CN114315855A - Curcumenol derivatives, preparation method and application thereof in preparation of anti-inflammatory drugs - Google Patents
Curcumenol derivatives, preparation method and application thereof in preparation of anti-inflammatory drugs Download PDFInfo
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Abstract
The invention relates to the technical field of medicaments, and discloses curcumenol derivatives, a preparation method and application thereof in preparation of anti-inflammatory medicaments. The invention designs and synthesizes curcumenol derivatives by using curcumenol as a precursor. The curcumenol derivatives have no influence on the growth of primary abdominal macrophages of mice, can obviously reduce the level of inflammatory cytokines, have anti-inflammatory activity, and provide a new choice for the research and development of anti-inflammatory drugs.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to curcumenol derivatives, a preparation method and application thereof in preparing anti-inflammatory medicaments.
Background
Inflammation is a pathophysiological process which takes defense reaction as a main part and is generated by the stimulation of living tissues with a vascular system to various injury factors, and is involved in the generation and development of various diseases (such as cardiovascular diseases, osteoporosis, diabetes, autoimmune diseases, atherosclerosis, neurodegenerative diseases and the like). At present, the anti-inflammatory drugs are the second main class of drugs which are second only to anti-infective drugs in clinical treatment, and clinically used anti-inflammatory drugs mainly comprise non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs, but have adverse reactions of different degrees, such as stimulation of the non-steroidal anti-inflammatory drugs to gastrointestinal tracts and kidney damage, possibly induced or aggravated infection by glucocorticoid drugs and the like.
The traditional Chinese medicine is an important resource for developing anti-inflammatory drugs, so that precursors with anti-inflammatory activity are searched from the traditional Chinese medicine, and the structure optimization has important significance for discovering new anti-inflammatory drugs. The zedoary is dried rhizome of Curcuma zedoaria Roscoe, Curcuma kwangsiensis and Curcuma wenyujin belonging to Zingiberaceae, wherein the zedoary turmeric oil is volatile oil extracted from Curcumae rhizoma, is main effective component of Curcumae rhizoma, and has good anti-tumor, anti-inflammatory and antivirus effects. The zedoary turmeric oil is reported to have good curative effect on acute erosive esophagitis, chronic atrophic gastritis and rotavirus enteritis. The curcumenol is one of the main components of the zedoary turmeric oil, and can be a lead compound of a novel anti-inflammatory drug with potential inhibitory activity on various inflammation mediators.
Disclosure of Invention
In view of the above, the invention designs and synthesizes curcumenol derivatives by using curcumenol as a precursor, so as to find a high-efficiency anti-inflammatory active chemical entity, and provide a new choice for further preparing anti-inflammatory drugs by using zedoary turmeric oil as a raw material.
The technical scheme of the invention is as follows:
on one hand, the structural formula of the curcumenol derivative is shown as formula I and formula II:
wherein R is independently selected from
Halogen, R1Is independently selected from
-OH。
More preferably, the curcumenol derivatives of formula I have the following structural formula:
on the other hand, the invention also provides a preparation method of the curcumenol derivatives, which comprises the following steps: performing epoxidation reaction on the double bond of the curcumenol at room temperature by using m-chloroperoxybenzoic acid as an oxidant; dissolving the reaction product in isopropanol, heating and refluxing by taking sodium hydroxide as alkali to obtain Intermediate curcumenol mono-alcohol (IM);
the curcumenol mono-alcohol is used as a precursor, and the curcumenol ester derivative is obtained by esterification reaction under the alkaline condition.
Preferably, the substituent of the esterification reaction is
Using curcumenol mono-alcohol (IM) as a precursor, and carrying out esterification to obtain a monoester derivative (1) and a diester derivative (2), wherein the structural formula is as follows:
one skilled in the art can select suitable reaction conditions and catalysts according to the characteristics of reactants of the esterification reaction, for example, the solvent can be N, N-dimethylformamide and dichloromethane, and the catalyst can be 4-dimethylaminopyridine and potassium iodide.
In one embodiment, curcumenol mono-alcohol is used as a precursor, and halogen substitution reaction is carried out under the catalysis of triphenylphosphine to obtain curcumenol halogen substituted derivative.
Preferably, the reactants of the halogen reaction are NCS (N-chlorosuccinimide) and NIS (N-iodosuccinimide), and the halogen substitution reaction is carried out by taking the Intermediate (IM) as a precursor under the catalysis of triphenylphosphine to obtain the chlorine substituted derivative (3) and the iodine substituted derivative (4), wherein the structural formula is as follows:
in one embodiment, the invention provides a method for preparing derivatives of the same class as the formula II by dissolving the curcumenol in a dry acetone and hydrobromic acid mixed solution and heating and refluxing the solution.
Preferably, the mixed solution of acetone and hydrobromic acid is dried by anhydrous sodium sulfate, and then phosphorus pentoxide is added for deep water removal.
On the other hand, the invention also provides the application of the curcumenol derivatives in preparing anti-inflammatory drugs.
Preferably, the medicament has the effect of inhibiting an inflammatory cytokine, preferably IL-6.
As an embodiment, the medicament comprises any one or more of the compounds and the medicinal salts thereof and pharmaceutically acceptable auxiliary materials.
As one embodiment, the medicament is an injection, a tablet, a powder, a granule, a pill, a capsule, an oral liquid, an ointment, a cream or a spray.
Compared with the prior art, the invention has the advantages that:
the invention designs and synthesizes curcumenol derivatives by using curcumenol as a precursor. LPS is adopted to stimulate mouse abdominal cavity macrophages to establish a cell inflammation model, and the anti-inflammatory activity evaluation is carried out on the curcumenol derivatives, so that the curcumenol derivatives have no influence on the growth of the mouse primary abdominal cavity macrophages, can obviously reduce the level of inflammatory cytokines, have anti-inflammatory activity, and provide a new choice for the research and development of anti-inflammatory drugs.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
All experimental results in the following examples were statistically analyzed using GraphPad Prism 8.0.2 software, and all values are mean. + -. standard deviation
Showing that statistical analysis is carried out by adopting one-way variance analysis and two-tail pairing-free t test.
Example 1
Synthesis of curcumenol monoester derivatives
Curcumenol (3g, 1equiv.) is dissolved in dichloromethane, m-chloroperoxybenzoic acid (3.28g, 1.5equiv.) is added, stirring is carried out at room temperature, TLC (5% sulfuric acid ethanol color development) is carried out until the reaction is completed, saturated sodium bisulfite, saturated sodium bicarbonate and saturated common salt water are sequentially used for washing, anhydrous sodium sulfate is dried and then is concentrated under reduced pressure to obtain oily liquid, the oily liquid is dissolved in isopropanol, sodium hydroxide (1.525g, 3equiv.) is added for reaction at 70 ℃, TLC (5% sulfuric acid ethanol color development) is carried out until the reaction is completed, saturated tartaric acid and saturated common salt water are sequentially used for washing, anhydrous sodium sulfate is dried and then is concentrated under reduced pressure, and 2.242g of white solid Intermediate (IM) is obtained by column chromatography (petroleum ether: ethyl acetate ═ 3: 1) and the yield is 70%.
Dissolving the intermediate IM (50mg, 1equiv.) in dichloromethane, sequentially adding 4-diphenic acid (47mg, 1.2equiv.), Dicyclohexylcarbodiimide (DCC) (123mg, 3equiv.) and catalytic amount of 4-Dimethylaminopyridine (DMAP), stirring at room temperature, tracking by TLC (5% sulfuric acid ethanol for color development) until the reaction is complete, sequentially washing with saturated sodium bicarbonate, saturated tartaric acid and saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain 40mg of colorless transparent oily liquid, namely the curcumenol monoester derivative (1) with the yield of 47%.
1H NMR(600MHz,Acetone-d6)δ:8.14(d,J＝8.5Hz,2H,H-3′and H-7′),7.84(d,J＝8.4Hz,2H,H-4′and H-6′),7.76(d,J＝8.4Hz,2H,H-9′and H-13′),7.53(t,J＝7.7Hz,2H,H-10′and H-12′),7.45(t,J＝7.4Hz,1H,H-11′),6.00(s,1H,H-7),4.90–4.76(m,2H,H-9),1.03(d,J＝6.5Hz,3H,H-11),0.99(d,J＝6.5Hz,3H,H-12),0.89(d,J＝6.6Hz,3H,H-13)；13C NMR(150MHz,Acetone-d6)δ:165.39(C-1′),145.53(C-5′),139.67(C-8′),138.17(C-8),129.99(C-10′and C-12′),129.11(C-2′),129.04(C-9′and C-13′),128.28(C-7),128.21(C-11′),127.13(C-4′and C-6′),127.07(C-3′and C-7′),103.01(C-6),85.93(C-3a),65.90(C-9),59.14(C-5),49.64(C-8a),40.07(C-3),36.24(C-4),31.32(C-2),30.80(C-10),27.54(C-1),22.30(C-11),20.96(C-12),11.24(C-13)；ESI-MS m/z:455.4[M+Na]+。
Example 2
Synthesis of curcumenol diester derivative
Intermediate IM was synthesized in the same manner as in example 1.
Dissolving the intermediate IM (50mg, 1equiv.) in N, N-Dimethylformamide (DMF), sequentially adding sodium hydride (48mg, 10equiv.) and a catalytic amount of potassium iodide, stirring at room temperature for 15min, then adding p-nitrobenzoyl chloride (110mg, 3equiv.), stirring at room temperature, tracking by TLC (5% sulfuric acid ethanol for color development) until the reaction is complete, adding water for quenching, sequentially washing with saturated tartaric acid and saturated common salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate: 15: 1) to obtain 43mg of white solid, namely the curcumenol diester derivative (2) with the yield of 40%.
1H NMR(600MHz,Acetone-d6)δ:8.39(t,J＝8.9Hz,4H,H-4′,H-6′and H-4″,H-6″),8.34–8.29(m,4H,H-3′,H-7′and H-3″,H-7″),6.35(s,1H,H-7),4.99–4.92(m,2H,H-9),1.09(d,J＝6.5Hz,3H,H-12),1.02(d,J＝6.5Hz,3H,H-11),0.98(d,J＝6.6Hz,3H,H-13)；13C NMR(150MHz,Acetone-d6)δ:164.14(C-1′),161.43(C-1″),150.82(C-5′),150.78(C-5″),136.54(C-8),135.97(C-2′),135.60(C-2″),130.85(C-3′and C-7′),130.76(C-3″and C-7″),126.27(C-7),123.73(C-4′and C-6′),123.70(C-4″and C-6″),106.19(C-6),89.27(C-3a),66.73(C-9),58.33(C-5),49.45(C-8a),39.86(C-3),34.60(C-4),31.05(C-2),30.32(C-10),27.47(C-1),21.93(C-11),21.03(C-12),11.10(C-13)；ESI-MS m/z:573.3[M+Na]+。
Example 3
Synthesis of curcumenol mono-alcohol chlorine substituted derivative
Intermediate IM was synthesized in the same manner as in example 1.
Dissolving the intermediate IM (50mg, 1equiv.) in dichloromethane, sequentially adding N-chlorosuccinimide (NCS) (40mg, 1.5equiv.) and triphenylphosphine (PPh3) (78mg, 1.5equiv.), stirring at room temperature, tracking by TLC (5% sulfuric acid ethanol for color development) until the reaction is complete, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate: 15: 1) to obtain 43mg of colorless transparent liquid, namely the curcumenol mono-alcohol-chlorine substituted derivative (3) with the yield of 81%.
1H NMR(600MHz,CDCl3)δ:5.92(s,1H,H-7),4.01(s,2H,H-9),1.03(d,J＝6.7Hz,3H,H-11),1.00(d,J＝6.5Hz,3H,H-12),0.89(d,J＝6.6Hz,3H,H-13)；13C NMR(150MHz,CDCl3)δ:140.06(C-8),128.75(C-7),103.27(C-6),87.44(C-3α),59.41(C-5),49.33(C-8a),46.65(C-9),40.31(C-3),36.30(C-4),31.09(C-2),30.66(C-10),27.14(C-1),22.65(C-11),21.42(C-12),11.75(C-13)；ESI-MS m/z:293.7[M+Na]+。
Example 4
Synthesis of curcumenol mono-alcohol iodine substituted derivative
Intermediate IM was synthesized in the same manner as in example 1.
Dissolving the intermediate IM (600mg, 1equiv.) in dichloromethane, sequentially adding N-iodosuccinimide (NIS) (804mg, 1.5equiv.) and triphenylphosphine (PPh3) (936mg, 1.5equiv.), stirring at room temperature, tracking by TLC (5% sulfuric acid ethanol for color development) until the reaction is complete, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate: 15: 1) to obtain 612mg of colorless transparent liquid, namely the curcumenol mono-alcohol iodine substituted derivative (4), with the yield of 71%.
1H NMR(600MHz,CDCl3)δ:6.03(s,1H,H-7),3.96(d,J＝9.4Hz,1H,H-9),3.84(d,J＝9.4Hz,1H,H-9),1.04(d,J＝6.6Hz,3H,H-11),1.01(d,J＝6.5Hz,3H,H-12),0.90(d,J＝6.6Hz,3H,H-13)；13C NMR(150MHz,CDCl3)δ:141.77(C-8),127.28(C-7),103.37(C-6),87.23(C-3α),60.03(C-5),49.78(C-8a),40.39(C-3),36.31(C-4),31.16(C-2),30.16(C-10),27.48(C-1),22.74(C-11),21.49(C-12),11.75(C-13),9.30(C-9)；ESI-MS m/z:385.5[M+Na]+。
Example 5
Synthesis of derivatives of the android
Adding 30mL of acetone into a reaction bottle, adding 5mL of 40% hydrobromic acid solution, drying the system for three hours by using anhydrous sodium sulfate, adding phosphorus pentoxide to deeply remove water, and filtering to obtain filtrate. Dissolving 100mg of curcumenol in the filtrate, heating and refluxing, tracking by TLC until the reaction is complete, adding saturated sodium bicarbonate solution to neutralize excessive hydrogen bromide in the system, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to obtain 35mg of white solid, namely the android similar derivative (5), wherein the yield is 33%.
1H NMR(CDCl3,400MHz)δ:7.08(s,1H,H-6),7.00(s,1H,H-9),3.46(hept,J＝6.8Hz,1H,H-11),3.07(p,J＝7.0Hz,1H,H-4),2.81(dd,J＝16.7,7.7Hz,1H,H-2),2.54(dd,J＝16.7,11.5Hz,1H,H-2),2.22(s,3H,H-14),1.92(m,1H,H-3),1.73(m,1H,H-6),1.17(d,J＝3.1Hz,3H,H-15),1.16(d,J＝3.1Hz,3H,H-12or H-13),1.04(d，J＝7.1Hz,3H,H-12or H-13),0.99(d,J＝2.0Hz,3H,H-17or H-18),0.98(d,J＝2.2Hz,3H,H-17or H-18)；13C NMR(CDCl3,100MHz)δ:185.34(C-8),158.57(C-7),151.83(C-5),144.92(C-1),144.82(C-10),138.84(C-9),130.71(C-6),48.70(C-3),46.66(C-4),38.57(C-2),29.66(C-11),28.30(C-16),25.03(C-14),22.60(C-12),22.41(C-13),21.65(C-17),21.56(C-18),14.22(C-15)；ESI-MS m/z:281.1[M+Na]+。
Example 6
Evaluation of anti-inflammatory Activity in LPS-induced mouse inflammation model
The main reagents are as follows: LPS (Lipopropylaccharides from Escherichia coli O55B5) L2880-500MG, Lot #127M4030V, Sigma, USA; mouse IL-6ELISA kit, Thermo Fisher Scientific, USA; cell proliferation and toxicity test kit (CCK-8), Dalian Meiren Biotechnology Ltd.
1. Preparation and culture of primary mouse Peritoneal Macrophages (PMs): 3% thioglycollic acid culture medium is injected into the abdominal cavity of the Kunming mouse for 3 mL/mouse, after three days, isoflurane inhales the mouse for anesthesia and death, the mouse is soaked in 75% alcohol for 1-2 minutes, and the operation is carried out on an ultra-clean workbench. Irrigating abdominal cavity with 10mL physiological saline, gently irrigating abdominal cavity for two minutes, enriching abdominal cavity free cells, centrifuging cell sap at 1000rpm/3min, discarding supernatant, culturing with appropriate amount of DMEM to obtain basic suspension cells, counting with cell counter, and adjusting viable cell density to 1.0 × 106The cells/mL were inoculated in a 96-well plate at 100. mu.L/well, incubated at 37 ℃ with 5% CO2Culturing in an incubator, and carrying out experiments after cells adhere to the wall for 2-3 h.
2. ELISA method for detecting influence of compound on LPS (lipopolysaccharide) stimulation of primary abdominal cavity macrophages of mice to release inflammatory cytokines
PMs after culturing adherent were treated as follows:
medium group: adding an equal volume of complete medium;
LPS50 group (model group): adding LPS with the final concentration of 50 ng/mL;
LPS50+ compound group: LPS was added to a final concentration of 50ng/mL and the compound of example 1-5 was added to a final concentration of 52.03. mu. mol/L and incubation was continued for 4 h.
Detecting the level of the cytokine IL-6 by collected cell supernatant according to an enzyme linked immunosorbent assay (ELISA) kit operation manual, wherein the specific steps of the detection method are as follows:
(1) the capture antibody is coated. Taking out the enzyme label plate, adding 100 mu L of diluted capture antibody into each hole, and incubating overnight at 4 ℃;
(2) and activating the enzyme label plate. Washing the overnight incubated enzyme label plate with PBS (phosphate buffer solution) for 4 times, adding 200 mu L of sample diluent into each hole, and incubating for 1h at 37 ℃;
(3) and (4) loading. Washing the ELISA plate with PBS (phosphate buffer solution) for 4 times, adding 100 mu L of standard substance and a sample to be detected which is diluted five times into each hole, and incubating for 2h at 37 ℃ or incubating overnight at 4 ℃;
(4) and detecting the antibody. Washing the ELISA plate with PBS (phosphate buffer solution) for 4 times, adding 100 mu L of diluted detection antibody into each hole, and incubating for 1h at 37 ℃;
(5) Avidin-HRP enzyme. Washing the ELISA plate with PBS (phosphate buffer solution) for 4 times, adding 100 mu L of diluted Avidin-HRP enzyme combined working solution into each hole, and incubating for 30min at 37 ℃;
(6) and (4) developing color. Washing the ELISA plate with PBS lotion for 5 times, adding 100 μ L of TMB color developing solution into each hole, and developing in dark for 15 min;
(7) the display is terminated. Add 100. mu.L of stop buffer to each well and immediately determine OD450And (4) light absorption value. Concentration gradient and OD according to standard450And drawing a standard curve, and calculating the concentration of the IL-6 in each sample according to a standard curve formula.
The inhibition rate is [ (mean cytokine content in model group-mean cytokine content after compound treatment)/mean cytokine content in model group ] × 100%.
3. CCK-8 method for detecting influence of compound on activity of mouse primary abdominal cavity macrophage
Primary Peritoneal Macrophages (PMs) were prepared and cultured as described in example 2.
PMs after culturing adherent were treated as follows:
medium group, adding equal volume of complete Medium;
in the compound group, the compound of example 1-5 was added to the mixture at a final concentration of 52.03. mu. mol/L, and the culture was continued for 4 hours.
Abandoning the supernatant, and adding CCK-8: DMEM 1: 10, mixing, adding 100 mu L of the mixture into each hole, and adding 3 holes of CCK-8 solution without cells and compoundsIncubation was continued for 1h and OD was immediately determined450And (4) light absorption value.
The cell survival rate is [ (the absorbance value of the compound group-the average value of the absorbance of the CCK-8 liquid)/(the average value of the absorbance of the Medium group-the average value of the absorbance of the CCK-8 liquid) ] × 100%.
After the mouse abdominal cavity macrophages are stimulated by LPS, a large amount of proinflammatory cytokine IL-6 is released from cell supernatant, and the obvious difference is obvious compared with the Medium group, which shows that the mouse abdominal cavity macrophages are stimulated by LPS to successfully establish an in vitro simulated in vivo inflammation model. After the compound is added, the release amount of the proinflammatory cytokines in the supernatant is reduced, and the obvious difference is shown compared with a model group, so that the compound disclosed by the invention can reduce the release amount of the proinflammatory cytokines in the supernatant of macrophages in abdominal cavities of mice stimulated by LPS, and has anti-inflammatory activity. And the compound of the invention has no influence on the growth of primary abdominal cavity macrophages of mice.
Table 1 Effect of Compounds on inflammatory cytokines and cell viability
Note:**,p<0.01vs Medium；
p<0.05；
p<0.01vs LPS50。
the above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. Curcumenol derivatives, wherein the curcumenol derivatives have structural formulas shown as formula I and formula II:
wherein R is independently selected from
Halogen, R1Is independently selected from
-OH。
2. The curcumenol derivative of claim 1, wherein the curcumenol derivative of formula I has the following structural formula:
3. the process for producing curcumenol derivatives according to claim 1 or 2, comprising the steps of: performing epoxidation reaction on the double bond of the curcumenol at room temperature by using m-chloroperoxybenzoic acid as an oxidant; dissolving the reaction product in isopropanol, heating and refluxing by taking sodium hydroxide as alkali to obtain an intermediate curcumenol monoalcohol; the curcumenol mono-alcohol is used as a precursor, and the curcumenol ester derivative is obtained by esterification reaction under the alkaline condition.
4. The method according to claim 3, wherein the substituent for the esterification reaction is
5. The preparation method according to claim 3, wherein the curcumenol mono-alcohol is used as a precursor, and halogen substitution reaction is carried out under the catalysis of triphenylphosphine to obtain the curcumenol halogen substituted derivative.
6. The method according to claim 5, wherein the reactant of the halogen reaction is NBS, NCS or NIS.
7. The method for preparing curcumenol derivatives as claimed in claim 1, wherein the curcumenol is dissolved in dry acetone and hydrobromic acid mixed solution, and heated under reflux to obtain the derivatives of formula II.
8. The method for preparing curcumenol derivatives of claim 7, wherein the acetone and hydrobromic acid mixed solution is dried with anhydrous sodium sulfate, and then phosphorus pentoxide is added to remove water deeply.
9. Use of curcumenol derivatives according to claim 1 or 2 and curcumenol derivatives prepared by any one of claims 3 to 8 in the preparation of anti-inflammatory drugs.
10. The use according to claim 9, wherein the medicament has an effect of inhibiting inflammatory cytokines.
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| CN116120335A (en) * | 2023-01-18 | 2023-05-16 | 国科大杭州高等研究院 | Curcumenol derivative as Wnt signal pathway agonist and preparation method and application thereof |
| CN116120335B (en) * | 2023-01-18 | 2024-03-01 | 国科大杭州高等研究院 | Curcumenol derivative as Wnt signal pathway agonist and preparation method and application thereof |
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