Nitroxyl polyphenol derivative, preparation method and application thereof

Abstract

The invention aims to provide a nitroxyl polyphenol derivative. The chemical formula of the nitroxyl polyphenol derivative is Q-(L-A) n, wherein Q is a group derived from polyphenol; l is an ester linking group containing 1 to 3 carbon atoms; a is a 5-or 6-membered heterocyclic group containing a nitrogen atom in the form of a nitroxyl radical (NO *) in which the two carbon atoms adjacent to the nitroxyl radical are substituted independently of each other by one or two C1-C3 alkyl groups; and n is an integer from 1 to 5. The invention also relates to a method for producing said derivatives and to the use thereof as antioxidants, in particular anti-aging agents.

Description

TECHNICAL FIELD

[0001] The object of the present invention is a nitrophenol derivative, a method for its preparation and its use as an antioxidant, in particular as an anti-aging agent in beauty, pharmacy and medicine. BACKGROUND ART

[0002] Cellular senescence is the main cellular process occurring in adult organisms and is also necessary for normal organogenesis (embryonic development). Cellular senescence is associated with all diseases defined as geriatric syndromes (such as type 2 diabetes, atherosclerosis, neurodegenerative diseases) and involves an increase in tissue and organ inflammation. The progress of civilization has increased the research on compounds that accelerate aging. In addition, methods for therapeutic purposes (radiotherapy and chemotherapy) cause faster senescence of normal cells, which is a side effect. Senescence is associated with overexposure to ultraviolet light (skin photoaging). An increase in the number of senescent cells is observed after transplantation (of organs). Preventing or reducing the effects of cellular senescence may contribute to maintaining the health and good performance of the body for a longer time and may help prevent and / or eliminate the effects of age-specific diseases and the adverse effects of treatments.

[0003] Currently, there is an ongoing search for new compounds with potential anti-aging activity, and polyphenols are a very promising class of compounds. However, the use of these compounds has many limitations, such as limited bioavailability and the need to use high concentrations to ensure an effective action.

[0004] In view of the above, there is a reason to search for new polyphenol-based derivatives whose use is not associated with the above disadvantages.

[0005] The prior art describes derivatives of resveratrol and curcumin that contain amino acids (such as phenylalanine, threonine, leucine or proline) added as a result of an esterification reaction. (J.R. Manjunatha, B.K. Bettadaiah, P.S. Negi and P.S. Srinivas, Food Chemistry, Vol. 139, Nos. 1-4, August 15, 2013, pp. 332-338, and A. Mattarei, M. Azzolini, M. La Spina, M. Zoratti, C. Paradisi, L. Biasutto, Scientific Reports, October 14, 2015, Vol. 5, pp. 1 to 11). However, no information on the antioxidant / anti-aging activity of the above derivatives was found in the cited disclosures.

[0006] EP 2 189 155 A1 only generally discloses that a composition showing anti-aging activity on human skin may contain polyphenols as antioxidants.

[0007] Accordingly, the object of the present invention is to design and synthesize polyphenol derivatives that exhibit antioxidant, especially anti-aging, activity, which will solve the problems of low bioavailability and the need to use high concentrations of compounds. Summary of the Invention

[0008] The object of the present invention is a nitroxyl polyphenol derivative having the chemical formula:

[0009] Q-(L-A) n

[0010] wherein Q is a group derived from a polyphenol;

[0011] L is an ester linking group containing 1 to 3 carbon atoms;

[0012] A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups; and

[0013] n is an integer from 1 to 5.

[0014] Preferably, Q is a derivative of curcumin, quercetin, genistein or daidzein, L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2, more preferably, Q is a derivative of curcumin, and L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2.

[0015] Also preferably, Q is a derivative of resveratrol.

[0016] Preferably, L in the nitroxyl derivative of resveratrol is an ester linking group of the formula -(CH2) x -C(O)O or -OC(O)-(CH2) x -, where x is an integer from 0 to 2, more preferably, L is an ester linking group of the formula -(CH2) x -C(O)O- group, where x is an integer from 0 to 2.

[0017] Preferably, A is piperidin-1-oxy, wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by two C1-C3 alkyl groups, more preferably, A is a 2,2,6,6-tetramethylpiperidin-1-oxyl group.

[0018] Preferably, n is 1 or 2.

[0019] Preferably, the above nitroxyl polyphenol derivative is a derivative of the following formula:

[0020]

[0021] Preferably, the above-mentioned nitroxyl polyphenol derivative is a derivative of the following formula:

[0022]

[0023] Preferably, the above-mentioned nitroxyl polyphenol derivative is a derivative of the following formula:

[0024]

[0025] The object of the present invention is a method for preparing a nitroxyl polyphenol derivative, the chemical formula of which is as follows:

[0026] Q-(L-A) n

[0027] wherein Q is a group derived from polyphenol;

[0028] L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2;

[0029] A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups; and

[0030] n is an integer from 1 to 5;

[0031] which comprises reacting a polyphenol with a 5- or 6-membered heterocyclic compound containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a carboxyl group of the general formula -(CH2) x -C(O)OH, where x is an integer from 0 to 2;

[0032] wherein the reaction is carried out at a temperature of -10 to 30 °C, in an organic solvent, in the presence of a hydroxyl deprotonating agent and a carboxyl activating agent.

[0033] Preferably, the reaction is carried out for 48 to 72 hours.

[0034] Preferably, a piperidine-1-oxyl compound, and more preferably a 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound, is used as the 5- or 6-membered heterocyclic compound containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical in the piperidine-1-oxyl compound are each independently substituted by two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a general formula -(CH2) x-C(O)OH carboxyl substitution, where x is an integer from 0 to 2, where in a 5- or 6-membered heterocyclic compound, two carbon atoms adjacent to the nitroxide radical are each independently substituted with one or two C1-C3 alkyl groups, and where one of the other carbon atoms is of the general formula -(CH2) x -C(O)OH carboxyl substitution, where x is an integer from 0 to 2.

[0035] Preferably, 4-dimethylaminopyridine is used as the deprotonating agent for the hydroxyl group.

[0036] Preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, more preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as the carboxyl activating agent.

[0037] Preferably, an aprotic polar solvent, more preferably dichloromethane, is used as the organic solvent.

[0038] Preferably, a polyphenol containing a keto group, such as curcumin, quercetin, genistein or daidzein, more preferably curcumin, is used as the polyphenol.

[0039] Preferably, when using a polyphenol containing a keto group, the reaction is carried out in the temperature range from -10°C to below room temperature, more preferably in the range from -10°C to 0°C.

[0040] Preferably, resveratrol is used as the polyphenol.

[0041] Preferably, when using resveratrol, the reaction is carried out in the temperature range from room temperature to 30°C.

[0042] The object of the present invention also lies in a method for preparing a nitroxide polyphenol derivative, as shown in the following formula:

[0043] Q-(L-A) n

[0044] Wherein:

[0045] Q is a derivative of resveratrol;

[0046] L is an ester linking group of the formula -(CH2) x -C(O)O-, where x is an integer from 0 to 2;

[0047] A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, in the form of a nitroxide radical (NO*), where two carbon atoms adjacent to the nitroxide radical are each independently substituted with one or two C1-C3 alkyl groups; and

[0048] n is an integer of 1 or 2;

[0049] comprising the following steps:

[0050] a) A reaction between a benzaldehyde derivative substituted by at least one hydroxyl group and a silylating agent to protect at least one hydroxyl group, wherein the reaction is carried out in an organic solvent at a temperature of 0 °C to room temperature in the presence of an activator of the silylating agent;

[0051] b) A reaction between the protected benzaldehyde derivative prepared in step a) and an alkyltriphenylphosphonium halide to convert the aldehyde group to an alkenyl group, wherein the reaction is carried out in an organic solvent in a temperature range of -78 °C to room temperature in the presence of a strong base;

[0052] c) A coupling reaction between the alkenyl group in the derivative prepared in step b) and a halogenated benzene derivative substituted by at least one ester group of the formula -(CH2) x -C(O)OR, where R is a C1-C3 alkyl group and x is an integer from 0 to 2; wherein the reaction is carried out in the presence of a catalyst, a phosphorus ligand and a base, optionally in an organic solvent, at a temperature of room temperature to 190 °C;

[0053] d) A reaction between the derivative prepared in step c) and a reducing agent to reduce at least one ester group to at least one alcohol group, wherein the reaction is carried out in an organic solvent at a temperature of -78 °C to room temperature;

[0054] e) A reaction between the derivative prepared in step d) and an oxidizing agent to oxidize at least one alcohol group to at least one aldehyde group, wherein the reaction is carried out in an organic solvent at a temperature of 0 °C to room temperature;

[0055] f) A reaction between the derivative prepared in step e) and an oxidizing agent to oxidize at least one aldehyde group to at least one acid group, wherein the reaction is carried out in an organic solvent or a mixture of organic solvents at a temperature of 0 °C to room temperature;

[0056] g) A reaction between the derivative prepared in step f) and a 5- or 6-membered heterocyclic compound containing one nitrogen atom, wherein the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted by a hydroxyl group, to prepare a nitrophenol derivative containing at least one protected hydroxyl group, wherein the reaction is carried out in an organic solvent at a temperature of room temperature to 30 °C in the presence of a hydroxyl deprotonating agent and a carboxyl activating agent; and

[0057] h) A reaction between the nitrophenol derivative containing at least one protected hydroxyl group prepared in step g) and a reagent used as a fluoride ion source to deprotect at least one hydroxyl group, wherein the reaction is carried out in an organic solvent at a temperature of 0 °C to room temperature.

[0058] Preferably, in step a), a hydroxy or dihydroxybenzaldehyde is used as the benzaldehyde derivative.

[0059] Preferably, in step a), an alkylsilyl halide, more preferably tert-butyldimethylsilyl chloride, is used as the silylating agent.

[0060] Preferably, in step a), a mixture of imidazole, triethylamine and 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene or a mixture of 18-crown-6 ether and potassium hydride, more preferably imidazole, is used as the activator for the silylating agent.

[0061] Preferably, the reaction in step a) is carried out for 4 to 24 hours.

[0062] Preferably, in step b), methyltriphenylphosphonium bromide is used as the alkyltriphenylphosphonium halide.

[0063] Preferably, the reaction in step b) is carried out for 4 to 24 hours.

[0064] Preferably, in step b), n-butyllithium, lithium diisopropylamide, potassium tert-butoxide or potassium bis(trimethylsilyl)amide, more preferably n-butyllithium, is used as the strong base.

[0065] Preferably, in step c), ethyl 4-iodobenzoate or dimethyl 5-bromoisophthalate is used as the halogenated benzene derivative substituted with at least one ester group of the formula -(CH2) x -C(O)OR, where R is a C1-C3 alkyl group and x is an integer from 0 to 2.

[0066] Preferably, in step c), a palladium(0) or (II) complex, more preferably palladium acetate, is used as the catalyst.

[0067] Preferably, in step c), tris(o-tolyl)phosphine is used as the phosphorus ligand.

[0068] Preferably, in step c), triethylamine is used as the base.

[0069] Preferably, in step c), the organic solvent is the base used.

[0070] Preferably, the reaction in step c) is carried out at a temperature of 50 °C to 90 °C.

[0071] Preferably, the reaction in step c) is carried out for 20 to 40 hours.

[0072] Preferably, in step d), diisobutylaluminum hydride or lithium aluminum hydride, more preferably diisobutylaluminum hydride, is used as the reducing agent.

[0073] Preferably, the reaction in step d) is carried out in the temperature range of -78°C to -50°C.

[0074] Preferably, the reaction in step d) is carried out for 1 to 24 hours.

[0075] Preferably, in step e), pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate in tetrahydrofuran or 4-methylmorpholine 4-oxide is used, and more preferably pyridinium dichromate, as the oxidizing agent.

[0076] Preferably, the reaction in step e) is carried out for 2 to 18 hours.

[0077] Preferably, the reaction in step e) is carried out at a temperature of 10°C to room temperature.

[0078] Preferably, in step f), NaClO2 and NaH2PO4·xH2O solution is used as the oxidizing agent.

[0079] Preferably, in step f), tert-butanol, tetrahydrofuran or 2-methylbut-2-ene or a mixture thereof is used as the organic solvent.

[0080] Preferably, the reaction in step f) is carried out for 2 to 8 hours.

[0081] Preferably, the reaction in step f) is carried out at a temperature of 0 to 3°C.

[0082] Preferably, in step g), a hydroxy-piperidine-1-oxyl compound, more preferably 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound, is used as a 5- or 6-membered heterocyclic compound containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein in the hydroxy-piperidine-1-oxyl compound, the two carbon atoms adjacent to the nitroxyl radical are each independently substituted by two C1-C3 alkyl groups, and wherein in the 5- or 6-membered heterocyclic compound, the two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted by a hydroxy group.

[0083] Preferably, in step g), 4-dimethylaminopyridine is used as the deprotonating agent for the hydroxy group.

[0084] Preferably, in step g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide, more preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, is used as the carboxyl activating agent.

[0085] Preferably, the reaction in step g) is carried out for 16 to 52 hours.

[0086] Preferably, in step h), tetrabutylammonium fluoride is used as the reagent serving as the fluoride ion source.

[0087] Preferably, the reaction in step h) is carried out for 1 to 5 hours.

[0088] Preferably, in steps a) to e), g) and h), an aprotic solvent is used, and more preferably dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether is used as the organic solvent.

[0089] The object of the present invention also lies in the use of the above-mentioned nitroxyl polyphenol derivatives as antioxidants, preferably as anti-aging agents.

[0090] The derivatives of the present invention are a combination of two compounds, namely polyphenols and compounds containing nitroxyl radicals. Research has shown that polyphenols alone and compounds containing nitroxyl radicals alone have certain antioxidant activities. However, the resulting derivatives have better activities than the components used as their building blocks. Due to their antioxidant activities, the derivatives of the present invention delay cell senescence caused by oxidants that increase the level of reactive oxygen species. They show bioactive effects on many molecular targets in cells. The antioxidant properties of the derivatives of the present invention can be changed by altering the parent molecule or the number of substituted / free hydroxyl groups. For example, by leaving at least one free OH group in the resveratrol derivative, a compound with activity in a wide pH range can be obtained, because the nitroxyl radical shows its effect at acidic pH, while the free OH group of resveratrol shows its effect at basic pH. In addition, the presence of a keto moiety that can be converted into an enol moiety (>C=O is converted to =C-OH) affects the antioxidant properties of curcumin, quercetin, genistein and daidzein derivatives. Therefore, it is not important to leave free OH groups in these derivatives. In addition, the type of group incorporating the nitroxyl radical is also very important for the antioxidant properties. It has been demonstrated that a heterocyclic group having a substituent in the form of a nitroxyl radical on the carbon atom adjacent to the nitrogen atom is most preferred, which increases the stability of the radical in cells and prevents its conversion to hydroxylamine. Description of the Drawings

[0091] Figures 1-6 The research results of the antioxidant / anti-aging properties of the derivatives of the present invention against induced senescence of human skin fibroblasts are shown.

[0092] Figure 1 The cytotoxicity of the test derivatives (H3 and H5) against human skin fibroblasts is shown.

[0093] Figure 2 The effects of the test derivatives (H3 and H5) on cell proliferation, which were determined based on the ability to incorporate bromodeoxyuridine (BrdU), are shown.

[0094] Figure 3 Shows the effects of the test compounds (H3 and H5) on the activity of senescence-associated β-galactosidase (SA-β-gal) in cells.

[0095] Figures 4-6 Shows the protective properties of the test compounds (H3 and H5) against the effects of oxidative stress induced by hydrogen peroxide in cells. Detailed implementation

[0096] The abbreviations and terms used in the specification, drawings and claims have the meanings commonly understood by those skilled in the art to which the present invention pertains. However, for clarity, the following terms and abbreviations should be understood as follows:

[0097] The term "5- or 6-membered heterocyclic group (heterocyclic compound) in the form of a nitroxyl radical (NO*) containing one nitrogen atom" refers to a saturated, unsaturated or aromatic 5- or 6-membered heterocyclic group containing a nitrogen atom in the form of a nitroxyl radical, such as piperidin-1-oxy, pyridin-1-oxy, pyrroline-1-oxy and pyrrole-1-oxy.

[0098] The term "group derived from polyphenols" refers to polyphenol molecules, such as resveratrol, curcumin, quercetin, genistein and daidzein, in which one or all of the hydroxyl groups can be substituted by the above-defined 5- or 6-membered heterocyclic group containing a nitrogen atom in the form of a nitroxyl radical.

[0099] The term "ester linking group containing 1 to 3 carbon atoms" refers to the formula -(CH2) x -C(O)O- or -OC(0)-(CH2) x - group, where x is an integer from 0 to 2, i.e., the group is, for example, -(CH2) x -C(O)O-, -CH2-C(O)O-, -C(O)O-, -OC(O)-(CH2)2-, -OC(O)-CH2-lub-OC(O)-. The type of ester linking group depends on the method of preparing the nitroxyl polyphenol derivative.

[0100] The term "C1-C3 alkyl" refers to methyl, ethyl or propyl.

[0101] The term "two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups" means that each of the two carbon atoms adjacent to the nitroxyl radical can be replaced by a different or the same number of C1-C3 alkyl groups, where the groups can be the same or different. Preferably, both carbon atoms are substituted by two C1-C3 alkyl groups.

[0102] Room temperature (rt) refers to a temperature in the range of 18°C to 25°C.

[0103] THF: Tetrahydrofuran

[0104] CH2Cl2: Dichloromethane

[0105] 4-Carboxy-TEMPO: 4-Carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl

[0106] 4-Hydroxy-TEMPO: 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl

[0107] TEMPO: 2,2,6,6-Tetramethylpiperidine-1-oxyl

[0108] EDCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0109] DMAP: 4-Dimethylaminopyridine

[0110] Pd(OAc)2: Palladium(II) acetate

[0111] DCC: N,N'-Dicyclohexylcarbodiimide

[0112] TBSCl: Tert-butyldimethylsilyl chloride

[0113] CH3PPh3Br: Methyltriphenylphosphonium bromide

[0114] Et3N: Triethylamine

[0115] ToP: Tris(ortho-tolyl)phosphine

[0116] DIBALH: Diisobutylaluminum hydride

[0117] TBAF: Tetra-n-butylammonium fluoride

[0118] PDC: Pyridinium dichromate

[0119] t-BuOH: tert-Butyl alcohol

[0120] nBuLi: n-Butyllithium

[0121] EtOAc: Ethyl acetate

[0122] Et2O: Diethyl ether

[0123] MeOH: Methanol

[0124] CHCl3: Chloroform

[0125] The present invention is illustrated by the following non-limiting examples. Unless otherwise specified, the known reaction methods commonly used in the art to which the present invention pertains and commercially available equipment and reagents were used in the following examples.

[0126] Example 1: Synthesis of nitroxide polyphenol derivatives, in which all hydroxyl groups are replaced by groups containing nitroxide radicals.

[0127] In a round-bottom flask under an argon atmosphere, curcumin (78.5 mg, 0.21 mmol), 4-carboxy-TEMPO (158.4 mg, 0.79 mmol), EDCI (86.1 mg, 0.55 mmol) as a carboxyl activator, and DMAP

[0128]

[0129] (30.3 mg, 0.25 mmol) were dissolved in 35 mL of dichloromethane and stirred at -4 °C for 48 hours. The reaction was also carried out using DCC instead of EDCI as the carboxyl activator. After 2 days, the product was purified by column chromatography using a CH2Cl2:MeOH (20:1) system as the eluent and silica gel as the stationary phase. In the subsequent step, the product was purified by preparative chromatography, in which CHCl3:MeOH (25:2) was used as the eluent. The resulting product was eluted from the silica gel with methanol to give compound H5 (72.5 mg, 46%) in the form of an orange solid.

[0130] The synthesis of resveratrol derivatives was carried out in a similar manner.

[0131] In a round-bottom flask under an argon atmosphere, resveratrol (100 mg, 0.44 mmol), 4-carboxy-TEMPO (562.4 mg, 2.6 mmol), EDCI (238.1 mg, 1.53 mmol) as a carboxyl activator, and DMAP (26.8 mg, 0.22 mmol) were dissolved in 35 mL of dichloromethane and stirred at room temperature for 48 hours. Subsequently, the product was purified using the above method.

[0132] The above reaction is carried out in the temperature range of -10 °C to 30 °C. However, the experiments conducted show that in the case of polyphenols containing a keto group (-C(O)-) (curcumin, quercetin, genistein, and daidzein), the reaction is preferably carried out at a temperature below room temperature (i.e., from -10 °C to a temperature below room temperature (about 17 °C)), more preferably in the temperature range of -10 °C to 0 °C. However, in the case of polyphenols without a keto group (resveratrol), the above-mentioned wider temperature range (i.e., -10 °C to 30 °C) can be used without problems, and considering the faster progress of the reaction, the preferred temperature range is room temperature to 30 °C. The difference in the temperatures used is caused by the keto-enol equilibrium. At room temperature, the keto-enol equilibrium shifts towards the enol form, which may lead to the esterification of the enol group and the substitution of the nitroxyl radical at this position. As a result, a mixture of different products can be obtained. Therefore, in the case of polyphenols containing a keto group, it is important to use a lower temperature at which the keto-enol equilibrium does not shift towards the enol form.

[0133] Regarding the reaction time, extending it to 72 hours can increase the yield of the reaction.

[0134] In the above synthesis, 4-carboxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound is used as a heterocyclic compound containing a nitroxyl radical in the form of one nitrogen atom. However, other nitroxyl radical-containing compounds can also be used under the same conditions, and these nitroxyl radicals are derivatives of piperidine, pyridine, pyrrolidine, pyrroline, and pyrrole, in which two carbon atoms adjacent to the nitrogen atom in the nitroxyl radical form are independently substituted by one or two (identical or different) methyl, ethyl, or propyl groups, and one of the other carbon atoms is substituted by a carboxyl group of the formula -C(O)OH, -CH2C(O)OH, or -(CH2)2C(O)OH.

[0135] Any polar aprotic solvent can be used for the above reaction.

[0136] Using the method defined above, with minor modifications within the knowledge of those skilled in the art, derivatives of any polyphenol can be obtained in which all hydroxyl groups are substituted by groups containing a nitroxyl radical. As mentioned above, when selecting the reaction parameters, attention should be paid to whether there is a keto group in the polyphenol.

[0137] Example 2: Synthesis of a nitroxyl resveratrol derivative containing at least one free hydroxyl group.

[0138] a) Synthesis of a nitroxyl radical resveratrol derivative containing two free hydroxyl groups:

[0139]

[0140] Step a): Imidazole as an activator of the silylating agent (5.923 g, 86.88 mmol) was added to a suspension of 3,5-dihydroxybenzaldehyde (1.2 g, 14.48 mmol) stirred in dichloromethane (40 mL). After 15 minutes, the solution became clear, cooled to 0 °C, and TBSCl as the silylating agent (5.019 g, 33.30 mmol) was added. The reaction mixture was heated to room temperature and stirred for 14 hours. Subsequently, the mixture was poured into 200 mL of cold water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:10) system as the eluent. Compound 2 in the form of a white solid was obtained (5.033 g, 95%).

[0141] In the above reaction, the silylating agent was added at approximately 0 °C. However, the further reaction was carried out at a temperature higher than 0 °C but not higher than room temperature.

[0142] TBSCl was used as the silylating agent in this reaction. However, other alkylsilyl halides commonly used for protecting hydroxyl groups can also be used in this reaction.

[0143] In addition, imidazole used as an activator of the silylating agent can be replaced by other reagents, such as a mixture of triethylamine and 4-dimethylaminopyridine, a mixture of triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene, or a mixture of 18-crown-6 ether and potassium hydride. In addition, other organic aprotic solvents, such as dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, or toluene, can also be used as solvents.

[0144] The reaction was carried out for 4 to 24 hours while monitoring the progress of the reaction using thin-layer chromatography (TLC). The reaction time specified in the example corresponds to the time point at which no obvious change occurred on the TCL plate in the system.

[0145] Step b): Strong base (n-BuLi, 1.6 M solution in THF, 10.306 mL, 16.5 mmol) was added to a suspension of CH3PPh3Br (5.890 g, 16.5 mmol) in anhydrous THF (18 mL) at -78 °C. After 20 minutes, a solution of aldehyde 2 (5.033 g, 13.75 mmol) in anhydrous THF (9.5 mL) was added using a cannula. The reaction mixture was adjusted to room temperature and stirred for an additional 4 hours. The reaction was quenched by adding 30 mL of brine. It was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with water, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexane (1:100) system as the eluent. A colorless oil compound 3 (4.611 g, 92%) was obtained.

[0146] The reagents in the above reaction were added at a temperature of about -78 °C. However, the further reaction can be carried out in the temperature range from -78 °C to room temperature.

[0147] Any alkyltriphenylphosphonium halide commonly used in the reaction for converting an aldehyde group to an alkenyl group can be used in the above reaction. In addition, other strong bases such as lithium diisopropylamide, potassium tert-butoxide, or potassium bis(trimethylsilyl)amide can be used instead of n-BuLi. In addition, toluene and dichloromethane are also suitable as solvents.

[0148] If TLC chromatographic analysis indicates that the reaction is not complete, the stirring of the reaction mixture at room temperature is extended to 24 hours.

[0149] Step c): Under an argon atmosphere, in a dry vial containing a magnetic stir bar, compound 3 (1 g, 2.73 mmol), ethyl 4-iodobenzoate (0.73 g, 2.60 mmol), Pd(OAc)2 catalyst (0.031 g, 0.14 mmol), and tris(o-tolyl)phosphine (ToP) ligand (0.063 g, 0.21 mmol) were placed in anhydrous triethylamine (4.5 mL). The mixture in the sealed vial was stirred at 60 °C for 2 hours and then continued to be stirred at 80 °C for 24 hours. After cooling, the mixture was diluted by adding CH2Cl2 and poured into water. The aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexane (1:9) system as the eluent. A white solid compound 4 (0.97 g, 71%) was obtained.

[0150] In the above reaction, by at least one formula -(CH2) x-C(O)OR ester group-substituted haloarene derivatives, where R is C1-C3 alkyl, x is an integer from 0 to 2, depending on how many OH groups in the final polyphenol derivative are substituted by nitroxyl radical-containing groups, and depending on the type of linking group that links the nitroxyl radical-containing group to the polyphenol molecule. If the final derivative contains one nitroxyl radical-containing group, the arene derivative is a derivative with one ester group, and if the final derivative contains two nitroxyl radical-containing groups, the arene derivative is a derivative with two ester groups (such as Example 2a below). In addition, the ester group can be a -C(O)OR, -CH2C(O)OR or -(CH2)2-C(O)OR group, where R is methyl, ethyl or propyl. Generally, regardless of the type of haloarene derivative used, the reaction conditions are the same.

[0151] In the above reaction, other palladium(0) or (II) complexes can be used as catalysts, and other phosphorus ligands commonly used in the coupling reaction between an olefin group and an arene derivative can be used as ligands.

[0152] Triethylamine is used as the base in the reaction. In this case, triethylamine is also the solvent. However, this reaction can also be carried out in other organic aprotic solvents, such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether.

[0153] In the above reaction, a temperature in the range of 50°C to 90°C is preferably used, i.e., initially 60°C and subsequently 80°C. However, according to generally available chemical knowledge, the palladium-catalyzed coupling reaction can be carried out in the temperature range from room temperature to 190°C.

[0154] Step d): Cool a solution of compound 4 (2 g, 4.0 mmol) in anhydrous CH2Cl2 (60 mL) to -78°C, add DIBALH as a reducing agent (1 M in CH2Cl2, 12 mL, 12.0 mmol) dropwise, and stir at this temperature for 2.5 hours. Quench the reaction by adding a solution of potassium sodium tartrate (1 M, 3 mL), HCl (1 M, 3 mL) and water (12 mL). Let the mixture stand for 2 hours (to reach room temperature). Subsequently, pour the mixture into 30 mL of water and separate the layers. Extract the aqueous layer with dichloromethane (3 x 60 mL). Wash the combined organic layers with brine, dry over anhydrous MgSO4 and evaporate the solvent. Purify the product by silica gel column chromatography using an EtOAc:hexane (1:4) system as the eluent. Obtain compound 5 (1.62 g, 86%) in the form of a white solid.

[0155] In the above reaction, when lithium aluminum hydride was used as the reducing agent, the same result was obtained. In addition, the reaction can also be carried out in other aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether.

[0156] The reaction was carried out for 1 to 24 hours while monitoring the progress of the reaction using thin layer chromatography (TLC). The reaction time specified in the example corresponds to the time point at which no significant change occurred on the TCL plate in the system.

[0157] The above reaction is preferably carried out in the temperature range of -78 °C to -50 °C because the reaction between DIBALH and compound 4 proceeds rapidly and there is no need to use a higher temperature. However, according to general available chemical knowledge, the reduction reaction from an ester group to an alcohol group can be carried out in the temperature range of -78 °C to room temperature. Considering the high reactivity of the reducing agent, the prerequisite is to add the reducing agent at a reduced temperature.

[0158] Step e): Compound 5 (1.62 g, 3.4 mmol) was dissolved in CH2Cl2 (18 mL), and PDC as the oxidizing agent (3.20 g, 8.5 mmol) was added in two equal portions. The reaction was carried out at room temperature for 6 hours. Subsequently, it was filtered through a layer of diatomaceous earth, and the filtrate was concentrated using an evaporator. The product was purified by silica gel column chromatography using an EtOAc:hexane (5:95) system as the eluent. Compound 6 (1.484 g, 92%) was obtained in the form of a white solid.

[0159] In the above reaction, pyridinium dichromate (PDC) was used as the oxidizing agent; however, in this reaction, other oxidizing agents commonly used to oxidize an alcohol group to an aldehyde group can be used, such as pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate or 4-methylmorpholine 4-oxide in tetrahydrofuran. In addition, other aprotic solvents known in the art can be used as solvents, such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether.

[0160] The reaction can also be carried out at a temperature close to 0 °C. However, this involves extending the reaction time to about 18 hours. Therefore, the reaction is preferably carried out at a temperature of 10 °C to room temperature.

[0161] Step f): Dissolve compound 6 (1.484 g, 3.17 mmol) in a mixture of t-BuOH (30 mL) and THF (9 mL) at room temperature. Subsequently, cool the solution to 0 °C and add 2-methylbut-2-ene (5.19 mL, 49.26 mmol). After 20 minutes, add dropwise a solution of NaH2PO4 x H2O (3.782 g, 9.57 mmol) and NaClO2 (80%, 0.863 g, 7.66 mol) in H2O (16 mL) as the oxidizing agent. Stir the reaction mixture at 0 - 3 °C for 5 h and quench by adding solid Na2SO3 (1.23 g, 9.75 mmol). Extract the aqueous layer with EtOAc (4 x 100 mL), dry over anhydrous MgSO4 and evaporate the solvent. Purify the product by silica gel column chromatography using an EtOAc:hexane (1:1) system as the eluent. Obtain compound 7 (0.967 g, 63%) in the form of a white solid.

[0162] The reagents in the above reaction are added at a temperature of about 0 °C. However, the further reaction can also be carried out at room temperature, but is preferably carried out in the range of 0 °C to 3 °C.

[0163] Step g): Dissolve compound 7 (0.967 g, 1.99 mmol) in CH2Cl2 (35 mL), and then add EDCI (0.770 g, 4.97 mmol) as the carboxyl activator, DMAP (0.243 g, 1.99 mol) as the hydroxyl deprotonating agent, and 4-hydroxy-TEMPO (0.515 g, 2.99 mmol). Carry out the reaction at room temperature for 16 h and quench by adding 20 mL of 10% sodium carbonate solution. Separate the layers and extract the aqueous layer with EtOAc (3 x 20 mL). Wash the combined organic layers with H2O, dry over anhydrous MgSO4 and evaporate the solvent. Purify the product by silica gel column chromatography using a MeOH:CH2Cl2 (5:95) system as the eluent. Obtain compound 8 (1.096 g, 86%) in the form of a brown solid.

[0164] DDC can also be used as the carboxyl activator.

[0165] In the above synthesis, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound is used as the heterocyclic compound containing a nitroxyl radical form of a nitrogen atom; however, other nitroxyl radical-containing compounds such as derivatives of piperidine, pyridine, pyrrolidine, pyrroline and pyrrole can also be used under the same conditions, in which two carbon atoms adjacent to the nitrogen atom in the nitroxyl radical form are each independently substituted by one or two (same or different) methyl, ethyl or propyl groups, and one of the other carbon atoms is substituted by a hydroxyl group.

[0166] The reaction can also be carried out in other organic aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether.

[0167] Slightly higher temperatures, up to 30 °C, can also give similar results in this reaction.

[0168] Step h): Dissolve compound 8 (1.096 g, 1.71 mmol) in anhydrous THF (50 mL), cool to 0 °C, and then add TBAF as a fluoride source (1 M THF solution, 4.27 mL, 4.27 mmol). Heat the reaction mixture to room temperature, stir the mixture for 2 hours, and quench with 20 mL of brine. Extract with EtOAc (3 x 40 mL). Wash the combined organic layers with H2O, dry over anhydrous MgSO4, and evaporate the solvent. Purify the product by silica gel column chromatography using a MeOH:CH2Cl2 (1:9) system as the eluent. A brown solid was obtained and then recrystallized from Et2O. Compound H3 was obtained as a beige solid (0.549 g, 78%).

[0169] The reaction can also be carried out in other organic aprotic solvents such as dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or diethyl ether.

[0170] In the above reaction, it is preferred to use a temperature of 0 °C to 5 °C when adding the reagents, and then let the mixture stand until it reaches room temperature and stir for an appropriate time at this temperature.

[0171] b) Synthesis of nitroxyl resveratrol derivatives containing one free hydroxyl group:

[0172]

[0173] Step a): Add imidazole as an activator of the silylating agent (3.35 g, 49.14 mmol) to a suspension of 4-hydroxybenzaldehyde (1.2 g, 16.38 mmol) stirred in dichloromethane (40 mL) and cool to 0 °C. Add TBSCl (2.96 g, 19.66 mmol). Place the mixture at room temperature and stir for 5 hours, then pour into 200 mL of cold water and extract with dichloromethane (3 x 50 mL). Wash the combined organic layers with brine, dry over anhydrous MgSO4, and evaporate the solvent. Purify the product by silica gel column chromatography using an EtOAc:hexane (1:10) system as the eluent. Compound 2 was obtained as a white solid (3.560 g, 92%).

[0174] Step b): At -78 °C, n-BuLi (1.6 M solution in THF, 11.31 mL, 18.10 mmol) was added to a suspension of CH3PPh3Br (6.461 g, 16.5 mmol) in anhydrous THF (19 mL). After 20 minutes, a solution of aldehyde 2 (3.560 g, 15.08 mmol) in anhydrous THF (10 mL) was added using a cannula. The mixture was warmed to room temperature over 1 hour and stirred for an additional 4 hours at this temperature. The reaction was quenched by the addition of 30 mL of brine. The mixture was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with water, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexane (1:100) system as the eluent. Colorless oily compound 3 (3.142 g, 89%) was obtained.

[0175] Step c): In a dry vial, compound 3 (2.0 g, 8.545 mmol), dimethyl 5-bromoisophthalate (2.123 g, 7.768 mmol), Pd(OAc)2 (0.096 g, 0.427 mmol), and tris(o-tolyl)phosphine (0.196 g, 0.644 mmol) were placed in anhydrous triethylamine (15 mL) under an argon atmosphere. The mixture in the sealed vial was stirred at 60 °C for 2 hours and then continued to stir at 80 °C for 38 hours. After cooling, the mixture was diluted in CH2Cl2 and poured into water. The aqueous layer was extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an Et2O:hexane (1:9) system as the eluent. Compound 4 (2.220 g, 67%) was obtained as a white solid.

[0176] Step d): A solution of compound 4 (2.22 g, 5.21 mmol) in anhydrous CH2Cl2 (78 mL) was cooled to -78 °C and DIBALH (1 M in CH2Cl2, 26.05 mL, 26.05 mmol) was added dropwise, and the mixture was stirred at this temperature for 2.5 hours. The reaction was quenched by the addition of a solution of potassium sodium tartrate (1 M, 6 mL), HCl (1 M, 6 mL), and water (24 mL), and after reaching room temperature, the mixture was stirred for 2 hours. Subsequently, the mixture was poured into 50 mL of water and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by silica gel column chromatography using an EtOAc:hexane (1:1) system as the eluent. Compound 5 (1.72 g, 89%) was obtained as a white solid.

[0177] Step e): Dissolve compound 5 (1.72 g, 4.6 mmol) in CH2Cl2 (24 mL), and add PDC (8.66 g, 23 mmol) in two equal portions. The reaction is carried out at room temperature for 16 h. Subsequently, the mixture is filtered through a layer of diatomaceous earth, and the filtrate is concentrated using an evaporator. The product is purified by silica gel column chromatography using an EtOAc:hexane (1:4) system as the eluent. Compound 6 (1.395 g, 82%) is obtained as a white solid.

[0178] Step f): Dissolve compound 6 (1.395 g, 3.81 mmol) in a mixture of t-BuOH (40 mL) and THF (12 mL) at room temperature. Subsequently, cool the solution to 0 °C and add 2-methylbut-2-ene (6.24 mL, 59.21 mmol). After 20 min, add dropwise a solution of NaH2PO4 x H2O (9.03 g, 22.86 mmol) and NaClO2 (80%, 2.06 g, 18.30 mol) in H2O (38 mL). Stir the reaction mixture at 0 - 3 °C for 5 h and quench by adding solid Na2SO3 (2.94 g, 23.29 mmol). Extract the aqueous layer with EtOAc (8 x 60 mL), dry over anhydrous MgSO4, and evaporate the solvent. The product is purified by silica gel column chromatography using MeOH:CH2Cl2 (1:1 to 3:2) and 0.1% AcCOOH as the eluent. Compound 7 (0.896 g, 59%) is obtained as a white solid.

[0179] Step g): Dissolve compound 7 (0.896 g, 2.25 mmol) in CH2Cl2 (39 mL), and then add EDCI (1.44 g, 9.29 mmol), DMAP (0.824 g, 6.75 mmol), and 4-hydroxy-TEMPO (1.35 g, 7.87 mmol). The reaction is carried out at room temperature for 52 h and quenched by adding 20 mL of 10% sodium carbonate solution. Separate the layers, and extract the aqueous layer with EtOAc (3 x 20 mL). Wash the combined organic layers with H2O, dry over anhydrous MgSO4, and evaporate the solvent. The product is purified by column chromatography using EtOAc:hexane (1:4) as the eluent. Compound 8 (1.176 g, 74%) is obtained as an orange solid.

[0180] Step h): Compound 8 (1.76 g, 1.83 mmol) was dissolved in anhydrous THF (52 mL), cooled to 0 °C, and then TBAF (1 M solution in THF, 2.75 mL, 2.75 mmol) was added. The reaction mixture was heated to room temperature, stirred for 2 h, and quenched by adding 20 mL of brine. The mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with H2O, dried over anhydrous MgSO4, and the solvent was evaporated. The product was purified by column chromatography using an EtOAc:hexane (2:3) system as the eluent. An orange solid was obtained and then recrystallized from Et2O. Compound H2 was obtained in the form of a beige solid (0.783 g, 80%).

[0181] Example 3: Antioxidant / Anti-aging Performance Test

[0182] Three human skin fibroblast cell lines obtained from healthy volunteers were used for cell-based tests to study the effect of biological variation on the efficacy of the test compounds. The cells were passaged and seeded onto 6-well or 12-well plates (cell density: 5000 / cm 2 area). The cells were placed in an incubator (37 °C, 5% CO2) optimal for proliferation for 24 h. After the required time, hydrogen peroxide (concentration: 200 μM, experimentally determined to be the optimal concentration for inducing fibroblast senescence) and test compounds H3 and H5 were added; alternatively, the compounds were tested individually on the cells to determine the cytotoxicity of the compounds. Compound H3 is a resveratrol derivative with one nitroxide radical, and compound H5 is a nitroxide curcumin derivative. The cells were then placed in the incubator for 24 h, 48 h, 72 h, or 7 days, depending on the type of experiment performed. Subsequently, the number of cells in the culture was counted, and the percentage of proliferating cells or the percentage of SA-β-gal positive cells was determined.

[0183] Figure 1 The number of cells in the culture after treatment with substances H3 and H5 is shown. The horizontal line in the graph represents the treatment point, and the results have been normalized to this number. From the data obtained, it can be seen that at concentrations up to 5 μM, both of the prepared compounds are not cytotoxic to human skin fibroblasts (experimentally determined values; the active concentrations of the test compounds are shown as such).

[0184] The next step was to determine cell proliferation based on the bromodeoxyuridine (BrdU) incorporation assay. As a synthetic nucleoside (thymidine) analogue, BrdU is incorporated into DNA molecules during the S phase of cell division. By immunocytochemically staining the cell nuclei with BrdU ( Figure 2) Information on the percentage of cultured cells undergoing division was obtained. The tests confirmed that compounds H3 and H5 had no cytotoxicity (the percentage of BrdU-positive cells was similar to that of the control group).

[0185] Subsequently, the activity of senescence-associated β-galactosidase (SA-β-gal) was tested. An increase in SA-β-gal activity was observed in cells undergoing senescence (one of the hallmarks of senescence). Figure 3 The results shown indicate that after treatment with H3 and H5, the percentage of cells with increased SA-β-gal activity was similar to that of the untreated control group.

[0186] The next step was to investigate whether the prepared compounds could protect cells from senescence induced by oxidative stress. For this purpose, 200 μM hydrogen peroxide (the concentration was determined experimentally) was used. Different concentrations of H3 and H5 were added to cell cultures induced to accelerate senescence. The results showed that these compounds could protect cells from the effects of oxidative stress (compared with the cultures treated only with hydrogen peroxide, their numbers increased, Figure 4 ). These compounds showed a protective effect, with the percentage of dividing cells being 10 times higher compared to cells treated with H2O2 alone (40% vs. 4%; Figure 5 ). When added to cells treated with hydrogen peroxide, H3 and H5 reduced the number of cells with increased SA-β-gal activity from 90% (H2O2) to 60% (H2O2 + H3 or H5), as Figure 6 shown. It is also worth emphasizing that it has been shown that the obtained compound H3 has better activity than its components (resveratrol (RSV) and TEMPO).

[0187] Based on the above results, it can be hypothesized that derivatives of other polyphenols, such as quercetin, genistein, and daidzein, after replacing their hydroxyl groups with groups containing nitroxyl radicals, will show antioxidant / anti-aging properties similar to those of the obtained derivatives, because similar major groups responsible for these properties are present in the molecules.

Claims

1. A nitroxyl polyphenol derivative, whose chemical formula is: Q-(L-A) n wherein Q is a group derived from polyphenol; L is an ester linking group containing 1 to 3 carbon atoms; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, and the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups; and n is an integer from 1 to 5.

2. The nitroxyl polyphenol derivative according to claim 1, wherein Q is a derivative of curcumin, quercetin, genistein or daidzein, and L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2.

3. The nitroxyl polyphenol derivative according to claim 2, characterized in that, Q is a derivative of curcumin, and L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2.

4. The nitroxyl polyphenol derivative according to claim 1, wherein Q is a derivative of resveratrol.

5. The nitroxyl polyphenol derivative according to claim 4, characterized in that, L is an ester linking group of formula -(CH2) x -C(O)O or -OC(O)-(CH2) x -, where x is an integer from 0 to 2.

6. The nitroxyl polyphenol derivative according to claim 5, wherein L is an ester linking group of formula -(CH2) x -C(O)O-, where x is an integer from 0 to 2.

7. The nitroxyl polyphenol derivative according to any one of claims 1 to 6, characterized in that, A is piperidin-1-oxy, wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by two C1-C3 alkyl groups.

8. The nitroxyl polyphenol derivative according to claim 7, characterized in that, A is 2,2,6,6-tetramethylpiperidin-1-oxyl group.

9. The nitroxyl polyphenol derivative according to any one of claims 1 to 8, characterized in that, n is 1 or 2.

10. The nitroxyl polyphenol derivative according to claim 1, characterized in that, The nitroxyl polyphenol derivative is a derivative of the following formula:

11. The nitroxyl polyphenol derivative according to claim 1, characterized in that, The nitroxyl polyphenol derivative is a derivative of the following formula:

12. The nitroxyl polyphenol derivative according to claim 1, wherein The nitroxyl polyphenol derivative is a derivative of the following formula:

13. A method for preparing a nitroxyl polyphenol derivative, whose chemical formula is as follows: Q-(L-A) n wherein Q is a group derived from polyphenol; L is an ester linking group of the formula -OC(O)-(CH2) x -, where x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, and the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups; and n is an integer from 1 to 5; It is characterized in that The method comprises the reaction of a polyphenol with a 5- or 6-membered heterocyclic compound containing one nitrogen atom, the nitrogen atom being in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a carboxyl group of the general formula -(CH2) x -C(O)OH, where x is an integer from 0 to 2; wherein the reaction is carried out at a temperature of -10 to 30 °C in an organic solvent in the presence of a hydroxyl deprotonating agent and a carboxyl activating agent.

14. The method according to claim 13, wherein The reaction is carried out for 48 to 72 hours.

15. The method according to claim 13 or 14, characterized in that Use a piperidine-1-oxy compound as a 5- or 6-membered heterocyclic compound containing one nitrogen atom in the form of a nitroxyl radical (NO*), wherein two carbon atoms adjacent to the nitroxyl radical in the piperidine-1-oxy compound are independently substituted by two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a carboxyl group of the general formula -(CH2) x -C(O)OH, where x is an integer from 0 to 2, wherein two carbon atoms adjacent to the nitroxyl radical in the 5- or 6-membered heterocyclic compound are independently substituted by one or two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a carboxyl group of the general formula -(CH2) x -C(O)OH, where x is an integer from 0 to 2.

16. The method according to claim 15, wherein Use a 4-carboxy-2,2,6,6-tetramethylpiperidin-1-oxyl compound as the piperidin-1-oxyl compound, wherein two carbon atoms adjacent to the nitroxyl radical are each independently substituted by two C1-C3 alkyl groups, and wherein one of the other carbon atoms is substituted by a carboxyl group of the general formula -(CH2) x -C(O)OH, where x is an integer from 0 to 2.

17. The method according to any one of claims 13 to 16, characterized in that, 4-Dimethylaminopyridine is used as the deprotonating agent for the hydroxyl group.

18. The method according to any one of claims 13 to 17, characterized in that 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide is used as the activating agent for the carboxyl group.

19. The method according to claim 18, characterized in that, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide is used as the activating agent for the carboxyl group.

20. The method according to any one of claims 13 to 19, characterized in that, An aprotic polar solvent is used as the organic solvent.

21. The method according to claim 20, characterized in that, Dichloromethane is used as the solvent.

22. The method according to any one of claims 13 to 21, characterized in that Curcumin, quercetin, genistein or daidzein is used as the polyphenol.

23. The method according to claim 22, characterized in that, Curcumin is used as the polyphenol.

24. The method according to any one of claims 13 to 23, characterized in that The reaction is carried out in the temperature range of -10 °C to below room temperature.

25. The method according to claim 24, wherein The reaction is carried out in the temperature range of -10 °C to 0 °C.

26. The method according to any one of claims 13 to 21, characterized in that Resveratrol is used as the polyphenol.

27. The method according to claims 13 to 21 and claim 26, characterized in that, The reaction is carried out in the temperature range of room temperature to 30 °C.

28. A method for preparing a nitroxyl polyphenol derivative, as shown in the following formula: Q-(L-A) n wherein: Q is a derivative of resveratrol; L is an ester linking group of formula -(CH2) x -C(O)O-, where x is an integer from 0 to 2; A is a 5- or 6-membered heterocyclic group containing one nitrogen atom, and the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein the two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups; and n is an integer of 1 or 2; characterized in that the method comprises the following steps: a) The reaction between a benzaldehyde derivative substituted by at least one hydroxyl group and a silylating agent to protect at least one hydroxyl group, wherein the reaction is carried out at a temperature of 0 °C to room temperature in an organic solvent in the presence of an activator of the silylating agent; b) The reaction of the protected benzaldehyde derivative prepared in step a) with an alkyltriphenylphosphonium halide to convert the aldehyde group into an alkenyl group, wherein the reaction is carried out in an organic solvent in the temperature range of -78 °C to room temperature in the presence of a strong base; c) Coupling reaction of the alkenyl group in the derivative prepared in step b) with a halogenated benzene derivative substituted with at least one ester group of the following formula: -(CH2) x -C(O)OR, where R is a C1-C3 alkyl group and x is an integer from 0 to 2; wherein the reaction is carried out in the presence of a catalyst, a phosphorus ligand and a base, optionally in an organic solvent, at a temperature from room temperature to 190 °C; d) The derivative prepared in step c) is reacted with a reducing agent to reduce at least one ester group to at least one alcohol group, wherein the reaction is carried out in an organic solvent at a temperature ranging from -78 °C to room temperature; e) The derivative prepared in step d) is reacted with an oxidizing agent to oxidize at least one alcohol group to at least one aldehyde group, wherein the reaction is carried out in an organic solvent at a temperature ranging from 0 °C to room temperature; f) The derivative prepared in step e) is reacted with an oxidizing agent to oxidize at least one aldehyde group to at least one acid group, wherein the reaction is carried out in an organic solvent or a mixture of organic solvents at a temperature ranging from 0 °C to room temperature; g) The reaction of the derivative prepared in step f) with a 5- or 6-membered heterocyclic compound containing one nitrogen atom, wherein the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein two carbon atoms adjacent to the nitroxyl radical are independently substituted by one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted by a hydroxyl group, to prepare a nitrophenol derivative containing at least one protected hydroxyl group, wherein the reaction is carried out in an organic solvent at a temperature ranging from room temperature to 30 °C, in the presence of a hydroxyl deprotonating agent and a carboxyl activating agent; and h) The nitroxyl phenol derivative containing at least one protected hydroxyl group prepared in step g) is reacted with a reagent serving as a fluoride ion source to deprotect at least one hydroxyl group, wherein the reaction is carried out in an organic solvent at a temperature ranging from 0 °C to room temperature.

29. The method according to claim 28, wherein, In step a), a hydroxy or dihydroxybenzaldehyde is used as the benzaldehyde derivative.

30. The method according to claim 28 or 29, characterized in that, In step a), an alkylsilyl halide is used as the silylating agent.

31. The method according to claim 30, wherein In step a), tert-butyldimethylsilyl chloride is used as the silylating agent.

32. The method according to any one of claims 28 to 31, characterized in that, In step a), a mixture of imidazole, triethylamine and 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene or a mixture of 18-crown-6 ether and potassium hydride is used as the activator for the silylating agent.

33. The method according to claim 32, wherein Imidazole is used as the activator for the silylating agent.

34. The method according to any one of claims 28 to 33, characterized in that The reaction in step a) is carried out for 4 to 24 hours.

35. The method according to any one of claims 28 to 34, characterized in that In step b), methyltriphenylphosphonium bromide is used as the alkyltriphenylphosphonium halide.

36. The method according to any one of claims 28 to 35, wherein The reaction in step b) is carried out for 4 to 24 hours.

37. The method according to any one of claims 28 to 36, wherein In step b), n-butyllithium, lithium diisopropylamide, potassium tert-butoxide or potassium bis(trimethylsilyl)amide is used as the strong base.

38. The method according to claim 37, wherein In step b), n-butyllithium is used as the strong base.

39. The method according to any one of claims 28 to 38, characterized in that, In step c), ethyl 4-iodobenzoate or dimethyl 5-bromoisophthalate is used as a halogenated benzene derivative substituted with at least one ester group of the following formula: -(CH2) x -C(O)OR, where R is a C1-C3 alkyl group and x is an integer from 0 to 2.

40. The method according to any one of claims 28 to 39, characterized in that, In step c), a palladium(0) or (II) complex is used as the catalyst.

41. The method according to claim 40, wherein Palladium acetate is used as the catalyst.

42. The method according to any one of claims 28 to 41, characterized in that, In step c), tris(o-tolyl)phosphine is used as the phosphorus ligand.

43. The method according to any one of claims 28 to 42, characterized in that, In step c), triethylamine is used as the base.

44. The method according to any one of claims 28 to 43, characterized in that In step c), the organic solvent is the base used.

45. The method according to any one of claims 28 to 44, characterized in that, The reaction in step c) is carried out at a temperature ranging from 50 °C to 90 °C.

46. The method according to any one of claims 28 to 45, characterized in that The reaction in step c) is carried out for 20 to 40 hours.

47. The method according to any one of claims 28 to 46, characterized in that, In step d), diisobutylaluminum hydride or lithium aluminum hydride is used as the reducing agent.

48. The method according to claim 47, characterized in that, In step d), diisobutylaluminum hydride is used as the reducing agent.

49. The method according to any one of claims 28 to 48, characterized in that The reaction in step d) is carried out in the temperature range of -78 °C to -50 °C.

50. The method according to any one of claims 28 to 49, characterized in that The reaction in step d) is carried out for 1 to 24 hours.

51. The method according to any one of claims 28 to 50, characterized in that, In step e), pyridinium dichromate, pyridinium chlorochromate, oxalyl chloride, triethylamine in dichloromethane, tetrapropylammonium perruthenate or 4-methylmorpholine 4-oxide in tetrahydrofuran is used as the oxidizing agent.

52. The method according to claim 51, wherein In step e), pyridinium dichromate is used as the oxidizing agent.

53. The method according to any one of claims 28 to 52, characterized in that, The reaction in step e) is carried out for 2 to 18 hours.

54. The method according to any one of claims 28 to 53, characterized in that, The reaction in step e) is carried out at a temperature of 10 °C to room temperature.

55. The method according to any one of claims 28 to 54, characterized in that In step f), NaClO2 and NaH2PO4·xH2O solution is used as the oxidizing agent.

56. The method according to any one of claims 28 to 55, characterized in that, In step f), tert-butanol, tetrahydrofuran or 2-methylbut-2-ene or a mixture thereof is used as the organic solvent.

57. The method according to any one of claims 28 to 56, characterized in that, The reaction in step f) is carried out for 2 to 8 hours.

58. The method according to any one of claims 28 to 57, characterized in that, The reaction in step f) is carried out at a temperature of 0 to 3 °C.

59. The method according to any one of claims 28 to 58, characterized in that In step g), a hydroxypiperidine-1-oxyl compound is used as a 5- or 6-membered heterocyclic compound containing one nitrogen atom, where the nitrogen atom is in the form of a nitroxyl radical (NO*), wherein in the hydroxypiperidine-1-oxyl compound, two carbon atoms adjacent to the nitroxyl radical are each independently substituted by two C1-C3 alkyl groups, and wherein in the 5- or 6-membered heterocyclic compound, two carbon atoms adjacent to the nitroxyl radical are each independently substituted by one or two C1-C3 alkyl groups, and one of the other carbon atoms is substituted by a hydroxyl group.

60. The method according to claim 59, wherein 4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl compound is used as the hydroxypiperidine-1-oxyl compound, wherein two carbon atoms adjacent to the nitroxyl radical are each independently substituted by two C1-C3 alkyl groups.

61. The method according to any one of claims 28 to 60, characterized in that, In step g), 4-dimethylaminopyridine is used as the deprotonating agent for the hydroxyl group.

62. The method according to any one of claims 28 to 61, characterized in that In step g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide is used as the carboxyl activating agent.

63. The method according to claim 62, characterized in that, In step g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is used as the carboxyl activating agent.

64. The method according to any one of claims 28 to 63, characterized in that, The reaction in step g) is carried out for 16 to 52 hours. The method according to any one of claims 28 to 64, characterized in that In step h), tetra-n-butylammonium fluoride is used as the reagent serving as a fluoride ion source.

66. The method according to any one of claims 28 to 65, characterized in that, The reaction in step h) is carried out for 1 to 5 hours.

67. The method according to any one of claims 28 to 66, characterized in that, In steps a) to e) and g) and h), an aprotic solvent is used as the organic solvent.

68. The method according to claim 67, wherein In steps a) to e) and g) and h), dichloromethane, dimethylformamide, toluene, tetrahydrofuran, acetonitrile or ether is used as the aprotic solvent.

69. Use of the nitroxyl polyphenol derivative according to any one of claims 1 to 12 as an antioxidant.

70. The use according to claim 69, characterized in that, The antioxidant is used as an anti-aging agent.

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