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Article

Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives

by
Meitao Duan
1,2,3,
Ahmed Mahal
4,*,
Anas Alkouri
5,
Chen Wang
1,2,
Zhiqiang Zhang
1,2,
Jungang Ren
1,2 and
Ahmad J. Obaidullah
6
1
School of Pharmacy, Xiamen Medical College, Xiamen 361023, China
2
Xiamen Medical College Research Center for Sustained and Controlled Release Formulations, Xiamen Medical College, Xiamen 361023, China
3
Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361023, China
4
Department of Medical Biochemical Analysis, College of Health Technology, Cihan University-Erbil, Erbil 44001, Kurdisan Region, Iraq
5
College of Pharmacy, Cihan University-Erbil, Erbil 44001, Kurdisan Region, Iraq
6
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(13), 3010; https://doi.org/10.3390/molecules29133010
Submission received: 31 March 2024 / Revised: 16 June 2024 / Accepted: 17 June 2024 / Published: 25 June 2024
(This article belongs to the Special Issue Synthesis of Heterocyclic Compounds via Cycloadditions: Applications in Medicinal Chemistry)
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Abstract

:
Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 μM against human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC–Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.

1. Introduction

One of the deadliest diseases worldwide is cancer, a disease in which the cells grow out of control. It causes economic and life losses. Therefore, there is an urgent need for the development of new potential anticancer agents [1]. Modification of natural products is considered one of potential methods leading to potent anticancer agents with good properties, including low resistance and toxicity [2,3]. Small molecules which are produced by any organism involving primary and secondary metabolites are called natural products, and these molecules have been widely used in the development of medicinal chemistry and drug discovery [4,5]. Curcumin is one of the important polyphenol compounds that exist in in the rhizome of Curcuma longa [6]. Curcumin has many potent bioactivities and acts as an antioxidant [7,8], anti-inflammatory [9], neuroprotective [10,11,12], antibacterial [13,14], and anticancer agent [8,15]. Curcumin has a unique symmetrical structure in which O-methoxyphenols are attached to a β-diketone moiety [16,17]. Hydrolysis and oxidation can cause in vitro and in vivo degradation of curcumin [18,19,20]. Tetrahydrocurcumin is one of the compounds that was found as a result of the transformation of curcumin at a physiological “pH” [11,21]. Tetrahydrocurcumin is a traditional Chinese medicine isolated from Curcuma wenyujin [22] which is found in turmeric, and tetrahydrocurcumin can be produced from the reduction of curcumin; in the laboratory, it can be prepared from the hydrogenation of curcumin [23]. Tetrahydrocurcumin has displayed potent anticancer activity against human breast cancer [24], cervical cancer [25], Leukemia [26], lung cancer [27], tumor metastasis [28], and colon carcinogenesis [29]. In physiological conditions and due to the limit of the α,β-double bond conjugated to the carbonyl group, tetrahydrocurcumin is more stable than curcumin, which has been found to not have efficient bioactivity because of its instability, high reactivity, and low bioavailability [30,31]. A few reports have demonstrated the synthesis and bioactivity of tetrahydrocurcumin [32,33,34,35,36], such as the preparation of 1,4-dihydropyridine tetrahydrocurcumin derivatives [11]. Nitrogen-containing heterocycles are considered to have strong bioactivity and are very important in the field of medicinal chemistry and drug discovery [37,38,39,40]. A five-membered ring with three nitrogen and two carbon atoms called triazole has demonstrated anticancer activity [41]. The 1,3-dipolar cycloaddition reaction between alkyne and azide lead to the formation of a triazole moiety [42], a promising scaffold for the development of various potent anticancer agents [43,44,45]. In the present work, as part of our search for novel potential bioactive agents [46,47,48,49,50], we report here on the synthesis of novel tetrahydrocurcumin derivatives that bear triazole moiety and are evaluated for their anticancer activities against four human cancer cell lines in vitro.

2. Results and Discussion

Scheme 1 summarizes the general procedure for the synthesis of tetrahydrocurcumin derivatives. Tetrahydrocurcumin was alkylated with propargyl bromide in the presence of potassium carbonate (K2CO3) using dimethylformamide (DMF) at room temperature in an inert atmosphere, resulting in compound 1. Various azides (3a–m) were obtained by the reaction of anilines (2a–m) with sodium azide using dichloromethane (DCM) as a solvent [51]. Click reaction was utilized for the synthesis of the tetrahydrocurcumin conjugates (4a–m) by the reaction between compound 1 and azides using copper (II) sulfate pentahydrate (CuSO4•5H2O), monosodium ascorbate in THF (2 mL), and a mixture of t-BuOH:H2O (2 mL, v:v = 1:1) at room temperature for 12 h. The column chromatography technique was used for purification of the newly prepared compounds (4a–m) by utilizing a mixture of DCM/EtOAc and 1H-NMR. 13C-NMR, HR-ESI-MS, and IR techniques were used for identification of their structures. 1The H-NMR spectrum of compounds indicated four singlets signals ranging from 7.60 to 7. 7.22 for the new aryl ring. 1The H-NMR spectrum of the compounds indicated two singlets signals ranging from 3.85 to 3.76 ppm corresponding to two OCH3 and three singlet signals corresponding to three OCH3 groups (compound 4f). 1The H-NMR spectrum of compounds indicated one singlet signal ranging from 8.20 to 8.00 ppm corresponding to one CH of the triazole group. 13The C-NMR of the compounds revealed the presence of signals ranging from 56.20 to 55.60 ppm corresponding to three OCH3 groups. 13The C-NMR of the compounds revealed the presence of signals ranging from 144.2 to 120.0 in the triazole ring. FTIR showed signals for OH (3300–3380 cm−1), CO (1600–1670 cm−1)) and C=N (1500–1570 cm−1).
The compounds were evaluated for their anticancer activity against four cancer cell lines including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) using an MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. Cisplatin and tetrahydrocurcumin were used as positive controls. A concentration of 50% was used for cell growth inhibition (IC50), which measured the anticancer activity of the compounds (4a–m). Table 1 summarizes the anti-proliferative activity data of the prepared compounds (4a–m) by IC50 values.
The compounds 4b–4d and 4l showed no significant cytotoxic activity against all four cancer cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Compounds 4a, 4h, 4j, and 4k exhibited moderate anticancer activity against the HCT116 cell line, with IC50 values in ranging from 62.63 to 89.38 μM compared to tetrahydrocurcumin while showing no anticancer activity compared to cisplatin. Compounds 4g, 4j, and 4k displayed lower anti-proliferative activities against the HeLa cell line, with IC50 values ranging from 129.50 to 190.00 μM compared to both tetrahydrocurcumin and cisplatin. Compounds 4e, 4j, and 4m showed no potent anticancer activity against the A549 cell line, with IC50 values ranging from 131.20 to 162.40 μM compared to both positive controls of tetrahydrocurcumin and cisplatin. Compound 4k showed weak anticancer activity against the HepG2 cell line, with an IC50 value of 104.23 μM compared to the positive controls of tetrahydrocurcumin and cisplatin. Compound 4f showed potent cytotoxic activity against HCT116 and HepG2 cancer cell lines, with IC50 values of 15.59 and 53.64 μM compared to tetrahydrocurcumin and cisplatin. Compound 4k displayed significant anticancer activity (against the A549 cancer cell line compared to tetrahydrocurcumin, while showing moderate anticancer activity (IC50 = 57.96 μM). Compound 4g showed strong cytotoxic activity against the HCT117 and HepG2 cancer cell lines, with IC50 values of 1.09 and 66.82 μM, respectively, compared to tetrahydrocurcumin and cisplatin, while showing moderate anticancer activity compared to A549 compared to tetrahydrocurcumin and cisplatin. The data showed that the incorporation of an electron-withdrawing group into the benzene ring led to significant improvement in cytotoxic activity compared to the electron-donating group. Through the prediction of the properties of the target compounds (Table 2), it was found that the molecular weight of the derivatives is greater than 500 (529.59~613.59), the lipid water distribution coefficient is greater than 3 (3.33~5.28), the total number of hydrogen bond acceptors and donors is greater than 10 (10–11), the number of rotatable bonds is 14–15, the molecular polarity range is 112.79~136.58, and the molecular volume is greater than 400 (482.19~613.59). The properties of derivatives do not comply with Lipinski’s “rule of five” but cater to the properties of small-molecule inhibitors of protein–protein interactions (PPIs).
The HCT-116 cell lines were treated with compounds 4g in order to evaluate the role of cell cycle arrest of GA derivatives, which caused growth inhibition. The cell cycle distribution was evaluated by flow cytometric analysis after staining of cellular DNA with propidium iodide at the different concentrations of compound 4g (1.56 μM~25 μM). As shown in Figure 1, the percentage of cells in the G1 phase of the cell cycle increased from 53.5% to 74.0%, the S phase decreased from 30.9% to 13.8%, and the G2 phase decreased from 15.6% to 12.2% after 72 h of treatment. The obtained result indicated that compound 4g induced accumulations in the G phase (DNA synthesis pre stage) of the cell cycle.
The binding of APC and Asef plays an important role in the development of colon cancer, and their binding belongs to the protein–protein interaction process. Considering the significant effect of compound 4g against HCT116 and its compliance with the properties of small-molecule PPIs, we further evaluated the interaction between compound 4g and APC–Asef using molecular docking techniques. The docking results showed that there are interactions between 4g and the APC–Asef crystal protein, mainly through hydrogen bonding and hydrophobic interactions (Figure 2). Among them, the aspartic acid (ASP459), glutamic acid (GLU460), arginine (ARG463), and arginine (ARG549) of the APC–Asef crystal protein interact with the C7 methoxy group (OCH3), C5 hydroxyl group (OH)/C10 carbonyl group (C=O), C10 ′carbonyl group (C=O), and triazole of 4g to form hydrogen bonds, respectively; The Aspartate (ASP459), histidine (HIS462), and phenylalanine (PHE510) form hydrophobic interactions with the benzene and triazole rings of 4g. Based on the results, it is speculated that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhibiting the binding of APC–Asef.

3. Experimental Procedure

3.1. General Experimental Procedures

Commercial sources of reagents and solvents were purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd. (Shanghai, China), Shanghai Macklin Biochemical Co., Ltd. (Shanghai, China), Guangzhou Chemical Reagent (Guangzhou, China), and Tianjin Damao Chemical Reagent Factory (Guangzhou, China). Shanghai D&B Biological Science and Technology Co., Ltd. (Shanghai, China). and Yantai Jiangyou Silica Gel Development Co., Ltd. (Yantai, China) were the sources of tetrahydrocurcumin and silica gel (200~300 mesh), respectively. UPLC data were collected using an Agilent 1290 Infinity II HDR-DAD instrument (Agilent, Santa Clara, CA, USA) and HRMS data were obtained by utilizing the ESI mode on an Orbitrap Eclipse device (Thermo Fisher Scientific, Waltham, MA, USA). An AVANCE IIITM HD 600 MHz device was used for the measurement of the NMR data, where the coupling constants (J) are in Hz and the chemical shifts (δ) are given in ppm. The abbreviations used for the splitting pattern are as follows: s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, t = triplet, m = multiplet, and brs = broad singlet.

3.1.1. General Procedure for the Synthesis of 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)heptane-3,5-dione (1)

Potassium carbonate (1.1 eq) and propargyl bromide were added to the THC (1.0 eq) dissolved in DMF (5 mL), and the reaction was allowed to stir at room temperature overnight. After the reaction, add 15 mL of water, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, evaporate under reduced pressure to remove solvent, and purify with silica gel column chromatography to give product 1.

3.1.2. General Procedure for the Synthesis of Azide Derivatives (3a~m)

Aniline (2a~m) (1.0 eq) was dissolved in CH3CN (5 mL) in a 25 mL round-bottomed flask and cooled to 0 °C in an ice bath. To this stirred mixture was added t-BuONO (1.5 eq) followed by TMSN3 (1.2 eq) dropwise. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and extracted with DCM (10 mL × 3) to give product 3a~m [50,51].

3.1.3. General Procedure for the Synthesis of 1,2,3-Riazole Linked THC Derivatives (4a~m)

To a solution of product 1 (1.2 eq) add aromatic azides (3a~m) (1.0 eq) in THF (2 mL) and t-BuOH-H2O (2 mL, v:v = 1:1) at room temperature and then add copper (II) sulfate pentahydrate (20 mg) and sodium ascorbate (2 g in 10 mL H2O, 0.6 mL). The reaction mixture must stir at room temperature till completion of the reaction (monitored by TLC). The solvent is evaporated and residue is chromatographed on silica gel using Petroleum Ether:EtOAC to offer the target 4a~m [50,51].

3.1.4. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy) phenyl)heptane-3,5-dione (4a)

Yellow oil, (139.52 mg, 0.340 mmol, 47%). IR (cm−1): 3313 (OH), 1600 (C=O), 1540 (C=N); 1H-NMR (600 MHz, CDCl3) δ 8.07 (s, 1H, triazole-H), 7.65–7.62 (dd, J = 7.8, 15.6 Hz, 3H, Ar-H), 7.52–7.48 (q, J = 7.8, 16.8 Hz, 2H, Ar-H), 6.79–6.76 (m, 2H, Ar-H), 6.66–6.56 (m, 4H, Ar-H), 5.48 (s, 2H, Et-H), 3.83 (s, 6H, OMe-H), 2.87–2.72 (m, 10H, Et-H). 13C-NMR (150 MHz, CDCl3) δ 206.21, 204.62, 146.53, 144.10, 132.92, 132.48, 129.89, 129.83, 128.87, 128.80, 125.01, 121.24, 121.10, 120.95, 120.51, 120.48, 119.15, 114.44, 114.39, 111.50, 111.21, 111.15, 70.28, 66.24, 56.06, 56.01, 44.70, 42.04, 29.16, 29.08. ESI-HRMS Calcd for C30H32N3O6 [M + H]+: 530.2286, found 530.2291.

3.1.5. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-(p-tolyl)-1H-1,2,3-triazol-5-yl)methoxy) phenyl)heptane-3,5-dione (4b)

Yellow oil, (235.10 mg, 0.436 mmol, 60%). IR (cm−1): 3352 (OH), 1590 (C=O), 1522 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H, triazole-H), 7.53 (d, 2H, J = 14.4 Hz, Ar-H), 7.31 (d, 2H, J = 14.0 Hz, Ar-H), 6.71–6.79 (m, 3H, Ar-H), 6.67–6.59 (m, 3H, Ar-H), 5.60 (s, 2H, Et-H), 3.86 (s, 6H, OMe-H), 2.98~2.43 (m, 10H, Et-H), 2.44 (s, 3H, Me-H). 13C-NMR (100 MHz, CDCl3) δ 206.30, 204.66, 162.71, 146.56, 144.79, 144.10, 143.06, 138.96, 138.86, 134.69, 132.91, 132.48, 130.34, 130.28, 121.46, 121.20, 120.93, 120.38, 120.24, 114.45, 111.50, 111.17, 70.30, 66.29, 56.05, 56.00, 44.69, 42.04, 29.14, 29.08, 21.20. ESI-HRMS Calcd for C31H34N3O6 [M + H]+: 544.2442, found 544.2439.

3.1.6. 1-(4-((1-(4-Ethylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (4c)

Yellow oil, (203.75 mg, 0.368 mmol, 50%). IR (cm−1): 3324 (OH), 1521 (C=O), 1509 (C=N); 1H-NMR (500 MHz, CDCl3) δ 8.00 (s, 1H, triazole-H), 7.55–7.51 (dd, J = 8.5, 10.5 Hz, 2H, Ar-H), 7.29–7.32 (t, J = 8.0 Hz, 2H, Ar-H), 6.78–6.76 (t, J = 7.0 Hz, 2H, Ar-H), 6.64–6.57 (m, 4H, Ar-H), 5.58 (d, J = 10.5 Hz, 2H, Et-H), 3.82 (d, J = 2.0 Hz, 6H, OMe-H), 2.82–2.70 (m, 12H, Et-H), 1.26 (td, J = 7.5, 1.5 Hz, 3H, Me-H). 13C-NMR (126 MHz, CDCl3) δ 206.30, 204.66, 146.52, 145.26, 145.17, 144.76, 144.06, 143.03, 134.79, 132.88, 132.45, 129.16, 129.10, 121.47, 121.17, 120.90, 120.47, 120.45, 120.24, 114.42, 111.45, 111.13, 70.27, 66.25, 56.00, 55.96, 44.67, 42.01, 29.10, 29.05, 28.54, 15.55. ESI-HRMS Calcd for C32H36N3O6 [M + H]+: 558.2599, found 558.2604.

3.1.7. 1-(4-Hydroxy-3-methoxyphenyl)-7-(4-((1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)heptane-3,5-dione (4d)

Yellow oil, (429.83 mg, 0.746 mmol, 100%). IR (cm−1): 3331 (OH), 1504 (C=O), 1539 (C=N); 1H-NMR (500 MHz, CDCl3) δ 8.00 (s, 1H, triazole-H), 7.54–7.52 (dd, J = 8.5, 10.5 Hz, 2H, Ar-H), 7.32–7.30 (t, J = 8.0 Hz, 2H, Ar-H), 6.78–6.76 (d, J = 7.0 Hz, 2H, Ar-H), 6.64–6.57 (m, 4H, Ar-H), 5.58 (d, J = 10.5 Hz, 2H, Et-H), 3.81 (d, J = 2.0 Hz, 6H, OMe-H), 2.87 (s, 1H, CH-H), 2.82–2.68 (m, 10H, Et-H),1.26 (m, 6H, Me-H). 13C-NMR (126 MHz, CDCl3) δ 206.30, 204.66, 146.52, 145.26, 145.17, 144.76, 144.06, 143.03, 134.79, 132.88, 132.45, 129.16, 129.10, 121.47, 121.17, 120.90, 120.47, 120.45, 120.24, 114.42, 111.45, 111.13, 70.27, 66.25, 56.00, 55.96, 44.67, 42.01, 29.10, 29.05, 28.54, 27.00, 23.93. ESI-HRMS Calcd for C33H38N3O6 [M + H]+: 572.2755, found 572.2740.

3.1.8. 1-(4-((1-(4-(Tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (4e)

Yellow oil, (289.39 mg, 0.498 mmol, 68%). IR (cm−1): 3345 (OH), 1542 (C=O), 1527 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H, triazole-H), 7.56–7.53 (d, J = 12.0 Hz, 4H, Ar-H), 6.80–6.65 (m, 6H, Ar-H), 5.64 (s, 2H, Et-H), 3.84 (s, 6H, OMe-H), 2.97–2.77 (m, 10H, Et-H), 1.38 (s, 9H, Me-H). 13C-NMR (100 MHz, CDCl3) δ 206.24, 204.57, 162.62, 152.01, 146.47, 144.00, 142.96, 134.44, 132.79, 132.36, 126.70, 126.61, 126.55, 121.42, 121.08, 120.82, 120.09, 120.04, 118.63, 114.37, 111.40, 111.08, 70.21, 66.19, 55.93, 55.89, 44.61, 41.95, 34.77, 31.47, 31.34, 31.27, 29.03, 28.99. ESI-HRMS Calcd for C34H40N3O6 [M + H]+: 586.2912, found 582.2916.

3.1.9. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)heptane-3,5-dione (4f)

Yellow oil, (256.67 mg, 0.462 mmol, 63%). IR (cm−1): 3375 (OH), 1518 (C=O), 1528 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.02 (s, 1H, triazole-H), 7.57–7.54 (d, J = 12.0 Hz, 2H, Ar-H), 7.00–6.63 (m, 8H, Ar-H), 5.84 (s, 2H, Et-H), 3.80 (d, J = 13.2 Hz, 9H, OMe-H), 2.96–2.76 (m, 10H, Et-H). 13C-NMR (100 MHz, CDCl3) δ 206.30, 204.67, 162.70, 159.84, 159.78, 146.60, 144.11, 132.39, 130.42, 122.02, 121.14, 120.99, 120.86, 120.39, 120.05, 115.20, 114.82, 114.77, 114.48, 111.55, 111.27, 111.21, 70.23, 66.22, 55.94, 55.70, 44.62, 36.58, 31.52, 29.07, 23.90. ESI-HRMS Calcd for C31H34N3O7 [M + H]+: 560.2391, found 560.2381.

3.1.10. 1-(4-((1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (4g)

Yellow oil, (114.29 mg, 0.210 mmol, 29%). IR (cm−1): 3358 (OH), 1503 (C=O), 1519 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H, triazole-H), 7.62–7.60 (d, J = 11.2 Hz, 2H, Ar-H), 7.30–7.23 (m, 2H, Ar-H), 6.80–6.62 (m, 6H, Ar-H), 5.58 (s, 2H, Et-H), 3.86 (s, 6H, OMe-H), 2.98–2.78 (m, 10H, Et-H). 13C-NMR (101 MHz, CDCl3) δ 206.09, 204.62, 161.27 (d, JF,C= 243.4 Hz, CF), 146.55, 144.11, 132.46, 122.48, 122.40, 121.28, 121.11, 121.02, 120.95, 120.48, 120.43, 116.94, 116.88, 116.71, 116.65, 114.45, 111.59, 111.29, 111.19, 66.24, 60.54, 56.07, 56.01, 44.64, 41.97, 29.14, 29.00. ESI-HRMS Calcd for C30H31FN3O6 [M + H]+: 548.2191, found 548.2182.

3.1.11. 1-(4-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (4h)

Yellow oil, (212.84 mg, 0.381 mmol, 52%). IR (cm−1): 3317 (OH), 1568 (C=O), 1542 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H, triazole-H), 7.61–7.51 (m, 2H, Ar-H), 6.81–6.65 (m, 2H, Ar-H), 5.61 (s, 2H, Et-H), 3.86 (s, 6H, OMe-H), 2.98–2.78 (m, 10H, Et-H). 13C-NMR (100 MHz, CDCl3) δ 206.03, 204.59, 146.55, 145.21, 144.11, 143.36, 135.46, 135.38, 134.59, 134.55, 132.44, 130.03, 129.98, 121.66, 121.45, 121.27, 121.09, 120.94, 120.20, 114.46, 111.58, 111.18, 66.20, 60.54, 56.06, 56.00, 44.63, 41.95, 29.13, 28.98. ESI-HRMS Calcd for C30H31ClN3O6 [M + H]+: 564.1896, found 564.1894.

3.1.12. 1-(4-((1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione (4i)

Yellow oil, (113.91 mg, 0.189 mmol, 26%). IR (cm−1): 3353 (OH), 1544 (C=O), 1531 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H, triazole-H), 7.65–7.56 (m, 4H, Ar-H), 6.79–6.64 (m, 6H, Ar-H), 5.45 (s, 2H, Et-H), 3.85 (s, 6H, OMe-H), 2.98–2.77 (m, 10H, Et-H). 13C-NMR (101 MHz, CDCl3) δ 204.58, 162.76 (d, JF,C= 241.5 Hz, CF), 146.56, 144.12, 135.93, 132.99, 132.94, 132.89, 132.42, 124.21, 122.45, 121.82, 121.25, 120.93, 120.78, 120.17, 114.46, 114.36, 111.20, 111.09, 66.18, 56.07, 56.00, 44.62, 36.64, 31.59, 31.41, 29.12, 28.96, 23.86. ESI-HRMS Calcd for C30H31BrN3O6 [M + H]+: 608.1391, found 608.1397.

3.1.13. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)heptane-3,5-dione (4j)

Yellow oil, (144.05 mg, 0.243 mmol, 28%). IR (cm−1): 3340 (OH), 1504 (C=O), 1515 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.00 (s, 1H, triazole-H), 7.68–7.67 (d, J=7.2 Hz, 2H, Ar-H), 7.37–7.35 (d, J = 7.2 Hz, 2H, Ar-H), 6.76–6.75 (d, J = 6.4 Hz, 3H, Ar-H), 6.61 (s, 3H, Ar-H), 5.63 (s, 2H, Et-H), 3.82 (s, 6H, OMe-H), 2.75–2.73 (m, 10H, Et-H). 13C-NMR (101 MHz, CDCl3) δ 206.73, 197.93, 146.61, 146.49, 144.18, 144.06, 142.07, 138.31, 132.80, 132.41, 132.31, 131.88, 131.79, 129.19, 129.16, 121.22, 120.98, 116.36, 116.14, 114.55, 114.39, 111.41, 111.34, 56.02, 46.01, 40.94, 30.00, 28.94. ESI-HRMS Calcd for C31H31F3N3O6 [M + H]+: 598.2159, found 598.2159.

3.1.14. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)heptane-3,5-dione (4k)

Yellow oil, (124.49 mg, 0.204 mmol, 33%). IR (cm−1): 3376 (OH), 1550 (C=O), 1534 (C=N); 1H-NMR (500 MHz, CDCl3) δ 8.01 (s, 1H, triazole-H), 7.78–7.66 (m, 4H, Ar-H), 6.76–6.62 (m, 6H, Ar-H), 5.54 (s, 2H, Et-H), 3.83 (s, 6H, OMe-H), 2.95–2.55 (m, 10H, Et-H). 13C-NMR (126 MHz, CDCl3) δ 204.58, 171.34, 162.76 (d, JF,C = 2444.1 Hz, CF), 149.01, 146.53, 145.25, 144.08, 135.31, 132.39, 122.37, 121.81, 121.62, 121.47, 121.06, 120.90, 120.64, 120.30, 119.41, 114.44, 114.39, 111.16, 66.15, 60.52, 55.95, 55.89, 44.60, 29.08. ESI-HRMS Calcd for C31H31F3N3O7 [M + H]+: 614.2109, found 614.2100.

3.1.15. 1-(4-Hydroxy-3-methoxyphenyl)-7-(3-methoxy-4-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)heptane-3,5-dione (4l)

Yellow oil, (40.87 mg, 0.072 mmol, 10%). IR (cm−1): 3352 (OH), 1511 (C=O), 1589 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.39–8.37 (d, J = 7.6 Hz, 2H, Ar-H), 8.00 (s, 1H, triazole-H), 7.86–7.84 (d, J = 7.6 Hz, 10.4 Hz, 2H, Ar-H), 6.76–6.57 (m, 6H, Ar-H), 5.53 (s, 2H, Et-H), 3.83 (s, 6H, OMe-H), 2.95–2.70 (m, 10H, Et-H). 13C-NMR (101 MHz, CDCl3) δ 205.67, 204.49, 147.29, 146.55, 145.88, 144.21, 144.13, 141.09, 140.99, 132.86, 132.39, 125.63, 121.57, 121.35, 121.14, 120.95, 120.54, 120.41, 120.23, 114.46, 111.70, 111.21, 66.09, 60.54, 56.13, 56.02, 44.57, 41.90, 29.14, 28.90. ESI-HRMS Calcd for C30H31N4O8 [M + H]+: 575.2136, found 575.2149.

3.1.16. 4-(4-((4-(7-(4-Hydroxy-3-methoxyphenyl)-3,5-dioxoheptyl)-2-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile (4m)

Yellow oil, (165.18 mg, 0.300 mmol, 41%). IR (cm−1): 3313 (OH), 1596 (C=O), 1552 (C=N); 1H-NMR (400 MHz, CDCl3) δ 8.00 (s, 1H, triazole-H), 7.80–7.76 (m, 4H, Ar-H), 6.75–6.58 (m, 6H, Ar-H), 5.64 (s, 2H, Et-H), 3.82 (s, 6H, OMe-H), 2.95–2.69 (m, 10H, Et-H). 13C-NMR (101 MHz, CDCl3) δ 204.41, 162.67, 146.46, 145.62, 144.02, 143.68, 139.62, 133.92, 132.28, 121.28, 121.21, 120.82, 120.47, 120.38, 120.19, 119.96, 117.75, 114.45, 114.37, 112.31, 111.61, 111.12, 65.99, 56.00, 55.91, 44.47, 36.55, 31.49, 29.01, 28.78, 23.71. ESI-HRMS Calcd for C31H31N4O6 [M + H]+: 555.2238, found 555.2247.

3.2. In Vitro Cytotoxicity Activity

Human lung adenocarcinoma (A549), human cervical carcinoma (HeLa), and human breast carcinoma (MCF-7) cell lines were obtained from Kunming Institute of Zoology, Chinese Academy of Sciences (Kunming, China). The cells were cultured in RPMI 1640 (for A549 and HeLa cells) and DMEM (for MCF-7 cell) medium supplemented with 10% heat-inactivated fetal bovine serum, as well as 1% penicillin and streptomycin in a 37 °C, 5% CO2 incubator. Cell viability was estimated by the MTT colorimetric assay, as previously reported [4,5,44]. The test compounds in DMSO (10 mM) were serially diluted with culture medium. Test cells (100 μL, 5 × 104 cells/mL) were seeded into a 96-well microplate and incubated for approximately 24 h; then, the supernatant was removed, and 100 μL of fresh medium and 100 μL of medium containing a test compound or vehicle control (0.5% DMSO) were added. The blank control contained 200 μL of medium without cells. The final concentrations of each compound in the wells were 100, 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78 μM, and the content of DMSO in each drug treatment was less than 0.5% (v/v). The experiments for each concentration were performed in quadruplicate. Cisplatin was used as a positive control. Cells were further incubated for 72 h and then treated with MTT (20 μL/well, 5 mg/mL in DMSO). After another 4 h of incubation, the supernatant per well was removed and 150 μL DMSO was added to each well. The optical density (OD) of each well was measured on a Genois microplate reader at a wavelength of 570 nm. The inhibitory rate of cell growth was calculated according to the following formula: Inhibition rate (%) = {1 − [OD (compounds) − OD (blank)]/[OD (controls) − OD (blank)]} × 100%. IC50 values were determined by nonlinear regression analysis of logistic dose–response curves (SPSS 17.0 statistic software). The IC50 values were derived from SPSS nonlinear regression analysis.

3.3. Analysis of Cell Cycle by Flow Cytometry

The cell cycle was analyzed by flow cytometry. Firstly, HCT116 cells were treated with different concentrations of compound 4g (0 μM, 1.56 μM, 3.125 μM, 6.25 μM, 12.5 μM, and 25 μM) for 72 h. After incubation, a total of (1–5) ×105 cells were harvested from the treated and normal samples. The cells were washed twice with PBS and fixed in 70% ice-cold ethanol at least overnight. The sample was concentrated by removing the ethanol and then cells were then washed three times with PBS, staining the cellular DNA with fluorescent solution (1% (v/v) Triton X-100, 0.01% RNase, 0.05% PI) for 15 min in darkness. The cell cycle distribution was then detected by flow cytometry (COULTER EPICS XL, Orange City, FL, USA). All experiments were performed three times.

3.4. Parameter Prediction of Drugs

Adenomatous Polyposis Coli (APC) and Guanine Nucleate Exchange Factor (Asef) are proteins closely related to the occurrence and development of colon cancer. Clinical studies found that over 85% congenital colon cancer patients and 80% acquired colon cancer patients experience frameshift or deletion mutations in the APC gene, leading to the production of pathological APC proteins [52]. The pathological APC protein binds to the Asef, activating the Asef, which was originally suppressed by its own function, thereby promoting the carcinogenesis, tissue growth, and metastasis of colon cancer. With the deepening of scientific research on APC–Asef protein interactions, inhibiting this interactions can effectively inhibit the proliferation and metastasis of colon cancer cells. This conclusion has been accepted by researchers and has become one of “hotspots” in anti-colon cancer research [53,54,55]. The binding between pathological APC and Asef is essentially a protein–protein interaction (PPI) process, which has strong hydrophobicity at the interface and generally contains 56% non-polar groups, 29% polar groups, and 15% charged groups [56]. Additionally, the small molecule PPIs through virtual screening technology tend to be rich in aromatic structures [57]. Compared with traditional small-molecule drugs (200~500 Da), compounds acting on PPIs must be of higher molecular weight (>500 Da), larger in size (spatial volume), have stronger hydrophobicity, have more hydrogen bond receptors and ligands, and contain at least 4 rings, making it difficult to meet the Lipinski’s “rule of five”. The active derivatives we designed and synthesized using the molecular hybridization strategy had large molecular weights and volumes, strong hydrophobicity, and multiple ring systems. Moreover, the derivatives are mostly planar and can be inserted into the interface of APC and Asef, which is consistent with the properties of small molecule PPIs. The Molinspiration online prediction tool (https://www.molinspiration.com/, Slovenský Gr) was utilized to predict the molecular properties of the synthesized derivatives, such as the lipid water partition coefficient (miLogP), hydrogen bond acceptor (noN), hydrogen bond donor (nOHNH), molecular volume (MV), number of rotatable bonds (nrotb), and size of polar spatial region (TPSA) to evaluate the similarity between derivatives and PPIs.

3.5. Docking Study

Analysis of the structural domains of APC and Asef proteins reveals that hydrophobic amino acid residues dominate. The “hot spot” amino acid residue region is 176SHPGGGGEQLAINELISDG194 [58], with hydrophobic amino acid residues accounting for 58%. The active derivative belongs to polyphenolic compounds with multiple ring systems and strong hydrophobicity. The highly hydrophobic nature of protein receptors and small molecule ligands facilitates the formation of hydrophobic–hydrophobic interactions, resulting in a high affinity. We conducted molecular docking studies on the most potent compound 4g with an APC–Asef crystal protein to observe whether it can block APC or Asef binding.
Preparation for protein and small molecule calculations: Use Discovery Studio 4.5 software to analyze the complex protein crystals of APC–Asef binding in pathological types (PDB ID: 3NMX). Use ChemBioDraw Ultra 14.0 to draw the 2D structure of the ligand small molecule (4g) to be calculated, and then use the MMFF94 function in the 3D software module of ChemBioDraw Ultra 14.0 to perform initial energy optimization and structural stretching and save the data in a 3000 mol file format.
Receptor ligand molecular docking: Using the Prepare protein function located in the Macroolecule module of DS, prepare and analyze protein receptors for PDB ID 3NMX protein crystals, including environmental cleavage, fragment repair, energy and conformation optimization, and action analysis. Analyze the protein binding region of APC–Asef in 3NMX protein, identify the physical binding center of the two, and delineate the binding site of the receptor protein lesion type APC to be calculated using the Define and Edit Binding Site function in the Receiver ligand interaction module, which is 1.5 times the size of the ligand molecule to be calculated. Import the previously prepared 3000 mol ligand file into DS software and further optimize the conformation of the ligand to be calculated using the Ligand Minimizing function in the Small Molecule module of DS. Using the CDOCKER function in the Receiver ligand interaction module, set the receptor as the lesion type APC protein and the ligand as the conformational optimized quasi computational molecular group, perform receptor ligand molecular docking, and obtain multiple randomly oriented specific receptor ligand binding conformations. Based on the specific situation of receptor binding, select the conformation with the highest negative value in the parameter CDOCKER-InterACTION-ENERGY (lowest binding energy, most stable binding) as the optimal conformation for each ligand. Visualize and analyze receptor ligand binding using the Show2D/3D Structure Diagram function in DS.

4. Conclusions

New derivatives of tetrahydrocurcumin were synthesized using a click reaction. The mono alkylation of the phenolic group with propargyl bromide followed by the copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) resulted in the formation of linked triazole moiety tetrahydrocurcumin derivatives. The synthesized tetrahydrocurcumin derivatives were tested for their anticancer activity against four cancer cell lines. One of the prepared compounds including g showed potent inhibitory activity against human colon carcinoma HCT-116, with an IC50 value of 1.09 ± 0.17 μM. Molecular docking was investigated for compound 4g, and the APC–Asef combined protein showed hydrophobic and hydrogen-bounding interactions between them. As a result of the obtained anticancer activity, these compounds serve as important building blocks for future anticancer agents and can be further improved by further modification of tetrahydrocurcumin. The results obtained herein are important for further structure modifications of THC and the exploitation of the therapeutic potential of THC derivatives as anticancer agents.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29133010/s1, Copies of the 1H NMR, 13C NMR, IR, and HRMS spectra for compounds 4a–4m.

Author Contributions

Conceptualization, A.M.; methodology, M.D.; investigation, C.W., Z.Z. and J.R.; writing—original draft preparation, A.M. and M.D.; writing—review and editing, A.M., A.A. and M.D.; supervision, A.M.; funding acquisition, M.D. and A.J.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Science and Technology Project of Xiamen Medical college (Grant NO. K2023-26), the Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University (Grant NO. XMMC-OP2023005), Xiamen Medical and Health Guidance Project (Grant NO. 3502Z20244ZD1138), and the Fujian Provincial Department of Education Young and Middle-aged Teacher Education Research Project (Grant NO. JAT231133).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

The authors express their gratitude to the Cihan University–Erbil, Iraq, for the financial support. The authors extend their appreciation to the Researchers Supporting Project number (RSPD2024R620), King Saud University, Saudi Arabia.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 29 03010 sch001
Scheme 1. Synthesis, structure, and numbering (as used in NMR signal assignment) of THC-triazole conjugates (4a–m). Reagents and conditions: (a) K2CO3, DMF, propargyl bromide, N2, r.t. 24 h; (b) ice bath, sodium azide, trichloromethane, trifluoroacetic acid, r.t. overnight; (c) THF, t-BuOH-H2O, copper (II) sulfate pentahydrate, sodium ascorbate, r.t. 12 h.
Scheme 1. Synthesis, structure, and numbering (as used in NMR signal assignment) of THC-triazole conjugates (4a–m). Reagents and conditions: (a) K2CO3, DMF, propargyl bromide, N2, r.t. 24 h; (b) ice bath, sodium azide, trichloromethane, trifluoroacetic acid, r.t. overnight; (c) THF, t-BuOH-H2O, copper (II) sulfate pentahydrate, sodium ascorbate, r.t. 12 h.
Molecules 29 03010 sch001
Molecules 29 03010 g001
Figure 1. Compound 4g arrests the cell cycle in HCT-116 cells. Flow cytometry analysis of HCT-116 cells stained with propidium iodide and treated with 4g for 72 h. (A) Control group; (B) Compound 4g, 1.56 μM; (C) Compound 4g, 3.125 μM; (D) Compound 4g, 6.25 μM; (E) Compound 4g, 12.5 μM; Compound 4g, 25 μM.
Figure 1. Compound 4g arrests the cell cycle in HCT-116 cells. Flow cytometry analysis of HCT-116 cells stained with propidium iodide and treated with 4g for 72 h. (A) Control group; (B) Compound 4g, 1.56 μM; (C) Compound 4g, 3.125 μM; (D) Compound 4g, 6.25 μM; (E) Compound 4g, 12.5 μM; Compound 4g, 25 μM.
Molecules 29 03010 g001
Molecules 29 03010 g002
Figure 2. Interaction between 4g and APC–Asef crystal protein.
Figure 2. Interaction between 4g and APC–Asef crystal protein.
Molecules 29 03010 g002
Table 1. The anti-proliferative activity data (IC50) of the prepared compounds (n = 3).
Table 1. The anti-proliferative activity data (IC50) of the prepared compounds (n = 3).
CompoundIC50 (μM)
HCT116HeLaA549HepG2
Tetrahydrocurcumin50.96 ± 0.2333.88 ± 0.3569.25 ± 0.4860.39 ± 0.19
Cisplatin8.22 ± 0.8610.12 ± 0.0628.10 ± 1.5898.22 ± 1.33
4a62.63 ± 3.06>200>200>200
4b>200>200>200>200
4c>200>200>200>200
4d>200>200>200>200
4e>200>200162.40 ± 2.20>200
4f15.59 ± 0.45>200>20053.64 ± 0.27
4g1.09 ± 0.17190 ± 0.6745.16 ± 0.9266.82 ± 0.42
4h69.74 ± 7.12>200>200>200
4i>200>200>200>200
4j89.38 ± 1.39175.9 ± 1.21131.20 ± 1.00>200
4k72.07 ± 3.88129.5 ± 3.4657.96 ± 3.78104.23 ± 0.23
4l>200>200>200>200
4m>200>200135.60 ± 4.80>200
Table 2. Parameter prediction of derivative drugs.
Table 2. Parameter prediction of derivative drugs.
CompoundMWNatomsmiLogPnONnOHNHNrotbTPSAMV
4a529.59393.589114112.79482.19
4b543.62404.029114112.79498.76
4c557.65414.499115112.79515.56
4d571.67425.099115112.79532.14
4e585.70435.289115112.79548.38
4f559.62413.6310115122.02507.74
4g547.58403.749114112.79547.58
4h564.04404.259114112.79495.73
4i608.49404.389114112.79500.08
4j613.59444.5410116122.02613.59
4k579.59434.479115112.79513.49
4l576.56422.8913115167.85497.71
4m554.60413.3310114136.58499.06
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Duan, M.; Mahal, A.; Alkouri, A.; Wang, C.; Zhang, Z.; Ren, J.; Obaidullah, A.J. Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives. Molecules 2024, 29, 3010. https://doi.org/10.3390/molecules29133010

AMA Style

Duan M, Mahal A, Alkouri A, Wang C, Zhang Z, Ren J, Obaidullah AJ. Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives. Molecules. 2024; 29(13):3010. https://doi.org/10.3390/molecules29133010

Chicago/Turabian Style

Duan, Meitao, Ahmed Mahal, Anas Alkouri, Chen Wang, Zhiqiang Zhang, Jungang Ren, and Ahmad J. Obaidullah. 2024. "Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives" Molecules 29, no. 13: 3010. https://doi.org/10.3390/molecules29133010

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