CN112409439A - Glycyrrhizic acid derivative, preparation method and application - Google Patents
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Abstract
The invention belongs to the field of medicines, and particularly relates to a glycyrrhizic acid derivative, a preparation method and application thereof. The invention provides a glycyrrhizic acid derivative, which has stronger inhibiting effect on tumor cells (A549 cells, HepG2 cells, 7721 cells and MCF-7 cells) and can be used for preparing antitumor drugs; the glycyrrhizic acid derivative has stronger inhibiting effect on inflammatory factors NO, HMGB1, TLR4, TNF-alpha, IL-1 beta and TGF-beta 1, has the same or better effect with glycyrrhetinic acid, and can be used for preparing various anti-inflammatory drugs; meanwhile, the glycyrrhizic acid derivative has strong inhibition effect on Col-1, alpha-SMA, ROS and Mitochondrial Membrane Potential (MMP) in lung cancer cells A549, can inhibit the content of HMGB1 in lung tissues of a pulmonary fibrosis model mouse, inhibits pulmonary fibrosis, and can be used as a novel candidate drug for coronavirus pneumonia, pulmonary fibrosis and acute lung injury.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a glycyrrhizic acid derivative, a preparation method and application thereof.
Background
The novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19) is called new coronavirus pneumonia for short, and is pneumonia caused by 2019 novel coronavirus infection. Acute lung injury ALI is one of the common critical cases of pneumonia, and is mainly caused by gram-negative bacterial infection, bacterial outer membrane lipopolysaccharide activates inflammatory cells, releases a large amount of inflammatory factors, and causes excessive inflammation and abnormal repair to cause pulmonary fibrosis. Studies have shown that alterations in pulmonary fibrosis can occur early after ALI, and fibrosis is a major cause of poor prognosis of ALI. Therefore, in the treatment of severe new coronary pneumonia patients, early intervention on fibrosis to improve the prognosis of patients reduces the mortality rate while resisting inflammation.
HMGB1 is a non-histone expressed in eukaryotic cell nucleus, and can be actively released after immune cells are stimulated by LPS, oxidizing factors or cytokines, or passively released during apoptosis or necrosis. HMGB1 can promote the release of various inflammatory factors such as interleukin IL-1 beta, TNF-alpha and the like, transmit signals to newborn immune cells, promote the newborn immune cells to secrete new proinflammatory factors, and the inflammatory factors in turn stimulate adjacent immune cells to secrete the same or other more inflammatory factors, amplify inflammatory response, further aggravate inflammatory injury of lung, and further aggravate tissue fibrosis. Therefore, inhibition of HMGB1 expression may be beneficial for relief of inflammation and fibrosis in acute lung injury.
Glycyrrhizic acid has wide pharmacological action, and the derivative has the activities of resisting inflammation, SARS virus, tumor, fibrosis and the like, is a good HMGB1 inhibitor, and has good inhibitory activity in cell experiments and in vivo experiments. It has recently been discovered that COVID-19 mediates infection through its receptor ACE2, where glycyrrhizic acid is an inhibitor of ACE 2. Disulfide bonds in the lipoic acid molecules can be combined with the active center of zinc ions of the ACE2 enzyme, so that the infection of viruses is further blocked; in addition, the lipoic acid has stronger anti-inflammatory and antioxidant effects and the like, and has an improvement effect on the findings of rats with pulmonary fibrosis caused by bleomycin.
The invention discovers that the C-3 hydroxyl of the glycyrrhetinic acid is connected with the lipoic acid through ester bonds, and the amino acid methyl ester is introduced into the 30 position, so that the physicochemical property of the glycyrrhetinic acid can be improved, and the obtained compound has better COVID-19 resistance, anti-inflammation, anti-fibrosis and anti-tumor activity.
Disclosure of Invention
The invention aims to provide a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:
wherein AA is an amino acid residue.
Preferably, the amino acids include glycine, valine, lysine, tryptophan, phenylalanine, methionine, leucine.
The invention also aims to provide application of the compound shown as the formula (I) or pharmaceutically acceptable salts thereof in preparing antitumor drugs.
The invention also aims to provide application of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof in preparing anti-inflammatory medicaments.
The invention also aims to provide application of the compound shown as the formula (I) or pharmaceutically acceptable salts thereof in preparing a medicament for inhibiting cytokines.
Preferably, the cytokine comprises NO, HMGB1, TLR4, TNF-alpha, IL-1 beta, TGF-beta1。
The invention also aims to provide application of the compound shown as the formula (I) or pharmaceutically acceptable salts thereof in preparing medicaments for preventing or treating pneumonia.
The invention also aims to provide application of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating pulmonary fibrosis.
The invention also aims to provide application of the compound shown as the formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating acute lung injury.
The invention also aims to provide application of the compound shown in the formula (I) or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating novel coronavirus pneumonia.
Preferably, the compound or the pharmaceutically acceptable salt thereof is added with pharmaceutically acceptable auxiliary materials, and can be prepared into any one of capsules, tablets, pills, granules, suspensions, dripping pills, oral liquid preparations, injections and aerosols.
Another object of the present invention is to provide a process for preparing a compound represented by formula (i): the glycyrrhetinic acid and the amino acid methyl ester are subjected to condensation reaction, and the obtained reactant is subjected to condensation reaction with the lipoic acid to obtain the glycyrrhetinic acid.
The invention has the beneficial effects that: the compound has stronger inhibition effect on tumor cells A549, HepG2, 7721, MCF-7 cells and the like, and can be used for preparing antitumor drugs; ② the compound of the invention has stronger inhibition effect on inflammatory factor NO, HMGB1, TLR4, TNF-alpha, IL-1 beta and TGF-beta 1, the effect is the same as or better than glycyrrhetinic acid, and the compound can be used for preparing various anti-inflammatory drugs; the compound has strong inhibition effect on Col-1, alpha-SMA, ROS and Mitochondrial Membrane Potential (MMP) in lung cancer cells A549, can inhibit the content of HMGB1 in lung tissues of a pulmonary fibrosis model mouse, inhibits pulmonary fibrosis, and can be used as a candidate drug for novel coronavirus pneumonia, pulmonary fibrosis and acute lung injury.
Drawings
FIG. 1 results of the effect of the compound on the ROS levels in A549 cells after LPS action;
FIG. 2 results of the effect of the compound on the mitochondrial membrane potential of A549 after LPS action;
FIG. 3 shows the lung HE staining results of paraquat-induced pulmonary fibrosis mice by using the compound;
FIG. 4 shows the result of Masson staining of lung of mice with paraquat-induced pulmonary fibrosis by using the compound.
Detailed Description
The invention provides a compound with lipoic acid and glycyrrhizic acid derivatives, a preparation method and application thereof. In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments. The scope of the invention is not limited to the examples described below.
Synthesis of the Compound of example 1
Dissolving glycyrrhetinic acid 480mg in 15ml CH2Cl2Dripping 0.5ml of DIPEA, adding HOBt and EDCI, and stirring at room temperature for 30 min; and respectively adding 300mg of methionine methyl ester, leucine methyl ester, phenylalanine methyl ester, tryptophan methyl ester, glycine methyl ester, valine methyl ester and N-Boc-lysine methyl ester, reacting for 12h at room temperature, and monitoring the reaction by TLC. After the reaction is finished, separating by column chromatography (petroleum ether: ethyl acetate: 1-3: 1) to obtain a product; lipoic acid (220mg) was dissolved in CH2Cl2DMAP and EDCI were added, and after stirring at room temperature for 15min, the above-mentioned product was added and reacted at room temperature for 24 hours.
Wherein the reaction products of methionine methyl ester, leucine methyl ester, phenylalanine methyl ester, tryptophan methyl ester, glycine methyl ester and valine methyl ester are subjected to column chromatography to obtain light yellow solids which are respectively identified as compounds 1-6, and the structural formulas of the compounds are shown in the following formulas (1) - (6).
The yellow solid obtained from the reaction of N-Boc-lysine methyl ester was dissolved again in 6ml of CH2Cl2Then, 2ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 4 hours, and then subjected to silica gel column chromatography (chloroform: methanol ═ 5: 1) to isolate a pale yellow solid, which was identified as compound 7, having a structural formula shown in the following formula (7).
(1) Compound 1
The yield of compound 1 was 57%;
IR(KBr,cm-1):3375s,2928vs,2870vs,1727vs,1649s,1523.1H NMR(CDCl3)δ6.39(d,J＝7.5Hz,1H,NH),5.70(s,1H,C12-H),4.68(d,J＝6.5Hz,1H,NCH),4.46(dd,J＝11.7,4.7Hz,1H,C4-H),3.71(s,3H,OCH3),3.49(dt,J＝12.5,6.4Hz,1H,SCH),3.15–3.02(m,2H,SCH2),2.46(t,J＝6.9Hz,2H,S-CH2),2.39(dt,J＝12.5,6.3Hz,2H,COCH2),2.05(s,3H,S-CH3),1.32(s,3H,CH3),1.10(s,6H,2CH3),1.07(s,3H,CH3),0.81(d,J＝2.4Hz,6H,2CH3),0.75(s,3H,CH3).13C NMR(CDCl3)δ199.0,172.3,171.4,166.0,127.5,79.5,60.7,55.3,54.0,51.6,50.5,46.8,44.4,42.8,42.2,40.8,39.2,37.8,37.5,37.1,36.4,35.9,33.6,33.6,31.7,30.9,30.4,29.2,28.4,27.8,27.5,27.1,25.5,25.4,23.8,22.6,22.3,17.7,16.4,15.8,15.4,14.6；
ESI-MS:calcd for C44H70NO6S3[M+H]+804.4365,found 804.3230；[M+Na]+826.4185,found 826.3002；
compound 1 is represented by the following formula (1):
(2) compound 2
The yield of compound 2 was 65%;
IR(KBr,cm-1):3382s,2953vs,2872vs,1731vs,1653s,1523.1H NMR(CDCl3)δ5.93(s,1H,NH),5.70(s,1H,C12-H),4.61(s,1H,NCH),4.46(dd,J＝11.6,4.6Hz,1H,C4-H),3.68(s,3H,OCH3),3.50(p,J＝6.8Hz,1H,S-CH),3.07(ddt,J＝24.8,11.3,6.0Hz,2H,S-CH2),2.25(t,2H,COCH2),1.31(s,3H,CH3),1.10(s,3H,CH3),1.07(s,3H,CH3),0.87(t,J＝4.4Hz,6H,2CH3),0.81(d,J＝2.3Hz,6H,2CH3),0.74(s,3H,CH3).13C NMR(CDCl3)δ173.3,169.2,128.5,80.5,77.2,77.0,61.8,56.4,55.1,50.4,47.8,45.4,43.2,41.9,41.7,40.2,38.8,38.5,38.1,37.4,36.9,34.6,34.6,32.8,31.9,31.4,29.4,28.8,28.5,28.1,26.5,26.4,25.0,24.9,23.6,23.3,22.9,21.8,18.7,17.4,16.8,16.4。
ESI-MS:calcd for C45H72NO6S2[M+H]+786.4801,found 786.3705；[M+Na]+808.4601,found 808.3490。
the structural formula of the compound 2 is shown as the following formula (2):
(3) compound 3
The yield of compound 3 was 59%;
IR(KBr,cm-1):3375s,2929vs,2884s,2279s,1731vs 1659s,1524.1H NMR(CDCl3)δ7.22(d,J＝6.7Hz,1H,Ar-H),7.20-7.15(m,2H,Ar-H)Ar-H,7.06–7.01(m,2H,Ar-H),5.90(d,J＝7.9Hz,1H,NH),5.54(s,1H,C12-H),4.86(q,J＝6.6Hz,1H,NCH),4.45(dd,J＝11.6,4.7Hz,1H,C4-H),3.70(s,3H,OCH3),3.49(dt,J＝12.8,6.3Hz,1H,SCH),3.16-3.07(m,2H,Ar-CH2),3.07-2.98(m,2H,SCH2),2.25(s,2H,COCH3),1.27(s,3H,CH3),1.09(s,3H,CH3),1.04(s,3H,CH3),0.98(s,3H,CH3),0.81(s,3H,CH3),0.80(s,3H,CH3),0.69(s,3H,CH3).13C NMR(CDCl3)δ198.9,174.3,172.3,171.0,167.9,134.9,128.2,127.7,126.3,79.5,76.0,60.7,55.3,54.0,51.6,51.5,46.7,44.3,42.6,40.8,39.2,37.8,37.5,37.1,36.8,36.2,35.9,33.6,33.5,31.7,30.8,30.3,28.3,27.8,27.3,27.1,25.4,25.3,23.9,22.6,22.3,17.6,16.4,15.8,15.4。
ESI-MS:calcd for C48H70NO6S2[M+H]+820.4645found 820.4617；
the structural formula of the compound 3 is shown as the following formula (3):
(4) compound 4
The yield of compound 4 was 71%;
IR(KBr,cm-1):3427s,3358s,2953vs,2976s,2875s,1728vs,1649s,1515.1H NMR(CDCl3)δ8.98(s,1H,NH),7.46(d,J＝7.4Hz,1H,Ar-H),7.12-7.01(m,3H,Ar-H),6.94(d,J＝2.3Hz,1H,Ar-H),5.91(s,1H,C12-H),4.83–4.68(m,1H,NCH-),4.53(s,1H,NH),4.51(d,J＝14.0Hz,1H,C3-H),3.67(s,3H,OCH3),3.51(p,J＝6.5Hz,1H,SCH),3.15-3.01(m,2H,SCH2),3.39(dd,J＝14.8,2.9Hz,1H,Ar-CH),3.23(dd,J＝14.8,5.9Hz,1H,Ar-CH),2.28(t,J＝7.5Hz,2H,COCH2),1.12(s,3H,CH3),1.03(s,3H,CH3),1.00(s,3H,CH3),0.97(s,3H,CH3),0.83(s,3H,CH3),0.83(s,3H,CH3),0.60(s,3H,CH3).13C NMR(CDCl3)δ201.1,175.9,173.4,172.2,136.5,127.8,126.5,122.8,122.3,119.9,118.2,112.1,80.5,77.0,61.7,56.4,55.0,52.4,52.3,47.3,45.3,43.8,42.9,41.6,40.2,39.0,38.5,38.1,37.1,36.9,34.6,34.6,32.7,31.8,31.1,29.3,28.8,28.1,28.1,26.5,26.1,25.9,24.9,23.7,22.7,18.6,17.3,16.8,16.4,14.2。
ESI-MS:calcd for C50H70NaN2O6S2[M+Na]+881.4473,found 881.4436；
the structural formula of the compound 4 is shown as the following formula (4):
(5) compound 5
The yield of compound 5 was 68%;
IR(KBr,cm-1):3386s,2953s,2871vs,1731vs,1656s,1511.1H NMR(CDCl3)δ6.03(d,J＝8.6Hz,1H,NH),5.70(s,1H,C12-H),4.54(dd,J＝8.6,4.5Hz,1H,N-CH),4.46(dd,J＝11.6,4.7Hz,1H,C4-H),3.70(s,3H,CH3),3.51(p,J＝6.7Hz,1H,SCH),3.17-3.01(m,2H,SCH2),2.25(t,J＝7.4Hz,2H,COCH2),1.32(s,6H,2CH3),1.10(s,3H,CH3),1.07(s,3H,CH3),0.81(d,J＝2.0Hz,6H,2CH3),0.75(s,3H,CH3).13C NMR(CDCl3)δ172.28,171.4,168.0,127.53,79.47,76.24,75.83,60.73,55.62,55.34,54.01,51.27,46.89,44.37,42.91,42.17,40.92,39.20,37.78,37.46,37.07,36.39,35.94,33.63,33.55,31.72,30.91,30.43,30.37,28.59,27.80,27.44,27.10,25.48,25.37,23.87,22.60,22.30,18.17,17.68,16.70,16.38,15.77,15.39；
ESI-MS:calcd for C44H69NO6S2[M+H]+772.4645,found 772.3564；[M+Na]+794.4464,found 794.3345
the structural formula of the compound 5 is shown as the following formula (5):
(6) compound 6
The yield of compound 6 was 51%;
IR(KBr,cm-1):3442s,2954vs,2930s,1755vs,1651s.1H NMR(CDCl3)δ5.66(s,1H,C12-H),4.46(dd,J＝11.5,4.8Hz,1H,C4-H),4.06-3.91(m,2H,NCH2),3.70(s,3H,OCH3),3.51(d,J＝7.4Hz,1H,SCH),3.09-3.02(m,2H,SCH2),2.26(t,J＝7.4Hz,2H,COCH2),1.31(d,J＝2.6Hz,3H,CH3),1.11–1.08(m,6H,2CH3),1.06(d,J＝3.2Hz,3H,CH3),0.81(d,J＝2.2Hz,6H,2CH3),0.76(s,3H,CH3).13C NMR(CDCl3)δ200.0,172.2,79.5,76.2,60.7,55.4,55.3,54.0,51.4,42.7,40.8,39.2,37.8,37.5,37.1,36.3,35.9,33.6,32.4,31.7,30.9,27.8,27.7,27.4,27.1,25.5,25.4,23.8,22.6,17.7,16.4,15.8,15.4；
ESI-MS:calcd for C41H64NO6S2[M+H]+730.4175,found 730.4166；[M+Na]+752.3994,found 752.3987；
compound 6 is represented by the following formula (6):
(7) compound 7
The yield of compound 7 was 43%;
IR(KBr,cm-1):3382s,3054s,2933vs,2956s,2870s,1727vs,1658s,1651s,1520.1H NMR(CDCl3)δ7.91(s,2H,-NH2),6.61(s,1H,-NH),5.68(s,1H,C12-H),4.52(s,1H,NCH),4.45(dd,J＝11.5,4.7Hz,1H,C4-H),4.01(s,2H,NCH2),3.70(s,3H,OCH3),3.50(p,J＝6.5Hz,1H,SCH),3.15-3.02(m,2H,SCH2),2.26(t,J＝7.4Hz,2H,COCH2),1.30(s,6H,2CH3),1.06(d,J＝5.3Hz,6H,2CH3),0.81(s,6H,2CH3),0.73(s,3H,CH3).13C NMR(CDCl3)δ199.1,174.7,172.3,172.0,168.4,79.4,76.21,76.0,60.7,57.0,55.4,54.0,51.5,50.8,46.8,42.7,42.2,40.8,40.3,39.2,37.8,37.5,37.1,36.4,36.0,33.6,33.6,31.7,31.1,28.4,27.8,27.5,27.1,25.5,25.4,23.9,22.6,22.3,21.6,17.7,16.4,15.8,15.4；
ESI-MS:calcd for C45H73N2O6S2[M+H]+801.4910,found 801.4978；
the structural formula of compound 7 is shown in the following formula (7):
example 2 cytotoxicity assay
Normal cells WI38 and 4 tumor cells (A549, HepG2, SMMC7721, MCF-7 cells) were selected and the cytotoxicity of all compounds was evaluated.
In RPMI1640 and DMEM medium, 10% CO at 37 ℃2A549, HepG2, SMMC-7721, MCF-7 and WI38 cells were cultured under 100% humidity conditions in a medium rich in glucose supplemented with 10% fetal calf serum, non-essential amino acids, antibiotics (penicillin/streptomycin) and antifungal drugs. The method specifically comprises the following steps: 0.04mM of each of compounds 1 to 7 was dissolved in 0.5mL of DMSO, homogenized, and at least 10mL of the medium was added, followed by vigorous stirring at 50 ℃. The cells were cultured at 1X 105Inoculating cells/underground into a 96-well plate, adding a certain volume of the solution, adding a culture medium to 0.1mL after 12 hours, wherein the final concentration of a compound in each well is 12.5-800 mu m; triplicate cultures were established for all compounds and controlsA compound (I) is provided. The mixture is 10% CO2Was incubated at 37 ℃ for 24h in a humid atmosphere. Cell viability after 24h was determined by the MTT method and half the inhibitory concentration IC of the cell lines was calculated using SPSS25.0 software50Descriptive data are expressed as mean ± standard deviation.
As shown in Table 1, compounds 1-7 all had low cytotoxicity, with all compounds except compounds 4 and 5 having IC's of WI38 for normal lung cells50IC with value less than GA50But all above 100. mu.M, indicating that compounds 1-7 are less cytotoxic; the compounds 1, 6 and 7 have strong reproduction inhibition effect on A549 lung cancer cells, and IC thereof50IC much smaller than GA50IC of the remaining Compounds50Close to 100 μ M; the compound 7 has strong inhibition effect on HepG2, SMMC7721 and MCF-7 cells, and the IC of the compound503.9. mu.M, 11.2. mu.M and 19.6. mu.M, respectively.
IC of Compounds of Table 1 on W138 and 4 tumor cells50Value of
The results show that the compounds of the invention all have certain antitumor activity, and the compound 7 shows stronger antitumor activity and high selectivity, and has IC (integrated Circuit) on all tumor cells50All values are less than 20. mu.M.
Example 3 cell Activity assay
1. Anti-inflammatory Activity
The inflammatory response is a protective mechanism of the body, and immune cells are involved in the initiation and regulation of the entire inflammatory process. The macrophage RAW264.7 cell line was therefore selected to evaluate the anti-inflammatory activity of the compounds. In order to make the anti-inflammatory results more pronounced, the cells were treated with higher concentrations of the compounds, and in order to make the anti-inflammatory results more accurate and to reduce the effect of cell death caused by the test compounds on the experimental results, the viability of the cells was determined by the MTT method after 24h treatment of RAW264.7 macrophages with compounds 1-7 (50. mu.M and 100. mu.M), respectively, prior to the study of the anti-inflammatory activity of the compounds. The results show that most compounds have greater toxicity to RAW264.7 macrophages when the concentration is 100 mu M, and the survival rate of RAW264.7 macrophages is below 70%; at a concentration of 50 μ M, most of the compounds and control GA were less toxic to RAW264.7 macrophages, and the survival rate of RAW264.7 macrophages was above 70%. And compound 7 showed strong killing effect on macrophages, with cell survival less than 30% at a concentration of 50 μ M.
1.1. Effect of Compound concentration on inflammatory factor NO in RAW cells
LPS activates macrophages to increase NO levels, LPS stimulates macrophages to form an inflammation model, and compound concentrations were tested for their effect on NO production by macrophages: after treating LPS-activated RAW264.7 macrophages with different concentrations (0, 6.25, 12.5, 25, 50 μ M) of the compound for 24 hours, the NO content in the cells was determined separately, with glycyrrhetinic acid as a positive control. Using the amount directly measured after LPS activation as the maximum value of NO, an NO content-compound concentration curve was prepared, and IC50 values for NO inhibition by compounds 1-6 in the range of 0-50 μ M were calculated based on the experimental results (Table 2), and the results showed that all compounds had inhibitory effects on inflammatory factor NO, wherein IC of compounds 3 and 450The values are 18.5 μ M and 13.4 μ M, respectively, which are significantly less than the IC50 value of control GA of 21.8 μ M, indicating that compounds 3 and 4 have stronger inhibitory effect on inflammatory factor NO than glycyrrhetinic acid.
IC for NO inhibition by Compounds of Table 250Value (μ M)
NO is one of the important inflammatory factors, and excessive NO up-regulates inducible nitric oxide synthase levels, which are important processes in the development and progression of inflammatory reactions. The results show that the compounds 1-6 have certain anti-inflammatory activity, the effect of the compounds is equivalent to or better than that of glycyrrhetinic acid, and the anti-inflammatory effect of the compounds 3 and 4 is better than that of the glycyrrhetinic acid.
1.2. Effect of Compounds on the cytokine HMGB1
To evaluate the effect of compound concentration on intracellular HMGB1 expression levels, compounds 3 and 4 (at concentrations of 10, 20, 30 μ M, respectively) were selected as subjects, and after 12 hours of activation of RAW264.7 cells with 10 μ g/L LPS, different concentrations of compounds 3 and 4 were added for 24 hours of co-incubation, and intracellular HMGB1 levels were tested by Elisa.
As a result, the concentration of HMGB1 in normal macrophage RAW264.7(Control) was 23ng/mL as shown in Table 3; after LPS induction (LPS), the concentration of HMGB1 in the cells rises sharply and approaches to 90 ng/mL; but the level of HMGB1 was significantly reduced after 24 hours of treatment of LPS-induced macrophages with compounds 3 and 4, respectively; the reduction was significant at a concentration of 30 μ M, with HMGB1 levels of approximately 40% and 35% of the LPS group. The results show that both compounds 3 and 4 can significantly reduce the expression level of HMGB1 in RAW264.7 cells, and the higher the compound concentration is, the greater the inhibition degree is, and the concentration-dependent trend is presented.
TABLE 3 Effect of Compounds 3 and 4 on HMGB1 content (ng/mL)
HMGB1 plays an important role in the development and course of lung inflammation and pulmonary fibrosis, HMGB1 can promote the release of various inflammatory factors such as IL-1 beta, TNF-alpha and the like, transmit signals to newborn immune cells and promote the secretion of new pro-inflammatory factors, and the inflammatory factors in turn stimulate adjacent immune cells to secrete the same or other more inflammatory factors, amplify the inflammatory response and further aggravate the inflammatory injury of the lung, thereby aggravating tissue fibrosis. Therefore, inhibition of HMGB1 expression may be beneficial for relief of inflammation and fibrosis in acute lung injury. According to the above results, compounds 3 and 4 are effective in relieving inflammation and fibrosis in acute lung injury, and can be used for the treatment of neocoronary pneumonia.
1.3. Effect of Compounds on the cytokine TLR4
To evaluate the inhibitory effect of compounds 3 and 4 on HMGB1 binding to the receptor TLR4, we examined the effect of compounds on the level of TLR4 expression on the surface of macrophage RAW 264.7.
The results are shown in Table 4, where in normal RAW264.7(Control), the expression level of TLR4 was 3.98ng/mL, but when it was induced by LPS, the level of TLR4 on the cell surface was significantly increased to 12.42 ng/mL. But TLR4 levels were significantly reduced after 24 hours of LPS-induced macrophages treated with compounds 3 and 4, respectively; when the concentration is 20 mu M, the reduction amplitude is obvious, and the TLR4 level is about 50 percent of that of LPS group; at a concentration of 30 μ M, TLR4 levels were significantly reduced, close to the Control group. The results show that the compounds 3 and 4 can significantly reduce the expression level of TLR4 in RAW264.7 cells, and the higher the concentration of the compound is, the greater the inhibition degree is, and the concentration dependence trend is shown.
TABLE 4 Effect of Compounds 3 and 4 on TLR4 levels (ng/mL)
Glycyrrhetinic acid can inhibit not only release of HMGB1 from cell nucleus, but also binding of HMGB1 to TLR4 receptor on cell surface, and inhibit cytokine expression through TLR 4/NF-kB signaling pathway, and the conduction of the signaling pathway is directly related to the expression level of TLR 4. The results show that the compounds 3 and 4 can obviously inhibit the combination of HMGB1 and a TLR4 receptor on the cell surface, inhibit the expression of cytokines, effectively relieve inflammation and fibrosis in acute lung injury, and can be used for treating new coronary pneumonia.
1.4. Effect of Compounds 3 and 4 on cytokines TNF-alpha and IL-1 beta
To examine the effect of inhibition of HMGB1 on downstream inflammatory mediators, the expression levels of TNF-a and IL-1 β were determined after treatment of cells with different concentrations of compound (10, 20, 30 μ M) using the LPS-induced RAW264.7 cell model.
As shown in Table 5, in normal RAW264.7(Control), the expression level of TNF-alpha was 32.89ng/mL, and after LPS induction, the expression level of TNF-alpha in the cells was significantly increased compared to that in the Control group, and the concentration was 118.33 ng/mL. However, when activated cells were treated with compounds 3 and 4 for 24 hours, intracellular TNF-. alpha.expression levels were down-regulated and concentration-dependent. When the concentration of the compound is 20 mu M, the expression level of TNF-alpha is 66% and 54% of that of LPS group; TNF- α expression levels were further reduced at a concentration of 30 μ M, approximately 43% and 38% of LPS group. The results show that the compounds 3 and 4 can obviously reduce the expression level of TNF-alpha, and the higher the concentration of the compound, the greater the inhibition degree, and the concentration-dependent trend is presented.
TABLE 5 Effect of Compounds 3 and 4 on TNF-. alpha.content (ng/ml)
As shown in Table 6, the expression level of IL-1. beta. in normal RAW264.7(Control) was 17.39ng/mL, and after LPS induction, the expression level of IL-1. beta. in cells was significantly increased as compared with that in Control group, and the concentration was 39.49 ng/mL. However, when activated cells were treated with compounds 3 and 4 for 24 hours, intracellular IL-1. beta. expression levels were down-regulated and concentration-dependent. When the concentration of the compound was 20. mu.M, the IL-1. beta. expression levels were 74% and 61% of the LPS group; the TIL-1. beta. expression level was further reduced at a concentration of 30. mu.M, which was about 57% and 55% of the LPS group. The results show that the compounds 3 and 4 can obviously reduce the expression level of the IL-1 beta, and the higher the concentration of the compounds, the greater the inhibition degree, and the concentration-dependent trend is shown.
TABLE 6 Effect of Compounds 3 and 4 on IL-1. beta. content (ng/ml)
The HMGB1 can promote the release of various inflammatory factors such as interleukin IL-1 beta, TNF-alpha and the like and transmit signals to newborn immune cells, and the results show that the compounds 3 and 4 can obviously inhibit the release of the inflammatory factors and have obvious anti-inflammatory activity.
1.5. Effect of Compounds 3 and 4 on TGF-. beta.1
Intracellular TGF- β 1 levels were tested 24 hours after treatment of LPS-induced RAW264.7 cells with different concentrations of compound. When RAW264.7 cells are activated by LPS, the expression level of TGF-beta 1 in the cells can reach 22.61 ng/mL; expression levels were down-regulated after co-incubation with test compounds. TGF- β 1 levels were significantly reduced, approximately 60% of LPS group, at compound 3 concentration of 20 μ M; at a concentration of 30. mu.M, TGF-. beta.1 levels decreased significantly, less than 30% of the LPS group, for Compound 3. TGF-. beta.1 approached control levels at a concentration of 30. mu.M for Compound 4.
Research shows that in lung tissues, HMGB1 can increase the expression of inflammatory factor TGF-beta 1 through a TLR 4/NF-kB pathway, so that fibroblasts are activated to cause pulmonary fibrosis; TGF-beta 1 is an important cell inflammation factor in fibrosis, can activate differentiation and proliferation of fibroblasts, and inhibits the expression and function of TGF-beta 1 is an important way for blocking lung tissue inflammation and fibrosis thereof. The results show that the compounds 3 and 4 can obviously inhibit the inflammation and the fibrosis of lung tissues and can be used for treating the neocoronary pneumonia.
2. Effect of Compounds 3 and 4 on Col-1 and alpha-SMA expression in Lung tissue cells
A549 cell is a kind of human lung cancer cell, still retains the characteristics of alveolar epithelial type II cell, and is often used for studying the response of alveolar epithelial cell to stimulation. A549 cell models were selected, and A549 cell activation was induced according to the literature with 5ng/ml TGF-. beta.1, and then expression levels of the fibrosis markers Col-1 and. alpha. -SMA were tested with Elisa.
The detection result of the protein level of the Col-1 is shown in Table 7, the level of the Col-1 in a normal A549 cell (Control) is 7.85pg/mL, and the level of the Col-1 in the cell is obviously increased to 23.34pg/mL after the TGF-beta 1 stimulates the A549 cell; significantly inhibited Col-1 expression in A549 cells after 24 hours of treatment with compounds 3 and 4, wherein Col-1 levels were approximately 60% and 56% of the TGF- β 1 group at a compound concentration of 20 μ M; at a compound concentration of 30. mu.M, the Col-1 levels were approximately 55% and 50% of the TGF-. beta.1 group, concentration dependent.
TABLE 7 Effect of Compounds 3 and 4 on Col-1 content (pg/mL)
The detection result of the alpha-SMA level is shown in Table 8, the alpha-SMA level in a normal A549 cell (Control) is 16.18pg/mL, and the alpha-SMA level in the cell is obviously increased to 110.65pg/mL after the TGF-beta 1 stimulates the A549 cell; significantly inhibited the expression of a-SMA in a549 cells 24 hours after treatment with compounds 3 and 4, wherein the levels of a-SMA are about 50% or less of the TGF- β 1 group at a compound concentration of 20 μ M; at a compound concentration of 30 μ M, α -SMA levels were approximately 43% and 35% of the TGF- β 1 group, concentration dependent.
TABLE 8 Effect of Compounds 3 and 4 on α -SMA content (pg/mL)
In new coronary pneumonia and acute lung injury, fibrosis of lung tissue often occurs due to an inflammatory storm caused by the production of a large amount of inflammatory factors. The results show that the compounds 3 and 4 can obviously inhibit the expression levels of Col-1 and alpha-SMA in lung cancer A549 cells, have a certain effect of inhibiting pulmonary fibrosis, and can be used for treating new coronary pneumonia and acute lung injury.
3. Effect of Compounds 3 and 4 on intracellular Reactive Oxygen Species (ROS) levels and Mitochondrial Membrane Potential (MMP)
3.1 Reactive Oxygen Species (ROS) level
LPS of 10 mu g/ml induces the activation of A549 cells, DCFH-DA is used as a fluorescent probe, and the concentration of ROS is detected by a flow cytometer.
The results are shown in fig. 1, compared with the Control group, the ROS level is significantly increased after LPS-induced a549 cells; the compound can obviously reduce the ROS level compared with the LPS group after being dried, wherein when the concentration of the compound is 10 mu M, the ROS level is obviously reduced compared with the LPS group; the reduction in ROS levels was more pronounced when the concentration reached 30 μ M.
3.2 Mitochondrial Membrane Potential (MMP)
Activated A549 was treated with 30. mu.M of compounds 3 and 4, and after 24 hours of incubation, changes in membrane potential of cell mitochondria were observed under a fluorescence microscope with JC-1 staining.
As shown in FIG. 2, in the control group of normal cells, the membrane potential was normal, JC-1 entered the mitochondria through the mitochondrial membrane polarity and formed multimers emitting red fluorescence due to the increase of concentration, and the red fluorescence was strong; after cells are induced by LPS, the transmembrane potential of mitochondria depolarizes, JC-1 is released from mitochondria, the concentration is reduced, and the cell is reversed to be in a monomer form emitting green fluorescence, and large-area green light is presented; when LPS-induced A549 cells were treated with the compound, they exhibited red fluorescence of different intensities as detected by JC-1, indicating a significant decrease in the membrane potential of the cell mitochondria.
The GA derivative can inhibit the mode recognition molecules HMGB1 and inflammatory factors, reduce the intracellular reactive oxygen level and the mitochondrial membrane potential, and the stabilization of MMP is beneficial to maintaining the normal physiological function of cells. The above results indicate that compounds 3 and 4 can significantly reduce intracellular Reactive Oxygen Species (ROS) levels and Mitochondrial Membrane Potential (MMP), and are beneficial for maintaining normal physiological functions of cells.
Example 4 animal Activity assay
1. Effect of Compounds 3 and 4 on HMGB1 in Lung tissue of Lung mice
Mice with paraquat-induced pulmonary fibrosis are used as animal models, and the level of HMGB1 in the lungs of mice with pulmonary fibrosis after compound intervention is determined. LD of Compounds tested before the experiment50The animals molded at a concentration of more than 100mg/kg. were divided into 4 groups, paraquat group, glycyrrhetinic acid group, compound 3 and compound 4. After the mice were gavaged for 14 days at the designed dose, the mice were sacrificed, lung tissues were isolated, and the content of HMGB-1 in the lung tissues was tested.
The result shows that the content of HMGB1 in the lung tissue of the normal mouse is 32 ng/mL; after the mice are injected with paraquat, the level of HMGB1 in the lung is obviously increased to 103.27 ng/ml; when the administration dose of the Glycyrrhetinic Acid (GA) is 15mg/kg, the HMGB1 level is slightly reduced, and when the administration dose is 30mg/kg, the HMGB1 level is about 65% of that of paraquat; when the compound 3 is administrated at the dose of 10mg/kg, the level of HMGB1 is equivalent to that of the GA group, and when the compound 3 is administrated at the dose of 20mg/kg, the level of HMGB1 is reduced to 54% of that of the paraquat group; while the same dose of compound 4 contained lower levels of HMGB 1. The results show that the compounds 3 and 4 can obviously inhibit the content of HMGB1 in mouse lung tissues, have obvious anti-fibrosis effect and have better effect than the glycyrrhetinic acid with the same dose.
2. Effect of Compounds 3 and 4 on pulmonary fibrosis mouse Lung tissue morphology and Structure
In order to determine the therapeutic effect of the compound on fibrotic mice and the toxic effect on lung tissues, paraquat-induced pulmonary fibrosis mice were used as an animal model, the lung tissues of the mice were stained, and the morphology and structure of the lung tissues were observed under a microscope.
The HE staining results are shown in FIG. 3, where A is Control group, B is paraquat model group, C is GA (15mg/kg) group, D is GA (30mg/kg) group, E is Compound 3(15mg/kg) group, F is Compound 3(30mg/kg) group, G is Compound 4(15mg/kg) group, H is Compound 4(30mg/kg) group, yellow arrow indicates cell swelling, green arrow indicates inflammatory cell infiltration, and blue arrow indicates bleeding point. The result shows that the pulmonary alveolar structure of the mice of the normal control group is normal and has no inflammatory reaction; the lung tissue structure of paraquat group is obviously damaged, the alveolar structure disappears, the alveolar cavity is narrow and atrophied, the alveolar wall is thickened, a large number of bleeding points are formed, and cell swelling and inflammatory cell infiltration are seen; when the mice with pulmonary fibrosis take glycyrrhetinic acid and the compounds 3 and 4, the fibrosis symptoms can be relieved to different degrees. When the GA concentration is 15mg/kg, the conditions of a small part of alveoli are slightly improved, obvious alveolar cavities are still narrow and atrophied, alveolar walls are thickened, the inflammatory reaction is serious, the concentration is 30mg/kg, the conditions are improved, the part of alveolar cavities are obvious, the thickening conditions of alveolar walls are still serious, and inflammatory cell infiltration is serious; when the concentration of the compound 3 is 15mg/kg, the conditions of alveolar stenosis atrophy and alveolar wall thickening are improved compared with those of the GA group, and when the concentration is 30mg/kg, the inflammatory response is reduced; when the concentration of the compound 4 is 15mg/kg, compared with the GA group, the conditions of alveolar stenosis atrophy and alveolar wall thickening are obviously improved, the inflammatory response is reduced, when the concentration is 30mg/kg, the inflammatory response is obviously reduced, the cell swelling is reduced, and part of alveolar cavities are recovered to be normal. The results show that the compounds 3 and 4 can obviously improve the tissue morphology and the structure of pulmonary tissues of pulmonary fibrosis mice, have obvious anti-fibrosis effect and have the effect superior to that of the glycyrrhetinic acid with the same dose.
The Masson staining results are shown in FIG. 4, wherein A is Control group, B is paraquat model group, C is GA (15mg/kg) group, D is GA (30mg/kg) group, E is Compound 3(15mg/kg) group, F is Compound 3(30mg/kg) group, G is Compound 4(15mg/kg) group, H is Compound 4(30mg/kg) group, and blue arrows represent collagen fibers. The result shows that the lung tissue structure of a normal mouse is clear, no blue collagen fiber exists, and the lumen and vacuole-like structures are obvious; in the paraquat-induced model group, the alveolar structure disappears, and a large amount of blue collagen fibers appear; when the GA concentration is 15mg/kg, the structure of part of alveolus is slightly improved, and obvious and more blue collagen fibers still exist; the concentration is 30mg/kg, and the collagen fiber is reduced; when the concentrations of the compounds 3 and 4 are 15mg/kg and 30mg/kg, the collagen fiber condition is improved compared with that of a paraquat model group, part of alveolar structures appear, the collagen fiber is reduced, and the effects of the two compounds are obviously superior to those of GA with the same concentration. The results show that the compounds 3 and 4 can obviously improve the tissue morphology and the structure of pulmonary tissues of pulmonary fibrosis mice, have obvious anti-fibrosis effect and have the effect superior to that of the glycyrrhetinic acid with the same dose.
The results show that the compounds 3 and 4 have certain healing effect on paraquat-induced pulmonary inflammation and pulmonary fibrosis, have better effect than the same dose of GA, and can be used for treating new coronary pneumonia and acute lung injury.
In conclusion, the compounds 1-7 of the invention have stronger inhibition effect on tumor cells (A549 cells, HepG2 cells, 7721 cells and MCF-7 cells) and can be used for preparing antitumor drugs; ② the compounds 1-7 of the invention have stronger inhibition effect on inflammatory factor NO in RAW264.7 cells, the effect is the same as or better than glycyrrhetinic acid, and the compounds can be used for preparing anti-inflammatory drugs; compound 3 or 4 has stronger inhibiting effect on inflammatory factors HMGB1, TLR4, TNF-alpha, IL-1 beta and TGF-beta 1 in RAW264.7 cells, has stronger effect than glycyrrhetinic acid, and can be used for preparing various anti-inflammatory drugs; the compounds 3 and 4 have strong inhibition effect on Col-1, alpha-SMA, ROS and Mitochondrial Membrane Potential (MMP) in lung cancer cells A549, can be used for preparing anti-pulmonary fibrosis drugs and can be used for treating new-crown pneumonia and acute lung injury; the compounds 3 and 4 can inhibit the content of HMGB1 in lung tissues of pulmonary fibrosis model mice and can be used as candidate drugs for new coronary pneumonia.
The above description is only for details of a specific exemplary embodiment of the present invention, and it is obvious to those skilled in the art that various modifications and changes may be made in the present invention in the practical application process according to specific preparation conditions, and the present invention is not limited thereto. All that comes within the spirit and principle of the invention is to be understood as being within the scope of the invention.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein AA is an amino acid residue.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the amino acid comprises any one of glycine, valine, lysine, tryptophan, phenylalanine, methionine, leucine.
3. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of an anti-neoplastic medicament.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-inflammatory medicament.
5. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of pneumonia.
6. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of pulmonary fibrosis.
7. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of acute lung injury.
8. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of novel coronavirus pneumonia.
9. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound or pharmaceutically acceptable salt thereof is added with pharmaceutically acceptable adjuvants and can be made into any one of capsules, tablets, pills, granules, suspensions, dripping pills, oral liquid preparations, injections, and aerosols.
10. A process for the preparation of a compound according to claim 1 or 2, wherein the process comprises: the glycyrrhetinic acid and the amino acid methyl ester are subjected to condensation reaction, and the obtained reactant is subjected to condensation reaction with the lipoic acid to obtain the glycyrrhetinic acid.
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