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CHEMICAL PROBLEMS 2024 no. 2 (22) ISSN 2221-8688
177
UDC 615.281:547.972
NEW CHALCONE DERIVATIVES AS ANTICANCER AND ANTIOXIDANT AGENTS: SYNTHESIS, MOLECULAR DOCKING STUDY AND BIOLOGICAL EVALUATION
Nabeel A. Abdul-Rida*, Kawther M. Talib
Department of Chemistry, College of Science, University ofAl-Qadisiyha,
Diwanyiah, 58002, Iraq *Email: [email protected], Kawthertallib [email protected]
Received 18.12.2023 Accepted 16.02.2024
Abstract: In this approach, a series of new chalcone derivatives bearing baclofen drug were synthesized via Claisen-Schmidt condensation and evaluated in vitro as anticancer and antioxidant agents. The newly synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR spectra, and elemental analysis. All products were screened in vitro against both cell lines HdFn and MCF-7. The cytotoxicity assay results revealed that derivatives 5a and 5d exhibited good inhibition for cell lines MCF-7 with IC50 values 32.5 and 37.6 pM, respectively while 5a and 5c exhibited acceptable inhibition for HdFn with IC50 values 76.7 and 78.6 pM, respectively, compared to the Tamoxifen drug. Molecular docking study of the target compounds confirmed the results of the cytotoxicity test. In addition, results of the DPPH investigation revealed good antioxidant activity for derivatives 5a, 5c and 5d with inhibition percentages 86.62, 81.38, and 76.42%, respectively, compared to ascorbic acid.
Keyword: Chalcone, Anticancer, Antioxidant, Molecular Docking, Cytotoxicity DOI: 10.32737/2221-8688-2024-2-177-186
Introduction
Cancer is a deadly disease that still threatens human lives despite scientific progress and continuous attempts to develop a mechanism to control and prevent the disease. Therefore, many researches and recent studies have sought to find an effective strategic treatment that meets the ambitions of the world [1]. Many synthesized chemical compounds have shown various biological activities [2-9]. Among those compounds, chalcones and their derivatives have received increasing attention
from researchers because of their various activities, such as anti-bacterial [10-12], antifungal [13, 14], anti-cancer [15-17], antiAlzheimer [18, 19], anti-inflammatory [20, 21], and antioxidant [22-24], in addition to their importance in the industrial field [25-27].
In this work, we created a number of chalcones combined with the baclofen drug and studied their anti-cancer and antioxidant activity, as well as studying their molecular docking.
Experimental part
General information
All the chemicals and solvents were obtained from commercial suppliers and were used as received without further purification. Melting points remained uncorrected and were determined on the Symmetric Multiprocessing
(SMP) device (Gallenkamp). Fourier-transform infrared (FT-IR) spectra were recorded with FT-IR spectrophotometer (Bruker). Nuclear magnetic resonance (NMR) measurements (!H NMR, 13C NMR) were measured on Bruker AMX 400 and 100 instruments using
www.chemprob.org
CHEMICAL PROBLEMS 2024 no. 2 (22)
tetramethylsilane (TMS) as a reference and DMSO-J<5 as a solvent. Analytical thin-layer chromatography (TLC) was carried out on Merck plates 60 F254 (0.2 mm thick). Microelements (C.H.N.) were analysed using a VEA3000 device (Shimadzu, Japan).
Synthesis
Synthesis of the 3-(4'-acetyl-[1,1'-biphenyl]-4-yl)-4-aminobutanoic acid 2 [28]
A mixture of 4-amino-3-(4-chlorophenyl) butanoic acid 1 (1 mmol), (4-acetylphenyl) boronic acid 2 (1 mmol), Pd(0)(pph3) (40 mg), sodium carbonate (5 ml) in propanol (15 ml) was refluxed for 12h, and the reaction was monitored by TLC. After the reaction completion, the reaction mixture was cooled to room temperature and poured over crushed ice with stirring. The result precipitate was collected by filtration, washed with cold water, dried and recrystallized from appropriate solvents to give target compounds good yields. The solid obtained was purified with flash chromatography using methanol-
dichloromethane (8:2). Physical state 3: Orange crystals; yield is 88%; m.p. 178-180°C. FT-IR (KBr, cm-1): v 3354 (oh), 3212 (N-H), 1732, 1685 (C=O), 1572 (C=C). 1H-NMR (DMSO-d6,ppm): 5 12.41 (s,1H, OH), 8.05-7.11 (d,8H,H-arom.), 3.54 (d,2H,CH2CO), 3.28 (s,1H, NH2), 2.64 (d,2H,CH2N), 2.11 (s,3H,Me), 1.78-170 (m,1H, CHtertiary). 13C-NMR (DMSO-d6, ppm): 5 197.3 (COOH), 177.1 (C=O), 137.6-121.3 (C-arom.), 42.1 (CH2-N), 36.2 (CH2-CO), 34.1 (C-tertiary), 26.2 (Me). Analytical calculated for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.11; H, 5.74; N, 4.01.
General procedure for the synthesis of the chalcone derivatives 5a-d [15]
Aldehydes 4a-d (2 mmol) were individually dissolved with the derivative 3 (2 mmol) in 30 mL of ethanol and reflexed for 6-8h in the presence of piperidine as a catalyst. After the reaction completion (TLC check), the reaction mixture was cooled to room temperature, washed with brine solution, and then extracted with chloroform three times. The organic extract obtained was dried and concentrated into a solid under a vacuum. The products obtained were purified with flash
chromatography using methanol-
dichloromethane (8:2). 4-Amino-3-(4'-(3-(4-
hydroxyphenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5a: light red crystals, yield 78%, m.p 190-192°C. FT-IR (KBr, cm-1): v 3368 (OH), 3185 (N-H), 1737, 1674 (C=O), 1615 (C=C). 1H-NMR (DMSO-d6,ppm): 5 12.03(s,1H, OH), 8.25-7.24 (d,12H,H-arom.), 3.36 (d,2H,CH2CO), 3.22 (s,1H, NH2), 2.52 (d,2H,CH2N) 1.94-184 (m,1H, CHtertiary). 13C-NMR (DMSO-d6, ppm): 5 177.2(C=O), 135.1123.4 (C-arom.), 39.6 (CH2-N), 36.5 (CH2-CO), 31.2 (C-tertiary). Analytical calculated for C25H23NO4: C, 74.80; H, 5.77; N, 3.49. Found: C, 74.2; H, 5.17; N, 2.89. 4-Amino-3-(4'-
(dimethylamino)phenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5b: Dark yellow crystals, yield 64%, m.p 203-205°C. FT-IR (KBr, cm-1): v 3375(OH), 3194 (N-H), 1729, 1678 (C=O), 1608 (C=C). 1H-NMR(DMSO-d6,ppm): 5 12.35 (s,1H, OH), 8.24-7.31 (d,12H,H-arom.), 3.28 (d,2H,CH2CO), 3.14 (s,1H, NH2), 2.41 (d,2H,CH2N) 1.82-175 (m,1H, CHtertiary). 13C-NMR (DMSO-d6, ppm): 5 175.8(C=o), 133.6-118.7 (C-arom.), 41.8(CH2-N), 37.7 (CH2-CO), 32.8 (C-tertiary). Analytical calculated for C27H28N2O3: C, 75.68; H, 6.59; N, 6.54. Found: C, 75.08; H, 5.99; N, 5.94.
4-Amino-3-(4'-(3-(4-nitrophenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5c: brown crystals, yield 68%, m.p 225-227°C. FT-IR (KBr, cm-1): v 3386 (OH), 3176 (N-H), 1732, 1675 (C=O), 1624 (C=C). 1H-NMR (DMSO-d6,ppm): 5 12.42 (s,1H, OH), 8.19-7.26 (d,12H,H-arom.), 3.16 (d,2H,CH2CO), 3.02 (s,1H, NH2), 2.35 (d,2H,CH2N) 1.94-186 (m,1H, CHtertiary). 13C-NMR (DMSO-d6, ppm): 5 177.3(C=O), 138.2-120.6(C-arom.), 43.5(CH2-N), 38.1(CH2-CO), 33.5(C-tertiary). Analytical calculated for C25H22N2O5: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.16; H, 4.55; N, 5.91. 4-Amino-3-(4'-(3-(4-hydrxy-3-methoxyphenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5d: Dark red crystals, yield 79%, m.p 212-215°C. FT-IR (KBr,cm-1): v 3423 (OH), 3183 (N-H), 1734, 1670 (C=O), 1611 (C=C). 1H-NMR (DMSO-d6,ppm): 5 12.63, 9.65 (s,1H, OH), 8.15-7.34 (d,4H,H-
arom.), 3.84 (s,3H,OCH3), 3.23 (d,2H,CH2CO), 3.05 (s,1H, NH2), 2.18 (d,2H,CH2N) 1.88-178 (m,1H, CHtertiary). 13C-NMR (DMSO-^6, ppm): 5 192.3(C=O), 176.4(COOH), 153.5(C-O), 132.5-122.6(C-arom.), 56.12(C-O), 44.8(CH2-N), 37.4(CH2-CO), 32.7(C-tertiary). Analytical calculated for C26H25NO5: C, 72.37; H, 5.84; N, 3.25. Found: C, 71.77; H, 5.24; N, 2.65. The cytotoxicity assay [29]
The cytotoxic activities of derivatives 5a-d were investigated in vitro against two human cancer cell lines (HdFn, MCF-7) using the MTT test. The cell cultures, 100 of 2x104 cells/mL in DMEM (Dulbecco's Modified Eagle's medium) containing 10% FBS (fetal bovine serum), were seeded in polystyrene microplates (96-well flat-bottom) and incubated at 37°C for 24h in 5% CO2 humidified atmosphere. Next, different concentrations of derivatives 5a-d (10, 20, 40, 60, and 80 ^M) were added to the plate and then incubated for 48 h. After that, the old medium was replaced and a solution of MTT (50 of 0.5 mg/mL in DMEM) was added to each well in the plate and then incubated for another 4 h. The formazan crystals obtained were solubilized by adding 100 of DMSO to each well. The solution absorbance obtained was determined at 570 nm on an ELISA microplate reader. The mean percentage of cell viability was calculated from the data obtained. A triplicate of experiments was performed for each test.
Antioxidant assay [30]
The antioxidant effect of compounds 5a-d
was evaluated in vitro using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Practically, a solution of DPPH (60 ^M) in 2ml of ethanol was individually added to different concentrations of derivatives 5a-d (12.5, 25, 50, 100, 250, and 500^M), and then the homogenized mixture was incubated in the dark for 30 min. After that, the absorbance of the solution was determined at wavelength 515 nm on a UV/Vis spectrophotometer Amersham Biospectro. The results obtained were compared with ascorbic acid and used to calculate the percentage of reduction of the DPPH. The percentage of inhibition was calculated using the following formula:
% of antioxidant activity= [(AC-AS) ^AC] x 100
Where: AC is absorbance of the control; AS is absorbance of the sample. Docking study analysis [31]
Four of the synthesized compounds underwent molecular docking studies and the target is to identify the potential binding with the estrogen receptor alpha (ERa) with ID 3ERT obtained from PDB page https://www.rcsb.org/. The selected derivatives were sketched in 2D and converted into 3D using molecular mechanics and then used as ligands. Autodock 4.2.6 program was used in calculating the result of the docking analysis as binding energy. Discovery Studio software was employed to set the receptor and shown the binding modes as 2D interaction poses.
Results and Discussion
According to the Suzuki-Mayura coupling reaction, 3-(4'-acetyl-[1,1'-biphenyl]-4-yl)-4-aminobutanoic acid was synthesized from reaction 4-amino-3-(4-chlorophenyl)butanoic
acid 1 (Baclofen) with (4-acetylphenyl)boronic acid 2 using a palladium catalyst and a base as sodium carbonate, as shown in Scheme 1.
Pd(ph3p)4,reflex
n-PrOH
HO
NH,
ci ho/B^OH A0
[1] [2] [3]
Scheme 1. Synthesis of compound 3 by Suzuki-Mayura coupling reaction
In the next step, the derivative 3 was reacted with some aromatic aldehydes 4a-d in the presence of piperidine as a catalyst to synthesize chalcone derivatives 5a-d according to the Claisen-Schmidt condensation mechanism, as shown in Scheme 2. The
structures of all synthesized compounds were spectroscopically characterized by (IR, NMR, 13C NMR) as well as micro-elements analysis. The spectroscopic data obtained were included in the Experimental part.
HO
HO
NH,
Ethanol
piperdine
Where Sa: R=OH, R1=H
5b: R=N(CH3)2, R1=H Sc: R=N02, R1=H 5d: R=OH, R2=OMe
Scheme 2. The experimental steps for synthesis of compounds 5a-d
Biological activity
Cytotoxicity of synthesized compounds
The four derivatives 5a-d were screened in vitro for evaluation of their antitumor activities against two cancer cell lines HdFn and
MCF-7 by the standard MTT method and using Tamoxifen drug as a positive control. The percentages of cell viability of the compounds 5 a and 5d are shown in Fig.1.
Fig. 1. Cell viability percentage of compounds 5c and 5d against two cancer cell lines HdFn and
MCF-7.
The cytotoxicity results of derivatives 5a-d against HdFn and MCF-7 were compared with the activity of Tamoxifen and presented as IC50 in Table 1. According to the results, found that some of the tested derivatives exhibited good inhibitory activity. Among those derivatives, 5a and 5d showed anti-proliferative effects against MCF-7 cells with an IC50 value of 32.5 and
37.6^M, respectively. For of HdFn cells, derivatives 5a and 5c showed acceptable cytotoxicity in comparison with the activity of Tamoxifen, while the other derivatives exhibited poor cytotoxic activity. Generally, the results of this test are preliminary evidence that calls on researchers to conduct many tests to use these derivatives as therapeutic agents in the future.
Table 1. The cytotoxicity results for synthesized compounds 5a-d against HdFn and MCF-7 cancer
cell lines in comparison to the Tamoxifen drug.
Compounds IC5o^ M±SD
HdFn MCF-7
5a 76.7 ± 3.24 32.5 ± 1.25
5b > 200 86.4±4.11
5c 78.6 ± 3.95 > 200
5d 88.6 ± 4.16 37.6 ± 1.31
Tamoxifen 36 ± 1.14 30 ± 1.02
Antioxidant activity study
The antioxidant activity of new compounds 5a-d was tested using a DPPH assay. The ascorbic acid is used as a reference for comparison. The test mechanism depends on using hydrogen donor antioxidants for the reduction of the DPPH radical solution and formation of the DPPH-H. Generally, the tested compounds showed potent activity as
antioxidants according to the results obtained in Table 2. At a concentration of 500 ^M, found that the % inhibition of 5a, 5c and 5d potency of 86.62, 81.38, and 76.42%, respectively. These results revealed that compounds 5a, 5c and 5d have the most potent levels of activity compared to that of standard ascorbic acid and this may be due to their structural properties that help in capturing free radicals.
Fig. 2. 2D conformations for simulation of 5a-d with the active site of the target protein
Table 2. Results of DPPH assay of derivatives 5a-d at wavelength 515 nm and concentration 500
pM.
Compounds Absorbance of Sample % Inhibition
5a 0.063 86.62±4.81
5b 0.214 32.64±1.39
5c 0.071 81.38±4.21
5d 0.104 76.42±4.05
Ascorbic-acid 0.065 86.24±4.76
Molecular Docking study
A molecular docking of derivatives 5a-d was studied in silico and the aim is to justify their biological activity. A derivatives 5a-d were docked as ligands with the receptor ERa (PDB: 3ERT). According to the docking results, the binding energy of derivatives 5a-d were -9.26, -7.34, -3.7 and -8.81 [kcal/mol], respectively. The results obtained revealed that the
Table 3. Docking results, the binding energy an
A series of chalcone derivatives bearing baclofen drug were synthesized via Claisen-Schmidt condensation and biologically evaluated in vitro as anticancer and antioxidant
derivatives 5a, 5c, and 5d bound with the active site of the protein selectively by various interactions such as hydrophobic, electrostatic interactions and hydrogen bonds. The binding pose of 5a, 5c and 5d with the active pocket in the protein was shown as 2D representations in Fig.2. The binding energies and types of interactions are shown in Table 3.
of interactions of derivatives 5a-d with the
agents. The results of the cytotoxicity assay indicated the possibility of using the compounds 4-Amino-3-(4'-(3-(4-hydroxyphenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5a and 4-
catalytic site of the target protein
Compound Ligand moiety Site(A.A) Interaction E (kcal/mol)
NH2 GLU 758 (A) H- Bond
OH LEU 861(A) H- Bond
5a 6-ring LEU 861(A) Pi-Alkyl -9.26
LYS 860(A) Pi-Alkyl
C=O ARG 836(A) H-Bond
Other Electrostatic
NH2 PRO 699(A) H- Bond
N-(Me)2 LEU 777(A) H- Bond
5b 6-ring ALA 702(A) Pi-Alkyl -7.34
ILE 1018(A) Pi-Alkyl
C=O ARG 831(A) H-Bond
Other Electrostatic
NH2 ALI 886(A) H- Bond
C=O LYS 875(A) H- Bond
5c 6-ring PRO 877(A) Pi-Alkyl -3.7
VAL 876(A) Pi-Alkyl
VAL 876(A) Pi-Sigma
Other Electrostatic
OH TYR 827(A) H- Bond
NH2 GLN 1020 (A) H-Bond
5d 6-ring ALA 702(A) Pi-Sigma -8.81
LEU 703(A) Pi-Alkyl
ARG 705(A) Pi-Alkyl
Other Electrostatic
Conclusions
Amino-3 -(4'-(3-(4-hydrxy-3 -methoxyphenyl)acryloyl)-[1,1'-biphenyl]-4-yl)butanoic acid 5d as antiproliferative agents
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Acknowledgements
The authors are thankful to the Department of Chemistry Al Qadisiyah for providing facilities.
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XALKONUN YENÍ TÔR9M9L9RÎ X8RÇ9NG9QARÇI V9 ANTÍOKSÍDANT AGENTL9R KÍMÍ: SÍNTEZ, MOLEKULYAR DOKÍNQ T9DQÍQATI V9 BÍOLOJÍ
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Nabeel A. Abdul-Rida, Kavter M.Talib
Kimya §obdsi, dl-Qadisiyyd Universiteti, Divaniyya, 58002, Iraq Email: [email protected], [email protected]
Xülasa: içda, tarkibinda baklofen preparati olan bir sira yeni xalkon toramalari Claisen-Schmidt kondensasiyasi ila sintez edilmiç, xarçang aleyhina va antioksidant agentlar kimi in vitro qiymatlandirilmiçdir. Yeni sintez edilmiç birlaçmalar FT-ÍK, 'Н-NMR, 13C-NMR spektrlari ila xarakteriza edilmiçdir va hamçinin element analizi aparilmiçdir. Bütün alinan maddalar ham HdFn, ham da MCF-7 hüceyralara qarçi in vitro olaraq yoxlanilmiçdir. Sitotoksik analizinin naticalari gostardi ki, IC50 dayarlari müvafiq olaraq 32,5 va 37,6 цМ olan 5a va 5d toramalari MCF-7 hüceyra sirasina qarçi yaxçi inhibisiya gostarirlar, 5a va 5c birlaçmalari isa IC50 üzra 76,7 va 778 цМ qiymatlarina malik olub Tamoksifen preparati ila müqayisada HdFn hüceyra sirasina qarçi qanaatbaxç inhibitorluq nûmayiç etdirirlar. Alinmiç birlaçmalarin molekulyar dokinq tadqiqi onlarin sitotoksiklik testinin naticalarini tasdiqladi. Bundan alava, DPPH tadqiqatlarinin naticalari asasinda müayyan edildi ki, 5a, 5c va 5d toramalari müvafiq olaraq 86.62, 81.38 va 76.42 % inhibitorluq faizlarina malikdirlar va askorbin turçusu ila müqayisada yaxçi antioksidant aktivliyi gostarirlar. Açar soztari: Xalkon, xarçanga qarçi, Antioksidant, Molekulyar Dokinq, Sitotoksik
НОВЫЕ ПРОИЗВОДНЫЕ ХАЛКОНА КАК ПРОТИВОРАКОВЫЕ И АНТИОКСИДАНТНЫЕ АГЕНТЫ: СИНТЕЗ, ИССЛЕДОВАНИЕ МОЛЕКУЛЯРНОГО
ДОКИНГА И БИОЛОГИЧЕСКАЯ ОЦЕНКА
Набиль А. Абдул-Рида, Каутер М. Талиб
Кафедра химии, Университет Аль-Кадисия, Дивания, 58002, Ирак
Email: [email protected], [email protected]
Аннотация: В работе посредством конденсации Клайзена-Шмидта были синтезированы новые производные халкона, содержащие препарат баклофен, и оценены in vitro как противораковые и антиоксидантные средства. Синтезированные соединения были
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охарактеризованы спектрами ИК-Фурье, Н-ЯМР, С-ЯМР и элементным анализом. Все продукты были проверены in vitro на клеточные линии HdFn и MCF-7. Результаты анализа цитотоксичности показали, что производные 5 a и 5d продемонстрировали хорошее ингибирование клеточных линий MCF-7 со значениями IC50: 32,5 и 37,6 мкМ соответственно, тогда как 5 a и 5 c продемонстрировали приемлемое ингибирование HdFn со значениями IC50 - 76,7 и 78,6 мкМ, соответственно, по сравнению с Препарат Тамоксифен. Исследование молекулярного докинга целевых соединений подтвердило результаты теста на цитотоксичность. Кроме того, результаты ДФПГ-исследования выявили хорошую антиоксидантную активность производных 5а, 5в и 5d с процентами ингибирования 86.62, 81.38 и 76.42%, соответственно, по сравнению с аскорбиновой кислотой. Ключевые слова: халкон, противораковое средство, антиоксидант, молекулярный докинг, цитотоксичность.
