Ceramide compounds containing cyclic carboxylic acid and preparation method and application thereof

Abstract

The present invention belongs to the technical field of biological medicine, and discloses a ceramide compound shown in Chemical Formula I: #imgabs0# wherein, R 1 is selected from the residues after condensation of sialic acid, chelidamic acid monohydrate, 2,5-furandicarboxylic acid, quinic acid, chlorogenic acid, ectoine, nicotinic acid, shikimic acid, glucuronic acid, salicylic acid, carnosic acid, dihydrooat acylanthranilic acid, abietic acid, ursolic acid, tranexamic acid, syringic acid, gentisic acid, vanillic acid, 5-hydroxyisovanillic acid, orotic acid, 5-aminoorotic acid, 3,5-dihydroxy-4-methylbenzoic acid, glycyrrhizic acid or gallic acid, R 2 is selected from one of the following structures: -C 15 H 29 、-C 15 H 31 、-C 15 H 27 、-CHOHC 14 H 27 、-CHOHC 14 H 29 . The present invention also discloses a preparation method and application of the ceramide compound. The present invention introduces a molecular fragment with physiological activity of a functional carboxylic acid into ceramide, which will enhance the original efficacy of this type of molecule and also improve the physicochemical properties of the ceramide compound.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to ceramide compounds containing cyclic carboxylic acid, and a preparation method and application thereof. Background Art

[0002] Ceramide is a compound composed of sphingosine and long-chain fatty acids bonded by amide bonds. The carbon chain length, unsaturation and number of hydroxyl groups of the sphingosine part and the fatty acid part can all be changed, so ceramide is a class of compounds rather than a single compound. At present, 15 types of ceramides have been detected in the skin, which can be roughly divided into three categories: short-chain ceramides, long-chain ceramides, and ceramides bonded to keratinocytes. The main ways to obtain ceramides include natural extraction, microbial fermentation and chemical synthesis. The ceramide obtained by the extraction method has low purity and is generally suitable for use as food. In addition, the sphingosine part and the fatty acid part of the ceramide are a homogeneous mixture, which belongs to a mixed type of ceramide, and the ratio of its functional components is difficult to adjust; at the same time, ceramide extracted from animal tissues may also be contaminated by pathogens, so its application in cosmetics and other fields is limited. Compared with the first two approaches, chemical synthesis has the characteristics of a single product component and a determined structure. More importantly, the chemical synthesis method can quickly construct ceramide derivatives with similar functions, which widely expands the application range of ceramide derivatives.

[0003] Ceramide has the functions of moisturizing, signal transduction, and immune regulation. Different factors (such as genetics, skin diseases, harsh external environment, improper use of drugs, excessive skin care, etc.) lead to changes in its content, which may cause damage to the skin barrier function and even the occurrence of some skin diseases, such as atopic dermatitis and psoriasis. Therefore, in recent years, ceramide has become a hot topic in the fields of daily chemicals, medical research, and cosmetics.

[0004] Due to the widespread demand for functional ceramides in the market, it is very necessary to quickly construct ceramide derivatives through chemical synthesis to further improve the properties of ceramide and enhance its efficacy. Summary of the invention

[0005] The purpose of the present invention is to provide a class of novel ceramide compounds, which contain cyclic carboxylic acids. Cyclic carboxylic acids refer to carboxylic acids in which the carbon atoms of the cyclic structure are directly connected to the carboxyl group. The cyclic structure can be an aromatic ring (especially a benzene ring), a heterocyclic ring (especially uracil, tetrahydropyran, pyridine, dihydropyridine, furan, tetrahydropyrimidine), a saponin, a terpene (especially a diterpene, a tricyclic diterpene, a pentacyclic triterpene), a cycloalkane (such as cyclohexane), a cycloolefin (such as cyclohexene), etc. The cycloalkane and the cycloolefin can have one or more heteroatoms, and the aromatic ring and the heterocyclic ring can have one or more substituents.

[0006] Another object of the present invention is to provide a method for synthesizing ceramide compounds.

[0007] Another object of the present invention is to provide uses of ceramide compounds.

[0008] In order to achieve one of the above purposes, the present invention adopts the following technical solution:

[0009] In the first aspect of the present invention, a ceramide compound has a structure of the general formula I or an enantiomer or diastereomer of the general formula I:

[0010]

[0011] Among them, R 1 A residue selected from the group consisting of sialic acid, chelidonic acid monohydrate, 2,5-furandicarboxylic acid, quinic acid, chlorogenic acid, ectoine, nicotinic acid, shikimic acid, glucuronic acid, salicylic acid, carnosic acid, dihydrooatmoyl anthranilic acid, abietic acid, ursolic acid, tranexamic acid, syringic acid, gentisic acid, vanillic acid, 5-hydroxyisovanillic acid, orotic acid, 5-aminoorotic acid, 3,5-dihydroxy-4-methylbenzoic acid, glycyrrhizic acid or gallic acid condensed residues,

[0012] R 2 Select one of the following structures:

[0013] -C 15 H 29 , -C 15 H 31 , -C 15 H 27 , -CHOHC 14 H 27 , -CHOHC 14 H 29 .

[0014] The residue after condensation refers to the carboxyl group of the corresponding carboxylic acid RCOOH condensed with the amino group of the sphingoid base to form a peptide bond, and the remaining carboxylic acid fragment R, such as the residue after condensation of nicotinic acid is The residue after condensation of shikimic acid is

[0015] Among them, Ecdoin can enhance the immune protection ability of skin cells and has good anti-allergic and anti-inflammatory effects; it increases cell repair ability, so that the skin can effectively resist the invasion of microorganisms and allergens, and has good protection and repair effects on the skin; in terms of fighting ultraviolet rays, Ecdoin can repair cell DNA damage caused by ultraviolet rays, can effectively reduce the generation of sunburned cells, and prevent damage to the cell membrane structure.

[0016] Shikimic acid not only has anti-inflammatory and analgesic effects, but can also be used as an intermediate for antiviral and anticancer drugs.

[0017] Furthermore, the R 2 Select one of the following structures:

[0018]

[0019] Furthermore, the R 2 Select one of the following structures:

[0020]

[0021] They correspond to sphingosine, dihydrosphingosine, and phytosphingosine respectively.

[0022] Furthermore, the R 1 The residue is selected from the condensation residues of ectoine, nicotinic acid, shikimic acid, 2,5-furandicarboxylic acid, gallic acid or salicylic acid.

[0023] Furthermore, the R 1 The residue is selected from the condensation residues of ectoine, nicotinic acid, shikimic acid, 2,5-furandicarboxylic acid or gallic acid.

[0024] Furthermore, the R 1 Selected from the residues after condensation of ectoine.

[0025] Furthermore, the R 1 Selected from the residues after condensation of nicotinic acid.

[0026] Furthermore, the R 1 Selected from the residues after condensation of shikimic acid.

[0027] Furthermore, the R 1 Selected from the residues after condensation of 2,5-furandicarboxylic acid.

[0028] Furthermore, the R 1 Selected from the residues after condensation of gallic acid.

[0029] Furthermore, the R 1 Selected from the residues after condensation of salicylic acid.

[0030] The ceramide compound is selected from one of the following compounds:

[0031]

[0032] A second aspect of the present invention is a method for preparing a ceramide compound, comprising the following steps:

[0033]

[0034] Compound S1 reacts with N-hydroxysuccinimide and a condensation agent to obtain compound S2;

[0035] Compound S2 reacts with a sphingoid base to give compound I.

[0036] Furthermore, the molar ratio of the compound S1, N-hydroxysuccinimide, condensing agent and sphingoid base is 1:(1-2):(1-2):(0.8-1).

[0037] Furthermore, the condensation agent is DCC.

[0038] Furthermore, the solvent of the reaction is THF.

[0039] A method for preparing a ceramide compound comprises the following steps:

[0040]

[0041] Compound S1 reacts with a sphingoid base and a condensing agent to obtain compound I.

[0042] Furthermore, the condensing agent includes EDCI and HOBT.

[0043] Furthermore, the molar ratio of the compound S1, EDCI, HOBT and sphingoid base is 1:(1-2):(1-2):(0.8-1).

[0044] Furthermore, the solvent of the reaction is DCM.

[0045] The third aspect of the present invention is the use of ceramide compounds as antioxidants, especially in cosmetics, health products and medicines.

[0046] The present invention has the following beneficial effects:

[0047] The present invention reacts functional carboxylic acid with sphingosine base to obtain a class of ceramide compounds with novel structures. The introduction of molecular fragments of functional carboxylic acid with physiological activity into ceramide will enhance the original efficacy of such molecules and also improve the physical and chemical properties of ceramide compounds, for example, enhance the antioxidant activity of ceramide compounds.

[0048] Instruction Manual

[0049] Figure 1 The test results of the antioxidant activity of the ceramide compound in Example 10 are shown in FIG. DETAILED DESCRIPTION

[0050] The present invention will be further described below in conjunction with specific embodiments.

[0051] All reactions were carried out under nitrogen atmosphere. Unless otherwise stated, chemicals were purchased from commercial products and were not further purified. Dichloromethane and tetrahydrofuran used in the experiments were anhydrous solvents. Thin layer chromatography (TLC) used 60F254 silica gel plates. Silica gel column chromatography used Qingdao Ocean Silica Gel (particle size 0.040-0.063 mm). TLC color development used UV light (254 nm) or iodine. NMR spectra were characterized using a Bruker DPX 400 nuclear magnetic resonance instrument, 1 H NMR is at 400 MHz, the solvent is deuterated methanol, deuterated DMSO or deuterated tetrahydrofuran, with tetramethylsilane (TMS) as the internal standard. The unit of chemical shift is ppm, and the unit of coupling constant is Hz. 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, and m represents multiplet.

[0052] DCC refers to N,N'-dicyclohexylcarbodiimide, THF refers to tetrahydrofuran, DCM refers to dichloromethane, EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and HOBT refers to 1-hydroxybenzotriazole.

[0053] General Synthesis Method of Ceramide Compounds

[0054] Method A

[0055]

[0056] Step 1: Compound S1 (50 mmol), N-hydroxysuccinimide (60-75 mmol, preferably 60 mmol), and DCC (60-75 mmol, preferably 60 mmol) were placed in a 250 mL round-bottom flask, 100 mL of tetrahydrofuran was added, and then stirred at room temperature for 4-24 hours, and detected by TLC until compound S1 completely disappeared. Post-treatment: Filter the reaction system, collect the filtrate and use it directly in the next step reaction.

[0057] Step 2: Add sphingoid base (40-50 mmol, preferably 45 mmol) to the filtrate of the previous step, then stir at room temperature for 24-72 hours, and detect by TLC until the sphingoid base disappears completely. Post-treatment: add saturated sodium bicarbonate aqueous solution to quench. Separate the organic layer, dry, filter and concentrate in vacuo. The residue thus obtained is purified by silica gel column to obtain the product (50-70% yield).

[0058] Method B

[0059]

[0060] Compound S1 (50 mmol), EDCI (60-75 mmol, preferably 60 mmol), HOBT (60-75 mmol, preferably 60 mmol) are placed in a 250 mL round-bottom flask, 100 mL of dichloromethane is added, and then stirred at room temperature for 1 hour, then sphingoid base (40-50 mmol, preferably 45 mmol) is added to the reaction system, and stirred at room temperature for 24-72 hours until the sphingoid base disappears completely. Post-treatment: quench with water. Separate the organic layer, dry, filter and concentrate in vacuo. The residue thus obtained is purified by silica gel column to obtain the product (50-65% yield).

[0061] Example 1

[0062] The condensation product of nicotinic acid and phytosphingosine by method A.

[0063]

[0064] 1 H NMR (400 MHz, DMSO-d 6 )δ9.02(d,J=2.2Hz,1H),8.68(dd,J=4.9,1.7Hz,1H),8.36(d,J=8.7Hz,1H),8.21( dt,J=8.0,2.0Hz,1H),7.49(dd,J=7.9,4.8Hz,1H),4.17(dtd,J=10.1,6.5,4.3Hz,1 H),3.70(dd,J=11.1,4.2Hz,1H),3.60(dd,J=11.1,7.0Hz,1H),3.53(t,J=5.8Hz,2H ),1.60–1.48(m,1H),1.41(d,J=9.7Hz,1H),1.34–1.11(m,24H),0.90–0.78(m,3H).

[0065] Example 2

[0066] The condensation product of shikimic acid and phytosphingosine by method A.

[0067]

[0068] 1 H NMR (400 MHz, Methanol-d 4)δ6.53–6.46(m,1H),4.42(dd,J=5.1,3.3Hz,1H),4.25(q,J=5.3Hz,1H),4.06(dt,J=7 .8,5.6Hz,1H),3.84(qd,J=12.4,11.8,5.6Hz,2H),3.71(dd,J=7.8,4.2Hz,1H),3.66( t,J=5.8Hz,1H),3.59(ddd,J=9.1,6.2,2.5Hz,1H),2.81(dd,J=17.7,5.0Hz,1H),2.27 (dd,J=17.7,6.2Hz,1H),1.64–1.59(m,1H),1.36(d,J=7.4Hz,25H),1.01–0.91(m,3H).

[0069] Example 3

[0070] The condensation product of shikimic acid and sphingosine by method A.

[0071]

[0072] 1 H NMR (400 MHz, Methanol-d 4 )δ6.37(dt,J=3.8,1.8Hz,1H),5.77–5.64(m,1H),5.47(ddt,J=15.3,7.2,1.4Hz,1 H),4.33(t,J=4.2Hz,1H),4.12(t,J=7.1Hz,1H),4.02–3.84(m,2H),3.73(d,J=5.1 Hz,2H),3.61(dd,J=8.0,4.2Hz,1H),2.70(ddt,J=17.6,5.2,1.6Hz,1H),2.18(ddt ,J=17.7,6.5,1.8Hz,1H),2.02(q,J=6.6Hz,2H),1.28(s,22H),0.96–0.79(m,3H).

[0073] Example 4

[0074] The product of the condensation of ectoine and phytosphingosine by method A.

[0075]

[0076] 1 H NMR (400 MHz, Methanol-d 4)δ4.18(dt,J=6.6,4.5Hz,1H),3.82(dd,J=11.3,4.2Hz,1H),3.71(dd,J=11.3,6.6Hz,1H),3.60–3.44(m,3H),1.95(s,4H), 1.79(dt,J=14.0,6.9Hz,1H), 1.68(t,J=10.6Hz,1H), 1.54(d,J=11.7Hz,1H), 1.29(d,J=8.8Hz,26H), 0.89(t,J=6.8Hz,3H).

[0077] Example 5

[0078] The product of the condensation of 2,5-furandicarboxylic acid with phytosphingosine by method A.

[0079]

[0080] 1 H NMR (400 MHz, Methanol-d 4 )δ7.68(d,J=2.0Hz,1H),7.52(d,J=2.0Hz,1H),4.17(dtd,J=10.1,6.5,4.3Hz,1H),3.70(dd,J=11.1,4.2Hz,1H),3.60(dd, J=11.1,7.0Hz,1H),3.53(t,J=5.8Hz,2H),1.60–1.48(m,1H),1.41(d,J=9.7Hz,1H),1.34–1.11(m,24H),0.90–0.78(m,3H).

[0081] Example 6

[0082] The condensation product of gallic acid and sphingosine by method B.

[0083]

[0084] 1 H NMR (400 MHz, Methanol-d 4)δ6.73(s,2H),5.70(dt,J=15.4,6.8Hz,1H),5.51(ddt,J=15.4,7.4,1.4H z,1H),4.20(t,J=7.4Hz,1H),4.12(ddd,J=7.4,5.5,4.1Hz,1H),3.86(dd,J =11.3,5.5Hz,1H),3.79(dd,J=11.3,4.2Hz,1H),2.98(s,1H),2.85(s,1H) ,1.99(dq,J=15.0,7.6,7.1Hz,2H),1.40–1.03(m,24H),0.96–0.80(m,3H).

[0085] Example 7

[0086] The condensation product of gallic acid and phytosphingosine by method B.

[0087]

[0088] 1 H NMR (400 MHz, Methanol-d 4 )δ6.73(s,2H),4.23(q,J=5.3Hz,1H),3.80(qd,J=11.2,5.0Hz,2H),3.64(t,J=5.8Hz,1H),3.56(ddd,J=8.9,5.9,2 .5Hz,1H),1.71–1.65(m,1H),1.53(d,J=8.4Hz,1H),1.46–1.38(m,1H),1.36–1.16(m,23H),0.89(t,J=6.7Hz,3H).

[0089] Example 8

[0090] The condensation product of salicylic acid and sphingosine by method A.

[0091]

[0092] 1 H NMR (400 MHz, Methanol-d 4)δ7.82(dd,J=8.2,1.7Hz,1H),7.43–7.25(m,1H),6.93–6.81(m,2H),5.70(dt,J= 15.4,6.8Hz,1H),5.51(ddt,J=15.4,7.4,1.4Hz,1H),4.20(t,J=7.4Hz,1H),4.12 (ddd,J=7.4,5.5,4.1Hz,1H),3.86(dd,J=11.3,5.5Hz,1H),3.79(dd,J=11.3,4.2 Hz,1H),1.99(dq,J=15.0,7.6,7.1Hz,2H),1.40–1.03(m,22H),0.96–0.80(m,3H).

[0093] Example 9

[0094] The condensation product of salicylic acid and dihydrosphingosine by method B.

[0095]

[0096] 1 H NMR (400 MHz, Methanol-d 4 )δ7.87(dd,J=8.3,1.7Hz,1H),7.38(td,J=7.8,1.7Hz,1H),6.96–6.87(m,2H),4.12(td,J=6.1,4.1Hz,1H) ,3.91–3.81(m,2H),3.82–3.76(m,1H),1.68–1.44(m,3H),1.30(dd,J=7.4,4.7Hz,25H),0.96–0.86(m,3H).

[0097] Example 10

[0098] The antioxidant activity of the ceramide compounds prepared in Examples 1, 4, 8 and 9 was tested by the antioxidant-ABTS method.

[0099] Experimental principle: The method of evaluating the antioxidant capacity of samples using ABTS (2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonicacid)diammonium salt) was first proposed by Miller et al. (1993), and the method currently used is generally the improved method by Re et al. (1999). This method uses the fact that ABTS can be oxidized by a series of compounds such as potassium persulfate, hydrogen peroxide, and manganese dioxide to generate blue-green ABTS+ cationic free radicals with a maximum absorption peak at 734nm. Under the action of antioxidants, ABTS+ is reduced to colorless ABTS. By measuring the absorbance value at 734nm, the antioxidant capacity of the reactant can be determined.

[0100] ABTS free radical scavenging test for antioxidant performance: 3 mL of ABTS aqueous solution (12 mmol / L) and 3 mL of potassium persulfate solution (2.45 mmol / L) were mixed evenly and kept stable at room temperature in the dark for 12 to 16 hours. DMSO was used as the dilution medium, and the appropriate dilution ratio was selected to adjust the absorbance of the potassium persulfate solution at 734 nm to 0.700 ± 0.025. Samples of different concentrations were added and shaken, kept in the dark for 10 minutes, and the absorbance was measured at 734 nm.

[0101] The results are as follows Figure 1 As shown, control 1 is ceramide 3 and control 2 is ceramide 3B.

[0102] It can be seen that the compounds of the present invention have better antioxidant effects than existing ceramide compounds, and the scavenging rate of free radicals is generally 40-80% higher.

[0103] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A ceramide compound having a structure of general formula I: in, R 1 is the residue after condensation of ectoin, The R 2 Select one of the following structures:

2. The ceramide compound according to claim 1, It is characterized in that Select one of the following compounds:

3. A method for preparing the ceramide compound according to claim 1, It is characterized in that The following steps are involved: Compound S1 reacts with N-hydroxysuccinimide and a condensation agent to obtain compound S2; Compound S2 reacts with sphingoid base to obtain compound I; R 1 , R 2 As defined in claim 1.

4. The method according to claim 3, It is characterized in that The molar ratio of the compound S1, N-hydroxysuccinimide, condensing agent and sphingoid base is 1:(1-2):(1-2):(0.8-1); the condensing agent is DCC; and the solvent of the reaction is THF.

5. Use of the ceramide compound according to any one of claims 1 or 2 in the preparation of antioxidants.

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