Hydroxide-Mediated SNAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents

Yu, Xiang; Xi, Yinkai; Sui, Yi; Liu, Yang; Chen, Guifen; Zhang, Minjie; Zhang, Yan; Luo, Guoyong; Long, Yi; Yang, Wude

doi:10.3390/molecules28114303

Open AccessCommunication

Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents

by

Xiang Yu

^1,2,†,

Yinkai Xi

^1,†,

Yi Sui

¹,

Yang Liu

³,

Guifen Chen

¹,

Minjie Zhang

¹,

Yan Zhang

¹,

Guoyong Luo

¹,

Yi Long

¹ and

Wude Yang

^1,*

¹

College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China

²

Guizhou Joint Laboratory for International Cooperation in Ethnic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China

³

School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China

^*

Author to whom correspondence should be addressed.

^†

These authors contribute equally to this work.

Molecules 2023, 28(11), 4303; https://doi.org/10.3390/molecules28114303

Submission received: 13 April 2023 / Revised: 13 May 2023 / Accepted: 14 May 2023 / Published: 24 May 2023

(This article belongs to the Special Issue Biological Activity of Natural and Synthetic Compounds 2.0)

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Abstract

:

A simple and efficient hydroxide-mediated S_NAr rearrangement was reported to synthesize new depside derivatives containing the diaryl ether skeleton from the natural product barbatic acid. The prepared compounds were determined using ¹H NMR, ¹³C NMR, HRMS, and X-ray crystallographic analysis and were also screened in vitro for cytotoxicity against three cancer cell lines and one normal cell line. The evaluation results showed that compound 3b possessed the best antiproliferative activity against liver cancer HepG2 cell line and low toxicity, which made it worth further study.

Keywords:

barbatic acid; diaryl ethers; S_NAr rearrangement; antitumor activity

1. Introduction

Depsides are dimers formed by ester bonds between two aromatic rings, which are the main secondary metabolites of lichens [1]. Previous research reported that depsides had good biological properties, such as antitumor, antioxidant, and antibacterial activities [2,3,4]. Barbatic acid (1, Figure 1) is one kind of depside that was widely discovered from the lichen [5] and was determined to have a variety of biological activities, including anticancer, schistosomicidal, diuretic, and the potential to inhibit the growth of plants and algal [6,7,8,9]. However, to the best of our knowledge, little attention has been paid to the further structural modification of barbatic acid for developing potential antitumor agents.

Diaryl ethers are an important class of organic compounds with two aromatic rings and a flexible oxygen bridge, which are widely used in various fields such as medicine and pesticides [10]. For instance, Sorafenib (I, Figure 1) is a highly effective small molecule inhibitor with anticancer properties, which is used to treat advanced renal cancer [11]. Nimesulide (II, Figure 1), a nonsteroidal anti-inflammatory drug, has been popularized for several decades [12]. Difenoconazole (III, Figure 1) and famoxadone (IV, Figure 1) have been utilized as fungicides to protect a wide range of plants, such as rice, cotton, and cereals, from diseases [13,14]. Usually, diaryl ethers are mainly achieved through the coupling of phenols and aryl halides under the action of catalysts to form C–O bonds. These methods have certain deficiencies, such as high temperatures, expensive catalysts, or toxic solvents [15,16,17,18,19].

Herein, we reported an interesting means of converting some barbatic acid esters to novel diaryl ethers through a hydroxide-mediated S_NAr rearrangement reaction. The synthesized compounds were also tested for antitumor activity, and some compounds demonstrated good effects.

2. Results and Discussion

As illustrated in Figure 2, firstly, 3-hydroxy-4-(isopropoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate (2a) was prepared by our previously reported method [20]. Subsequently, 2a reacted with potassium hydroxide in the mixed solvent (DMSO/water = 10/1, v/v) at room temperature. To our delight, the reaction did not undergo hydrolysis to produce corresponding benzoic acid and phenol as we expected but instead underwent a rearrangement reaction to produce diaryl ethers with a yield of 81% (3a). This was proven by comparison with the partial ¹H NMR spectra of compounds 2a and 3a (Figure 3). Compared to compound 2a, compound 3a had only one phenolic hydroxyl group, and the chemical shift of aromatic signals was shifted from 6.37 ppm to 5.77 ppm due to the steric effects. There was no significant change in the other chemical shifts. Moreover, the X-ray crystal structure (Figure 4) of compound 3a further demonstrated this conclusion.

In order to test the reliability of the method, compounds 3b–j continued to be synthesized with a 70–95% yield under the same reaction conditions, as shown in Figure 5. The structures of all target compounds were characterized using ¹H NMR, ¹³C NMR, and HRMS. The stereochemistry of 3d was further confirmed by X-ray crystallographic analysis (Figure 6).

In addition, a probable reaction mechanism for this rearrangement was proposed and is illustrated in Figure 7. The sequence began with a simple acid-base reaction wherein hydroxide deprotonated the hydroxyl group, as shown in pink in structure 2. The resulting phenoxide then participated in an intramolecular S_NAr cyclization onto the second ring, as illustrated by the conversion of structure 4 to the spirocyclic intermediate 5. The re-establishment of aromaticity was accompanied by the formation of the carboxylate anion shown in structure 6, and then acidification delivered the target structures 3.

Compounds 3a–j were screened for their antitumor activities against three human cancer cell lines (lung cancer A549 cells, liver cancer HepG2 cells, and prostatic cancer 22RV1 cells) in vitro by the standard MTT method, and the IC₅₀ values are presented in Table 1. The experimental results showed that compounds 3a, 3c, 3e, and 3f exhibited moderate cytotoxic activities against A549 cells with IC₅₀ values of 2.61, 1.43, and 2.21 mmol/L, respectively. Compounds 3a–d, i–j induced high cytotoxic activity against HepG2 cells, which exhibited excellent activities with IC₅₀ values of 0.41–1.56 mmol/L. Compound 3d afforded the best antiproliferation activities toward 22RV1 cells, with an IC₅₀ value of 0.78 mmol/L. The results demonstrated that diaryl ethers synthesized in this study possessed potential antitumor activities.

Selective killing of cancer cells without affecting normal cell growth is an important feature that must be considered in cancer chemotherapy. Therefore, the target compounds 3a–j were estimated for cytotoxicity toward normal madin-daby canine kidney cells (MDCK) and as shown in Figure 8. Compared to the blank control, most compounds could influence the growth of normal MDCK cells with cell survival rates below 90%, except for compound 3b (97.47%), suggesting that 3b had almost no toxicity to normal cells and could selectively inhibit the growth of liver cancer HepG2 cells.

3. Materials and Methods

3.1. Chemistry

All reagents and solvents were of reagent grade or were purified according to standard methods before use. Analytical thin-layer chromatography (TLC) was performed with silica gel plates using silica gel 60 GF₂₅₄ (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China). Melting points were determined on an XT-4 digital melting point apparatus (Beijing Tech Instrument Co., Ltd., Beijing, China) and were uncorrected. Proton nuclear magnetic resonance spectra (¹H NMR) were recorded on a Bruker Avance DMX 400 MHz instrument (Bruker, Bremerhaven, Germany) in CDCl₃ or DMSO-d₆ using TMS (tetramethylsilane) as the internal standard. High-resolution mass spectrometry (HRMS) was carried out with a Xevo G2-SQTOF instrument (Waters, Milford, MA, USA).

3.1.1. Synthesis of Intermediates 2a–j

Compounds 2a–j were prepared, as described in our previous publication [20], and their spectra data are shown below.

Data for 3-hydroxy-4-(isopropoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate (2a): Yield: 48%, white solid, mp 135–138 °C; ¹H NMR (400 MHz, CDCl₃): δ 12.05 (s, 1H), 11.53 (s, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.34 (p, J = 6.3 Hz, 1H), 3.90 (s, 3H), 2.69 (s, 3H), 2.55 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 1.41 (d, J = 6.3 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 171.3, 170.2, 162.9, 162.8, 162.2, 152.3, 140.7, 139.6, 116.9, 116.2, 111.3, 110.4, 106.4, 104.3, 69.8, 55.5, 25.1, 24.2, 21.9 × 2, 9.3, 7.8; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1570, found 425.1566.

Data for Benzyl 2-hydroxy-4-((2-hydroxy-4-methoxy-3,6-dimethylbenzoyl)oxy)-3,6-dimethyl benzoate (2b): Yield: 50%, white solid, mp 113–115 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.92 (s, 1H), 11.51 (s, 1H), 7.48–7.34 (m, 5H), 6.51 (s, 1H), 6.38 (s, 1H), 5.43 (s, 2H), 3.90 (s, 3H), 2.69 (s, 3H), 2.52 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 172.0, 170.6, 163.5 × 2, 162.7, 153.0, 141.2, 140.3, 135.5, 129.2 × 2, 129.1, 128.9 × 2, 117.5, 116.9, 111.8, 110.4, 106.9, 104.8, 67.9, 56.0, 25.5, 24.8, 9.8, 8.3; HRMS m/z calcd. for C₂₆H₂₆O₇Na ([M + Na]⁺) 473.1570, found 473.1569.

Data for benzyl 4-(4-ethoxy-2-hydroxy-3,6-dimethylbenzoyloxy)-2-hydroxy-3,6-dimethylbenzoate (2c): Yield: 36%, white solid, mp 129–131 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.93 (s, 1H), 11.52 (s, 1H), 7.47–7.33 (m, 5H), 6.51 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 4.12 (q, J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.53 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 1.46 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.6, 170.2, 163.1, 163.0, 161.8, 152.6, 140.6, 139.8, 135.1, 128.7 × 2, 128.6, 128.5 × 2, 117.0, 116.4, 111.3, 109.8, 107.3, 104.1, 67.5, 63.8, 25.1, 24.4, 14.8, 9.3, 7.9; HRMS m/z calcd for C₂₇H₂₈O₇Na ([M + Na]⁺) 487.1727, found 487.1729.

Data for 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-3,6-dimethyl-4-propoxybenzoate (2d): Yield: 33%, white solid, mp 110–113 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.91 (s, 1H), 11.50 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.96 (s, 3H), 2.65 (s, 3H), 2.52 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.85 (p, J = 6.9 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 172.3, 170.2, 163.0, 162.8, 161.9, 152.5, 140.6, 139.6, 116.9, 116.4, 111.4, 109.9, 107.3, 104.0, 69.7, 52.2, 25.0, 24.0, 22.6, 10.5, 9.3, 7.8; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1570, found 425.1564.

Data for 3-hydroxy-4-(isopropoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-3,6-dimethyl-4-propoxybenzoate (2e): Yield: 37%, white solid, mp 112–115 °C; ¹H NMR (400 MHz, CDCl₃): δ 12.05 (s, 1H), 11.53 (s, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 5.38-5.29 (m, 1H), 4.01 (t, J = 6.4 Hz, 2H), 2.67 (s, 3H), 2.54 (s, 3H), 2.11 (s, 3H), 2.08 (s, 3H), 1.89–1.80 (m, 2H), 1.42 (s, 3H), 1.41 (d, J = 6.3 Hz, 6H), 1.07 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.3, 170.3, 163.0, 162.8, 161.9, 152.3, 140.6, 139.6, 116.9, 116.3, 111.4, 110.4, 107.3, 104.1, 69.8, 69.7, 25.0, 24.2, 22.6, 21.9 × 2, 10.5, 9.3, 7.8; HRMS m/z calcd for C₂₄H₃₀O₇Na ([M + Na]⁺) 453.1883, found 453.1883.

Data for benzyl 2-hydroxy-4-(2-hydroxy-3,6-dimethyl-4-propoxybenzoyloxy)-3,6-dimethylbenzoate (2f): Yield: 30%, white solid, mp 111–114 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.92 (s, 1H), 11.51 (s, 1H), 7.51–7.29 (m, 5H), 6.51 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 4.02 (t, J = 6.4 Hz, 2H), 2.67 (s, 3H), 2.52 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H), 1.86 (q, J = 6.5 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.6, 170.2, 163.0, 163.0, 161.9, 152.6, 140.6, 139.7, 135.1, 128.7 × 2, 128.6, 128.4 × 2, 117.0, 116.4, 111.4, 109.9, 107.3, 104.1, 69.7, 67.4, 25.0, 24.3, 22.6, 10.5, 9.3, 7.8; HRMS m/z calcd for C₂₈H₃₀O₇Na ([M + Na]⁺) 501.1883, found 501.1880.

Data for 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-isopropoxy-3,6-dimethylbenzoate (2g): Yield: 36%, white solid, mp 60–63 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.92 (s, 1H), 11.53 (s, 1H), 6.51 (s, 1H), 6.37 (s, 1H), 4.67 (p, J = 6.1 Hz, 1H), 3.97 (s, 3H), 2.66 (s, 3H), 2.53 (s, 3H), 2.09 (s, 6H), 1.38 (d, J = 6.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 172.3, 170.2, 163.4, 162.8, 161.0, 152.6, 140.3, 139.6, 116.9, 116.4, 112.3, 109.9, 108.6, 103.8, 70.3, 52.2, 25.1, 24.0, 22.2 × 2, 9.3, 8.0; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1570, found 425.1568.

Data for benzyl 2-hydroxy-4-(2-hydroxy-4-isopropoxy-3,6-dimethylbenzoyloxy)-3,6-dimethylbenzoate (2h): Yield: 40%, white solid, mp 83–86 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.91 (s, 1H), 11.53 (s, 1H), 7.47–7.33 (m, 5H), 6.50 (s, 1H), 6.36 (s, 1H), 5.42 (s, 2H), 4.66 (p, J = 6.1 Hz, 1H), 2.65 (s, 3H), 2.51 (s, 3H), 2.08 (s, 6H), 1.37 (d, J = 6.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 171.6, 170.2, 163.4, 163.0, 161.0, 152.6, 140.3, 139.7, 135.1, 128.7 × 2, 128.6, 128.4 × 2, 117.0, 116.4, 112.3, 109.8, 108.6, 103.8, 70.3, 67.5, 25.1, 24.3, 22.2 × 2, 9.3, 8.0; HRMS m/z calcd for C₂₈H₃₀O₇Na ([M + Na]⁺) 501.1883, found 501.1883.

Data for 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate (2i): Yield: 35%, white solid, mp 131–134 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.93 (s, 1H), 11.54 (s, 1H), 7.48–7.33 (m, 5H), 6.52 (s, 1H), 6.45 (s, 1H), 5.18 (s, 2H), 3.98 (s, 3H), 2.67 (s, 3H), 2.54 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 172.7, 170.6, 163.6, 163.3, 161.8, 152.9, 141.1, 140.1, 137.1, 129.1 × 2, 128.4, 127.5 × 2, 117.3, 116.8, 112.2, 110.4, 108.1, 105.0, 70.4, 52.7, 25.5, 24.4, 9.7, 8.5; HRMS m/z calcd for C₂₆H₂₆O₇Na ([M + Na]⁺) 473.1570, found 473.1569.

Data for 4-(ethoxycarbonyl)-3-hydroxy-2,5-dimethylphenyl 4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoate (2j): Yield: 40%, white solid, mp 123–126 °C; ¹H NMR (400 MHz, CDCl₃): δ 12.00 (s, 1H), 11.54 (s, 1H), 7.47–7.32 (m, 5H), 6.51 (s, 1H), 6.44 (s, 1H), 5.17 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 2.55 (s, 3H), 2.17 (s, 3H), 2.08 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 171.8, 170.2, 163.1, 162.8, 161.4, 152.4, 140.6, 139.7, 136.6, 128.6 × 2, 128.0, 127.0 × 2, 116.9, 116.3, 111.8, 110.1, 107.6, 104.5, 69.9, 61.7, 25.1, 24.1, 14.2, 9.3, 8.1; HRMS m/z calcd for C₂₇H₂₈O₇Na ([M + Na]⁺) 487.1727, found 487.1721.

3.1.2. Synthesis of Target Compounds 3a–j

To a stirred solution of potassium hydroxide (67.3 mg, 1.2 mmol) in a mixed solvent (20 mL, DMSO/water = 10/1, v/v) at room temperature, 2a–j (0.6 mmol) was added. The reaction mixture was stirred for 1–2 h. Subsequently, the pH of the reaction mixture was adjusted to 1–2 with 1 mol/L hydrochloric acid, and the crude solid was collected by filtration before it was recrystallized with ethanol to afford 3a–j in 70–95%.

Data for 2-(3-hydroxy-4-(isopropoxycarbonyl)-2,5-dimethylphenoxy)-4-methoxy-3,6-dimethylbenzoic acid (3a): Yield: 81%, white solid, mp 206–208 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.04 (s, 1H), 6.61 (s, 1H), 5.78 (s, 1H), 5.27 (p, J = 6.3 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 1.89 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 162.6, 159.7, 159.6, 150.9, 139.8, 137.0, 134.6, 117.8, 111.1, 109.4, 108.3, 106.5 × 2, 69.1, 55.7, 24.6, 22.0 × 2, 20.6, 8.9, 8.1; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1571, found 425.1569 (Figures S1–S3).

Data for 2-(4-(benzyloxycarbonyl)-3-hydroxy-2,5-dimethylphenoxy)-4-methoxy-3,6-dimethylbenzoic acid (3b): Yield: 73%, white solid, mp 186–188 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.43–7.30 (m, 5H), 6.60 (s, 1H), 5.78 (s, 1H), 5.36 (s, 2H), 3.87 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 1.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 169.9, 162.8, 160.0, 159.6, 150.8, 139.9, 136.9, 135.4, 128.6 × 2, 128.4 × 2, 128.3, 119.6, 117.7, 111.2, 109.4, 108.4, 106.0, 66.9, 55.7, 24.7, 20.6, 8.9, 8.1; HRMS m/z calcd for C₂₆H₂₆O₇Na ([M + Na]⁺) 473.1570, found 473.1567 (Figures S4–S6).

Data for 2-(4-(benzyloxycarbonyl)-3-hydroxy-2,5-dimethylphenoxy)-4-ethoxy-3,6-dimethylbenzoic acid (3c): Yield: 87%, white solid, mp 190–192 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.45–7.27 (m, 5H), 6.59 (s, 1H), 5.75 (s, 1H), 5.36 (s, 2H), 4.08 (q, J = 6.9 Hz, 2H), 2.43 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 1.88 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 170.7, 162.9, 159.9, 159.5, 151.3, 139.9, 137.6, 135.5, 128.6 × 2, 128.4 × 2, 128.3, 118.2, 118.1, 111.3, 110.5, 108.3, 106.1, 66.9, 64.0, 24.7, 20.9, 14.7, 9.0, 8.0; HRMS m/z calcd for C₂₇H₂₈O₇Na ([M + Na]⁺) 487.1727, found 487.1729 (Figures S7–S9).

Data for 2-(3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenoxy)-3,6-dimethyl-4-propoxybenzoic acid (3d): Yield: 77%, white solid, mp 234–236 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 6.60 (s, 1H), 5.80 (s, 1H), 3.98 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 1.90 (s, 3H), 1.84 (p, J = 7.1 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 170.0, 162.6, 159.9, 159.3, 151.0, 139.8, 137.2, 118.9, 118.0, 111.1, 110.4, 108.4, 106.1, 69.9, 51.8, 24.4, 22.6, 20.7, 10.6, 8.9, 8.1; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1571, found 425.1566 (Figures S10–S12).

Data for 2-(3-hydroxy-4-(isopropoxycarbonyl)-2,5-dimethylphenoxy)-3,6-dimethyl-4-propoxybenzoic acid (3e): Yield: 95%, white solid, mp 226–228 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.05 (s, 1H), 6.60 (s, 1H), 5.76 (s, 1H), 5.33–5.22 (m, 1H), 3.99 (t, J = 6.6 Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H), 1.89 (s, 3H), 1.84 (dt, J = 13.9, 7.0 Hz, 2H), 1.37 (s, 3H), 1.36 (s, 3H), 1.06 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 170.9, 162.7, 159.6, 159.6, 151.3, 139.8, 137.6, 118.2, 118.1, 111.2, 110.4, 108.2, 106.6, 69.9, 69.1, 24.6, 22.6, 22.0 × 2, 20.9, 10.5, 8.9, 8.0; HRMS m/z calcd for C₂₄H₃₀O₇Na ([M + Na]⁺) 453.1883, found 453.1878 (Figures S13–S15).

Data for 2-(4-(benzyloxycarbonyl)-3-hydroxy-2,5-dimethylphenoxy)-3,6-dimethyl-4-propoxybenzoic acid (3f): Yield: 72%, white solid, mp 176–178 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.43-7.29 (m, 5H), 6.60 (s, 1H), 5.76 (s, 1H), 5.36 (s, 2H), 3.98 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 1.89 (s, 3H), 1.84 (dt, J = 13.9, 7.0 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 162.8, 160.0, 159.9, 159.6, 151.2, 139.9, 137.6, 135.4, 128.6 × 2, 128.4 × 2, 128.3, 118.1, 111.3, 110.5, 108.3, 106.1, 106.1, 69.9, 66.9, 24.7, 22.6, 20.9, 10.5, 8.9, 8.1; HRMS m/z calcd for C₂₈H₃₀O₇Na ([M + Na]⁺) 501.1884, found 501.1878 (Figures S16–S18).

Data for 2-(3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenoxy)-4-isopropoxy-3,6-dimethylbenzoic acid (3g): Yield: 92%, white solid, mp 232–234 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 6.63 (s, 1H), 5.78 (s, 1H), 4.62 (hept, J = 6.0 Hz, 1H), 3.90 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 1.87 (s, 3H), 1.37 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 171.1, 162.7, 159.8, 158.6, 151.5, 139.8, 137.3, 119.1, 118.2, 112.1, 111.2, 108.3, 106.2, 70.8, 51.8, 24.4 × 2, 22.1, 20.9, 9.2, 8.0; HRMS m/z calcd for C₂₂H₂₆O₇Na ([M + Na]⁺) 425.1571, found 425.1563 (Figures S19–S21).

Data for 2-(4-(benzyloxycarbonyl)-3-hydroxy-2,5-dimethylphenoxy)-4-isopropoxy-3,6-dimethylbenzoic acid (3h): Yield: 88%, white solid, mp 156–158 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.44–7.29 (m, 5H), 6.62 (s, 1H), 5.76 (s, 1H), 5.36 (s, 2H), 4.61 (hept, J = 6.1 Hz, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 1.86 (s, 3H), 1.40-1.33 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 170.6, 162.8, 159.9, 158.6, 151.5, 139.9, 137.4, 135.4, 128.6 × 2, 128.4 × 2, 128.3, 119.1, 118.1, 112.2, 111.3, 108.3, 106.1, 70.8, 66.9, 24.7 × 2, 22.1, 20.9, 9.2, 8.0; HRMS m/z calcd for C₂₈H₃₀O₇Na ([M + Na]⁺) 501.1883, found 501.1884 (Figures S22–S24).

Data for 4-(benzyloxy)-2-(3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenoxy)-3,6-dimethylbenzoic acid (3i): Yield: 74%, white solid, mp 223–225 °C; ¹H NMR (400 MHz, CDCl₃) δ 11.91 (s, 1H), 7.48–7.31 (m, 5H), 6.70 (s, 1H), 5.80 (s, 1H), 5.13 (s, 2H), 3.90 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 1.95 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.5, 169.9, 162.6, 159.9, 158.8, 151.0, 139.9, 137.0, 136.6, 128.6 × 2, 128.0, 127.2 × 2, 119.7, 118.3, 111.1, 110.8, 108.4, 106.2, 70.3, 51.8, 24.4, 20.6, 9.2, 8.1; HRMS m/z calcd for C₂₆H₂₆O₇Na ([M + Na]⁺) 473.1571, found 473.1564 (Figures S25–S27).

Data for 4-(benzyloxy)-2-(4-(ethoxycarbonyl)-3-hydroxy-2,5-dimethylphenoxy)-3,6-dimethylbenzoic acid (3j): Yield: 70%, white solid, mp 184-186 ^oC; ¹H NMR (400 MHz, CDCl₃) δ 11.99 (s, 1H), 7.50–7.31 (m, 5H), 6.71 (s, 1H), 5.78 (s, 1H), 5.14 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.95 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 170.4, 162.7, 159.7, 159.0, 151.2, 139.9, 137.4, 136.5, 128.6 × 2, 128.1, 127.2 × 2, 119.2, 118.4, 111.2, 110.9, 108.3, 106.4, 70.3, 61.2, 24.5, 20.8, 14.2, 9.2, 8.1; HRMS m/z calcd for C₂₇H₂₈O₇Na ([M + Na]⁺) 487.1727, found 487.1725 (Figures S28–S30).

3.2. In Vitro Cytotoxicity Assay

The cytotoxicity of test compounds against three different tumor cell lines (A549 cells, HepG2 cells, and 22RV1 cells) and one normal cell line (madin-daby canine kidney cells, DMCK) were evaluated using an MTT assay in vitro [21]. Logarithmic growth phase cells were seeded in a 96-well plate (10⁴ cells/well) and incubated in a cell culture incubator for 24 h. The culture medium was then removed and replaced with a drug-containing medium for the treatment groups (3a–j, 100 μmol/L) and normal saline for the control group. Each well was treated with 100 µL of the respective solution and incubated for an additional 24 h. The culture medium was then removed and replaced with a DMEM solution containing 20 µL of MTT (5 mg/mL). After incubating for 4 h, the liquid in each well was removed and replaced with 150 µL of DMSO, which was shaken for 10 min to ensure thorough mixing. The absorbance at 490 nm was measured to determine the optical density (OD) of each well. Cell growth inhibition rate (%) = (OD_Blank − OD_Experimental)/OD_Blank × 100%. Cell survival rate (%) = OD_Experimental/OD_Blank × 100%. Subsequently, the inhibition rates versus seven concentrations of 3a–j against A549 cells, HepG2 cells, and 22RV1 cells were obtained, and then IC₅₀ values were calculated according to the Logit method.

4. Conclusions

In summary, we have described an interesting S_NAr rearrangement to convert barbatic acid ester derivatives to novel diaryl ethers. The products were characterized by ¹H NMR, ¹³C NMR, HRMS, and X-ray crystallographic analysis. In vitro, anticancer activity tests on a panel of three human cancer cell lines and one normal cell line using an MTT assay revealed that the compound 3b had excellent activity for HepG2 cell lines and low toxicity, which could be used as a valuable lead compound for further study.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114303/s1. Figures S1–S30: ¹H NMR, ¹³C NMR and HRMS spectrum of the compounds 3a–j.

Author Contributions

Data curation, X.Y., Y.X., Y.S., G.C., M.Z. and Y.L. (Yang Liu); formal analysis, X.Y. and Y.Z.; resourse: G.L. and Y.L. (Yi Long); methodology, X.Y., Y.X. and Y.S.; project administration, X.Y. and W.Y.; supervision, W.Y.; writing—original draft, X.Y., Y.S. and Y.Z.; writing—review and editing, X.Y. and W.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82160773), the Guizhou Provincial Natural Science Foundation [QKHJ-ZK(2022)G503], Science and Technology Planning Project of Guizhou Province [QKHF-ZK(2023)G426] and the Natural Science Foundation of Guizhou Provincial Department of Education (QJH-KY [2021]068).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are included within the manuscript or the Supporting Information File.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Figure 1. Design of novel diaryl ethers as antitumor agents.

Figure 2. An unanticipated S_NAr reaction leading to 3a.

Figure 3. The ¹H NMR spectra of 2a and 3a.

Figure 4. X-ray crystallographic structures of 3a.

Figure 5. The synthetic route to compound 3b–j.

Figure 6. X-ray crystallographic structures of 3d.

Figure 7. Possible mechanism for synthesis of compounds 3a–j.

Figure 8. The cytotoxicity of compounds 3a–j on normal MDCK Cells at 100 μmol/L.

Table 1. IC₅₀ values (mmol/L) of compounds 3a–j against three human cancer cell lines.

Compound	A549	HepG2	22RV1
3a	2.61	0.48	32.84
3b	/ ^a	0.82	/
3c	21.52	0.56	/
3d	/	1.26	0.78
3e	1.43	/	/
3f	2.21	/	6.16
3g	14.83	/	/
3h	26.94	/	3.24
3i	/	0.41	/
3j	/	1.56	/

^a No inhibition action.

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Yu, X.; Xi, Y.; Sui, Y.; Liu, Y.; Chen, G.; Zhang, M.; Zhang, Y.; Luo, G.; Long, Y.; Yang, W. Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents. Molecules 2023, 28, 4303. https://doi.org/10.3390/molecules28114303

AMA Style

Yu X, Xi Y, Sui Y, Liu Y, Chen G, Zhang M, Zhang Y, Luo G, Long Y, Yang W. Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents. Molecules. 2023; 28(11):4303. https://doi.org/10.3390/molecules28114303

Chicago/Turabian Style

Yu, Xiang, Yinkai Xi, Yi Sui, Yang Liu, Guifen Chen, Minjie Zhang, Yan Zhang, Guoyong Luo, Yi Long, and Wude Yang. 2023. "Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents" Molecules 28, no. 11: 4303. https://doi.org/10.3390/molecules28114303

APA Style

Yu, X., Xi, Y., Sui, Y., Liu, Y., Chen, G., Zhang, M., Zhang, Y., Luo, G., Long, Y., & Yang, W. (2023). Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents. Molecules, 28(11), 4303. https://doi.org/10.3390/molecules28114303

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Hydroxide-Mediated S_NAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents

Abstract

1. Introduction

2. Results and Discussion

3. Materials and Methods

3.1. Chemistry

3.1.1. Synthesis of Intermediates 2a–j

3.1.2. Synthesis of Target Compounds 3a–j

3.2. In Vitro Cytotoxicity Assay

4. Conclusions

Supplementary Materials

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Conflicts of Interest

Sample Availability

References

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