google Scholar
  12. Leite FF, De Sousa NF, De Oliveira BHM, Duarte GD, Ferreira MDL, Scotti MT, et al. Anticancer Activity of Chalcones and Its Derivatives: Review and in Silico Studies. Molecules [Internet]. 2023 May 10 [cited 2024 Jul 21];28(10):4009. . ;:. Google Scholar
  13. Mahapatra DK, Bharti SK, Asati V. Anticancer chalcones: Structural and molecular target perspectives. Eur J Med Chem [Internet]. 2015 Jun [cited 2024 Feb 3]; 98:69–114. . ;:. Google Scholar
  14. Padhye S, Ahmad A, Oswal N, Dandawate P, Rub RA, Deshpande J, et al. Fluorinated 2′-hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities. Bioorg Med Chem Lett [Internet]. 2010 Oct [cited 2024 Feb 3];20(19):5818–21. . ;:. Google Scholar
  15. Nakamura C, Kawasaki N, Miyataka H, Jayachandran E, Kim IH, Kirk KL, et al. Synthesis and biological activities of fluorinated chalcone derivatives. Bioorg Med Chem [Internet]. 2002 Mar [cited 2024 Feb 3];10(3):699–706. . ;:. Google Scholar
  16. Torrence PF, editor. Biomedical chemistry: applying chemical principles to the understanding and treatment of disease. New York: Wiley; 2000. 415 p. . ;:. Google Scholar
  17. Smart BE. Fluorine substituent effects (on bioactivity). J Fluor Chem [Internet]. 2001 Jun [cited 2024 Jun 8];109(1):3–11. . ;:. Google Scholar
  18. Burmaoglu S, Algul O, Anıl DA, Gobek A, Duran GG, Ersan RH, et al. Synthesis and anti-proliferative activity of fluoro-substituted chalcones. Bioorg Med Chem Lett [Internet]. 2016 Jul [cited 2024 Feb 3];26(13):3172–6. . ;:. Google Scholar
  19. Polat MF, Anil DA, Ozkemahli G, Turkmenoglu B, Hepokur C, Burmaoglu S, et al. New Fluoro‐ and Trifluoromethyl‐Substituted Trimethoxychalcones as Anticancer Agents: Synthesis, Bio‐evaluation, and Computational Studies. ChemistrySelect [Internet]. 2023 Aug 31 [cited 2024 Feb 3];8(32): e202301189. . ;:. Google Scholar
  20. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods [Internet]. 1983 Dec [cited 2024 Jun 7];65(1–2):55–63. . ;:. Google Scholar
  21. Ballini R, Bosica G, Ricciutelli M, Maggi R, Sartori G, Sartorio R, et al. Clay-catalyzed solventless synthesis of trans-chalcones. Green Chem [Internet]. 2001 [cited 2024 Jun 7];3(4):178–80. . ;:. Google Scholar
  22. Varma RS. Clay and clay-supported reagents in organic synthesis. Tetrahedron [Internet]. 2002 Feb [cited 2024 Jul 21];58(7):1235–55. . ;:. Google Scholar
  23. Nagendrappa G. Organic synthesis using clay and clay-supported catalysts. Appl Clay Sci [Internet]. 2011 Aug [cited 2024 Feb 3];53(2):106–38. . ;:. Google Scholar
  24. Bomfim DS, Ferraz RPC, Carvalho NC, Soares MBP, Pinheiro MLB, Costa EV, et al. Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma H ep G 2 Cells. Basic Clin Pharmacol Toxicol [Internet]. 2013 Nov [cited 2024 Sep 22];113(5):300–6. . ;:. Google Scholar
  25. Le MT, Chau NTN, et al. In vitro cytotoxic activity against human hepatoma HepG2 cells, antioxidant activity, total phenol and flavonoid content of methanol extracts from four plants in Bay Nui, An Giang Province. Sci Technol Dev J - Health Sci [Internet]. 2020 [cited 2024 Sep 22]. . ;:. Google Scholar
  26. Pascale F, Bedouet L, Baylatry M, Namur J, Laurent A. Comparative Chemosensitivity of VX2 and HCC Cell Lines to Drugs Used in TACE. Anticancer Res. 2015 Dec;35(12):6497–503. . ;:. Google Scholar
  27. Sesang W, Punyanitya S, Pitchuanchom S, Udomputtimekakul P, Nuntasaen N, Banjerdpongchai R, et al. Cytotoxic Aporphine Alkaloids from Leaves and Twigs of Pseuduvaria trimera (Craib). Molecules [Internet]. 2014 Jun 25 [cited 2024 Sep 22];19(7):8762–72. . ;:. Google Scholar
  28. Lalitha LJ, Sales TJ, Prince PC, Agastian P, Kim YO, Mahmoud AH, et al. In vitro phytopharmacological and anticancer activity of Loranthus Longiflorus Desv. Var. Falcatuskurz against the human lung cancer cells. J King Saud Univ - Sci [Internet]. 2020 Jan [cited 2024 Sep 22];32(1):1246–53. . ;:. Google Scholar
  29. Al-Shafie TA, Mahrous EA, Shukry M, Alshahrani MY, Ibrahim SF, Fericean L, et al. A Proposed Association between Improving Energy Metabolism of HepG2 Cells by Plant Extracts and Increasing Their Sensitivity to Doxorubicin. Toxics [Internet]. 2023 Feb 16 [cited 2024 Sep 22];11(2):182. . ;:. Google Scholar
  30. Elshahawy ZR, Saad EA, El-Sadda RR. Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats. Liver Res [Internet]. 2023 Dec [cited 2024 Sep 22];7(4):352–60. . ;:. Google Scholar
  31. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci [Internet]. 2001 Mar 13 [cited 2024 Jun 7];98(6):3404–9. . ;:. Google Scholar
  32. Dinkova-Kostova AT, Abeygunawardana C, Talalay P. Chemoprotective Properties of Phenylpropenoids, Bis(benzylidene)cycloalkanones, and Related Michael Reaction Acceptors: Correlation of Potencies as Phase 2 Enzyme Inducers and Radical Scavengers. J Med Chem [Internet]. 1998 Dec 1 [cited 2024 Jul 21];41(26):5287–96. . ;:. Google Scholar
  33. Srinivasan B, Johnson TE, Lad R, Xing C. Structure−Activity Relationship Studies of Chalcone Leading to 3-Hydroxy-4,3′,4′,5′-tetramethoxychalcone and Its Analogs as Potent Nuclear Factor κB Inhibitors and Their Anticancer Activities. J Med Chem [Internet]. 2009 Nov 26 [cited 2024 Jun 7];52(22):7228–35. . ;:. Google Scholar
  34. Maydt D, De Spirt S, Muschelknautz C, Stahl W, Müller TJJ. Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds. Xenobiotica [Internet]. 2013 Aug [cited 2024 Jun 7];43(8):711–8. . ;:. Google Scholar
  35. Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem Rev [Internet]. 2017 Jun 28 [cited 2024 Jun 7];117(12):7762–810. . ;:. Google Scholar
  36. Dias TA, Duarte CL, Lima CF, Proença MF, Pereira-Wilson C. Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin. Eur J Med Chem [Internet]. 2013 Jul [cited 2024 Feb 3]; 65:500–10. . ;:. Google Scholar


Author's Affiliation
Article Details

Issue: Vol 27 No 4 (2024)
Page No.: 3623-3632
Published: Dec 31, 2024
Section: Section: NATURAL SCIENCES
DOI: https://doi.org/10.32508/stdj.v27i4.4350

 Copyright Info

Creative Commons License

Copyright: The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 How to Cite
Ho, P., Nguyen, T. L., Nguyen, T. N. A., Ha, A. Q. T., & Hoang, H. (2024). Fluorine containing chalcones as anticancer agents: Solvent-free synthesis and cytotoxicity against HepG2 cancer cells. Science and Technology Development Journal, 27(4), 3623-3632. https://doi.org/https://doi.org/10.32508/stdj.v27i4.4350


 Download Citation
 Cited by

Article level Metrics by Paperbuzz/Impactstory
Article level Metrics by Altmetrics

 Article Statistics
HTML = 0 times
PDF   = 0 times
XML   = 0 times
Total   = 0 times