Abstract
Prostate cancer (PCa) is a malignant tumor with a higher mortality rate in the male reproductive system. In this study, the hydroxyazine derivatives were synthesized with different structure from traditional anti-prostate cancer drugs. In the evaluation of in vitro cytotoxicity and antagonistic activity of PC-3, LNCaP, DU145 and androgen receptor, it was found that the mono-substituted derivatives on the phenyl group (4, 6, 7, and 9) displayed strong cytotoxic activities, and compounds 11–16 showed relatively strong antagonistic potency against AR (Inhibition% >55). Docking analysis showed that compounds 11 and 12 mainly bind to AR receptor through hydrogen bonds and hydrophobic bonds, and the structure-activity relationship was discussed based on activity data. These results suggested that these compounds may have instructive implications for drug structural modification in prostate cancer.
1 Introduction
Targeted anti-tumor drugs are the focus of modern anti-cancer research, because of their special targeting, they can greatly reduce the toxicity to normal cells (). In addition, cells in rapid division were more sensitive to the most drugs due to the differences in cell dynamics (Tannock, 1978). Therefore, targeted antitumor drugs can simultaneously inhibit the proliferation and differentiation of tumor cells and greatly accelerate the death of tumor cells (Vinaya et al., 2011). Prostate cancer (PCa) is a malignant tumor with a higher mortality rate in the male reproductive system (). Prostate cancer is driven by the androgen receptor (Yap et al., 2016; ), and is directly associated with nuclear steroidal AR (; ; ). Androgens bind to the AR and form a hormone-receptor complex, which can bind to the DNA and induce downstream biological effects (). This complex also induces the proliferation of prostate cells, and ultimately causes tumorigenesis (). Although some current treatments (hormonotherapy, radical prostatectomy, chemotherapy, or local radiotherapy) can treat androgen-dependent prostate cancer (). However, drug resistance problems hinder its therapeutic efficacy. Therefore, early detection and elimination of both types of prostate cancer cells are very important for decreasing prostate cancer-related death ().
Piperazine moieties play an important role in many drugs (), and piperazine derivatives also have exhibited biological importance, such as receptor high-affinity properties (; ; ; ; ) and anti-proliferative properties (; ; ; ; ; ; ). Hydroxyzine (Figure 1) has antihistamine effect and can be quickly absorbed and distributed by oral or muscle injection. The arylpiperazine derivatives were reported to exhibit significant antagonism against AR with an IC50 of 0.11 μM, whereas the IC50 of bicaluramide is 50 μM. Results of animal experiments have shown that the mass of prostate in rats is significantly reduced, and the concentration of serum testosterone is not significantly changed (; ; ). However, there have been few studies on hydroxyzine derivatives. Based on the results of our group’s previous anti-prostate cancer study (; ; ; ; ; ), we tried to design and synthesize a series of novel hydroxyzine derivatives (Scheme 1) with 2-p-tolylethanol group instead of 2-ethoxyethanol group in hydroxyzine. Unexpectedly, some derivatives exhibited strong anti-cancer activities and antagonistic activities. These results can provide valuable information for further designing hydroxyzine derivatives as potential prostate cancer therapeutics.
FIGURE 1
SCHEME 1
2 Materials and methods
2.1 Materials and instruments
Reagents and solvents were of analytical purity and dried and using standard procedures. The melting point was measured using the Shanghai electrical optical SGW X-4 micromelting point instrument. The HRMS mass spectrometry was measured using the LCQ DECA XP LC-MS. The NMR spectra were measured using the Bruker AV-400 NB, with TMS as the internal standard, and DMSO-d6 or CDCl3 as the solvent. Column chromatography silica gel was the 300–400 mesh silicone of Qingdao Marine Chemical Plant.
2.2 Synthesis of 2-[4-(bromomethyl)phenyl]ethanol (2)
The borane–dimethyl sulfide (20.0 ml, 0.038 mol, 2 M in THF) was added to the tetrahydrofuran (THF, 100 ml) solution, supplemented with carboxylic acid 1 (5 g, 0.021 mol), and stirred at 0°C for 1 h. Then stirred at r. t. for 10 h. Extracted with ethyl acetate (100 ml) and water (20 ml). Concentrated organic phase, the resulting residue was directly used without further purification.
2.3 Preparation of derivatives 3–17
Piperazines (1.3 equiv), potassium carbonate (5.5 equiv), acetonitrile (CH3CN, 10 ml), and 2 (50 mg, 0.11 mmol) were successively added to the flask, stirred with reflux for 10 h. The reaction solution was filtered and concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/5).
2.3.1 2-(4-((4-benzhydrylpiperazin-1-yl)methyl)phenyl)ethan-1-ol (3)
White solid (ethyl acetate), yield: 85% (from compound 1); M.p. 122°C–123°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.75–7.10 (m, 14H), 4.26 (br s, 2H), 3.64 (br s, 10H), 3.56 (t, J = 6.9 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H); MS (ESI, m/z): 387.1 [M+1]+; HRMS (EI) calcd for C26H29ClN2O, 386.2358; found, 386.2354.
2.3.2 2-(4-((4-(phenyl(p-tolyl)methyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (4)
White solid (ethyl acetate), yield: 82% (from compound 1); M.p. 125°C–126°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.80–7.11 (m, 13H), 4.27 (br s, 2H), 3.66 (br s, 10H), 3.57 (t, J = 6.9 Hz, 2H), 2.72 (t, J = 6.9 Hz, 2H); 2.34 (s, 3H), MS (ESI, m/z): 401.2 [M+1]+; HRMS (EI) calcd for C27H32N2O, 400.2515; found, 400.2510.
2.3.3 2-(4-((4-(di-p-tolylmethyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (5)
White solid (ethyl acetate), yield: 82% (from compound 1); M.p. 128°C–129°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.75 (br s, 4H), 7.45 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.1 Hz, 4H), 4.25 (br s, 2H), 3.64 (br s, 10H), 3.56 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H); 2.36 (s, 6H), MS (ESI, m/z): 415.1 [M+1]+; HRMS (EI) calcd for C28H34N2O, 414.2671; found, 414.2668.
2.3.4 2-(4-((4-((4-methoxyphenyl)(phenyl)methyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (6)
White solid (ethyl acetate), yield: 87% (from compound 1); M.p. 116°C–117°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.76–7.13 (m, 13H), 4.25 (br s, 2H), 3.77 (s, 3H), 3.67 (br s, 10H), 3.54 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), MS (ESI, m/z): 417.1 [M+1]+; HRMS (EI) calcd for C27H32N2O2, 416.2464; found, 416.2462.
2.3.5 2-(4-((4-((4-fluorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (7)
White solid (ethyl acetate), yield: 87% (from compound 1); M.p. 116°C–117°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.70–7.11 (m, 13H), 4.27 (br s, 2H), 3.64 (br s, 10H), 3.57 (t, J = 6.9 Hz, 2H), 2.72 (t, J = 6.9 Hz, 2H), MS (ESI, m/z): 405.1 [M+1]+; HRMS (EI) calcd for C26H29FN2O, 404.2264; found, 404.2260.
2.3.6 2-(4-((4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)phenyl)ethanol (8)
White solid (ethyl acetate), yield: 70% (from compound 1); M.p. 133°C–134°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 1H NMR (400 MHz, DMSO-d6) δ 7.70 (br s, 4H), 7.46 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 8.2 Hz, 4H), 4.27 (br s, 2H), 3.66 (br s, 10H), 3.55 (t, J = 6.9 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H); MS (ESI, m/z): 423.2 [M+1]+; HRMS (EI) calcd for C26H28F2N2O, 422.2170; found, 422.2168.
2.3.7 2-(4-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)phenyl)ethanol (9)
White solid (ethyl acetate), yield: 75% (from compound 1); M.p. 130°C–131°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.89–7.13 (m, 13H), 4.29 (br s, 2H), 3.66 (br s, 10H), 3.57 (t, J = 6.9 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H); MS (ESI, m/z): 421.1 [M+1]+; HRMS (EI) calcd for C26H29ClN2O, 420.1968; found, 420.1962.
2.3.8 2-(4-((4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (10)
White solid (ethyl acetate), yield: 72% (from compound 1); M.p. 127°C–128°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.67 (br s, 4H), 7.42 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 4H), 4.23 (br s, 2H), 3.68 (br s, 10H), 3.57 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H); MS (ESI, m/z): 455.2 [M+1]+; HRMS (EI) calcd for C26H28Cl2N2O, 454.1579; found, 454.1575.
2.3.9 2-(4-((4-benzylpiperazin-1-yl)methyl)phenyl)ethan-1-ol (11)
White solid (ethyl acetate), yield: 82% (from compound 1); M.p. 119°C–120°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.43 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 4.25 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.62 (s, 2H), 3.54 (t, J = 5.0 Hz, 4H), 2.72 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 5.0 Hz, 4H); MS (ESI, m/z): 311.1 [M+1]+; HRMS (EI) calcd for C20H26N2O, 310.2045; found, 310.2040.
2.3.10 2-(4-((4-(1-phenylethyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (12)
White solid (ethyl acetate), yield: 78% (from compound 1); M.p. 114°C–115°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.58–7.09 (m, 9H), 4.23 (q, J = 6.6 Hz, 1H), 3.64 (br s, 8H), 3.62 (t, J = 6.8 Hz, 2H), 3.55 (s, 2H), 2.68 (t, J = 6.8 Hz, 2H), 1.12 (d, J = 6.6 Hz, 3H); MS (ESI, m/z): 325.2 [M+1]+; HRMS (EI) calcd for C21H28N2O, 324.2202; found, 324.2200.
2.3.11 2-(4-((4-(4-methylbenzyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (13)
White solid (ethyl acetate), yield: 75% (from compound 1); M.p. 112°C–113°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.41 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 4.27 (s, 2H), 3.74 (t, J = 6.8 Hz, 2H), 3.66 (s, 2H), 3.56 (t, J = 5.0 Hz, 4H), 2.70 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 5.0 Hz, 4H); MS (ESI, m/z): 325.1 [M+1]+; HRMS (EI) calcd for C21H28N2O, 324.2202; found, 324.2200.
2.3.12 2-(4-((4-(4-methoxybenzyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (14)
White solid (ethyl acetate), yield: 82% (from compound 1); M.p. 117°C–118°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.43 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 4.25 (s, 2H), 3.81 (s, 3H), 3.72 (t, J = 6.8 Hz, 2H), 3.67 (s, 2H), 3.54 (t, J = 5.0 Hz, 4H), 2.72 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 5.0 Hz, 4H); MS (ESI, m/z): 341.0 [M+1]+; HRMS (EI) calcd for C21H28N2O2, 340.2151; found, 340.2149.
2.3.13 2-(4-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (15)
White solid (ethyl acetate), yield: 70% (from compound 1); M.p. 114°C–115°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.42 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.26 (s, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.64 (s, 2H), 3.55 (t, J = 5.0 Hz, 4H), 2.70 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 5.0 Hz, 4H); MS (ESI, m/z): 329.1 [M+1]+; HRMS (EI) calcd for C20H25FN2O, 328.1951; found, 328.1948.
2.3.14 2-(4-((4-(4-chlorobenzyl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (16)
White solid (ethyl acetate), yield: 72% (from compound 1); M.p. 109°C–110°C; 1H NMR (400 MHz, CDCl3) δ in ppm: 7.43 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 4.24 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 3.67 (s, 2H), 3.56 (t, J = 5.0 Hz, 4H), 2.72 (t, J = 6.8 Hz, 2H), 2.66 (t, J = 5.0 Hz, 4H); MS (ESI, m/z): 345.1 [M+1]+; HRMS (EI) calcd for C20H25ClN2O, 344.1655; found, 344.1653.
2.3.15 2-(4-((4-(9H-thioxanthen-9-yl)piperazin-1-yl)methyl)phenyl)ethan-1-ol (17)
White solid (ethyl acetate), yield: 78% (from compound 1), M.p. 121°C–122°C; 1H NMR (400 MHz, DMSO-d6) δ in ppm: 7.73–7.08 (m, 12H), 4.24 (br s, 2H), 3.67 (br s, 10H), 3.57 (t, J = 6.9 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H); MS (ESI, m/z): 417.1 [M+1]+; HRMS (EI) calcd for C26H28N2OS, 416.1922; found, 416.1920.
2.4 Biological evaluation
2.4.1 Cell culture
LNCaP, PC-3 and WPMY-1 cells were cultured in Ham’s F-12K (PM150910) supplemented with 10% FBS (164210-50) and 1% P/S (PB180120). DU145 cells were cultured in MEM (PM150410) supplemented with 10% FBS (164210–50) and 1% P/S (PB180120). The cells were incubated at 37°C with 5% CO2 ().
2.4.2 Assessment of antitumor activity by CCK-8 assay
Cell proliferation was measured using the CCK-8 assay kit (; ; ). Cells were seeded into 96-well plates (>5*104) with approximately 100 ul of cell suspension per well and incubated in 37°C incubator for 4 h. Various concentrations of the compounds were then added and incubated for a further 24 h in a 37°C incubator. Finally, 10 ul CCK8 was added and incubated for 0.5–4 h, absorbance at 450 nm was determined. (; ; ).
2.5 AR reporter gene assay
Firefly and Renilla luciferase activities, were determined using the Dual-Glo™luciferase assay kit. RLUs were determined using the GloMax®96-Microplate Luminometer. IC50 was calculated using the GraphPad Prism 5.0 (; ).
2.6 Molecular docking simulation
Binding mechanism experiments performed docking analysis of the three active pockets (LBP, AF2 and BF3) (; ) in AR receptors using AutoDock software (Trott and Olson, 2010). Its PDB protein data (2OZ7, 2YHD and 2YLO) was downloaded from the protein data bank (PDB) (), and the proteins were optimized by the addition of hydrogen atoms and the removal of foreign ligands before docking. A docking space of 40 Å × 40 Å × 30 Å was constructed centered on the ligand of the AR active pocket, with compounds 11 and 12 as template molecules, docked into the optimized cavity and repeated 10 times to find a conformation of the one with the lowest binding free energy.
3 Results and discussions
3.1 Chemistry
Compounds 3–17 were synthesized by the following two-step method as depicted in Scheme 1. The compound 1 was reduced to compound 2 with BH3.S(CH3)2. Then, the compound 2 was heated at reflux with various piperines in an alkaline environment for 16 h.
3.2 Cytotoxic activity and AR antagonist activity
The in vitro cytotoxic activity results of the synthesized derivatives 3–17 against human prostate cancer lines (PC-3, LNCaP, and DU145) and the human prostate epithelial cell line (WPMY-1) were evaluated, as shown in Table 1.
TABLE 1
| Compd. | IC50 (μM)a | |||
|---|---|---|---|---|
| PC-3 | LNCaP | DU145 | WPMY-1 | |
| 3 | 8.13 ± 0.12 | 6.14 ± 0.58 | 11.12 ± 0.76 | >50 |
| 4 | 2.56 ± 0.32 | 4.67 ± 1.02 | 6.14 ± 0.24 | >50 |
| 5 | 12.14 ± 0.29 | 3.73 ± 0.58 | 9.82 ± 0.24 | 37.51 ± 0.37 |
| 6 | 3.15 ± 0.48 | 6.17 ± 1.02 | 2.17 ± 0.72 | >50 |
| 7 | 1.87 ± 0.22 | 5.17 ± 0.63 | 2.17 ± 1.12 | 48.26 ± 0.41 |
| 8 | 10.12 ± 0.08 | 4.92 ± 0.29 | 12.35 ± 0.16 | 35.53 ± 0.13 |
| 9 | 1.53 ± 0.16 | 4.13 ± 0.06 | 7.63 ± 0.12 | >50 |
| 10 | 15.24 ± 0.14 | 7.14 ± 0.29 | 10.78 ± 1.14 | >50 |
| 11 | 20.36 ± 0.48 | 11.24 ± 0.14 | 11.26 ± 0.27 | >50 |
| 12 | 13.67 ± 1.12 | 7.76 ± 0.19 | 16.28 ± 0.63 | >50 |
| 13 | 15.36 ± 0.42 | 22.13 ± 0.76 | 17.17 ± 1.02 | 47.14 ± 0.42 |
| 14 | 11.13 ± 0.67 | 16.16 ± 0.53 | 24.14 ± 0.47 | >50 |
| 15 | 10.46 ± 1.14 | 18.45 ± 0.16 | 16.17 ± 0.62 | >50 |
| 16 | 14.42 ± 0.35 | 16.41 ± 0.19 | 31.46 ± 1.21 | >50 |
| 17 | 6.42 ± 0.52 | 5.61 ± 0.86 | 8.35 ± 0.28 | >50 |
| Finasteride | 17.80 | 13.53 | 14.55 | — |
| Naftopidil | 42.10 ± 0.79 | 22.36 ± 0.61 | 34.58 ± 0.31 | >50 |
In vitro cytotoxicity of derivatives 3–17.
IC50 values are taken as means ± standard deviation from three experiments.
The compounds 3–10 and 12–17 showed strong cytotoxic activity against PC-3 cells and were more potent than finasteride; the compounds 3–12 and 17 showed strong cytotoxic activity against LNCaP cells; the compounds 3–11 and 17 showed strong cytotoxic activity against DU145 cells. In addition, mono-substituted derivatives on the phenyl group (4, 6, 7, and 9) displayed strong cytotoxic activities against all the tested cancer cells. And these compounds exhibited low cytotoxicity to normal human prostate epithelial WPMY-1 cells.
Structure-activity relationship investigation was focused on the effects of changes in different substituents on the phenyl group. For instance, compared to compound 3, the compounds with mono-substituted group on the phenyl group (4, 6, 7, and 9) exhibited potent anticancer activity against LNCaP, DU145, and PC-3 cells. However, Dimethyl-substituted derivative 5 displayed moderate activity against PC-3 and DU145 cells, compounds 8 and 10 also had the similar properties. Moreover, compound 6 with electron-donating group also demonstrated strong cytotoxic activities against all the tested cancer cells. In order to compare the cytotoxic activity of compounds 3–10, the compounds 11–16 were synthesized, and the substitution of R1 and R2 groups with two phenyl groups showed high cytotoxic activity against the tested cancer cells. In summary, the introduction of this piperazine moiety contributes to its activity. Both PC-3 and DU145 cells are androgen-insensitive cell lines, but the compounds have different inhibitory activities against PC-3 and DU145 cells. The p53 is one of the most commonly mutated genes in human cancer, and the expression of p53 gene may be a key determinant of derivatives sensitivity in prostate cancer DU145 cells (). The literatures have reported that the p53 in DU145 cells were significantly activated by drugs, but in PC-3 cells the expression of the p53 gene was undetectable (; ). So the compounds have different inhibitory activities against PC-3 and DU145 cells, and PC-3 cells are insensitive to derivatives.
The antagonistic activity of these derivatives against AR was assessed using luciferase assays (Xu et al., 2014; Xu et al., 2015; Zuo et al., 2017; Xu et al., 2018). As shown in Table 2, the compounds 3–10 exhibited weak antagonistic potency against AR. However, compounds 11–16 demonstrated relatively potent antagonistic potency (>55% inhibition).The above results were be contrary to the tested cancer cells antiproliferation activity. The results indicated that a small group introduction to the piperazine ring may be helpful for antagonistic activity against AR.
TABLE 2
| Compd. | AR antagonistic activity % (10 μM) |
| 3 | 40.17 ± 0.24 |
| 4 | 32.46 ± 0.65 |
| 5 | 22.68 ± 0.72 |
| 6 | 30.75 ± 0.17 |
| 7 | 38.67 ± 0.83 |
| 8 | 25.16 ± 0.71 |
| 9 | 28.42 ± 0.25 |
| 10 | 20.47 ± 0.18 |
| 11 | 65.15 ± 0.57 |
| 12 | 68.62 ± 0.38 |
| 13 | 64.18 ± 0.45 |
| 14 | 58.88 ± 0.23 |
| 15 | 64.35 ± 0.17 |
| 16 | 60.25 ± 0.35 |
| 17 | 36.49 ± 0.79 |
| R1881 | N.Ea |
| Enzalutamide | 84.7 ± 1.4 |
AR antagonist activity of compounds 3–17.
N.E, no antagonistic effect.
3.3 Docking study
In order to better understand the binding site of derivatives targets, the docking simulation into the three binding sites of AR (LBP, AF2, and BF3) of compounds 11 and 12 were performed using AutoDock Vina software, as shown in Table 3.
TABLE 3
| Binding site | Compound 11 | Compound 12 |
|---|---|---|
| LBP (PDB ID: 2OZ7) | −8.1 | −8.5 |
| AF2 (PDB ID: 2YHD) | −5.9 | −6.0 |
| BF3 (PDB ID: 2YLO) | −6.5 | −6.6 |
The binding affinities (kcal/mol) of compounds 11 and 12 in three binding sites of AR.
As displayed in Table 3, the binding free energies of the compounds 11 and 12 to all three sites of the AR were calculated, both of the LBP sites had the lowest binding free energy, as measured at −8.1 and −8.5 kcal/mol, respectively. As shown in Figure 2, both compounds 11 and 12 could form hydrophobic interactions with over a dozen amino acid residues, such as Gln711, Met745, and Ala877. More importantly, they were all able to form hydrogen bonds with the amino acid residue Phe697, at a distance of between 3.5 Å.
FIGURE 2
4 Conclusion
In summary, in this study a series of novel hydroxyazine derivatives were synthesized and evaluated for antagonistic activity against AR and cytotoxic activity against human prostate cancer cells. The results showed that the derivative 4, 6, 7, and 9 displayed strong cytotoxic activities against the LNCaP, DU145 and PC-3 cells, and compounds 11–16 showed strong AR antagonism (Inhibition% >55). The SAR results suggested that mono-substituted derivatives on the phenyl group contributed to improve the cytotoxic activity against human prostate cancer cells. These hydroxyzazine piperazine derivatives may be instructive for structural modification of novel anti-prostate cancer drugs.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Author contributions
YQ, BX, and SC performed synthesis experiments. YQ, BX, and WW conducted the biological evaluation and molecular docking. YQ, HZ, and HC designed experiments. YQ and HC interpreted the data and wrote the paper. All authors contributed to the article and approved the submitted version.
Funding
The work was supported by the Henan Province Science and Technology Attack Plan Foundation (Nos 212102110241 and 222102310356), the Key Scientific Research Project of Higher Education of Henan Province (Nos 21A350006 and 22B350004), the National Natural Science Foundation of China (No. 22278244), and 111 Project (No. D20015).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2022.1053675/full#supplementary-material
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Summary
Keywords
hydroxyzine derivatives, cytotoxic activity, antagonistic activity, docking study, AR antagonists
Citation
Qi Y, Xue B, Chen S, Wang W, Zhou H and Chen H (2022) Synthesis, biological evaluation, and molecular docking of novel hydroxyzine derivatives as potential AR antagonists. Front. Chem. 10:1053675. doi: 10.3389/fchem.2022.1053675
Received
26 September 2022
Accepted
20 October 2022
Published
03 November 2022
Volume
10 - 2022
Edited by
Yu Huo, Sichuan Normal University, China
Reviewed by
Hang Gao, Taiyuan University of Technology, China
Bingchao Qiang, Baiyao Group Co. Ltd. New medicine R&D, China
Updates
Copyright
© 2022 Qi, Xue, Chen, Wang, Zhou and Chen.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Haifeng Zhou, zhouhf@ctgu.edu.cn; Hong Chen, chenwexpo@sina.com
This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry
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