CN113304129A - Application of mono-ketene monocarbonyl curcumin analogue in preparing antioxidant drugs - Google Patents

Application of mono-ketene monocarbonyl curcumin analogue in preparing antioxidant drugs Download PDF

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CN113304129A
CN113304129A CN202110665962.9A CN202110665962A CN113304129A CN 113304129 A CN113304129 A CN 113304129A CN 202110665962 A CN202110665962 A CN 202110665962A CN 113304129 A CN113304129 A CN 113304129A
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吴建章
何文斐
金琪玲
王靖松
张佳枫
沈梦雅
胡越
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Second Affiliated Hospital and Yuying Childrens Hospital of Wenzhou Medical University
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Abstract

The invention belongs to the field of medicinal chemistry, and particularly provides application of a monoene monocarbonyl curcumin analogue with stable structure and good safety in medicines, especially application in treating diseases caused by oxidative stress as an antioxidant medicine, aiming at the defects of unstable curcumin, high toxicity and high stability of the dienone monocarbonyl curcumin analogue to be improved. The compounds have good in vitro and in vivo antioxidation effects: in vitro, the compounds have excellent antioxidant protection effect in a cell oxidative damage model induced by hydrogen peroxide; in a mouse body, the compounds have good antioxidant protection effect in cerebral ischemia-reperfusion injury related to oxidative stress.

Description

Application of mono-ketene monocarbonyl curcumin analogue in preparing antioxidant drugs
Technical Field
The invention belongs to the field of medicinal application, and particularly relates to application of a mono-ketene monocarbonyl curcumin analogue in preparation of an antioxidant medicament.
Background
Curcumin (figure 1.Cur.) is an active ingredient widely existing in plants of Zingiberaceae, and has wide pharmacological activities of anti-inflammation, antioxidation, anti-tumor, etc. Due to its good pharmacological activity, over 260 clinical trials have been conducted: (https://clinicaltrials.gov) However, most of them have failed so far, and have not been approved for clinical use for the time being. The drug deficiency caused by instability is one of the main reasons for clinical failure of curcumin, so the stability of curcumin is improvedThe research of sex retention of the pharmacological activity is a research hotspot in the field.
The beta-diketone structure of the molecular skeleton of curcumin is the most main reason for causing the instability of curcumin, and the diketone structure of the beta-diketone structure is transformed into a diketene monocarbonyl curcumin analogue (the molecular skeleton is shown in figure 1.Ac) with a monoketone structure, so that the stability of the analogue can be effectively improved, and the good pharmacological activity of curcumin can be well kept (Current pharmaceutical design 2013,19(11): 2114; CN, ZL200710066787.1 and the like). However, through literature research (ACS chem. neurosci.2019,10,4545) and experimental comparison research, the compounds actually have high toxicity, and the stability of the molecular skeleton of the compounds is to be improved (fig. 1). The monoalkenone monocarbonyl curcumin analogue (a compound with a general formula (I)) is mainly used as a chemical raw material for synthesizing other curcumin analogues at present, and no related literature reports the pharmacological activity of the analogue.
Figure RE-GDA0003152666800000011
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the application of the monocarbonyl curcumin analogue in preparing the antioxidant drugs.
The technical scheme adopted by the invention is as follows:
the application of the compound with the general formula (I) in preparing antioxidant drugs,
Figure RE-GDA0003152666800000021
ar is a benzene ring or a naphthalene ring or an aromatic heterocyclic ring which is mono-substituted, poly-substituted or unsubstituted by a substituent R;
the substituent R is one or more of alkyl, alkenyl, alkynyl, alkoxy, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkoxy, cycloalkyl alkyl, carboxyl and amino;
wherein, the substituent R in the polysubstituted Ar is the same substituent or different substituents.
Preferably, the medicament is for use in one or more of the following diseases: sepsis due to oxidative stress, ischemia and ischemia reperfusion injury of organs of brain, heart, kidney, and liver, acute mild and moderate pain (such as postoperative, traumatic, strain, primary dysmenorrhea, toothache, and headache); parkinson's disease, Alzheimer's disease, atherosclerosis, diabetic complications caused by oxidative stress.
A pharmaceutical composition for the treatment of oxidative stress injury comprising a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof;
Figure RE-GDA0003152666800000022
ar is a benzene ring or a naphthalene ring or an aromatic heterocyclic ring which is mono-substituted, poly-substituted or unsubstituted by a substituent R;
the substituent R is one or more of alkyl, alkenyl, alkynyl, alkoxy, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkoxy, cycloalkyl alkyl, carboxyl and amino;
wherein, the substituent R in the polysubstituted Ar is the same substituent or different substituents.
Preferably, the compound of formula (I) or a salt or solvate thereof is used as the sole active ingredient.
The preparation form of the pharmaceutical composition is selected from one of injection, tablet, suppository, membrane, capsule, ointment, aerosol, dripping pill, controlled release or sustained release agent and nano preparation.
The invention has the following beneficial effects: the invention finds the new application of the compound in the general formula (I) in preparing the medicines for treating oxidative stress injury, and compared with the existing molecular skeleton of curcumin and diketene analog curcumin with the effect of treating oxidative stress injury, the compound in the general formula (I) has the advantages of improved stability and reduced toxicity, so the compound has good application prospect in treating diseases caused by oxidative stress as an antioxidant medicine.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 (A) design, (B) stability, (C) cytotoxicity and (D) antioxidant activity of monoalkenone monocarbonylcurcumin analogs. (A) The design process from parent compound curcumin (Cur.), curcumin skeleton (Cur-S), diketene monocarbonyl curcumin analogue skeleton (Ac) to monoalkenyl monocarbonyl curcumin analogue skeleton (sAc). (B) Cur., Cur-S, Ac and (time-light absorption profile of sAc in phosphate buffer). (C) PC12 cells were subjected to Cur-S, Ac and sAc (10. mu.M) for 42h, and cytotoxicity was detected by MTT method. (D) PC12 cells were preincubated with Cur, Cur-S, Ac and sAc (10. mu.M) for 18H, followed by H2O2(640. mu.M) for 24h (D) and the protective activity of the compound was determined by the MTT method. The cell viability of the (C, D) solvent (DMSO) group was defined as 100%. Data are expressed as mean ± SD, with n ═ 3.####p<0.0001，##p<0.01vs DMSO，****p<0.0001，**p＜0.01vs H2O2；
FIG. 2 cytotoxicity of compounds in normal human liver cell (MIHA) cells and rat kidney cell (NRK) cells. MIHA cells (A) and NRK (B) cells were seeded in 96-well plates, and the cell viability was measured by MTT method after 42h treatment with different concentrations of compound (5, 10, 20. mu.M). The results are expressed as mean ± sd, n is 3.*P<0.05,**P<0.01,****P<0.0001 compared to DMSO group;
FIG. 3 is a synthetic scheme for compounds;
FIG. 4 cytotoxicity screening of Compounds on PC12 cells (A) and on H2O2Antioxidant protection of PC12 cells in the injury model. (A) Using sAc1-sAc32, TBHQ, PL and curcuminCells were incubated (10. mu.M) for 42h and cytotoxicity was detected by MTT method. (B) PC12 cells were preincubated with curcumin and its derivatives sAc1-sAc32 (10. mu.M) for 18H, followed by H2O2The cells were stimulated (640. mu.M) for 24h and the cell activity was determined by the MTT method. The cell activity of the solvent (DMSO) group was defined as 100%. Data are expressed as mean ± SD, with n ═ 3.####p<0.0001vs DMSO，****p＜0.0001，***p＜0.001，**p<0.01，*p<0.05vs H2O2；
FIG. 5sAc (or sAc 1; Compound sAc, i.e., sAc1, of the present invention) vs. H2O2Protective effect of induced oxidative damage of PC12 cells. (A) sAc promoting H2O2Colony formation of PC12 cells in the oxidative damage model. PC12 cells were preincubated with compound (2.5, 5, 10. mu.M) for 18h, followed by 300. mu. M H2O2The treatment is carried out for 6 days. Pictures were taken after crystal violet staining. (B) sAc can increase the survival rate of oxidative damage cells in a dose-dependent manner. PC12 cells were exposed to 510 μ M H after sAc pretreatment at various concentrations for 18h2O2In (1). The MTT method detects the cell survival rate. (C) sAc dose-dependent reduction of intracellular ROS levels. PC12 cells were treated with 2.5, 5, 10. mu.M sAc for 18H, respectively, followed by 1mM H2O2Stimulation was performed for 2h, and finally, 1. mu.L of DCFH-DA (10. mu.M) was used for 30min of dark incubation at 37 ℃. The fluorescence microscope takes images. The results are expressed as mean ± sd, n is 3.####P<0.0001 compared with the DMSO group,*P<0.05, **P<0.01 vs. H2O2Group (d);
FIG. 6sAc15 vs. H2O2Protective effect of induced oxidative stress injury of PC12 cells. (A) Compound sAc15 at H2O2Colony formation of PC12 cells was promoted under injury. PC12 cells were preincubated with sAc15(0.625, 1.25 and 2.5. mu.M) and TBHQ (2.5. mu.M) for 18H, followed by addition of H2O2(200. mu.M) for 8 days. (B) Compound sAc15 protected PC12 cells from H in a dose-dependent manner2O2Induced cell damage. PC12 cells were preincubated with sAc15 and TBHQ (20. mu.M) at various doses (0.625, 1.25, 2.5, 5, 10 and 20. mu.M) for 18H, followed by H2O2Cells were stimulated (650. mu.M) for 24 h. Cell viability was measured by the MTT method and the viability of the solvent (DMSO) group was defined as 100%. (C, D, E) PC12 cells were incubated with sAc15(1, 5 and 10. mu.M) and TBHQ (5. mu.M) for 18H, followed by H2O2(1mM) effect for (C)6h or (D, E)2h, and (C) MDA level and (D, E) intracellular ROS level were determined according to kit instructions. Data are expressed as mean ± SD, n ═ 3.####p<0.0001，###p<0.001 vs DMSO，****p<0.0001，***p<0.001，**p<0.01，*p<0.05vs H2O2；
FIG. 7sAc (or named sAc 1; Compound sAc in this patent is sAc1) reduced oxidative damage to PC12 cells by activating the Nrf2/HO-1 signaling pathway. (A) sAc increased HO-1 protein expression in a dose-dependent manner. PC12 cells were incubated with sAc (2.5, 5, 10. mu.M) for 18h and the levels of HO-1 and GAPDH protein were measured by Western Blot. (B-C) silencing Nrf2 reversed sAc antioxidant protection. PC12 cells silenced with Nrf2 were seeded in 96-well plates, pretreated with 10. mu.M sAc for 18h, and then exposed to 510. mu. M H2O2In (1). The MTT method detects the survival rate of the cells. The results are expressed as mean ± sd, n is 3.###P<0.001,####P<0.0001 compared with the DMSO group,**P<0.01 vs. H2O2Group (d);
compound sAc15 of figure 8 protected PC12 cells from oxidative stress damage by activating the Nrf2 signaling pathway. (A) Compound sAc15 induced nuclear translocation of Nrf2 in PC12 cells. PC12 cells were incubated with sAc15(10 μ M) and TBHQ (5 μ M) for 6h, followed by incubation with Nrf2 antibody and staining with DAPI. Images of nuclear translocation were taken under a fluorescent microscope. (B) Compound sAc15 upregulated HO-1 protein expression in PC12 cells. Cells were incubated with sAc15(1, 5 and 10. mu.M) and TBHQ (5. mu.M) for 18h and the level of HO-1 protein was measured by the western blot method. The cytoprotective effect of (C, D) sAc15 was attenuated upon downregulation of Nrf2 levels by siRNA. PC12 cells were transfected with Nrf2 siRNA (si-Nrf2) and control siRNA (NC), respectively, pretreated with sAc15(0.625 μ M) for 18H, and then with H2O2(650. mu.M) for 24 h. MTT method for determining cell viability, and western blot method for detecting protein waterAnd (7) flattening. Data are expressed as mean ± SD, with n ═ 3.####p<0.0001，##p＜0.01，#p＜0.05vs DMSO，*p<0.05vs H2O2，&p＜0.05vs NC；
FIG. 9sAc (or sAc1) protective effect on MCAO rats. (A) Representative images of groups of brain sections after TTC staining. (B-C) cerebral infarct size and neurological score for each group. Representative images of Sham (Sham) rats and brain sections of MCAO rats injected ventricles with saline (NS), solvent (DMSO: NS ═ 1: 100) and sAc (0.15 mg/kg). The results are expressed as mean ± sd, n is 6.####P<0.0001 compared to the Sham group,**P<0.01,****P<0.0001 compared to the Vehicle group;
figure 10 compound sAc15 showed pre-protection of mouse brain tissue following MCAO. (A) Representative images of TTC stained brain sections of different experimental groups. (B) Infarct (%) level and neurological score (C) for each group. Sham (Sham) or MCAO-reperfused mice received intraperitoneal injections of saline (NS), solvent (DMSO: castor oil: saline 1: 19: 80), sAc15(10 or 20mg/kg), and BNP (10mg/kg), respectively. Data are expressed as mean + -SD, with n ≧ 6.####p<0.0001 represents the statistical difference between NS and sham,****p＜0.0001，***p<0.001，*p<0.05 represents the statistical difference between the solvent group and the drug treatment group;
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Synthesis of the Compound of example 1
L-proline is used as a catalyst to synthesize the mono-ketene mono-carbonyl curcumin analogue in one step. All compounds were obtained by reacting acetone with the corresponding aldehyde at room temperature, and after purification by column chromatography, higher yields (40-71%) were obtained as shown in table 1.
Figure RE-GDA0003152666800000061
Synthesis and structure of mono-ketone mono-carbonyl curcumin analog. Reaction regulation (I) L-proline, DMSO, room temperature.
TABLE 1 Structure and yield of Monoketene Monocarbonyl curcumin analogs
Figure RE-GDA0003152666800000071
The compound is structurally identified by mass spectrum and H1-NMR, and the spectral and physicochemical data are shown in the following
. (E) -4-phenylbut-3-en-2-one (sAc or sAc1)
Yellow powder,70％yield,mp 34.8～36.0℃.1H-NMR(600MHz,CDCl3),δ: 7.558-7.542(m,2H,Ar-H2,β-H),7.520(d,J＝16.2Hz,1H,Ar-H6),7.409-7.398(m, 3H,Ar-H3,Ar-H4,Ar-H5),6.725(d,J＝16.2Hz,1H,α-H),2.390(s,3H,CH3). LC-MS m/z:147.08(M+H)+,calcd for C10H10O:146.07.
2.(E)-4-(2-methoxyphenyl)but-3-en-2-one(sAc2)
Yellow powder,66％yield,mp 43.9～45.7℃.1H-NMR(600MHz,DMSO-d6), δ:7.770(d,J＝16.2Hz,1H,β-H),7.682(t,J＝6.6Hz,1H,Ar-H6),7.425-7.396(m, 1H,Ar-H4),7.086(d,J＝8.4Hz,1H,Ar-H3),6.983(t,J＝7.2Hz,1H,Ar-H5),6.821 (d,J＝16.8Hz,1H,α-H),3.859(s,3H,2-OCH3),2.293(s,3H,CH3).LC-MS m/z: 177.09(M+H)+,calcd for C11H12O2:176.08.
3.(E)-4-(3-methoxyphenyl)but-3-en-2-one(sAc3)
Orange oil,68％yield.1H-NMR(600MHz,DMSO-d6),δ:7.578(d,J＝16.2Hz,
1H,β-H),7.330(t,J＝8.4 Hz,1H,Ar-H5),7.264(d,J＝7.2 Hz,2H,Ar-H2,Ar-H6), 6.983(t,J＝7.8 Hz,1H,Ar-H4),6.814(d,J＝16.8 Hz,1H,α-H),3.780(s,3H, 3-OCH3),2.317(s,3H,CH3).LC-MS m/z:177.09(M+H)+,calcd for C11H12O2: 176.08.
4.(E)-4-(4-methoxyphenyl)but-3-en-2-one(sAc4)
Yellow powder,71％yield,mp 67.4～68.2℃.1H-NMR(600 MHz,CDCl3),δ: 7.505-7.463(m,3H,Ar-H2,Ar-H6,β-H),6.917(d,J＝8.4 Hz,2H,Ar-H3,Ar-H5), 6.608(t,J＝7.2 Hz,1H,α-H),3.838(d,J＝7.2 Hz,3H,4-OCH3),2.354(d,J＝7.2 Hz,3H,CH3).LC-MS m/z:177.09(M+H)+,calcd for C11H12O2:176.08.
5.(E)-4-(2,3-dimethoxyphenyl)but-3-en-2-one(sAc5)
Yellow oil,65％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.724(d,J＝16.2 Hz, 1H,β-H),7.315(dd,J＝1.8 Hz,J＝4.8 Hz,1H,Ar-H6),7.114(d,J＝2.4 Hz,2H, Ar-H4,Ar-H5),6.815(d,J＝16.8 Hz,1H,α-H),3.814(s,3H,2-OCH3),3.762(s,3H, 3-OCH3),2.317(s,3H,CH3).LC-MS m/z:207.10(M+H)+,calcd for C12H14O3: 206.09.
6.(E)-4-(2,4-dimethoxyphenyl)but-3-en-2-one(sAc6)
White powder,67％yield,mp 56.1～57.2℃.1H-NMR(600 MHz,CDCl3),δ: 7.806(d,J＝16.2 Hz,1H,Ar-H6),7.487(d,J＝9.0 Hz,1H,β-H),6.675(d,J＝16.2 Hz,1H,Ar-H5),6.517(dd,J＝2.4 Hz,J＝6.6 Hz,1H,Ar-H3),6.455(d,J＝2.4 Hz, 1H,α-H),3.877(s,3H,2-OCH3),3.844(s,3H,4-OCH3),2.360(s,3H,CH3).LC-MS m/z:207.10(M+H)+,calcd for C12H14O3:206.09.
7.(E)-4-(2,5-dimethoxyphenyl)but-3-en-2-one(sAc7)
Yellow powder,64％yield,mp 41.2～42.1℃.1H-NMR(600 MHz,CDCl3),δ: 7.859(d,J＝16.2 Hz,1H,β-H),7.076(d,J＝3.0 Hz,1H,Ar-H3),6.931(dd,J＝3.0 Hz,J＝6.0 Hz,1H,Ar-H6),6.859(d,J＝9.0 Hz,1H,Ar-H4),6.713(d,J＝16.2 Hz, 1H,α-H),3.855(s,3H,2-OCH3),3.791(s,3H,5-OCH3),2.391(s,3H,CH3).LC-MS m/z:207.10(M+H)+,calcd for C12H14O3:206.09.
8.(E)-4-(3,4-dimethoxyphenyl)but-3-en-2-one(sAc8)
Yellow powder,61％yield,mp 78.1～79.9℃.1H-NMR(600 MHz,DMSO-d6), δ:7.541(d,J＝16.2 Hz,1H,β-H),7.305(d,J＝1.2 Hz,1H,Ar-H2),7.236(dd,J＝ 1.2 Hz,J＝7.2 Hz,1H,Ar-H5),6.986(d,J＝8.4 Hz,1H,Ar-H6),6.720(d,J＝16.2 Hz,1H,α-H),3.785(d,J＝6.0 Hz,6H,3-OCH3,4-OCH3),2.287(s,3H,CH3). LC-MS m/z:207.10(M+H)+,calcd for C12H14O3:206.09.
9.(E)-4-(3,5-dimethoxyphenyl)but-3-en-2-one(sAc9)
White powder,67％yield,mp 68.5～69.4℃.1H-NMR(600 MHz,DMSO-d6),δ: 7.529(d,J＝16.2 Hz,1H,β-H),6.873(d,J＝1.8 Hz,2H,Ar-H2,Ar-H6),6.820(d,J ＝16.8 Hz,1H,α-H),6.542(s,1H,Ar-H4),3.761(s,6H,3-OCH3,5-OCH3),2.310(s, 3H,CH3).LC-MS m/z:207.10(M+H)+,calcd for C12H14O3:206.09.
10.(E)-4-(2,4,5-trimethoxyphenyl)but-3-en-2-one(sAc10)
White powder,59％yield,mp 94.5～95.0℃.1H-NMR(600 MHz,CDCl3),δ: 7.732(d,J＝16.2 Hz,1H,β-H),7.225(s,1H,α-H),6.734(t,J＝16.2 Hz,2H,Ar-H3, Ar-H5),3.839(d,J＝11.4 Hz,6H,2-OCH3,5-OCH3),3.733(s,3H,4-OCH3),2.251 (s,3H,CH3).LC-MS m/z:237.11(M+H)+,calcd for C13H16O4:236.10.
11.(E)-4-(2,4,6-trimethoxyphenyl)but-3-en-2-one(sAc11)
Yellow powder,57％yield,mp 116.8～117.6℃.1H-NMR(600 MHz,CDCl3),δ: 7.937(d,J＝16.8 Hz,1H,β-H),7.063(d,J＝16.8 Hz,1H,α-H),6.115(s,2H,Ar-H3, Ar-H5),3.858(d,J＝15.6 Hz,9H,2-OCH3,4-OCH3,6-OCH3),2.343(s,3H,CH3). LC-MS m/z:237.11(M+H)+,calcd for C13H16O4:236.10.
12.(E)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one(sAc12)
White powder,57％yield,mp 87.0～88.1℃.1H-NMR(600 MHz,CDCl3),δ: 7.433(d,J＝16.2 Hz,1H,β-H),6.775(s,2H,Ar-H2,Ar-H6),6.631(d,J＝16.2 Hz, 1H,α-H),3.893(d,J＝4.2 Hz,9H,3-OCH3,4-OCH3,5-OCH3),2.384(s,3H,CH3). LC-MS m/z:237.11(M+H)+,calcd for C13H16O4:236.10.
13.(E)-4-(3-hydroxyphenyl)but-3-en-2-one(sAc13)
White powder,50％yield,mp 91.3～92.1℃.1H-NMR(600 MHz,DMSO-d6),δ: 9.654(s,1H,3-OH),7.508(d,J＝16.2 Hz,1H,β-H),7.214(t,J＝7.8 Hz,1H,Ar-H5), 7.110(d,J＝7.8 Hz,1H,Ar-H6),7.025(s,1H,Ar-H4),6.819(dd,J＝1.2 Hz,J＝6.6 Hz,1H,Ar-H2),6.665(d,J＝16.2 Hz,1H,α-H),2.304(s,3H,CH3).LC-MS m/z: 163.07(M+H)+,calcd for C10H10O2:162.07.
14.(E)-4-(4-hydroxyphenyl)but-3-en-2-one(sAc14)
Yellow powder,48％yield,mp 83.2～85.5℃.1H-NMR(600 MHz,CDCl3),δ: 7.495(d,J＝16.2 Hz,1H,β-H),7.453(dt,J＝8.4 Hz,J＝9.6 Hz,2H,Ar-H2,Ar-H6), 6.889(dd,J＝1.8 Hz,J＝4.8 Hz,2H,Ar-H3,Ar-H5),6.609(d,J＝16.2 Hz,1H,α-H), 2.383(s,3H,CH3).LC-MS m/z:163.07(M+H)+,calcd for C10H10O2:162.07.
15.(E)-4-(3,4-dihydroxyphenyl)but-3-en-2-one(sAc15)
Brown powder,45％yield,mp 162.8～164.0℃.1H-NMR(600 MHz, DMSO-d6),δ:9.587(s,1H,3-OH),9.159(s,1H,4-OH),7.432(d,J＝16.2 Hz,1H, β-H),7.042(d,J＝1.8 Hz,1H,Ar-H2),6.990(dd,J＝1.8 Hz,J＝6.6 Hz,1H,Ar-H5), 6.758(d,J＝8.4 Hz,1H,Ar-H6),6.462(d,J＝16.2 Hz,1H,α-H),2.258(s,3H,CH3). LC-MS m/z:179.07(M+H)+,calcd for C10H10O3:178.06.
16.(E)-4-(3-hydroxy-4-methoxyphenyl)but-3-en-2-one(sAc16)
Beige powder,52％yield,mp 84.0～85.5℃.1H-NMR(600 MHz,CDCl3),δ: 7.428(d,J＝16.2 Hz,1H,β-H),7.155(d,J＝2.4 Hz,1H,Ar-H2),7.059(dd,J＝2.4 Hz,J＝6.0 Hz,1H,Ar-H5),6.861(d,J＝7.8 Hz,1H,Ar-H6),6.588(d,J＝16.2 Hz, 1H,α-H),3.936(s,3H,4-OCH3),2.358(s,3H,CH3).LC-MS m/z:193.08(M+H)+, calcd for C11H12O3:192.08.
17.(E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one(sAc17)
Beige powder,56％yield,mp 115.9～117.8℃.1H-NMR(600 MHz,CDCl3),δ: 7.451(d,J＝16.2 Hz,1H,β-H),7.093(dd,J＝1.8 Hz,J＝6.6 Hz,1H,Ar-H2),7.060 (d,J＝1.8 Hz,1H,Ar-H5),6.935(d,J＝8.4 Hz,1H,α-H),6.589(d,J＝16.2 Hz,1H, Ar-H6),3.937(s,3H,3-OCH3),2.368(s,3H,CH3).LC-MS m/z:193.08(M+H)+, calcd for C11H12O3:192.08.
18.(E)-4-(4-hydroxy-3,5-dimethoxyphenyl)but-3-en-2-one(sAc18)
Beige powder,44％yield,mp 131.2～132.5℃.1H-NMR(600 MHz,CDCl3),δ: 7.429(d,J＝16.2 Hz,1H,β-H),6.794(s,2H,Ar-H2,Ar-H6),6.597(d,J＝16.2 Hz, 1H,α-H),3.926(s,6H,3-OCH3,5-OCH3),2.369(s,3H,α-CH3).LC-MS m/z:223.09 (M+H)+,calcd for C12H14O4:222.09.
19.(E)-3-(3-oxobut-1-en-1-yl)benzaldehyde(sAc19)
White powder,40％yield,mp 47.9～48.8℃.1H-NMR(600 MHz,CDCl3),δ: 10.052(s,1H,3-CHO),8.048(t,J＝1.8 Hz,1H,Ar-H6),7.905(dt,J＝7.8 Hz,J＝ 7.2 Hz,1H,Ar-H4),7.798(dd,J＝1.2 Hz,J＝6.6 Hz,1H,β-H),7.601-7.547(m,2H, Ar-H2,Ar-H5),6.809(d,J＝16.2 Hz,1H,α-H),2.406(s,3H,CH3).LC-MS m/z: 175.07(M+H)+,calcd for C11H10O2:174.07.
20.(E)-4-(3-fluorophenyl)but-3-en-2-one(sAc20)
Yellow oil,57％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.604(t,J＝4.2 Hz, 2H,β-H,Ar-H6),7.537(d,J＝7.2 Hz,1H,Ar-H5),7.481-7.444(m,1H,Ar-H4), 7.266-7.235(m,1H,Ar-H2),6.863(d,J＝16.2 Hz,1H,α-H),2.322(s,3H,CH3). LC-MS m/z:165.07(M+H)+,calcd for C10H9FO:164.06.
21.(E)-4-(4-fluorophenyl)but-3-en-2-one(sAc21)
Yellow oil,60％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.788-7.764(m,2H, Ar-H3,Ar-H5),7.613(d,J＝16.8 Hz,1H,β-H),7.261(t,J＝9.0 Hz,2H,Ar-H2, Ar-H6),6.762(d,J＝16.2 Hz,1H,α-H),2.312(s,3H,CH3).LC-MS m/z:165.07 (M+H)+,calcd for C10H9FO:164.06.
22.(E)-4-(3,4-difluorophenyl)but-3-en-2-one(sAc22)
Yellow oil,51％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.893-7.860(m,1H, β-H),7.578(d,J＝16.8 Hz,2H,Ar-H5,Ar-H6),7.491(d,J＝10.2 Hz,1H,Ar-H2), 6.829(d,J＝16.2 Hz,1H,α-H),2.310(s,3H,CH3).LC-MS m/z:183.06(M+H)+, calcd for C10H8F2O:182.05.
23.(E)-4-(3,5-difluorophenyl)but-3-en-2-one(sAc23)
Yellow oil,55％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.572(d,J＝16.2 Hz, 1H,β-H),7.501(d,J＝6.6 Hz,2H,Ar-H2,Ar-H6),7.312-7.282(m,1H,α-H),6.928 (d,J＝16.2 Hz,1H,Ar-H4),2.319(s,3H,CH3).LC-MS m/z:183.06(M+H)+,calcd for C10H8F2O:182.05.
24.(E)-4-(3-chlorophenyl)but-3-en-2-one(sAc24)
Yellow oil,56％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.812(s,1H,β-H), 7.671(d,J＝7.2 Hz,1H,Ar-H6),7.587(d,J＝16.2 Hz,1H,Ar-H5),7.477-7.430(m, 2H,Ar-H2,Ar-H4),6.880(d,J＝16.2 Hz,1H,α-H),2.319(s,3H,CH3).LC-MS m/z: 181.04(M+H)+,calcd for C10H9ClO:180.03.
25.(E)-4-(4-chlorophenyl)but-3-en-2-one(sAc25)
White powder,61％yield,mp 51.6～52.2℃.1H-NMR(600 MHz,CDCl3),δ: 7.485-7.448(m,3H,Ar-H2,Ar-H6,β-H),7.387-7.365(m,2H,Ar-H3,Ar-H5),6.689(d, J＝16.2 Hz,1H,α-H),2.382(s,3H,CH3).LC-MS m/z:181.04(M+H)+,calcd for C10H9ClO:180.03.
26.(E)-4-(3,5-dichlorophenyl)but-3-en-2-one(sAc26)
White powder,57％yield,mp 72.0～72.5℃.1H-NMR(600 MHz,CDCl3),δ: 7.407(d,J＝1.8 Hz,2H,β-H,Ar-H4),7.367(t,J＝1.8 Hz,2H,Ar-H2,Ar-H6),6.700 (d,J＝16.2 Hz,1H,α-H),2.379(s,3H,CH3).LC-MS m/z:215.99(M+H)+,calcd for C10H8Cl2O:214.00.
27.(E)-4-(4-bromophenyl)but-3-en-2-one(sAc27)
White powder,62％yield,mp 74.9～76.4℃.1H-NMR(600 MHz,CDCl3),δ: 7.532(d,J＝8.4 Hz,2H,Ar-H3,Ar-H5),7.442(d,J＝16.2 Hz,1H,β-H),7.405(d,J ＝8.4 Hz,2H,Ar-H2,Ar-H6),6.700(d,J＝16.2 Hz,1H,α-H),2.376(s,3H,CH3). LC-MS m/z:224.99(M+H)+,calcd for C10H9BrO:223.98.
28.(E)-4-(4-(dimethylamino)phenyl)but-3-en-2-one(sAc28)
Yellow powder,61％yield,mp 129.7～130.7℃.1H-NMR(600 MHz,CDCl3),δ: 7.453(t,J＝16.8 Hz,3H,Ar-H2,Ar-H6,β-H),6.678(d,J＝8.4 Hz,2H,Ar-H3,Ar-H5), 6.546(d,J＝16.8 Hz,1H,α-H),3.031(s,6H,4-N(CH3)2),2.340(s,3H,CH3). LC-MS m/z:190.12(M+H)+,calcd for C12H15NO:189.12.
29.(E)-4-(4-(diethylamino)phenyl)but-3-en-2-one(sAc29)
Yellow oil,58％yield.1H-NMR(600 MHz,DMSO-d6),δ:7.480-7.451(m,3H, Ar-H2,Ar-H6,β-H),6.658(d,J＝9.0 Hz,2H,Ar-H3,Ar-H5),6.485(d,J＝16.2 Hz, 1H,α-H),3.388-3.353(m,4H,N(CH2)2),2.235(s,3H,CH3),1.086(t,J＝6.6 Hz,6H, C(CH3)2).LC-MS m/z:218.15(M+H)+,calcd for C14H19NO:217.15.
30.(E)-4-(4-(piperidin-1-yl)phenyl)but-3-en-2-one(sAc30)
Yellow powder,54％yield,mp 98.4～99.4℃.1H-NMR(600 MHz,DMSO-d6), δ:7.490(t,J＝8.4 Hz,3H,Ar-H2,Ar-H6,β-H),6.913(d,J＝9.0 Hz,2H,Ar-H3, Ar-H5),6.545(d,J＝16.2 Hz,1H,α-H),3.031(s,4H,N(CH2)2),2.250(s,3H,CH3), 1.557(s,6H,CH2CH2CH2).LC-MS m/z:230.15(M+H)+,calcd for C15H19NO: 229.15.
31.(E)-4-(4-morpholinophenyl)but-3-en-2-one(sAc31)
Yellow powder,51％yield,mp 131.7～132.8℃.1H-NMR(600MHz,CDCl3),δ: 7.466-7.415(m,3H,Ar-H2,Ar-H6,β-H),6.884(t,J＝7.8Hz,2H,Ar-H3,Ar-H5), 6.603-6.524(m,1H,α-H),3.841(d,J＝30.0Hz,4H,O(CH2)2),3.257-3.206(m,4H, N(CH2)2),2.351-2.298(m,3H,CH3).LC-MS m/z:232.13(M+H)+,calcd for C14H17NO2:231.13.
32.(E)-4-(naphthalen-2-yl)but-3-en-2-one(sAc32)
White powder,55％yield,mp 97.0～98.3℃.1H-NMR(600MHz,CDCl3),δ: 7.965(s,1H,Ar-H3),7.878-7.836(m,3H,Ar-H2,Ar-H6,Ar-H7),7.698-7.672(m,2H, Ar-H8,β-H),7.539-7.519(m,2H,Ar-H4,Ar-H5),6.842(d,J＝16.2Hz,1H,α-H), 2.431(s,3H,CH3).LC-MS m/z:197.09(M+H)+,calcd for C14H12O:196.09.
Example 2
The mono-carbonyl curcumin analogue molecular skeleton (sAc or sAc1) has good stability, low toxicity and good cell protection activity.
In phosphate buffer, the stability of curcumin (Cur.), curcumin skeleton (Cur-S), diketene monocarbonyl curcumin analogue molecular skeleton (Ac) and the monoene monocarbonyl curcumin analogue molecular skeleton (sAc) of the invention (figure 1B) were determined. The results show that the light absorption of Cur, Cur-S, Ac decreased greatly in a time-dependent manner within 30 minutes, while sAc remained unchanged. Therefore, the material sAc has a more stable structure than Cur and Cur-S, Ac.
The cytotoxicity of the molecular skeleton (Ac) of the diketene monocarbonyl curcumin analogue and the molecular skeleton (sAc) of the monoalkenyl monocarbonyl curcumin analogue on normal liver cells (MIHA) and kidney cells (NRK) is determined by an MTT method (figure 2). The results show that the cell survival rate of sAc group was much greater than that of Ac group in both cells at the same concentration, i.e., Ac had a greater growth inhibition rate on the cells. sAc is therefore relatively less cytotoxic than Ac.
The adrenal pheochromocytoma cell line from rats (PC12) exhibits the general characteristics of neuroendocrine cells and is widely used in neurophysiological and neuropharmacological studies. Further cytotoxicity tests on PC12 cells found that sAc was also relatively less cytotoxic to PC12 cells compared to curcumin and Ac (fig. 1C).
Hydrogen peroxide (H2O2) is an important oxygen Radical (ROS) and is commonly used in the study of oxidative stress injury models for various diseases. Therefore, the H2O 2-induced oxidative damage model was used to evaluate the antioxidant protective activity of compounds on cells. The cell viability of PC12 after oxidative injury by H2O2 was about 55% of the solvent [ dimethyl sulfoxide (DMSO) ] group (fig. 2B). After the mono-ketene monocarbonyl curcumin analogue molecular skeleton (sAc) is added, the cell survival rate is obviously increased, namely sAc shows obvious antioxidant protection activity on PC12 cells, and neither curcumin nor Ac group is active (figure 1D).
Example 3
The monocarbonyl curcumin analogues (sAc) have good antioxidant protection activity on PC12 cells and low cytotoxicity
The cytotoxicity of 32 sAc-class compounds on PC12 cells was determined by MTT method, and the results showed that all compounds showed significantly significant cytotoxicity on PC12 cells at the determined concentrations compared to curcumin control group (fig. 4A).
In a H2O 2-induced PC12 cell oxidative damage model, the antioxidant protection activity of 32 sAc compounds is measured. The results show that cell viability increased to 70-80% in most groups pre-incubated with compound (fig. 4B). Among them, 20 compounds (sAc (1-5), sAc7, sAc9, sAc14, sAc (15-24), sAc27 and sAc32) had better protective activity than even the antioxidant TBHQ. While the cell survival rate of curcumin group was lower than that of H2O2 group.
Example 4
sAc1 and sAc15 protection against H2O 2-induced oxidative damage to PC12 cells
The protective effect of active compounds sAc1 (sAc and sAc1 are the same compounds of the invention) and sAc15 on H2O 2-induced oxidative damage to PC12 cells was further investigated. MTT experiments showed that both sAc1 (fig. 5B) and sAc15 (fig. 6B) were able to increase the survival rate of oxidative damage of PC12 cells induced by hydrogen peroxide in a concentration-dose-dependent manner. In the PC12 cell colony formation experiment, H2O2 obviously inhibits the cell colony formation (FIG. 4A), but the effect is reversed by sAc1 (FIG. 5A) and sAc15 (FIG. 6A), and the effect is far better than that of positive control drug TBHQ, so that both compounds have antioxidant protection effect on the cell colony formation.
ROS is the main cause of oxidative damage, so the effect of the compound on ROS production of PC12 cells induced by hydrogen peroxide is determined. ROS levels were measured by dichlorodihydrofluorescein diacetate (DCFH-DA) assay. ROS levels were significantly increased in PC12 cells exposed to H2O2 compared to the DMSO group. Compounds sAc1 (fig. 5C) and sAc15 (fig. 6DE) were both able to eliminate intracellular ROS in a dose-dependent manner after 18 hours of pretreatment.
An imbalance in the production and clearance of ROS results in oxidative stress, destruction of cellular components such as proteins, enzymes, lipids, etc., and the formation of the lipid peroxidation product Malondialdehyde (MDA). Therefore, the influence of the compound on MDA production of PC12 cells induced by hydrogen peroxide is determined. The results show that the MDA content in the H2O2 damage group is significantly higher than the MDA content in the solvent group. After 18 hours of preincubation with compound sAc15 (fig. 6C), MDA content decreased significantly.
Example 5
Active compounds reduce oxidative damage to PC12 cells by activating Nrf2/HO-1 signaling pathway
Compounds sAc1 and sAc15 showed excellent antioxidant properties, and their mechanism of action was further explored. Nrf2 is a "primary" regulator of oxidative damage to cells. Therefore, immunofluorescence assays were used to determine if sAc15 could promote accumulation of Nrf2 in the nucleus. Blue and red staining represent nuclei and Nrf2, respectively. Compared to the DMSO group, the sAc 15-treated group showed red fluorescence in nuclei and was stronger than the positive control group (TBHQ) (fig. 9A). These results indicate that sAc15 can promote accumulation of Nrf2 in the nucleus. During oxidative stress, Nrf2 is activated to induce downstream expression of heme oxygenase-1 (HO-1) and other antioxidant enzymes. The effect of sAc1 (FIG. 8A) and sAc15 (FIG. 9B) on HO-1 protein expression in PC12 cells was evaluated. Increased expression of antioxidant enzyme HO-1 was observed in cells incubated with both compounds; furthermore, the expression of HO-1 protein was higher with increasing concentration of the compound. To further demonstrate the protective effect of compounds on H2O 2-induced oxidative stress damaged cells, expression of Nrf2 protein was down-regulated by transfection of Nrf2 small interfering (si) RNA into PC12 cells. The protective effect of the compounds on oxidative stress injury was evaluated against cells in the Nrf2 siRNA and control siRNA groups. Downregulation of Nrf2 expression inhibited protection of sAc1 (fig. 7BC) and sAc15 (fig. 8 CD). Thus, both sAc1 and sAc15 can protect PC12 cells from oxidative damage by targeting Nrf2 to enhance HO-1 expression.
Example 6
Protection effect of compound on oxidative stress injury after cerebral ischemia reperfusion of MCAO rat
Cerebral ischemia-reperfusion can bring irreversible damage to nerve cells, wherein oxidative stress is a core mechanism of the damage, so the cerebral ischemia-reperfusion damage of mice can be used as a classical model for evaluating the in vivo antioxidant activity of the compound. Middle Cerebral Artery Occlusion (MCAO) is a common focal cerebral ischemia model, and because the pathogenesis of the MCAO is similar to that of human ischemic stroke, the MCAO is widely used for researching the pathogenesis of cerebral ischemia and screening therapeutic drugs. Thus, using the mouse MCAO model, the antioxidant protective activity of sAc1 and sAc15 in vivo was investigated. The brain sections of the sham-operated group had no infarcted tissue, while the infarct incidence of the brain tissue of the model group was-30%. The cerebral infarction incidence rate of the solvent group and the model group has no statistical difference, which indicates that the solvent has no neuroprotective effect. Compared with the model group or the solvent group, the infarct size was significantly reduced in the administration groups sAc1 (FIG. 9) and sAc15 (FIG. 10), and the nervous system score was significantly improved. sAc15 has activity similar to that of clinical medicine butylphthalide. Therefore, active compounds sAc1 and sAc15 have a good protective effect against oxidative stress injury in cerebral ischemia-reperfusion.
Example 7
Effect of active Compounds on survival of LPS-induced mouse death
Male B6 mice were given a dose of 15mg/kg i.p. (sAc1 and sAc15) and 15 minutes later LPS (20 mg/kg). Survival was recorded every 12h for 7 consecutive days. The LPS group mice all die within 5 days, and the lethality of the mice in the drug adding group is obviously reduced. Therefore, sAc1 and sAc15 can obviously increase the survival rate of LPS to mice lethality, and have the prospect of being developed into antioxidant drugs.
The above embodiments are described in detail for the purpose of further illustrating the present invention and should not be construed as limiting the scope of the present invention, and the skilled engineer can make insubstantial modifications and variations of the present invention based on the above disclosure.

Claims (5)

1. The application of the compound with the general formula (I) in preparing antioxidant drugs,
Figure FDA0003117418170000011
ar is a benzene ring or a naphthalene ring or an aromatic heterocyclic ring which is mono-substituted, poly-substituted or unsubstituted by a substituent R;
the substituent R is one or more of alkyl, alkenyl, alkynyl, alkoxy, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkoxy, cycloalkyl alkyl, carboxyl and amino;
wherein, the substituent R in the polysubstituted Ar is the same substituent or different substituents.
2. Use according to claim 1, characterized in that: the medicament is for use in one or more of the following diseases: sepsis caused by oxidative stress, ischemia and ischemia reperfusion injury of organs of brain, heart, kidney and liver, acute mild and moderate pain; parkinson's disease, Alzheimer's disease, atherosclerosis, diabetic complications caused by oxidative stress.
3. A pharmaceutical composition for the treatment of oxidative stress injury comprising a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof;
Figure FDA0003117418170000012
ar is a benzene ring or a naphthalene ring or an aromatic heterocyclic ring which is mono-substituted, poly-substituted or unsubstituted by a substituent R;
the substituent R is one or more of alkyl, alkenyl, alkynyl, alkoxy, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkoxy, cycloalkyl alkyl, carboxyl and amino;
wherein, the substituent R in the polysubstituted Ar is the same substituent or different substituents.
4. The pharmaceutical composition of claim 3, wherein: a compound of formula (I) or a salt or solvate thereof as the sole active ingredient.
5. The pharmaceutical composition of claim 3, wherein: the preparation form of the pharmaceutical composition is selected from one of injection, tablet, suppository, membrane, capsule, ointment, aerosol, dripping pill, controlled release or sustained release agent and nano preparation.
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