Selenium-containing sulindac derivative and electrochemical synthesis method thereof

Abstract

The invention discloses a selenium-containing sulindac derivative and an electrochemical synthesis method thereof.According to the method, an electrochemical oxidation technology is adopted, clean and mass-free electrons serve as an oxidizing agent, and carboxylic acid with low oxidation potential of sulindac serves as a source of free radicals to start a reaction, so that the selenium-containing sulindac derivative is obtained. The bifunctional activation of sulindac which is a traditional non-steroidal anti-inflammatory drug (NSAIDs) and a diselenide compound is realized, and the multi-functional selenium-containing sulindac derivative with anti-inflammatory activity is constructed in one step. The synthesis method provided by the invention has remarkable green chemical characteristics, avoids the use of an expensive transition metal catalyst, an excessive oxidant and strong alkali, solves the problems of substrate pre-functionalization and multi-step reaction in traditional synthesis, and provides a synthesis approach with mild conditions and controllable reaction process. The compound also has good anti-inflammatory activity, and the product obtained after modification greatly improves the anti-inflammatory activity of the original drug.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, and in particular relates to a selenium-containing sulindac derivative and an electrochemical synthesis method thereof. Background Art

[0002] Sulindac, a classic nonsteroidal anti-inflammatory drug (NSAID), primarily exerts its anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity and blocking prostaglandin synthesis. Unlike traditional NSAIDs, this drug has attracted considerable attention due to its unique multi-target activity. Current research is exploring its potential applications in cancer prevention, metabolic regulation, and neuroprotection. Sulindac is a prodrug that undergoes reductive metabolism in vivo to a highly active sulfide. It can also be oxidized to a sulfone, which has increased hydrophilicity but significantly reduced activity. While its chiral sulfoxide group reduces the lipophilicity of the parent nucleus and improves solubility, commercially available preparations are racemic. The reversible cycling between methyl sulfide and methyl sulfoxide destabilizes the chiral center, making precise in vivo studies of chiral effects at this site difficult. Notably, the oxidation to the sulfone is irreversible, and the hydrophilic product exhibits significantly reduced COX inhibitory activity. Therefore, the synthesis and modification of sulindac's structure and the enhancement of its activity have long been key research areas for medicinal chemists.

[0003] At present, some research progress has been made on structural modification of different reaction sites of sulindac structure, and a series of sulindac derivatives have been synthesized, showing excellent biological activity. The main focus is on two types of strategies. The first type is the dehydration condensation reaction of the carboxyl group of sulindac with amine and alcohol compounds using condensation reagents to construct amide and ester compounds. The second type is the use of different substituted aldehyde compounds and indanoic acid skeleton to reconstruct the synthesis of sulindac derivatives. However, these activation processes often require the participation of metal reagents, equivalent oxidants and bases. Their limited substrate range, harsh reaction conditions and many by-products remain problems that need to be solved. It is particularly noteworthy that the sulindac molecule contains multiple olefin structural units, which makes it an extremely attractive candidate substrate for derivatization research. However, there is currently no relevant research on the direct derivatization of the olefin skeleton of sulindac to construct sulindac derivatives, which restricts the further clinical application of sulindac compounds.

[0004] Organic electrochemical synthesis uses inexpensive, readily available, and inherently safe electrons as redox reagents. Compounds react on electrode surfaces to produce active intermediates, achieving efficient conversion. This overcomes the need for expensive transition metal catalysts and equivalent amounts of redox reagents in traditional synthetic reactions. Furthermore, electrochemistry offers a wide range of controllable redox potentials, enabling precise control of reaction selectivity. Currently, knowledge of electrochemical modification of sulindac to construct derivatives is relatively limited and warrants further investigation. Summary of the Invention

[0005] The present invention aims to provide selenium-containing sulindac derivatives and electrochemical synthesis methods thereof, which exhibit anti-inflammatory effects. The present invention also provides a green, mild, and efficient modular electrochemical oxidation method that can efficiently and selectively construct difunctionalized sulindac products in a single step, resolving the issues of multiple steps and harsh reaction conditions in the synthesis of sulindac derivatives. This method provides a novel approach and methodological reference for the development of green and inexpensive synthesis of sulindac derivatives.

[0006] This study proposes a method for the difunctionalization of olefins in the five-membered ring skeleton of sulindac for the electrochemical synthesis of selenium-containing sulindac derivatives. This process is not only efficient but also highly selective. This reaction exhibits several significant advantages: (a) it can be carried out without the use of metal catalysts or bases; (b) electrons serve as the sole oxidant, thus avoiding the need for a stoichiometric oxidant; (c) the reaction conditions are mild, do not require high temperatures, and are compatible with a variety of substrates; (d) extremely high chemical selectivity is achieved to construct sulindac derivatives with a lactone ring. (e) The synthesized compounds have superior NO inhibition rates and regulatory abilities against the inflammatory factors IL-6 and IL-1β compared to the sulindac API at the same dose.

[0007] The technical solutions of the present invention are as follows: A selenium-containing sulindac derivative is described. Sulindac is used as a parent core structure, and esterification and selenization reactions are carried out on the olefin of its five-membered ring. The general chemical structure of the selenium-containing sulindac derivative is as follows: , Wherein, R is selected from any one of C1-C3 alkyl, phenyl, and substituted phenyl, and the substituent in the substituted phenyl is any one of alkyl, halogen, halogenated hydrocarbon, C1-C6 alkyl, C1-C3 alkylthio, and cyano.

[0008] Preferably, R is selected from the group consisting of phenyl, p-iodophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-tolyl, m-tolyl, ethyl, p-isopropylphenyl, 3,4-xylyl, o-bromophenyl, m-chlorophenyl, methyl, m-fluorophenyl, p-chlorophenyl, p-ethylphenyl, o-fluorophenyl, 2,4,6-trimethylphenyl, o-tolyl, p-cyanophenyl, o-methylthiophenyl, m-methylthiophenyl, and p-methylthiophenyl.

[0009] Specifically, the selenium-containing sulindac derivative is selected from the following structural formula:

[0010] The present invention also provides an electrochemical synthesis method for a selenium-containing sulindac derivative. The electrochemical synthesis method uses sulindac and a diselenide compound as starting materials, clean electrons as the oxidant, and tetrabutylammonium tetrafluoroborate as the electrolyte. Under electrochemical conditions, the diselenide compound is first oxidized at the anode to generate a radical cation intermediate (A). This intermediate then undergoes cleavage to produce a selenium-centered free radical (B) and a selenium cation (C). The selenium cation (C) is then reduced at the cathode to regenerate the diselenide compound for subsequent catalytic cycles. Simultaneously, sulindac is oxidized at the anode to form a carbon-centered free radical intermediate (D). This intermediate (D) undergoes an intramolecular free radical cyclization reaction to generate a carbon-centered free radical intermediate (E). Finally, the selenium-centered free radical (B) and the carbon-centered free radical intermediate (E) undergo a free radical-free radical cross-coupling reaction to obtain the target product.

[0011] The specific steps of the electrochemical synthesis method are: setting an anode and a cathode in an electrolytic cell, adding sulindac, a diselenide compound, an electrolyte and a solvent in sequence, reacting under constant current conditions, and collecting the reaction liquid after the reaction is completed to obtain a selenium-containing sulindac derivative.

[0012] Preferably, the molar ratio of the sulindac, the diselenide compound, and the electrolyte is 1:1:1, the electrolyte is tetrabutylammonium tetrafluoroborate, and the solvent is acetonitrile.

[0013] The structural formula of the sulindac drug is: ; The chemical structure formula of the diselenide compound is: RSeSeR, where R represents different substituents in the structure of the diselenide compound and is consistent with the chemical structure formula of the above-mentioned selenium-containing sulindac derivative. For example, when the diselenide compound is diphenyl diselenide, R is phenyl.

[0014] Preferably, the diselenide compound is selected from the group consisting of diphenyl diselenide, 1,2-di-p-iodophenyl diselenide, 1,2-di-p-bromophenyl diselenide, 1,2-di-p-trifluoromethylphenyl diselenide, 1,2-di-p-tolyl diselenide, 1,2-di-m-tolyl diselenide, diethyl diselenide, 1,2-di-p-isopropylphenyl diselenide, 1,2-bis(3,4-xylyl) diselenide, 1,2-di-o-bromophenyl diselenide, 1,2-di-m-chlorophenyl diselenide, 1,2-dimethyl diselenide, 1,2-di-m-fluorophenyl diselenide, 1,2-di-p-chlorophenyl diselenide, 1,2-di-p-ethylphenyl diselenide, 1,2-di-o-fluorophenyl diselenide, 1,2-bis(2, Any one of 4,6-trimethylphenyl) diselenide, 1,2-di-o-tolyl) diselenide, 1,2-di-p-cyanophenyl diselenide, 1,2-di-o-methylthiophenyl diselenide, 1,2-di-m-methylthiophenyl diselenide, and 1,2-di-p-methylthiophenyl diselenide.

[0015] Preferably, the anode is a carbon rod, and the cathode is a platinum sheet.

[0016] Preferably, the constant current is 12-15 mA, and the reaction time is 6.5-12 h. More preferably, the constant current is 15 mA, and the reaction time is 6.5 h.

[0017] Preferably, in the above electrochemical synthesis method, after the reaction is completed, the reaction solution is concentrated and purified by column chromatography to obtain the selenium-containing sulindac derivative, and the column chromatography conditions are: petroleum ether / ethyl acetate = 5 / 1, volume ratio.

[0018] The present invention also provides the use of the selenium-containing sulindac derivative in the preparation of anti-inflammatory drugs.

[0019] The present invention also provides a pharmaceutical preparation comprising the selenium-containing sulindac derivative and one or more pharmaceutically acceptable carriers or excipients.

[0020] Beneficial effects of the present invention:

[0021] 1. The selenium-containing sulindac derivatives obtained in the present invention have significant anti-inflammatory effects. At the same dose, the NO inhibition rate of the synthesized compounds and their ability to regulate the inflammatory factors IL-6 and IL-1β are better than those of the sulindac raw material.

[0022] 2. The present invention uses electrochemical oxidation and clean electrons as oxidizing agents. In the absence of metals, exogenous oxidants, and equivalent bases, it achieves the first dual-functionalization activation of the sulindac five-membered ring olefin skeleton, and constructs a series of selenized five-membered ring lactone compounds with high selectivity and efficiency.

[0023] 3. The present invention solves the problems of traditional synthesis of sulindac active molecules, which involve many steps, harsh reaction conditions, difficult synthesis routes, and the need for pre-functional group activation of substrates. At the same time, it can also avoid the use of large amounts of expensive transition metal catalysts and equivalent oxidizing reagents during the synthesis process. Most importantly, this method can well control the site selectivity of the reaction under mild conditions, providing ideas and methodological references for the research and development of green and inexpensive synthesis of selenium-containing sulindac derivatives.

[0024] 4. The synthesis method of the present invention efficiently achieves the regioselective activation of the sulindac olefin skeleton through free radical / free radical cross-coupling, which not only improves the synthesis efficiency but also significantly enhances the application potential and industrial application value of the method. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The general chemical structure formula of the selenized sulindac derivatives prepared by the present invention is: Figure 2This is the reaction mechanism of the electrochemical synthesis of the present invention. DETAILED DESCRIPTION

[0026] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0027] Unless otherwise specified, all reagents involved in the embodiments of the present invention are commercially available products and can be purchased through commercial channels.

[0028] The present invention provides a method for synthesizing selenium-containing sulindac derivatives, and its reaction mechanism is shown in FIG. Figure 2 The general structural formula of the obtained selenium-containing sulindac derivative is shown in Figure 1 .

[0029] 1. Electrochemical Synthesis of Compounds Example 1 Synthesis of Compound 1

[0030] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), diphenyl diselenide (0.3 mmol, 93.6 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After argon was evacuated three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 1) with an isolation yield of 92%.

[0031] 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.4 Hz,1H), 7.40-7.15 (m,5H) 7.10 (d, J = 8.3 Hz, 2H), 6.93 (s, 1H), 6.90-6.73 (m,2H), 3.42 (d, J = 7.8 Hz, 2H), 2.78 (s, 3H), 2.01 (s, 3H).

[0032] 13 C NMR (101 MHz, DMSO- d 6) δ 172.97, 163.11 (d, J = 247.5 Hz), 148.94(d, J = 8.4 Hz), 146.34 (d, J = 2.6 Hz), 139.21 (d, J = 142.9 Hz), 137.54, 133.12(d, J = 2.6 Hz), 131.32, 129.95 (d, J = 5.8 Hz), 129.37, 129.16 (d, J = 2.2 Hz),128.34, 126.72, 125.80, 125.63 (d, J = 9.3 Hz), 124.37 (d, J = 4.4 Hz),116.39 (d, J = 23.2 Hz), 113.43, 96.89, 58.38 (d, J = 2.2 Hz), 43.51 (d, J = 5.5 Hz), 21.31.

[0033] 19 F NMR (376 MHz, DMSO- d 6) δ -110.04.

[0034] HRMS (ESI) calculation for C 26 H 21 FO3SSe: 513.0433 (M+H + ), found: 513.0430.

[0035] Example 2 Synthesis of Compound 2

[0036] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-iodophenyl diselenide (0.3 mmol, 169.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After argon was evacuated three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 2) with an isolation yield of 69%.

[0037] 1 H NMR (400 MHz, CDCl3) δ7.69-7.49(m,5H),7.06-6.75(m,7H),3.46-3.40(m,2H), 2.79(d, J = 3.9 Hz, 3H), 1.97(s, 3H).

[0038] 13 C NMR (101 MHz, CDCl3) δ 177.59, 167.94 (d, J = 248.0 Hz), 153.57 (d, J = 8.4 Hz), 151.11 (d, J = 4.7 Hz), 144.25, 143.79(d, J = 110.09 Hz), 143.18 (d, J =8.5 Hz), 142.85, 138.02 (d, J = 20.5 Hz), 133.88 (d, J = 2.9 Hz), 131.44, 130.42(d, J = 9.3 Hz), 129.93 (d, J = 2.2 Hz), 129.24, 121.38 (d, J = 23.3 Hz), 118.08(d, J = 23.1 Hz), 102.53 (d, J = 3.8 Hz), 101.56, 63.28 (d, J = 2.3 Hz), 48.40 (d, J= 16.1 Hz), 43.72, 25.89.

[0039] 19 F NMR (376 MHz, CDCl3) δ -104.86 (d, J = 7.8 Hz).

[0040] HRMS (ESI) calculation for C 26 H 20 FIO3SSe: 638.9400 (M+H + ), found: 638.9464.

[0041] Example 3 Synthesis of Compound 3

[0042] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-bromophenyl diselenide (0.3 mmol, 140.4 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 3) with an isolation yield of 88%.

[0043] 1 H NMR (400 MHz, DMSO- d 6) δ 7.65 (d, J = 8.2 Hz, 2H), 7.58-7.52 (m,1H),7.38 (d, J = 8.6 Hz, 2H), 7.13-6.77(m,7H), 3.43 (d, J = 7.2 Hz, 2H), 2.78 (s, 3H), 1.99 (s, 3H).

[0044] 13 C NMR (101 MHz, DMSO- d 6) δ 172.84, 163.19 (d, J = 247.9 Hz), 148.76(d, J = 8.6 Hz), 146.42 (d,J = 4.0 Hz), 139.67, 139.58, 138.40 (d, J = 4.6 Hz),133.15 (d, J = 2.5 Hz), 133.11 (d, J = 64.2 Hz), 132.25, 129.09 (d, J = 2.6 Hz),126.76, 125.68 (d, J = 9.2 Hz), 124.52 (d, J = 48.6 Hz), 124.40 (d, J = 4.5 Hz),116.65 (d, J = 23.4 Hz), 113.36 (d, J = 23.4 Hz), 96.81, 58.59 (d, J = 2.1 Hz),43.62 (d, J = 12.2 Hz), 39.01, 21.17.

[0045] 19 F NMR (376 MHz, DMSO- d 6) δ -104.83.

[0046] HRMS (ESI) calculation for C 26 H 20 FBrO3SSe: 590.9539 (M+H + ), found: 590.9538.

[0047] Example 4 Synthesis of Compound 4

[0048] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-trifluoromethylphenyl diselenide (0.3 mmol, 135.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 4) with an isolation yield of 39%.

[0049] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63-7.39 (m, 7H), 7.08 - 6.77 (m, 5H),3.56-3.38 (m, 2H), 2.77 (d, J = 3.4 Hz, 3H), 2.02 (s, 3H)。

[0050] 13 C NMR (101 MHz, CDCl3) δ 171.61, 163.51 (d, J = 252.3 Hz), 147.74 (dd, J = 8.0, 2.8 Hz), 145.57 (d, J = 5.2 Hz), 139.80 (d, J = 3.3 Hz), 138.59 (d, J =11.5 Hz), 137.56, 132.80 (t, J = 2.6 Hz), 131.60 (dd, J = 32.7, 5.2 Hz), 130.01,128.87 (d, J = 5.6 Hz), 126.21, 126.11, 125.50 (d, J = 3.7 Hz), 124.02 (d, J = 5.2Hz), 116.66 (d, J = 23.0 Hz), 112.26 (d, J = 23.0 Hz), 96.43 (d, J = 1.9 Hz),58.28, 53.48, 43.80 (d, J = 5.9 Hz), 40.01, 21.65。

[0051] 19 F NMR (376 MHz, CDCl3) δ -62.81, -108.43。

[0052] HRMS (ESI) calcd for C 27 H 20 F4O3SSe: 581.0307 (M+H +), found: 581.0302.

[0053] Example 5 Synthesis of Compound 5

[0054] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-tolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 5) with an isolation yield of 81%.

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.15-6.94 (m, 7H), 6.86-6.63 (m, 3H), 3.18-3.01 (m, 2H), 2.77 (s, 3H), 2.33 (s, 3H), 1.99 (s, 3H).

[0056] 13 C NMR (101 MHz, CDCl3) δ 172.23, 163.42 (d, J = 251.2 Hz), 148.46 (d, J = 7.8 Hz), 145.27 (d, J = 8.5 Hz), 140.37 (d, J = 4.8 Hz), 139.95, 139.09 (d, J =8.9 Hz), 137.40, 132.66 (d, J = 3.0 Hz), 129.74, 129.18 (d, J = 3.3 Hz), 126.01(d, J = 8.9 Hz), 125.54, 123.86 (d, J = 3.0 Hz), 122.08, 116.16 (d, J= 22.7 Hz),112.25 (d, J = 23.0 Hz), 96.71 (d, J = 3.0 Hz), 57.42, 43.87 (d, J = 11.5 Hz),40.40 (d, J = 5.9 Hz), 21.52, 21.27.

[0057] 19 F NMR (376 MHz, CDCl3) δ -109.12.

[0058] HRMS (ESI) calculation for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0595.

[0059] Example 6 Synthesis of Compound 6

[0060] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-dimethyltolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 6) with an isolation yield of 76%.

[0061] 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.18-7.01 (m, 6H), 6.97 (s, 1H), 6.86-6.77 (m, 1H), 6.74 (s, 1H), 6.72-6.62 (m, 1H), 3.17-3.00(m, 2H), 2.77 (d, J = 5.3 Hz, 3H), 2.17 (s, 3H), 1.99 (s, 3H).

[0062] 13C NMR (101 MHz, CDCl3) δ 172.19, 163.40 (d, J = 250.8 Hz), 148.42 (dd, J = 8.0, 2.8 Hz), 145.21 (d, J = 7.1 Hz), 140.30 (d, J = 4.5 Hz), 139.02 (d, J = 6.3Hz), 138.84, 137.92, 134.35, 132.71 (d, J = 2.6 Hz), 130.29, 129.15 (d, J = 2.2Hz), 128.75, 125.94 (dd, J = 8.9, 4.5 Hz), 125.72 (d, J = 2.6 Hz), 125.37, 123.84(d, J = 3.3 Hz), 116.05 (d, J = 22.7 Hz), 112.35 (d, J = 21.2 Hz), 96.72 (d, J = 2.2Hz), 57.49, 43.84 (d, J = 9.7 Hz), 40.40 (d, J = 4.1 Hz), 21.60, 21.17.

[0063] 19 F NMR (376 MHz, CDCl3) δ -109.25.

[0064] HRMS (ESI) calculation for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0592.

[0065] Example 7 Synthesis of Compound 7

[0066] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), diethyl diselenide (0.3 mmol, 65.4 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 7) with an isolation yield of 61%.

[0067] 1 H NMR (400 MHz, DMSO- d 6) δ 7.68 (dd, J = 69.2, 8.2 Hz, 4H), 7.51 (d, J =8.9 Hz, 1H), 7.17-6.97 (m, 3H), 3.35-3.21 (m, 2H), 2.81 (s, 3H), 2.39-2.13(m, 2H), 1.89 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).

[0068] 13 C NMR (101 MHz, DMSO- d 6) δ 173.25, 163.42 (d, J = 247.8 Hz), 149.84(d, J = 8.5 Hz), 146.57 (d, J = 2.6 Hz), 140.38 (d, J = 3.3 Hz), 138.69 (d, J = 3.3Hz), 132.71 (d, J = 2.6 Hz), 129.29, 126.99, 126.02 (d, J = 8.9 Hz), 124.72,116.62 (d, J = 23.0 Hz), 113.10 (d, J = 23.4 Hz), 96.89, 54.45, 43.67, 43.63, 21.38, 18.16, 15.40.

[0069] 19 F NMR (376 MHz, DMSO- d 6) δ -109.55.

[0070] HRMS (ESI) calculation for C 22 H 21 FO3SSe: 465.0433 (M+H + ), found: 465.0440.

[0071] Example 8 Synthesis of Compound 8

[0072] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-diisopropylphenyl diselenide (0.3 mmol, 104.7 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 8) with an isolation yield of 69%.

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 5.1 Hz, 2H), 7.22-6.61 (m, 10H), 3.16-3.01 (m, 2H), 2.91-2.82 (m, 1H), 2.76 (d, J = 5.0 Hz, 3H), 1.99 (s, 3H), 1.21 (d, J = 7.0 Hz, 6H).

[0074] 13 C NMR (101 MHz, CDCl3) δ 172.27, 163.41 (d, J = 251.2 Hz), 150.83,148.49 (d, J = 7.8 Hz), 145.32 (d, J = 7.8 Hz), 140.40 (d, J = 3.7 Hz), 139.12 (d, J= 8.5 Hz), 137.46 (d, J = 2.6 Hz), 132.58 (d, J = 2.6 Hz), 129.14 (d, J = 3.3 Hz),127.13, 125.89 (dd, J = 8.7, 3.5 Hz), 125.54, 123.89, 122.51, 116.09 (d, J =23.0), 112.32 (d, J = 22.7 Hz), 96.74, 57.39, 43.89 (d, J = 11.1 Hz), 40.58 (d, J = 4.1 Hz), 33.85, 23.85 (dd, J = 21.0, 3.2 Hz), 21.59.

[0075] 19 F NMR (376 MHz, CDCl3) δ -109.15.

[0076] HRMS (ESI) calculation for C 29 H 27 FO3SSe: 555.0903 (M+H + ), found: 555.0909.

[0077] Example 9 Synthesis of Compound 9

[0078] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1, 2-bis(3, 4-dimethylphenyl) diselenide (0.3 mmol, 102.3 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 9) with an isolation yield of 62%.

[0079] 1 H NMR (400 MHz, CDCl3) δ 7.60-7.50 (d,J = 10.6 Hz, 2H), 7.16-6.98 (m,4H), 6.97-6.63 (m, 5H), 3.15-2.99(m, 2H), 2.77 (d, J = 5.4 Hz, 3H), 2.23(s,3H), 2.07(s, 3H), 1.98(s, 3H)。

[0080] 13 C NMR (101 MHz, CDCl3) δ 172.35, 163.42 (d, J = 251.2 Hz), 148.63 (d, J = 10.4 Hz), 145.20 (d, J = 8.5 Hz), 140.36 (d, J = 4.5 Hz), 139.12 (d, J = 8.5 Hz),138.30,137.99 (d, J = 107.4 Hz) 134.86, 132.72 (d, J = 3.0 Hz), 130.13, 129.12(d, J = 3.0 Hz), 125.87 (d, J = 8.9Hz), 125.51, 123.84 (d, J = 2.6 Hz), 122.27,116.02 (d, J = 20.8 Hz), 112.36 (d, J = 23.0 Hz), 96.77 (d, J = 2.6 Hz), 57.32,43.86 (d, J = 12.3 Hz), 40.34 (d, J = 5.6 Hz), 21.51, 19.57 (d, J = 6.7 Hz)。

[0081] 19 F NMR (376 MHz, CDCl3) δ -109.33。

[0082] HRMS (ESI) calcd for C 28 H 25 FO3SSe: 541.0746 (M+H +), found: 541.0756.

[0083] Example 10 Synthesis of Compound 10

[0084] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-o-bromophenyl diselenide (0.3 mmol, 140.4 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 10) with an isolation yield of 57%.

[0085] 1 H NMR (400 MHz, CDCl3) δ 8.12-6.50 (m, 12H), 3.18 (s, 2H), 2.76 (s, 3H), 2.00 (s, 3H).

[0086] 13 C NMR (101 MHz, CDCl3) δ 172.18, 163.13 (d, J = 251.5 Hz), 147.63 (d, J = 8.2 Hz), 145.41 (d, J = 5.2 Hz), 140.07 (d, J = 3.0 Hz), 139.22, 138.92 (d, J =5.2 Hz), 133.48, 132.58 (d, J = 3.0 Hz), 131.86, 131.25, 129.27, 129.19 (d, J =2.6 Hz), 127.64, 126.28, 126.07 (dd, J = 8.7, 2.8 Hz), 124.04 (d, J = 3.0 Hz),116.34 (d, J = 23.0 Hz), 112.49 (d, J= 23.8 Hz), 96.88, 58.88, 43.82 (d, J = 7.4Hz), 41.29 (d, J = 4.1 Hz), 21.25.

[0087] 19 F NMR (376 MHz, CDCl3) δ -109.01.

[0088] HRMS (ESI) calculation for C 26 H 20 BrFO3SSe: 590.9539 (M+H + ), found: 590.9589.

[0089] Example 11 Synthesis of Compound 11

[0090] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-dichlorophenyl diselenide (0.3 mmol, 114.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 11) with an isolation yield of 56%.

[0091] 1 H NMR (400 MHz, DMSO- d 6) δ 7.71-7.40 (m, 4H), 7.31-6.79 (m, 8H), 3.45(d, J = 12.8 Hz, 2H), 2.79 (s, 3H), 2.00 (s, 3H).

[0092] 13 C NMR (101 MHz, DMSO- d 6) δ 172.82, 163.22 (d, J = 248.2 Hz), 148.59(d, J = 8.9 Hz), 146.47 (d, J= 3.0 Hz), 139.71, 138.39 (d, J = 3.0 Hz), 136.32 (d, J = 30.5 Hz), 133.37, 133.18 (d, J = 2.6 Hz), 130.97, 129.95, 129.11, 127.51,127.04, 125.69 (d, J = 8.5 Hz), 124.37, 116.63 (d, J = 23.4 Hz), 113.44 (d, J =23.0 Hz), 96.81, 58.91, 55.37, 43.55 (d, J = 6.3 Hz), 39.18, 21.38.

[0093] 19 F NMR (376 MHz, DMSO- d 6) δ -109.78.

[0094] HRMS (ESI) calculation for C 26 H 20 ClFO3SSe: 547.0044 (M+H + ), found: 547.0039.

[0095] Example 12 Synthesis of Compound 12

[0096] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-dimethyl diselenide (0.3 mmol, 57 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 12) with an isolation yield of 53%.

[0097] 1 H NMR (400 MHz, DMSO- d6) δ 7.89-6.92 (m, 8H), 2.84 (s, 3H), 2.55 (s, 2H), 1.93 (s, 3H), 1.74 (s, 3H).

[0098] 13 C NMR (101 MHz, DMSO- d 6) δ 173.30, 163.45 (d, J = 247.8 Hz), 149.49(d, J = 8.2 Hz), 146.52 (d, J = 2.6 Hz), 140.40 (d, J = 3.0 Hz), 138.74 (d, J = 3.0Hz), 132.88 (d, J = 2.6 Hz), 129.32, 126.88, 125.87 (d, J = 8.9 Hz), 124.71,116.60 (d, J = 23.4 Hz), 112.94 (d, J = 23.8 Hz), 96.71, 53.47 (d, J = 2.6 Hz),43.62 (d, J = 4.1 Hz), 39.90, 21.03, 4.37.

[0099] 19 F NMR (376 MHz, DMSO- d 6) δ -109.70.

[0100] HRMS (ESI) calculation for C 21 H 19 FO3SSe: 451.0277 (M+H + ), found: 451.0283.

[0101] Example 13 Synthesis of Compound 13

[0102] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-difluorophenyl diselenide (0.3 mmol, 105.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 12) with an isolation yield of 81%.

[0103] 1 H NMR (400 MHz, DMSO- d 6) δ 7.73 (s, 2H), 7.55 (s, 1H), 7.46-6.36 (m,9H), 2.84 (s, 3H), 2.56 (s, 3H), 2.06 (s, 2H).

[0104] 13 C NMR (101 MHz, DMSO- d 6) δ 172.85, δ 162.39 (dd, J = 248.2, 153.5 Hz),148.61 (d, J = 8.2 Hz), 146.45, 139.77, 138.46, 133.74, 133.12, 131.07 (d, J =8.2 Hz), 129.05, 127.35 (d, J = 5.9 Hz), 126.98, 125.69 (d, J = 9.3 Hz), 124.59,124.43 (d, J = 4.1 Hz), 123.89 (d, J = 21.6 Hz), 116.81 (dd, J = 48.7, 22.3 Hz),113.44 (d, J = 23.4 Hz), 96.83, 58.87, 43.52 (d, J = 5.9 Hz), 21.37.

[0105] 19 F NMR (376 MHz, DMSO-d 6) δ -109.87, -112.03.

[0106] HRMS (ESI) calculation for C 26 H 20 F2O3SSe: 531.0339 (M+H + ), found: 531.0337.

[0107] Example 14 Synthesis of Compound 14

[0108] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-chlorophenyl diselenide (0.3 mmol, 114.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 14) with an isolation yield of 73%.

[0109] 1 H NMR (400 MHz, CDCl3) δ 7.65-7.58 (m, 2 H), 7.18-6.67 (m, 10 H), 3.23-2.97 (m, 2 H), 2.77 (s, 3H), 1.98 (s, 3H).

[0110] 13 C NMR (101 MHz, CDCl3) δ 171.80, 163.48 (d, J = 251.9 Hz), 147.96 (d, J = 7.8 Hz), 145.48 (d, J = 6.3 Hz), 140.01, 138.77 (d, J = 9.3 Hz), 138.62, 136.44(d, J = 3.3 Hz), 132.82 (d, J = 3.3 Hz), 129.11, 129.05 (d, J= 4.5 Hz), 126.21(d), 126.16 (d, J = 2.2 Hz), 125.90 (d, J = 2.2 Hz), 124.10, 123.62 (d, J = 3.7Hz), 116.49 (d, J = 23.4 Hz), 112.22 (d, J = 23.0 Hz), 96.49, 43.84 (d, J = 8.9Hz), 40.05 (d, J = 4.1 Hz), 21.59.

[0111] 19 F NMR (376 MHz, CDCl3) δ -108.57.

[0112] HRMS (ESI) calculation for C 26 H 20 ClFO3SSe: 547.0044 (M+H + ), found: 547.0044.

[0113] Example 15 Synthesis of Compound 15

[0114] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-ethylphenyl diselenide (0.3 mmol, 101.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 15) with an isolation yield of 62%.

[0115] 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz, 2H), 7.10-6.87 (m, 7H), 6.76-6.54 (m, 3H), 3.08-2.92 (m, 2H), 2.68 (d, J= 4.9 Hz, 3H), 2.58-2.47 (m,2H), 1.90 (s, 3H), 1.15-1.06 (m, 3H).

[0116] 13 C NMR (101 MHz, CDCl3) δ 172.28, 163.38 (d, J = 251.2 Hz), 148.47 (d, J = 7.8 Hz), 146.15, 145.22 (d, J = 8.2 Hz), 140.31 (d, J = 4.1 Hz), 139.05 (d, J =7.8 Hz), 137.44, 132.63 (d, J = 2.6 Hz), 129.15 (d, J = 3.7 Hz), 128.53, 125.92(dd, J = 8.5, 3.7 Hz), 125.57, 123.85 (d, J = 2.6 Hz), 122.32 (d, J = 1.9 Hz),116.09 (d, J = 25.3 Hz), 112.30 (d, J = 23.0 Hz), 96.73, 57.40, 43.84 (d, J = 11.5Hz), 40.39 (d, J = 5.2 Hz), 28.54, 21.54, 15.40.

[0117] 19 F NMR (376 MHz, CDCl3) δ -109.11.

[0118] HRMS (ESI) calculation for C 28 H 25 FO3SSe: 541.0746 (M+H + ), found: 541.0755.

[0119] Example 16 Synthesis of Compound 16

[0120] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-o-fluorophenyl diselenide (0.3 mmol, 105.0 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 16) with an isolation yield of 59%.

[0121] 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 2H), 7.42-7.12 (m, 4H), 7.08-6.76 (m, 5H), 6.65 (d, J = 8.2 Hz, 1H), 3.23-3.03 (m, 2H), 2.77 (s, 3H), 2.03 (s, 3H).

[0122] 13 C NMR (101 MHz, CDCl3) δ 172.05, 164.77-161.58 (m), 147.67 (dd, J =8.2, 3.3 Hz), 145.31 (d, J = 6.7 Hz), 139.87, 139.78, 138.94 (d, J = 6.7 Hz),132.56, 132.48, 129.18 (d, J = 2.2 Hz), 126.08, 125.99 (d, J = 5.2 Hz), 124.57(d, J = 3.7 Hz), 123.94 (d, J = 3.7 Hz), 116.02 (dd, J = 49.2, 24.0 Hz), 112.60(dd, J = 44.8, 22.5 Hz), 96.87 (d, J = 2.2 Hz), 58.34, 43.82 (d, J = 8.9 Hz), 40.53(d,J = 3.7 Hz), 29.67, 21.14.

[0123] 19 F NMR (376 MHz, CDCl3) δ -97.93, -109.11.

[0124] HRMS (ESI) calculation for C 26 H 20 F2O3SSe: 531.0339 (M+H + ), found: 531.0332.

[0125] Example 17 Synthesis of Compound 17

[0126] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-bis(2,4,6-trimethylphenyl) diselenide (0.3 mmol, 105.9 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 17) with an isolation yield of 49%.

[0127] 1 H NMR (400 MHz, CDCl3) δ 7.68-7.36 (m, 4H), 6.97-6.76 (m, 4H), 6.57(s, 1H), 5.67 (s, 1H), 3.42-3.28 (m, 2H), 2.71 (s, 3H), 2.21(s,3H), 2.13(s,6H), 1.94(s,3H).

[0128] 13 C NMR (101 MHz, CDCl3) δ 173.05, δ 162.45 (d, J = 250.8 Hz), 147.83(d, J = 8.2 Hz), 145.40 (d, J = 5.2 Hz), 144.93, 140.39, 140.33 (d, J= 3.3 Hz),139.25 (d, J = 6.3 Hz),131.84, 129.24 (d, J = 3.3 Hz), 128.96, 126.34, 125.84 (d, J = 11.1 Hz), 124.99, 124.18, 115.48 (d, J = 23.0 Hz), 112.26 (d, J = 23.8 Hz).96.95, 56.65, 44.00, 29.70, 24.42, 21.04, 19.49.

[0129] 19 F NMR (376 MHz, CDCl3) δ -110.44.

[0130] HRMS (ESI) calculation for C 29 H 27 FO3SSe: 555.0903 (M+H + ), found: 555.0911.

[0131] Example 18 Synthesis of Compound 18

[0132] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-o-tolyl diselenide (0.3 mmol, 98.1 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 18) with an isolation yield of 83%.

[0133] 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.3 Hz, 2H), 7.52 (d, J= 8.9 Hz,1H), 7.10-6.73 (m, 9H), 3.38 (s, 2H), 2.78 (s, 3H), 2.27 (s, 3H), 1.99 (s,3H).

[0134] 13 C NMR (101 MHz, DMSO- d 6) δ 173.14, δ 162.70 (d, J = 247.5 Hz), 148.80(d, J = 8.5 Hz), 146.50 (d, J = 3.0 Hz), 143.24, 139.28 (d, J = 140.8 Hz), 138.97,132.84 (d, J = 2.6 Hz), 130.57, 130.37, 129.24, 127.51, 127.03, 126.72, 125.67(d, J = 8.5 Hz), 124.54 (d, J = 3.7 Hz), 116.16 (d, J = 23.4 Hz), 113.12 (d, J = 23.4Hz), 97.03, 58.46, 43.58 (d, J = 5.2 Hz), 23.34, 20.69.

[0135] 19 F NMR (376 MHz, DMSO- d 6) δ -110.05.

[0136] HRMS (ESI) calculation for C 27 H 23 FO3SSe: 527.0590 (M+H + ), found: 527.0597.

[0137] Example 19 Synthesis of Compound 19

[0138] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-cyanophenyl diselenide (0.3 mmol, 109.2 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 15 mA for 6.5 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 19) with an isolation yield of 43%.

[0139] 1 H NMR (400 MHz, DMSO- d 6) δ 7.67 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.9 Hz,1H), 7.46 (t, J = 7.1 Hz, 1H), 7.33-7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06(s, 1H), 6.97 (s, 1H), 6.92 (t, J = 8.7 Hz, 1H), 6.86-6.82 (m, 1H), 3.58-3.38(m, 2H), 2.79 (s, 3H), 2.00 (s, 3H).

[0140] 13 C NMR (101 MHz, DMSO- d 6) δ 172.81, 163.22 (d, J = 248.2 Hz), 148.60(d, J = 8.2 Hz), 146.49 (d, J = 3.3 Hz), 139.70, 138.38 (d, J = 2.6 Hz), 136.33 (d, J = 29.7 Hz), 133.36, 133.18 (d, J = 2.6 Hz), 130.98, 129.96, 129.09 (d, J = 2.2Hz), 127.51, 127.04, 125.68 (d,J = 8.5 Hz), 124.38 (d, J = 3.0 Hz), 116.63 (d, J =23.0 Hz), 113.45 (d, J = 23.8 Hz), 96.81, 58.90 (d, J = 2.6 Hz), 43.54 (d, J = 6.3Hz), 39.16, 21.38.

[0141] 19 F NMR (376 MHz, DMSO- d 6) δ -109.82.

[0142] HRMS (ESI) calculation for C 27 H 20 FNO3SSe: 538.0386 (M+H + ), found: 538.0389.

[0143] Example 20 Synthesis of Compound 20

[0144] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-o-methylthiophenyl diselenide (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After argon was evacuated three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 20) with an isolation yield of 91%.

[0145] 1 H NMR (400 MHz, DMSO- d 6)δ 7.79 – 7.67 (m, 2H), 7.45 – 7.30 (m, 3H), 7.22 – 7.01 (m, 4H), 6.98 – 6.79 (m, 3H), 3.58 – 3.37 (m, 2H), 2.80 (s, 3H), 2.32 (s, 3H), 2.06 (s, 3H).

[0146] 13 C NMR (101 MHz, DMSO- d 6)δ 173.09, 162.63 (d, J = 247.1 Hz), 148.17 (d, J = 8.5 Hz), 146.54, 146.44 (d, J = 2.6 Hz), 139.89, 138.84, 138.63 (d, J = 2.6Hz), 133.13 (d, J = 2.6 Hz), 130.97, 129.28, 127.06, 125.51 (d, J = 8.9 Hz),124.73, 124.54, 116.31 (d, J = 23.4 Hz), 113.45 (d, J = 23.8 Hz), 97.22, 59.03, 43.58, 40.47, 21.04, 15.87.

[0147] 19 F NMR (376 MHz, DMSO- d 6) δ-110.59.

[0148] HRMS (ESI) calculation for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0311.

[0149] Example 21 Synthesis of Compound 21

[0150] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-dimethylthiophenyl diselenide (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 21) with an isolation yield of 89%.

[0151] 1 H NMR (400 MHz, DMSO- d 6)δ 7.82 – 7.50 (m, 4H), 7.32 – 6.78 (m, 8H), 3.43 (d, J = 7.5 Hz, 2H), 2.79 (s, 3H), 2.30 (s, 3H), 2.00 (s, 3H).

[0152] 13 C NMR (101 MHz, DMSO- d 6)δ 172.89, 163.21 (d, J = 247.5 Hz), δ148.94(d, J = 8.2 Hz), 146.40 (d, J = 3.3 Hz), 139.85, 139.58, 138.43 (d, J = 3.7 Hz),133.81 (d, J = 13.0 Hz), 133.24 (d, J = 2.6 Hz), 129.72, 129.17, 127.48, 126.81,126.40, 125.75, 125.65, 124.30, 116.51 (d, J = 23.4 Hz), 113.38 (d, J = 23.4 Hz),96.87, 58.51 (d, J = 2.2 Hz), 43.56 (d, J = 5.9 Hz).39.25, 21.29, 14.84.

[0153] 19 F NMR (376 MHz, DMSO- d 6) δ -110.04.

[0154] HRMS (ESI) calculation for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0303.

[0155] Example 22 Synthesis of Compound 22

[0156] (1) In a 21 mL three-necked reaction tube equipped with a stirrer, a carbon rod was used as the anode and a platinum sheet was used as the cathode. Sulindac (0.3 mmol, 106.9 mg), 1,2-di-p-methylthiophenyl diselenide (0.3 mmol, 121.8 mg), and the electrolyte tetrabutylammonium tetrafluoroborate (0.3 mmol, 98.8 mg) were added in sequence. After evacuating the argon three times, acetonitrile was added and the reaction was carried out at a constant current of 12 mA for 12 h. (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1, volume ratio) to obtain the pure selenium-containing sulindac derivative (Compound 22) with an isolation yield of 92%.

[0157] 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 – 7.51 (m, 4H), 7.12 – 6.99 (m, 5H), 6.96 – 6.84 (m, 2H), 6.84 – 6.75 (m, 1H), 3.39 (s, 2H), 2.77 (s, 3H), 2.40(d, J = 5.1 Hz, 3H), 1.98 (s, 3H).

[0158] 13 C NMR (101 MHz, DMSO- d 6) δ 172.94, δ 163.17 (d, J = 247.5 Hz),149.06(d, J = 8.5 Hz), 146.41, 141.45, 139.83, 138.45, 137.91, 133.19 (d, J = 2.6 Hz),132.82, 130.41, 129.16, 125.93, 125.65 (d, J = 8.5 Hz), 124.56 (d, J = 3.0 Hz),124.31, 120.98, 116.46 (d, J = 23.0 Hz), 113.27 (d, J = 23.0 Hz), 96.89, 58.41, 43.54, 39.06, 21.20, 14.63.

[0159] 19 F NMR (376 MHz, DMSO- d 6) δ -109.73.

[0160] HRMS (ESI) calculation for C 27 H 23 FNO3S2Se: 559.0311 (M+H + ), found: 559.0318.

[0161] 2. Anti-inflammatory activity experiments of compounds 1. Experimental methods 1. Cell culture and passaging RAW264.7 mouse macrophage cells were cultured in DMEM high-glucose complete medium supplemented with 20% fetal bovine serum and 1% penicillin-streptomycin in a 37°C, 5% CO2, saturated humidity incubator. Cells were passaged every 2-3 days at a 1:3 ratio.

[0162] 2. CCK-8 assay to determine the effect of compounds on RAW264.7 cell viability The CCK-8 assay was used to evaluate the effects of selenium-containing sulindac derivatives on the viability of RAW264.7 cells. A normal group, a sulindac group, and a 20 μmol / L drug administration group were set up in a 96-well plate, with three replicates in each group. RAW264.7 cells in the logarithmic growth phase were plated at 5×10 5 Cells were seeded at a density of 100 μL / well (100 μL / well) and cultured for 24 hours until adherence. The treatment group was treated with culture medium containing 20 μmol / L of a selenium-containing sulindac derivative, the sulindac group was treated with culture medium containing 20 μmol / L of sulindac, and the normal control group was treated with culture medium containing 1% serum (all at 100 μL / well). After 24 hours of incubation at 37°C and 5% CO2, 10 μL of CCK-8 solution was added to each well and incubated for another 4 hours. The OD values ​​were measured at 450 nm on a microplate reader, and cell viability was calculated according to the formula: Cell viability (%) = (OD value of the treatment group or OD value of the sulindac group / OD value of the normal group) × 100%.

[0163] The experimental results are shown in Table 1, indicating that most selenium-containing sulindac derivatives did not show cytotoxicity under the condition of 20 μmol / L. Among them, compounds 4, 7, and 12 showed a certain degree of damage to cells and can be used as drugs by reducing the dosage.

[0164] Table 1 Evaluation of RAW264.7 cell viability by CCK-8 assay using selenium-containing sulindac derivatives at 20 μmol / L

[0165] 3. NO kit detection and determination of the inhibitory effect of compounds on the inflammatory factor NO in RAW264.7 cells stimulated by LPS (lipopolysaccharide) The inhibitory effect of selenium-containing sulindac derivatives (20 μmol / L) on NO production was evaluated using the LPS-induced RAW264.7 cell inflammation model and sulindac (20 μmol / L) as a positive control. RAW264.7 cells in the logarithmic growth phase were cultured at 3×10 5 Cells were seeded at a density of 100 ng / mL in 12-well plates and cultured for 24 hours until adherence. The cells were then divided into three groups: normal group, model group, sulindac group, and drug-treated group (containing a selenium-containing sulindac derivative) (each with triplicate wells). The culture medium was discarded, and 500 μL of the corresponding drug or culture medium was added for 2 hours. All groups except the normal group were treated with LPS solution at a final concentration of 100 ng / mL and cultured for an additional 18 hours. The supernatant was collected, and NO concentration was determined according to the NO kit instructions. The NO generation rate was calculated according to the formula: NO generation rate (%) = (NO concentration in the drug-treated group, sulindac group, or normal group / NO concentration in the model group) × 100%.

[0166] The experimental results are shown in Table 2. The selenium-containing sulindac derivatives significantly improved the NO inhibition effect of the raw material sulindac at 20 μmol / L. Compounds 4, 7, and 12 were slightly toxic, so they may have inhibited the NO generation rate.

[0167] Table 2 Inhibitory effects of selenium-containing sulindac derivatives on NO at 20 μmol / L

[0168] 4. RT-qPCR was used to determine the effects of the compounds on the levels of pro-inflammatory factors TNF-α (tumor necrosis factor), IL-1β (interleukin-1β), and IL-6 (interleukin-6) in LPS-stimulated RAW264.7 cells The LPS-induced RAW264.7 cell inflammation model was used to evaluate the effect of selenium-containing sulindac derivatives (20 μmol / L) on the mRNA expression of pro-inflammatory factors. RAW264.7 cells in the logarithmic growth phase were cultured at 5×10 5Cells were seeded at a density of 100 μg / mL in 6-well plates (2 mL / well). After culturing for 24 hours and adhering to the wall, cells were divided into normal, model, positive drug (sulindac), and drug-treated (selenium-containing sulindac derivative) groups. The culture medium was discarded, and each group was pretreated with 2 mL of the corresponding drug or culture medium for 2 hours. All groups, except the normal group, were then incubated with LPS solution at a final concentration of 100 ng / mL for an additional 18 hours. Cells were harvested, and total RNA was extracted using the SteadyPure kit. Purity was assessed by NanoDrop 2000 (A260 / A280 = 1.8-2.0), and cDNA was obtained by reverse transcription using the 5XEvo M-MLV kit and stored at -20°C. qPCR was performed using SYBR Green Pro Taq HS premix reagent: the reaction system contained 10 μL of 2× Premix, 0.4 μL of each forward / reverse primer (10 μM), and 2 μL of cDNA, and ddH2O was added to 20 μL. The reaction procedure was 95°C for 30 s (pre-denaturation), followed by 40 cycles of 95°C for 5 s / 60°C for 30 s, and melting curve analysis was performed.

[0169] The 2^(-ΔΔCt) method was used to calculate the relative expression of the target gene, with β-actin as the internal reference. The experimental results are shown in Tables 3 and 4. For the inflammatory factor IL-6, the selenium-containing sulindac derivatives were able to significantly downregulate its level at a concentration of 20 μmol / L compared with the model group, and showed better inhibitory effect than the positive drug sulindac (20 μmol / L); for the inflammatory factor IL-1β, the selenium-containing sulindac derivatives also showed better downregulation ability than sulindac at 20 μmol / L; in addition, for the inflammatory factor TNF-α, although the selenium-containing sulindac derivatives were able to downregulate it at a concentration of 20 μmol / L, their downregulation ability was not obvious compared with IL-6 and IL-1β.

[0170] Table 3 Effects of selenium-containing sulindac derivatives on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3)

[0171] Table 4 Effects of selenium-containing sulindac derivatives on LPS-induced IL-6, IL-1β, and TNF-α levels in RAW 264.7 cells (X±s, n=3)

[0172] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or substitute equivalents for some of the technical features. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A selenium-containing sulindac derivative, characterized in that: The selenium-containing sulindac derivative uses sulindac as a parent core structure, and undergoes esterification and selenization reactions on the olefin of its five-membered ring. The general chemical structure of the selenium-containing sulindac derivative is as follows: ， Wherein, R is selected from any one of C1-C3 alkyl, phenyl, and substituted phenyl, and the substituent in the substituted phenyl is any one of alkyl, halogen, halogenated hydrocarbon, C1-C6 alkyl, C1-C3 alkylthio, and cyano.

2. The selenium-containing sulindac derivative according to claim 1, wherein: R is selected from the group consisting of phenyl, p-iodophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-tolyl, m-tolyl, ethyl, p-isopropylphenyl, 3,4-xylyl, o-bromophenyl, m-chlorophenyl, methyl, m-fluorophenyl, p-chlorophenyl, p-ethylphenyl, o-fluorophenyl, 2,4,6-trimethylphenyl, o-tolyl, p-cyanophenyl, o-methylthiophenyl, m-methylthiophenyl, and p-methylthiophenyl.

3. A selenium-containing sulindac derivative, characterized in that: The selenium-containing sulindac derivative is selected from the following structures: 。 4. An electrochemical synthesis method of a selenium-containing sulindac derivative according to claim 1, characterized in that: The following steps are involved: In an electrolytic cell, an anode and a cathode are set, and sulindac, a diselenide compound, an electrolyte, and a solvent are added in sequence, reacting under constant current conditions. After the reaction is completed, the reaction liquid is collected to obtain a selenium-containing sulindac derivative; The general chemical structure formula of the diselenide compound is: RSeSeR.

5. The electrochemical synthesis method according to claim 4, characterized in that: The diselenide compound is selected from the group consisting of diphenyl diselenide, 1,2-di-p-iodophenyl diselenide, 1,2-di-p-bromophenyl diselenide, 1,2-di-p-trifluoromethylphenyl diselenide, 1,2-di-p-tolyl diselenide, 1,2-di-m-tolyl diselenide, diethyl diselenide, 1,2-di-p-isopropylphenyl diselenide, 1,2-bis(3,4-xylyl) diselenide, 1,2-di-o-bromophenyl diselenide, 1,2-di-m-chlorophenyl diselenide, 1,2-dimethyl diselenide, 1,2-di-m-fluorophenyl diselenide, 1,2-di-p-chlorophenyl diselenide, 1,2-di-p-ethylphenyl diselenide, 1,2-di-o-fluorophenyl diselenide, 1,2-bis(2, 4, Any one of 1,2-di-6-trimethylphenyl) diselenide, 1,2-di-o-tolyl diselenide, 1,2-di-p-cyanophenyl diselenide, 1,2-di-o-methylthiophenyl diselenide, 1,2-di-m-methylthiophenyl diselenide, and 1,2-di-p-methylthiophenyl diselenide.

6. The electrochemical synthesis method according to claim 4, characterized in that: The molar ratio of the sulindac, the diselenide compound and the electrolyte is 1:1:1, the electrolyte is tetrabutylammonium tetrafluoroborate, and the solvent is acetonitrile.

7. The electrochemical synthesis method according to claim 4, characterized in that: The anode is a carbon rod, the cathode is a platinum sheet, the constant current is 12-15 mA, and the reaction time is 6.5-12 hours.

8. The electrochemical synthesis method according to claim 4, characterized in that: The electrochemical synthesis method further comprises: concentrating the reaction solution and purifying it by column chromatography to obtain a selenium-containing sulindac derivative, wherein the column chromatography conditions are: petroleum ether / ethyl acetate = 5 / 1, volume ratio.

9. Use of the selenium-containing sulindac derivative according to any one of claims 1 to 3 in the preparation of anti-inflammatory substances.

10. A pharmaceutical preparation, characterized in that The invention comprises the selenium-containing sulindac derivative according to any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers or excipients.

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