CN109608388B - Dicarbonylcurcumin derivative and application thereof - Google Patents
Dicarbonylcurcumin derivative and application thereof Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract
The invention discloses a dicarbonyl curcumin derivative, which has a structure shown in a formula (I), wherein in the formula (I), an R substituent is selected from alkoxy, halogen or other electron-withdrawing groups. Research results show that the dicarbonyl curcumin derivative has a good effect of slowly releasing acute lung injury induced by LPS, and can avoid the defect of drug-forming property of curcumin serving as a contrast drug.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a dicarbonyl curcumin derivative and application thereof.
Background
Acute Lung Injury (ALI) is the damage of alveolar epithelial cells and capillary endothelial cells caused by various direct and indirect injury factors, causing diffuse interstitial pulmonary and alveolar edema, and resulting in acute hypoxic respiratory insufficiency. Absent effective treatment of acute lung injury, ALI survivors are subjected to great economic and mental stress, severely affecting the quality of life of the patient. Recent studies have shown that inhibition of inflammatory factors and reduction of inflammatory responses can be effective in treating ALI. Although there are some anti-inflammatory drugs currently available for acute lung injury, such as glucocorticoids, surfactants, propylcysteine, etc., they have entered clinical stage III. However, the subsequent clinical data are not optimistic, and therefore the development of anti-inflammatory drugs targeting ALI patients is urgently needed.
Curcumin is a chemical component extracted from rhizomes of some plants in Zingiberaceae and Araceae, is a pigment with diketone which is rare in plant world, and is a diketone compound. A large number of basic experimental researches and clinical data show that curcumin not only has the effects of reducing blood fat, resisting tumors, resisting inflammation, benefiting gallbladder, resisting oxidation and the like, but also has the effect of protecting liver due to lower toxic and side effects on normal cells. Despite the efficacy of curcumin, its chemical structure instability and poor water solubility greatly limit its clinical application. Therefore, it is imperative to design and develop curcumin derivatives that are chemically stable and water-soluble.
Disclosure of Invention
The invention provides a dicarbonyl curcumin derivative and application thereof, wherein the dicarbonyl curcumin derivative can effectively relieve inflammatory reaction caused by acute lung injury and can avoid the defect of drug property of curcumin serving as a contrast drug.
A dicarbonyl curcumin derivative has a structure shown in formula (I):
in the formula (I), R is selected from alkoxy, halogen, alkyl, hydroxyl, alkanoyloxy and NO2Or one or more of trifluoromethyl; preferably, R is C1～C4Alkoxy, halogen, C1～C4Alkyl, hydroxy, C1～C4One or more of alkanoyloxy, nitro or trifluoromethyl; more preferably, R is F, Cl, Br, CF3、NO2One or more of methoxyl, methyl, hydroxyl and acetoxyl.
The invention designs a novel dicarbonyl curcumin derivative by a conformation limited drug design method on the basis of a curcumin skeleton. In vitro anti-inflammatory activity test results show that most of the dicarbonyl curcumin derivatives have higher anti-inflammatory activity.
Preferably, the dicarbonyl curcumin derivative is one of compounds 5a 01-5 a29, wherein the structures and the synthetic reaction formulas of the compounds 5a 01-5 a29 are as follows:
the invention also provides application of the dicarbonyl curcumin derivative, and the dicarbonyl curcumin derivative is used for preparing anti-inflammatory drugs.
Preferably, the dicarbonyl curcumin derivatives treat acute lung injury and inflammation-related diseases by inhibiting the secretion of TNF-alpha and IL-6.
Preferably, the inflammation-related disorder includes acute lung injury, sepsis, rheumatoid arthritis, systemic lupus erythematosus and related syndromes, osteoarthritis, digestive tract inflammation, polymyositis, dermatomyositis, vasculitic syndromes, gouty arthritis, neuroinflammation, rheumatoid arthritis, chemical pain, inflammatory pain, granuloma, granulomatous vasculitis, arteritis, skin inflammation, autoimmune diseases, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, sepsis, septic shock.
Preferably, the dicarbonyl curcumin derivative is a compound 5a27 or 5a 28;
the invention also provides a pharmaceutical preparation which comprises an effective component and pharmaceutic adjuvant, wherein the effective component comprises the dicarbonyl curcumin derivative.
Preferably, the pharmaceutical preparation is any one of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, ointment, controlled release agent, sustained release agent or nano preparation.
Compared with the prior art, the invention has the beneficial effects that:
the research is based on a curcumin framework, and designs a novel dicarbonyl curcumin derivative by a conformation restriction drug design method. In vitro anti-inflammatory activity test results show that most of the compounds have better inhibition capability on proinflammatory factors TNF-alpha and IL-6, particularly the compounds 5a27 and 5a28 have highest inhibition capability on proinflammatory factors TNF-alpha and IL-6 caused by acute lung injury, the inhibition rate at the concentration of 10 mu M can reach 90.9-92.5% (TNF-alpha) and 99.3-99.7% (IL-6), and reference can be provided for further designing novel inflammation drugs with higher synthetic activity and stronger selectivity for relieving acute lung injury.
Drawings
FIG. 1 shows the inhibition data of LPS-induced secretion of TNF-. alpha.and IL-6 by the compounds obtained in test examples 5a27 and 5a 28.
Detailed Description
The invention is further described with reference to specific examples.
Instruments and reagents: the melting point was measured using an X-4 micro melting point apparatus (temperature not corrected); hydrogen nuclear magnetic resonance spectroscopy adopts BrukeraVANCE III 500 nuclear magnetic resonanceInstrumental determination (CDCl)3As solvent, TMS as internal standard); the mass spectrum is measured by an Agilent1100 quadrupole liquid chromatography-mass spectrometer. Silica gel GF for thin layer chromatography254Purchased from aladin reagent, inc (aladdin, Shanghai crystal purificationization science and technology, Inc.); silica gel FCP (200-300 mesh) for column chromatography is purchased from chemical reagents of national drug group, Inc.; other used reagents and solvents are all domestic analytical purifiers and are used after being dried without water according to requirements.
The synthetic route of the compound to be protected in the invention is as follows:
the synthesis method is further specifically described below by taking compound 5a27 as an example.
Example 1 Synthesis of (E) -3- (3,4, 5-trimethoxyphenyl) piperidin-2-one (4)
0.5g (2.51mmol) of tert-butyl 2-oxopiperidine-1-carboxylate and 0.54g (2.76mmol) of 3,4, 5-trimethoxybenzene are dissolved in 2mL of dry THF and added dropwise to 0.376g (12.55mmol) of NaH in THF and reacted at room temperature for 4 hours. 40mL of saturated NH were added4The reaction was quenched with Cl solution and then extracted 3 times with 50mL EtOAc. The organic phase was washed with 100mL of distilled water and 100mL of saturated NaCl, respectively. Followed by anhydrous MgSO4Drying, vacuum concentrating, purifying with silica gel column chromatography, and obtaining yield of 28.7%.
EXAMPLE 2 Synthesis of cinnamoyl chloride Compound (2a27)
1.0mmol of cinnamoyl acid 1a27 was dissolved in anhydrous dichloromethane (CH)2Cl2) To the solution was added dropwise a mixed solution containing 5.0mmol of oxalyl chloride and 0.01mmol of DMF. After the whole reaction device is reacted for 5 hours at room temperature, the solvent is discarded, and vacuum drying is carried out, so as to obtain 2a 27.
EXAMPLE 35 a general procedure for the synthesis of 272-methoxy-4- { (E) -3-oxo-3- [ (E) -2-oxo-3- (3,4, 5-trimethoxybenzylidene) piperidin-1-yl ] prop-1-ene-1-acetic acid phenyl ester
0.36mmol of (E) -3- (3,4, 5-trimethoxyphenyl) piperidin-2-one (4) was dissolved in 4mL of anhydrous tetrahydrofuran THF with stirring bar1.6M n-butyllithium (0.26mL, 0.43mmol) was slowly added dropwise thereto, the reaction system was stirred at-78 ℃ for 2 hours under the protection of liquid nitrogen, 2mL of an anhydrous THF solution containing 1.0mmol of 2a27 was added dropwise thereto, the reaction was continued for 10 minutes, and the temperature was raised to room temperature and the reaction was continued for 2 hours. 40mL of saturated NH was added to the reaction solution4The reaction was quenched with Cl solution and then extracted 3 times with 50mL EtOAc. The organic phase was dried over anhydrous MgSO4, filtered, concentrated in vacuo, and purified by column chromatography on silica gel to afford our desired product in 38.4% yield.
The characterization data of the resulting compounds are as follows:
compound 4:
1H NMR(500MHz,CDCl3)(ppm):7.72(s,1H),6.89(s,1H),6.62(s,2H),3.85(s,10H),3.43(s,2H),2.83(t,J＝5.5Hz,2H),1.95-1.80(m,2H).
1H NMR(500MHz,CDCl3)(ppm):7.86(s,1H),7.69(d,J＝15.52Hz,1H),7.52(d,J＝15.58Hz,1H),7.21(d,J＝7.98Hz,1H),7.17(s,1H),7.05(d,J＝8.13Hz,1H),6.69(s,2H),3.93-3.90(m,2H),3.90(s,3H),3.88(s,9H),2.90(t,2H),2.32(s,3H),1.99-1.93(m,2H).
13C NMR(125MHz,CDCl3)(ppm):164.4,163.5,162.6,147.8,146.0,137.2,135.9,134.2,133.8,129.0,125.6,124.5,117.8,117.3,116.0,106.4,102.5,55.7,51.0,50.7,38.8,21.2,17.2,15.4.
ESI-MS m/z:496.27(M)+.
test example 1 Compounds 5a27 and 5a28 alleviate LPS-induced acute lung injury
The inhibitory activity of the target compound on the secretion of TNF- α and IL-6 induced by LPS was tested by enzyme-linked immunosorbent assay (ELISA). mouse macrophage RAW264.7 was cultured in DMEM high-glucose medium containing 10% FBS and 1% streptomycin, and placed at 37 deg.C with 5% CO2The cell is added with LPS (0.5ug/ml) 2h after the drug is added, the cell is incubated for 22h, and then culture medium is collected, the expression of proinflammatory cytokines TNF- α and IL-6 is detected by double antibody sandwich ELISA by using an ELISA kit, the experimental steps are briefly described as follows, coating the ELISA with coating buffer firstlyAdding Phosphate Buffer Solution (PBST) of Tween-20 into a plate, washing the plate overnight at 4 ℃ for 3 times, spin-drying the plate, adding assay solution into the plate, blocking the plate, adding collected culture medium into the plate, washing the PBST to remove a sample which is not combined with the coated antibody, adding detection antibody into the plate, incubating the plate, adding avidin-labeled HRP into the plate, adding enzyme substrate TMB into the plate for color development, adding 2M H into the plate after 15min, and performing electrophoresis2SO4The reaction was stopped and the OD measured at 450 nm.
To evaluate the efficacy of the synthesized compounds in alleviating acute lung injury of LPS. We used LPS to make an animal model of acute lung injury at the mouse level. Mouse lung tissues before and after drug treatment were characterized by histomorphology and immunohistochemistry. We used the LPS-induced acute lung injury mouse model to evaluate the ability of Curcumin (CUR) and 5a27 and 5a28 to alleviate acute lung injury-induced inflammation, and the results are shown in fig. 1. These results demonstrate that 5a27 and 5a28 are effective in reducing the dry-to-wet ratio (fig6.a) of lung tissue. At the same time, 5a27 and 5a28 inhibited tissue infiltration of inflammatory cells. After LPS treatment, both total cell number and white blood cells in bronchoalveolar lavage fluid were significantly increased, but were significantly inhibited by 5a27 and 5a28 (fig6. b-C). The lung tissue morphology of the mouse model of acute lung injury is changed, and the interstitium is subjected to edema, pulmonary congestion, alveolar septum thickening, inflammatory cell infiltration, alveolar tissue and the like (FIG. 6D). However, 5a27 and 5a28 were effective in alleviating this pathological change. In addition, significant reduction in lymphocyte and macrophage infiltration was seen with immunohistochemistry (FIG. 6D). As can be seen from FIG. 1, 5a27 and 5a28 are effective in relieving LPS-induced acute lung injury and inhibiting the secretion of proinflammatory associated factors TNF-alpha and IL-6; and 5a27 and 5a28 have much higher ability to relieve inflammation induced by acute lung injury induced by LPS than Curcumin (CUR).
Claims (7)
1. The dicarbonyl curcumin derivative is characterized in that the dicarbonyl curcumin derivative is a compound 5a27 or 5a28
2. Use of a dicarbonyl curcumin derivative as defined in claim 1 wherein said dicarbonyl curcumin derivative is used for the preparation of an anti-inflammatory medicament.
3. The use of dicarbonyl curcumin derivatives as claimed in claim 2, wherein said anti-inflammatory agent is used to treat acute lung injury.
4. The use of dicarbonyl curcumin derivatives as claimed in claim 2 wherein said dicarbonyl curcumin derivatives treat inflammation and inflammation-related disorders by inhibiting the secretion of TNF- α and IL-6.
5. Use of dicarbonyl curcumin derivatives according to claim 4 wherein said inflammatory related disorders comprise acute lung injury, sepsis, rheumatoid arthritis, systemic lupus erythematosus and related syndromes, osteoarthritis, inflammation of the digestive tract, polymyositis, dermatomyositis, vascular inflammatory syndromes, gouty arthritis, neuroinflammation, rheumatoid arthritis, chemical pain, inflammatory pain, granuloma, granulomatous vasculitis, arteritis, skin inflammation, autoimmune diseases, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, sepsis, septic shock.
6.A pharmaceutical preparation comprising an active ingredient and a pharmaceutical excipient, wherein the active ingredient comprises the bis-carbonyl curcumin derivative of claim 1.
7. The pharmaceutical preparation of claim 6, wherein the pharmaceutical preparation is any one of an injection, a tablet, a capsule, an aerosol, a suppository, a membrane, a dropping pill, an ointment, a controlled release agent, a sustained release agent or a nano-preparation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919778A (en) * | 2013-12-19 | 2014-07-16 | 温州医科大学 | Application of curcumin analog S1 containing piperidone structure in preparation of anti-inflammation drugs |
| CN104557558A (en) * | 2015-01-21 | 2015-04-29 | 温州医科大学 | Nitro-containing curcumin derivative as well as preparation method and application thereof |
| CN105037252A (en) * | 2015-05-21 | 2015-11-11 | 温州医科大学 | N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative, preparation method and application thereof |
| WO2016014625A1 (en) * | 2014-07-22 | 2016-01-28 | Board Of Trustees Of The University Of Arkansas | Compositions and methods for selectively depleting senescent cells |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919778A (en) * | 2013-12-19 | 2014-07-16 | 温州医科大学 | Application of curcumin analog S1 containing piperidone structure in preparation of anti-inflammation drugs |
| WO2016014625A1 (en) * | 2014-07-22 | 2016-01-28 | Board Of Trustees Of The University Of Arkansas | Compositions and methods for selectively depleting senescent cells |
| CN104557558A (en) * | 2015-01-21 | 2015-04-29 | 温州医科大学 | Nitro-containing curcumin derivative as well as preparation method and application thereof |
| CN105037252A (en) * | 2015-05-21 | 2015-11-11 | 温州医科大学 | N-substituted-3,5-bis(2-trifluoromethyl)benzal)piperidine-4-one derivative, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation;Xingui Liu，等;《Bioorganic & Medicinal Chemistry》;20180807;第26卷(第14期);第3925-3938页 * |
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