Anti-photoaging skin care, oxidation-resistant anti-aging compounds and uses

Abstract

The application discloses an anti-photoaging skin care product, an oxidation-resistant anti-aging compound and application, and can solve the anti-aging problem of skin. The oxidation-resistant anti-aging compound has a structure shown in formula (1): wherein R is a C1-C18 alkyl chain.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of skin care compounds. More particularly, the present application relates to anti-photoaging skin care products, oxidation-resistant anti-aging compounds and uses. BACKGROUND

[0002] Retinol is a commonly used anti-aging ingredient in skin care products, but it has the disadvantage of easily causing skin irritation and allergy.

[0003] Bakuchiol also has good anti-aging effect and is a very potential skin care active ingredient. Moreover, compared with retinol, bakuchiol has less side effects and lower skin irritation, so it can be used as a substitute for retinol to play an anti-aging role.

[0004] However, the preservation condition of bakuchiol is relatively harsh, and the stability is poor, so it is difficult to preserve the anti-aging effect of the skin care product containing bakuchiol.

[0005] Therefore, how to effectively provide an anti-aging ingredient while overcoming the above-mentioned defects is a technical difficulty in the field. SUMMARY

[0006] An object of embodiments of the present application is to solve the above problems and provide the advantages to be described later.

[0007] Another object of embodiments of the present application is to provide an anti-photoaging skin care product, oxidation-resistant anti-aging compound and use, which can solve the problem of skin anti-aging.

[0008] The present application embodiments find that bakuchiol is easily oxidized in the air due to the presence of exposed phenolic hydroxyl groups in its structure, thereby losing its efficacy, and thus has poor oxidation resistance and stability. Therefore, it is a feasible improvement measure to replace bakuchiol with a derivative having similar function and high stability by reasonably modifying the structure of bakuchiol. Based on the above idea, the present application embodiments provide the following technical solutions.

[0009] In a first aspect, the present application embodiments provide an oxidation-resistant anti-aging compound having a structure shown in formula (I):

[0010]

[0011] wherein R is a C1-C18 alkyl chain.

[0012] In some technical solutions, R is a C3-C18 alkyl chain.

[0013] In some technical solutions, R is a C1-C18 saturated or unsaturated straight-chain alkyl chain.

[0014] In some embodiments, R is a C1-C18 saturated or unsaturated branched alkyl chain.

[0015] In some embodiments, the R group contains 1-2 alkenyl groups.

[0016] In some embodiments, the oxidation-resistant anti-aging compound is selected from any one of compounds 1a-9a:

[0017]

[0018]

[0019] In a second aspect, the embodiments of the present application provide a use of the oxidation-resistant anti-aging compound for HaCaT cell anti-UVB photoaging.

[0020] In a third aspect, the embodiments of the present application provide a use of the oxidation-resistant anti-aging compound according to the first aspect for preparing an anti-photoaging skin care product or a drug.

[0021] In a fourth aspect, the embodiments of the present application further provide an anti-photoaging skin care product, comprising: the oxidation-resistant anti-aging compound according to the first aspect.

[0022] In yet another aspect, the embodiments of the present application further provide a use of a compound having a structure shown in formula (1) as an oxidation-resistant anti-aging compound.

[0023] The beneficial effects that can be achieved by the embodiments of the present application include:

[0024] The oxidation-resistant anti-aging compound shown in formula (1) provided by the embodiments of the present application has similar pharmacological activity to that of bakuchiol, can achieve very good anti-aging effect, and has oxidation-resistant stability, which can overcome the defects of bakuchiol. Therefore, the oxidation-resistant anti-aging compound shown in formula (1) as an anti-aging active ingredient applied in the field of skin care can improve or improve the skin condition.

[0025] Other advantages, objects, and features of the present application will be partly embodied by the following description, and partly understood by those skilled in the art through research and practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 A cell survival rate diagram of the embodiments of the present application;

[0027] Figure 2 Another cell survival rate diagram of the embodiments of the present application. DETAILED DESCRIPTION

[0028] The application will be described in further detail below with reference to the drawings. Those skilled in the art will be able to carry out the application in view of the description herein.

[0029] The term "comprising", used in the embodiments of the present application, and any variations thereof, is intended to mean a non-exclusive inclusion. For example, a process, method, system, product, or apparatus that comprises a list of steps or elements is not necessarily limited to the listed steps or elements, but can optionally further include additional steps or elements not expressly listed or inherent to such process, method, system, product, or apparatus.

[0030] In addition to the above, it is still emphasized that a reference herein to "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the application. The appearances of the phrase that the phrase in various places in the specification are not necessarily all referring to the same embodiment, nor are they necessarily mutually exclusive of one another. It is explicitly contemplated that embodiments described herein can be combined with each other.

[0031] As mentioned above, the embodiments of the present application find that bakuchiol has relatively poor oxidation stability. Therefore, it is a feasible improvement measure to replace bakuchiol with a derivative having similar functions and high stability by reasonably modifying bakuchiol. However, how to reasonably modify bakuchiol is still a technical difficulty, because the product obtained after modification of bakuchiol can not have good fat solubility, and if the fat solubility is low, it will affect the entry of the modified product of bakuchiol into the cell level, and it is difficult to have good drug efficacy.

[0032] Therefore, the ideal modified product of bakuchiol pursued by the embodiments of the present application not only needs to have good oxidation stability, but also should have fat solubility not lower than that of bakuchiol, and good anti-photoaging efficacy.

[0033] Based on the above idea, the embodiments of the present application provide the following technical solutions.

[0034] Oxidation-resistant anti-aging compounds

[0035] In a first aspect, the embodiments of the present application provide a light-oxidation-resistant anti-aging compound having a structure shown in formula (1):

[0036]

[0037] wherein the R group is a C1-C18 alkyl chain.

[0038] The light-oxidation-resistant anti-aging compound shown in formula (1) provided by the embodiment of the present application is a psoralen phenol ester derivative, has similar pharmacological activity to psoralen phenol, can play a very good anti-aging effect, and has oxidation resistance stability, can overcome the defects of psoralen phenol, and can be applied to skin care products or other drugs as an anti-aging active ingredient, and can improve or improve the skin condition.

[0039] Specifically, in one aspect, due to the introduction of a specific R group, the exposed phenolic hydroxyl group of psoralen phenol is eliminated, so the psoralen phenol ester derivative shown in formula (1) has better stability compared with psoralen phenol, can reduce and reduce the occurrence of oxidation, and is easy to store.

[0040] In another aspect, due to the fact that the R group contains an alkyl group, the psoralen phenol ester derivative shown in formula (1) has very good fat solubility, is easy to enter cells, is hydrolyzed under the action of ester hydrolase, and releases psoralen phenol, thereby better playing the anti-aging effect and the like.

[0041] It should be noted that in the embodiment of the present application, the alkyl chain refers to a carbon chain containing an alkyl group. C1-C18 refers to the number of carbon atoms in the alkyl chain. For example, the alkyl chain of C1-C18 refers to an alkyl chain having 1-18 carbon atoms.

[0042] In some embodiments, the R group is a C1-C18 saturated or unsaturated straight chain alkyl chain. In other embodiments, the R group is a C1-C18 saturated or unsaturated branched alkyl chain.

[0043] In some embodiments, the R group is a C1-C18 saturated straight chain alkyl chain. Due to the unsaturated chain, for example, the alkyl chain containing an alkenyl group, the fat solubility will be reduced to some extent. Therefore, in this embodiment, the fat solubility of the light-oxidation-resistant anti-aging compound can be improved.

[0044] In some embodiments, the R group is a C3-C18 saturated straight chain alkyl chain. The fat solubility of the psoralen phenol ester derivative can be further improved.

[0045] In some embodiments, the R group contains 1-2 alkenyl groups. The unsaturated psoralen phenol ester derivative has better physiological activity than the saturated psoralen phenol ester derivative, and the addition of the unsaturated fatty acid chain can make the product have better activity.

[0046] In some embodiments, the oxidation-resistant anti-aging compound is selected from any one of compounds 1a-9a in Table 1:

[0047] Table 1

[0048]

[0049]

[0050] Use of oxidation-resistant anti-aging compounds for UVB photoprotection of HaCaT cells

[0051] In still another aspect, the embodiments of the present application provide the use of the oxidation-resistant anti-aging compound of the first aspect, in particular the use for anti-UVB photoaging of HaCaT cells.

[0052] Photoaging caused by UVB irradiation is a common form of cellular senescence. After the HaCaT cells treated by UVB irradiation are treated with the oxidation-resistant anti-aging compound of the embodiments of the present application, the cell survival rate can be significantly improved. Therefore, the oxidation-resistant anti-aging compound provided by the embodiments of the present application can play a very good role in anti-UVB photoaging of HaCaT cells.

[0053] Use of photoprotective anti-aging compounds for the preparation of anti-aging skin care products

[0054] In still another aspect, the embodiments of the present application also provide the use of the oxidation-resistant anti-aging compound of the first aspect for preparing an anti-photoaging skin care product or a drug.

[0055] The skin care product is often exposed to the air during use. Therefore, compared with the existing psoralen, the anti-aging skin care product prepared by using the oxidation-resistant anti-aging compound of the embodiments of the present application as an anti-aging component has better oxidation resistance and is easier to store.

[0056] In addition, after the oxidation-resistant anti-aging compound provided by the embodiments of the present application is applied to the anti-photoaging skin care product, the anti-aging effect on the skin can also be improved. For example, the skin care product is easily affected by the air after being applied to the skin, so if the skin care product prepared by using psoralen as an anti-aging component is applied to the skin, the psoralen in the skin care product is easy to be oxidized and lose or reduce the effect, and the oxidation-resistant anti-aging compound of the embodiments of the present application can overcome the foregoing defects.

[0057] In still another aspect, the embodiments of the present application also provide the use of the oxidation-resistant anti-aging compound of the first aspect for preparing a drug.

[0058] In still another aspect, the embodiments of the present application also provide the use of the compound with the structure shown in formula (1) as an oxidation-resistant anti-aging compound.

[0059] Anti-aging skin care products

[0060] In still another aspect, the embodiments of the present application also provide an anti-photoaging skin care product, which comprises the oxidation-resistant anti-aging compound of the first aspect. In still another aspect, the embodiments of the present application also provide an anti-photoaging skin care product, which comprises the oxidation-resistant anti-aging compound of the first aspect.

[0061] Compared with the prior art, the anti-photoaging skin care product provided by the embodiments of the present application has better oxidation resistance stability and anti-aging effect.

[0062] Process for the preparation of oxidation-resistant anti-aging compounds

[0063] There are various methods for preparing the oxidation-resistant anti-aging compound, which can be prepared by esterification, etherification and other derivatization methods to modify the structure of the psoralenol.

[0064] Regarding the esterification synthesis method:

[0065] The psoralenol used as the raw material is subjected to esterification reaction with the corresponding acid, acid anhydride or acyl chloride, so as to generate the psoralenol ester derivative with the structure of formula (1).

[0066] The synthesis path of the psoralenol ester derivative with the structure of formula (1) generated by the esterification reaction of the acid, acid anhydride or acyl chloride can be shown as follows:

[0067]

[0068] Unless otherwise specified, in the embodiments of the present application, base refers to a base, which can be an organic base, and further can be triethylamine.

[0069] EDCI refers to a carbodiimide.

[0070] RCOOH refers to a carboxylic acid. For example, the acid used for preparing the oxidation-resistant anti-aging compound can be selected from any one of acetic acid, propionic acid, butyric acid, oleic acid, octadecanoic acid, linoleic acid, palmitic acid and arachidonic acid.

[0071] RCOOOCR refers to an acid anhydride.

[0072] RCOCl refers to an acyl chloride.

[0073] Solvent refers to a solvent.

[0074] The method process route adopted in the embodiments of the present application is very simple, the cost is low, the yield of the product is high, and the needs of industrialization and expanded production can be met.

[0075] Preparation examples of oxidation-resistant anti-aging compounds

[0076] Example 1

[0077] Preparation of compound 1a

[0078]

[0079] Synthesis method 1: Psoralen (380 mg) was weighed into a 50 mL flask, dissolved in THF (10 mL) with stirring, acetic acid (122 mg) was added, EDCI (460 mg) and DMAP (4-dimethylaminopyridine) (20 mg) were added, and finally TEA (triethanolamine) (550 μL) was added. The reaction was stirred at room temperature for 12 hours. The reaction solvent THF was removed on a rotary evaporator, and the resulting reaction mixture was purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 1a, mass 470 mg.

[0080] Synthesis method 2: Psoralen (190 mg) was weighed into a 30 mL flask, dissolved in THF (10 mL) with stirring, and finally TEA (triethanolamine) (250 μL) was added. The resulting reaction system was placed in an ice bath, and acetic anhydride (135 μL) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction solvent THF was removed on a rotary evaporator, and the resulting reaction mixture was purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 1a, mass 230 mg.

[0081] The nuclear magnetic resonance data of compound 1a are as follows:

[0082] 1 H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 2H), 7.07-6.98 (m, 2H), 6.30 (d, J = 16.3 Hz, 1H), 6.16 (d, J = 16.2 Hz, 1H), 5.88 (dd, J = 17.5, 10.7 Hz, 1H), 5.15-4.97 (m, 3H), 2.29 (s, 3H), 1.95 (q, J = 7.5 Hz, 2H), 1.67 (s, 3H), 1.58 (s, 3H), 1.54-1.46 (m, 2H), 1.20 (s, 3H).

[0083] 13 C NMR (101 MHz, CDCl3) δ 169.44, 149.50, 145.58, 138.13, 135.65, 131.26, 126.91, 126.22, 124.64, 121.48, 112.07, 42.58, 41.15, 25.63, 23.23, 23.16, 21.03, 17.58.

[0084] Example 2

[0085] Preparation of compound 2a

[0086]

[0087] Experimental procedure: Take 380 mg of bakuchiol in a 50 mL flask, stir and dissolve in THF (tetrahydrofuran) 10 mL, add 132 mg of propionic acid, 460 mg of EDCI and 20 mg of DMAP (4-dimethylaminopyridine), finally add 550 μL of TEA (triethanolamine). The resulting reaction system is stirred at room temperature for 12 hours. The reaction solvent THF is removed in a rotary evaporator, the resulting reaction mixture is purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE: EA = 30: 1) to obtain compound 2a, mass 400 mg.

[0088] The nuclear magnetic resonance data of compound 2a are as follows:

[0089] 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.34 (d, J = 16.3 Hz, 1H), 6.19 (d, J = 16.2 Hz, 1H), 5.91 (dd, J = 17.4, 10.7 Hz, 1H), 5.22-4.99 (m, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.99 (q, J = 7.4 Hz, 2H), 1.71 (s, 3H), 1.62 (s, 3H), 1.57-1.51 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.24 (s, 3H).

[0090] 13 C NMR (101 MHz, CDCl3) δ 172.79, 149.60, 145.54, 137.97, 135.46, 131.18, 126.84, 126.24, 124.64, 121.44, 112.03, 42.54, 41.13, 27.61, 25.60, 23.20, 23.14, 17.54, 8.96.

[0091] Example 3

[0092] Preparation of compound 3a

[0093]

[0094] Preparation step: Take 128 mg of bakuchiol in a 50 ml flask, then add 51 mg of TEA (triethanolamine) and 3 mL of dichloromethane (DCM), then slowly drop 72 mg of valeryl chloride at 0°C, then stir at room temperature (25°C) for 12 hours for full reaction. After the reaction, remove the reaction solvent DCM in the rotary evaporator, and the obtained reaction mixture is purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE: EA = 30: 1), to obtain the final product, that is, compound 3a, the mass of compound 3a is 141 mg.

[0095] The nuclear magnetic data of compound 3a is as follows:

[0096] 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 16.3 Hz, 1H), 6.16 (d, J = 16.3 Hz, 1H), 5.88 (dd, J = 17.5, 10.7 Hz, 1H), 5.15-4.97 (m, 3H), 2.55 (t, J = 7.5 Hz, 2H), 1.95 (dd, J = 10.5, 6.3 Hz, 2H), 1.74 (p, J = 7.5 Hz, 2H), 1.68 (s, 3H), 1.58 (s, 3H), 1.54-1.42 (m, 4H), 1.21 (s, 3H), 0.97 (t, J = 7.4 Hz, 3H).

[0097] 13 C NMR (101 MHz, CDCl3) δ 172.33, 149.63, 145.64, 138.08, 135.56, 131.34, 126.91, 126.29, 124.67, 121.53, 112.08, 42.61, 41.19, 34.10, 26.98, 25.66, 23.26, 23.19, 22.22, 17.61, 13.70.

[0098] Example 4

[0099] Preparation of compound 4a

[0100]

[0101] Experimental procedure: Frullanolide 128 mg was taken in 50 mL flask, TEA (triethanolamine) 51 mg, DCM (dichloromethane) 3 mL was added, slowly dropwise added octanoyl chloride 97 mg at 0 °C, the reaction was stirred at room temperature for 12 hours. The reaction solvent DCM was removed in a rotary evaporator, the resulting reaction mixture was purified by silica gel column chromatography (silica gel grade 200-300 mesh, mobile phase was petroleum ether (PE) and ethyl acetate (EA) in the ratio of PE: EA = 30: 1) to get compound 4a, mass 134 mg.

[0102] NMR data of compound 4a is as follows:

[0103] 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.6 Hz, 2H), 7.00 (s, 2H), 6.31 (d, J = 16.3 Hz, 1H), 6.16 (d, J = 16.2 Hz, 1H), 5.88 (dd, J = 17.5, 10.7 Hz, 1H), 5.15 - 4.96 (m, 3H), 2.54 (t, J = 7.5 Hz, 2H), 1.96 (q, J = 7.4 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.55 - 1.47 (m, 2H), 1.46 - 1.30 (m, 8H), 1.21 (s, 3H), 0.94 - 0.86 (m, 3H).

[0104] 13 C NMR (101 MHz, DMSO) δ 172.33, 149.63, 145.64, 138.07, 135.55, 131.33, 126.91, 126.29, 124.68, 121.53, 112.08, 42.61, 41.19, 34.38, 31.63, 29.04, 28.89, 25.66, 24.92, 23.26, 23.19, 22.57, 17.61, 14.03.

[0105] Example 5

[0106] Preparation of compound 5a

[0107]

[0108] Experimental procedure: Frullanolide 128 mg was taken in 50 mL flask, TEA (triethanolamine) 51 mg, DCM (dichloromethane) 3 mL was added, and dodecanoyl chloride 131 mg was added slowly drop wise at 0 °C. The reaction was stirred at room temperature for 12 h. The reaction solvent DCM was removed in a rotary evaporator and the obtained reaction mixture was purified by silica gel column chromatography (silica gel grade 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA) in the ratio of PE:EA = 30:1) to get compound 5a, mass 180 mg.

[0109] NMR data of compound 5a is as follows:

[0110] 1 H NMR (400 MHz, CDC13) δ 7.36 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 16.2 Hz, 1H), 6.16 (d, J = 16.2 Hz, 1H), 5.88 (dd, J = 17.4, 10.7 Hz, 1H), 5.11 (tdd, J = 6.9, 2.9, 1.5 Hz, 1H), 5.08 - 4.97 (m, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.96 (q, J = 7.4 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H), 1.68 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.3 Hz, 3H), 1.54 - 1.47 (m, 2H), 1.45 - 1.27 (m, 16H), 1.21 (s, 3H), 0.93 - 0.85 (m, 3H).

[0111] 0.85 (m, 3H).

[0112] 13 C NMR (101 MHz, DMSO) δ 172.34, 149.63, 145.64, 138.07, 135.55, 131.33, 126.91, 126.29, 124.68, 121.53, 112.08, 42.61, 41.19, 34.39, 31.89, 29.57, 29.43, 29.31, 29.23, 29.09, 25.66, 24.93, 23.26, 23.19, 22.66, 17.61, 14.09.

[0113] Example 6

[0114] Preparation of compound 6a

[0115]

[0116] Experimental procedure: Frullanolide 512 mg was weighed into a 50 mL flask, and then 615 mg of n-hexadecanoic acid, 460 mg of EDCI and 20 mg of DMAP (4-dimethylaminopyridine) were added. The mixture was dissolved in 10 mL of THF (tetrahydrofuran) and stirred, and then 550 μL of TEA (triethylamine) was added. The reaction was stirred at room temperature for 12 hours. The reaction solvent was removed on a rotary evaporator, and the resulting reaction mixture was purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 6a, mass 922 mg.

[0117] NMR data of compound 6a are as follows:

[0118] 1 H NMR (400 MHz, CDC13) δ 7.28 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.23 (d, J = 16.3 Hz, 1H), 6.08 (d, J = 16.3 Hz, 1H), 5.80 (dd, J = 17.5, 10.8 Hz, 1H), 5.07 - 4.89 (m, 3H), 2.46 (t, J = 7.5 Hz, 2H), 1.88 (q, J = 7.5 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.60 (s, 3H), 1.50 (s, 3H), 1.46 - 1.39 (m, 2H), 1.35 - 1.19 (m, 24H), 1.13 (s, 3H), 0.85 - 0.77 (m, 3H).

[0119] 13 C NMR (101 MHz, CDC13) δ 172.34, 149.64, 145.64, 138.08, 135.56, 131.80, 126.92, 126.30, 124.68, 121.54, 112.09, 42.62, 41.20, 34.40, 31.91, 29.68, 29.66, 29.64, 29.58, 29.44, 29.35, 29.24, 29.10, 25.67, 24.93, 23.27, 23.20, 22.68, 17.62, 14.10.

[0120] Example 7

[0121] Preparation of compound 7a

[0122]

[0123] Experimental procedure: Frullanolide 128 mg was weighed into a 50 mL flask, and then octadecanoic acid 170 mg, EDCI 115 mg and DMAP (4-dimethylaminopyridine) 5 mg were added. The mixture was dissolved in THF (tetrahydrofuran) 10 mL and stirred, and then TEA (triethylamine) 550 μL was added. The reaction was stirred at room temperature for 12 hours. The reaction solvent THF was removed on a rotary evaporator, and the resulting reaction mixture was purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 7a, mass 143 mg.

[0124] NMR data of compound 7a are as follows:

[0125] 1 H NMR (400 MHz, CDC13) δ 7.36 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 16.3 Hz, 1H), 6.16 (d, J = 16.3 Hz, 1H), 5.88 (dd, J = 17.5, 10.7 Hz, 1H), 5.18 - 4.94 (m, 3H), 2.54 (t, J = 7.5 Hz, 2H), 1.75 (p, J = 7.5 Hz, 2H), 1.68 (s, 3H), 1.59 (s, 3H), 1.54 - 1.48 (m, 2H), 1.44 - 1.26 (m, 28H), 1.21 (s, 3H), 0.89 (t, J = 6.7 Hz, 3H).

[0126] 13 C NMR (101 MHz, CDC13) δ 172.34, 149.64, 145.64, 138.08, 135.56, 131.33, 126.91, 126.30, 124.68, 121.53, 112.09, 42.62, 41.20, 34.40, 31.91, 29.68, 29.66, 29.64, 29.63, 29.58, 29.44, 29.35, 29.24, 29.10, 25.67, 24.93, 23.27, 23.20, 22.68, 17.61, 14.10.

[0127] Example 8

[0128] Preparation of compound 8a

[0129]

[0130] Experimental procedure: Frullanolide 380 mg was weighed in a 50 mL flask, oleic acid 565 mg, EDCI 460 mg and DMAP (4-dimethylaminopyridine) 20 mg were added, and the mixture was stirred and dissolved in THF (tetrahydrofuran) 10 mL, and finally TEA (triethanolamine) 550 μL was added. The reaction was stirred at room temperature for 12 hours. The reaction solvent THF was removed on a rotary evaporator, and the resulting reaction mixture was purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 8a, mass 600 mg.

[0131] NMR data of compound 8a are as follows:

[0132] 1 H NMR (400 MHz, CDC13) δ 7.37 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 16.3 Hz, 1H), 6.17 (d, J = 16.2 Hz, 1H), 5.90 (dd, J = 17.4, 10.7 Hz, 1H), 5.47 - 5.29 (m, 4H), 5.17 - 4.98 (m, 3H), 2.80 (t, J = 6.4 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.14 - 2.02 (m, 4H), 1.97 (q, J = 7.4 Hz, 2H), 1.77 (p, J = 7.4 Hz, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.56 - 1.48 (m, 2H), 1.48 - 1.26 (m, 16H), 1.22 (s, 3H), 0.96 - 0.86 (m, 3H).

[0133] 13 C NMR (101 MHz, CDC13) δ 172.22, 149.61, 145.60, 138.05, 135.53, 131.27, 130.16, 129.96, 128.04, 127.86, 126.89, 126.28, 124.67, 121.50, 112.07, 42.59, 41.18, 34.34, 31.49, 29.55, 29.31, 29.29, 29.12, 29.06, 29.04, 27.17, 27.15, 25.65, 25.60, 24.89, 23.25, 23.18, 22.54, 17.59, 14.04.

[0134] Example 9

[0135] Preparation of compound 9a

[0136]

[0137] Experimental procedure: Take 512 mg of bakuchiol in a 50 mL flask, add 673 mg of linoleic acid, 460 mg of EDCI and 20 mg of DMAP (4-dimethylaminopyridine), stir and dissolve in 10 mL of THF (tetrahydrofuran), and finally add 550 μL of TEA (triethanolamine). The reaction is stirred at room temperature for 12 hours. The reaction solvent THF is removed on a rotary evaporator, and the resulting reaction mixture is purified by silica gel column chromatography (silica gel type 200-300 mesh, mobile phase petroleum ether (PE) and ethyl acetate (EA), volume ratio PE:EA = 30:1) to obtain compound 9a, mass 600 mg.

[0138] The nuclear magnetic resonance data of compound 9a are as follows:

[0139] 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.32 (d, J = 16.2 Hz, 1H), 6.17 (d, J = 16.2 Hz, 1H), 5.89 (dd, J = 17.5, 10.7 Hz, 1H), 5.45-5.32 (m, 2H), 5.17-4.98 (m, 3H), 2.55 (t, J = 7.5 Hz, 2H), 2.12-1.91 (m, 6H), 1.76 (p, J = 7.5 Hz, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 1.55-1.49 (m, 2H), 1.46-1.29 (m, 18H), 1.22 (s, 3H), 0.94-0.85 (m, 3H).

[0140] 13 C NMR (101 MHz, CDCl3) δ 172.22, 149.61, 145.60, 138.05, 135.53, 131.27, 130.16, 129.96, 128.04, 127.86, 126.89, 126.28, 124.67, 121.50, 112.07, 42.59, 41.18, 34.34, 31.49, 29.55, 29.31, 29.29, 29.12, 29.06, 29.04, 27.17, 27.15, 25.65, 25.60, 24.89, 23.25, 23.18, 22.54, 17.59, 14.04.

[0141] In the embodiments of the present application, the term "℃" refers to Celsius degrees, indicating temperature, unless otherwise specified.

[0142] NMR spectra were recorded in CDC13 or DMSO, (as otherwise specified) on a 400 MHz instrument d6 H and 1 H and 13 C, chemical shifts are reported in ppm with TMS as a reference, coupling constants are reported in Hz.

[0143] NMR data acquisition instrument: Bruker 400 MHz superconducting Fourier NMR spectrometer (Bruker AVANCE III 400 MHz Superconducting Fourier), model: AVANCE III HD 400.

[0144] Determination of the liposolubility of compounds

[0145] Lipophilicity refers to the tendency of a compound to partition between a non-polar lipid medium and an aqueous medium, and is an important factor in determining the properties of a compound. Both LogP and LogD are parameters that reflect the lipophilicity of a molecule, LogP is suitable for the lipophilicity characterization of neutral molecules, and LogD is suitable for molecules that have different charge states due to pH.

[0146] Based on the structural characteristics of the compounds of the present application, LogP is suitable for characterizing the lipophilicity of the compounds described in the present application. The logP value refers to the logarithmic value of the partition coefficient ratio of a substance in n-octanol (oil) and water. It reflects the partitioning of the substance between oil and water. The smaller the logP value, the more hydrophilic it is, and the larger the value, the more oil-loving the substance is, and the better the fat solubility.

[0147] Therefore, in the present application, logP values are used to determine the fat solubility of compounds 1a-9a and bakuchiol as an index to judge the anti-aging efficacy of these compounds.

[0148] Liposolubility determination experiment

[0149] Tested compounds: compounds 1a-9a and bakuchiol, respectively.

[0150] Experimental reagents: n-octanol, DMF (N,N-dimethylformamide) and anhydrous sodium sulfate were purchased from Bide Pharmaceutical.

[0151] Experimental method: n-octanol-water was used for the dispersion system, the shake-flask method was used for the determination method, and UV-visible spectrophotometry was used to determine compounds 1-9 and bakuchiol. The concentration ratio of the oil phase (n-octanol) and the aqueous phase after the compound partitioning equilibrium was calculated to obtain LogP.

[0152] The experimental procedure is as follows: 0.5 mg of the corresponding test compound is weighed in a volumetric flask, dissolved in 100 μL of DMF, and diluted with n-octanol to a 25 mL solution. 5 mL of this solution is taken and diluted with n-octanol to 10 mL. The absorbance of the test compound in n-octanol is measured by UV-Vis spectroscopy. Subsequently, 4 mL of each n-octanol solution and 8 mL of water are shaken on a mechanical shaker for 30 minutes. After phase separation of the n-octanol and water layers, the n-octanol layer is dried over anhydrous sodium sulfate and the absorbance of this layer is measured. The concentration of each compound before and after treatment on the mechanical shaker is recorded. The logP value of each compound is calculated using the equation logP = log(y / x-y), where x represents the concentration of the compound in the n-octanol phase before shaking and y represents the concentration of the compound in the n-octanol phase after shaking.

[0153] As shown in Table 2, the following are the LogP data of each compound:

[0154] Table 2

[0155]

[0156]

[0157] According to the results in Table 2, it can be seen that the compounds 1a-9a provided by the embodiments have good fat solubility, all of which are higher than that of the existing art bakuchiol. It is shown that the compounds 1-9a provided by the embodiments are more likely to enter the cells and have efficacy.

[0158] In addition, the fat solubility of compounds 3a-9a is more than 6, which is much higher than that of compounds 1a-2a, indicating that when the number of C atoms in the C chain of the compound is greater than or equal to 3, the fat solubility can be greatly improved.

[0159] Cytotoxicity experiment

[0160] Experimental reagents: MTT (thiazolyl blue) was purchased from Solarbio (M8180-1000); trypsin, double antibodies, DMEM medium, MEM medium, and PBS buffer were all purchased from Gibco company; fetal bovine serum was purchased from Biological Industries. DMEM medium is a complete culture medium, which is obtained by combining 90% of MEM basic medium, 9% of fetal bovine serum, and 1% of double antibodies.

[0161] Experimental equipment: SpectraMax microplate reader (Meigu molecular, SpectraMax i3x), optical microscope, digital ultraviolet crosslinking instrument: Talboys.

[0162] Experimental method:

[0163] A blank control group, a positive control group and 9 experimental groups were set. The cell survival rates of each group were calculated respectively, and the experimental results are shown in Table 1. Figure 1 .

[0164] The steps of experimental groups 1-9 are as follows:

[0165] 1) Each experimental group used HaCaT cells for experiment. The cells were taken out from liquid nitrogen for recovery. After two to three generations of subculture and expansion, when the cell viability was good, the cell suspension was obtained by trypsinization, and was inoculated into a 96-well plate at a density of 50,000 cells / ml, with 100 ul of cell suspension added to each well.

[0166] 2) After 24 hours, the cells adhered to the wall, and the old culture medium was discarded. Each experimental group was replaced with a new serum-free MEM culture medium containing the same concentration of compounds 1a-9a.

[0167] 3) After 24 hours, 100 ul of MTT (diluted to 0.5 mg / ml with the MEM culture medium in step 2) was added to each well of the 96-well plate, and the plate was wrapped with tin foil and placed in the incubator for 4 hours. The old liquid was discarded, 100 ul of DMSO was added to each well, and the plate was shaken for 10 minutes. The absorbance value of each experimental group was measured at 570 nm on the enzyme label instrument, and the cell survival rates of experimental groups 1-9 were calculated respectively. The experimental results are shown in Table 1. Figure 1 .

[0168] The blank control group and the positive control group can be specifically set according to the steps of the experimental group. The main difference between the blank control group, the positive control group and the experimental group is:

[0169] Experimental groups 1-9 have HaCaT cells, and are administered with serum-free MEM culture medium containing compounds 1a-9a at a concentration of 2 uM;

[0170] The blank control group has HaCaT cells, and the experiment is cultured with complete culture medium throughout the experiment. After the absorbance is measured, MTT is added after the complete culture medium is discarded;

[0171] The positive control group has HaCaT cells, and is administered with MEM serum-free culture medium containing psoralen at the same concentration as experimental groups 1-9.

[0172] The results of the cytotoxicity experiment are as follows:

[0173] According to Figure 1 , compared with the blank control group, the cell survival rates of the positive control group and experimental groups 1-9 are roughly equal, indicating that the compounds 1a-9a provided in the application do not produce cytotoxicity to HaCat cells.

[0174] Cellular UV photaging experiment

[0175] Experimental reagents: MTT (thiazolyl blue) was purchased from Solarbio (M8180-1000); trypsin, double antibodies, DMEM medium, MEM medium and PBS buffer were all purchased from Gibco company; serum was purchased from Biological Industries; β-galactosidase cell aging kit was purchased from Beyotime. DMEM medium is a complete culture medium, which is obtained by combining 90% of MEM basic medium, 9% of fetal bovine serum and 1% of double antibodies.

[0176] Experimental equipment: SpectraMax microplate reader (Meigu molecular, SpectraMax i3x), optical microscope, digital ultraviolet crosslinking instrument: Talboys.

[0177] Experimental methods and steps:

[0178] I. Determination of the optimal dose of ultraviolet:

[0179] 1) HaCat cells were used for the experiment, and the cells were taken out from liquid nitrogen for recovery. After two to three generations of subculture expansion, when the cell viability was good, 5,000 cells / ml were inoculated in a 96-well plate, and 100ul of cell suspension was added to each well.

[0180] 2) After 24 hours, the cells adhered to the wall, and the old culture medium was discarded, and then new serum-free culture medium containing the aforementioned compound was added.

[0181] 3) After adding new PBS, UVB was irradiated at 100mJ / cm 2 , 200mJ / cm 2 , 300mJ / cm 2 , 400mJ / cm 2 , 500mJ / cm 2 , 600mJ / cm 2 , 700mJ / cm 2 , 800mJ / cm 2 , 900mJ / cm 2 , and then new serum-free culture medium was added.

[0182] 4) After 24 hours, 100ul of MTT (0.5mg / ml, MEM medium dilution) was added to each well of the 96-well plate, wrapped in tin foil paper and placed in the incubator for 4h, the old liquid was discarded, 100ul of DMSO was added to each well, and the shaker was shaken for 10min. The absorbance value was measured at 570nm on the microplate reader, and the cell survival rate was calculated.

[0183] 5) The optimal ultraviolet modeling dose was determined by MTT method to be 700mJ / cm 2 , and under this dose, the cell survival rate was about 60%.

[0184] II. Ultraviolet light aging experiment:

[0185] A blank control group, a positive control group and 9 experimental groups were set up. The 9 experimental groups were experimental groups 1-9. The blank control group did not add HaCaT cells, and was used for absorbance correction wells; the blank group, the positive control group and the 9 experimental groups all added HaCaT cells for treatment, wherein the blank group was not treated with UVB light, and the other groups were treated with UVB light. After treatment, the cell survival rates of the blank group, the positive control group and the 9 experimental groups were calculated, and the experimental results are shown in Table 1. Figure 2 .

[0186] The steps of experimental groups 1-9 are as follows:

[0187] 1) Each experimental group used HaCaT cells for the experiment. The cells were taken out from liquid nitrogen for recovery, and after two to three generations of subculture and expansion, when the cell viability was good, HaCat cells were inoculated in a 96-well plate at a density of 5,000 cells / ml, and 100 uL of HaCat cell suspension was added to each well.

[0188] 2) After 24 hours, the cells adhered, and the old culture medium was discarded. New PBS buffer was added to each experimental group.

[0189] 3) After adding new PBS buffer to each experimental group, UVB was used for irradiation at 700 mJ / cm 2 , and then new serum-free medium containing compounds 1a-9a at a concentration of 2 uM (i.e. MEM medium) was added. It should be noted that each experimental group added serum-free medium containing the corresponding compound, for example, experimental group 1 added serum-free medium containing 2 uM of compound 1a, and the same applies to experimental group 9, which added serum-free medium containing 2 uM of compound 9a.

[0190] 4) After 24 hours, 100 uL of MTT (diluted to a concentration of 0.5 mg / ml in the serum-free medium of step 3) was added to each well of the 96-well plate of each experimental group, and then wrapped in tin foil and placed in an incubator for 4 hours. The old liquid was then discarded, 100 uL of DMSO (dimethyl sulfoxide) was added to each well, and the shaking bed was shaken for 10 minutes. The absorbance values of each experimental group were measured at 570 nm on an enzyme marker, and the cell survival rates of experimental groups 1-9 were calculated.

[0191] The blank group, the blank control group, the positive control group and the model group can be specifically set up according to the steps of the experimental groups, and the main difference from the experimental groups is:

[0192] Experimental groups 1-9 have HaCaT cells, and are given serum-free MEM medium containing different compounds 1a-9a at a concentration of 2 uM;

[0193] The blank control group is a control group without HaCaT cells, and PBS buffer is added during the experiment, and the PBS is discarded when the absorbance is measured, and then DMSO is added for absorbance correction holes;

[0194] The blank group is a group with HaCaT cells, and the complete culture medium is used for cultivation throughout, and the absorbance is measured by discarding the complete culture medium and adding MTT;

[0195] The positive control group is a group with HaCaT cells, and the serum-free MEM culture medium containing the same concentration of bakuchiol as the experimental group is used for administration;

[0196] The model group is a group with HaCaT cells, and is not administered together with the UVB irradiation of each administration group.

[0197] Experimental results: from the results in Table 1, Figure 2 It can be seen from the results in Table 1 that the cell survival rates of the compounds 1a-9a provided in the embodiments of the present application are higher than those of the model group, and the cell survival rates of most of the compounds are equivalent to those of the positive control group. However, the compounds provided in the embodiments of the present application have better oxidation resistance stability, and therefore, from the overall effect, the compounds provided in the embodiments of the present application are better than the positive compounds, that is, because the anti-aging compounds provided in the prior art.

[0198] Although the embodiments of the present application have been disclosed as above, they are not limited to the application listed in the specification and the embodiments, and can be fully applied to various fields suitable for the present application, and other modifications can be easily realized by those skilled in the art, and therefore, the present application is not limited to specific details and the figures shown and described herein, without departing from the general concept defined by the claims and the equivalent scope.

Claims

1. An antioxidant and anti-aging compound, characterized in that, It has the structure shown in equation (1): ； Wherein, R is a C1-C18 alkyl chain; The antioxidant and anti-aging compound is selected from any one of compounds 5a, 7a-9a: 。 2. The use of the antioxidant and anti-aging compound according to claim 1 for the anti-UVB photoaging of HaCaT cells in humans or animals for non-diagnostic or therapeutic purposes.

3. The use of the antioxidant and anti-aging compound according to claim 1 in the preparation of anti-photoaging skin care products.

4. Anti-photoaging skincare products, characterized in that, include: The antioxidant and anti-aging compound according to claim 1.

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