CN112209989A - Polygala tenuifolia sapogenin derivative, pharmaceutical composition and application thereof - Google Patents
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Abstract
The invention discloses a series of pre-polygala tenuifolia saponins prepared by using pre-polygala tenuifolia sapogenin as a lead compound through corresponding chemical reactionsThe structural formula of the derivative of the polygala tenuifolia sapogenin is shown in a general formula (1),
Description
Technical Field
The invention relates to the technical field of compounds, in particular to the field of pharmaceutical chemistry, and specifically relates to a polygala tenuifolia sapogenin derivative, a pharmaceutical composition thereof and application thereof.
Background
Oxidative Stress (OS) refers to a state of imbalance between Oxidative and antioxidant effects in the body, and it causes inflammatory infiltration of neutrophils, increased secretion of proteases, and the production of a number of Oxidative intermediates. Oxidative stress is a negative effect produced in vivo by free radicals and is considered to be an important factor in aging and diseases. Evidence from experimental and clinical studies suggests that oxidative stress plays an important role in the development and progression of many diseases.
Extensive research in the field of pathogenesis has shown that oxidative stress and Reactive Oxygen Species (ROS) are involved in a variety of diseases. Inflammation caused by many diseases may cause oxidative stress, which is also involved in many other diseases.
The deleterious effects of oxidative stress have long been thought to cause neurodegenerative diseases. There is evidence that oxidative stress, including free radicals, plays a major role in Alzheimer's Disease (AD) and Parkinson's Disease (PD). ROS produced in the brain can cause severe damage to neurons, leading to memory loss and cognitive impairment. Oxidative stress caused by ROS in the brain is associated with a number of debilitating diseases including parkinson's disease, alzheimer's disease, autism and down syndrome. Although the mechanisms leading to neurodegenerative diseases may differ, overproduction of reactive oxygen species has been thought to lead to neuronal damage. The constant accumulation of oxidative damage may be responsible for the late onset and slow progression of these chronic diseases.
At the cellular and molecular level, redox imbalances can cause activation of redox-sensitive transcription factors, leading to inflammation. Thus, uncontrolled ROS due to increased oxidative stress is a major factor in acute and chronic inflammation and inflammation-related diseases. Oxidative stress plays an important role in both the development and progression of cancer. ROS, as a carcinogenesis promoter, are involved in the initiation of nuclear or mitochondrial DNA mutations, including point mutations, deletions, insertions, chromosomal translocations, and the like. ROS can also cause DNA damage by producing oxidative DNA modifications in tumor tissue.
In recent years, the number of diabetic cases has proliferated, leading to a dramatic increase in end-stage renal disease, and hundreds of thousands of patients are forced to undergo routine dialysis for detoxification. The mechanism of development of diabetic end stage renal disease (or diabetic nephropathy) is not clear. However, in the microvasculature, oxidative stress is a common link in all pathways involved in complications associated with diabetes. Some macromolecules are involved in the increase of reactive oxygen species production, including NADPH oxidase, advanced glycation end products (AGEs), polyol pathway defects, Nitric Oxide Synthase (NOS), and mitochondrial complexes I and III. Unbalanced ROS production affects activation of protein kinase C, various cytokines and transcription factors, resulting in enhanced expression of extracellular matrix (ECM) genes, leading to fibrosis and nephropathy.
At present, great progress has been made in antioxidants from natural products, including tea polyphenols, flavones, alkaloids, terpenoids, and the like. Especially terpenoids are recently reported to have good anti-inflammatory and anti-oxidation effects and are often used for cardiovascular and oxidative stress related diseases.
Polygalaxolide is one of pentacyclic triterpene compounds, is rich in nature, has good antiinflammatory and antioxidant effects as proved by pharmacological research, and has neuroprotective effect as proved by tenuifolin.
The polygala tenuifolia sapogenin structure modification based on a specific action mechanism can improve the antioxidation of polygala tenuifolia sapogenin in a targeted manner through reasonable medicine design on one hand, and has more significance for the development of new medicines due to high content and easy availability in nature on the other hand.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the polygala tenuifolia sapogenin derivative, the pharmaceutical composition and the application thereof, which can be used for preparing the medicines for treating the diseases related to the antioxidant stress.
In order to achieve the above object, the present invention provides a polygala root sapogenin derivative, which is characterized in that the structural formula of the polygala root sapogenin derivative is shown as the general formula (1),
wherein the content of the first and second substances,
R1、R2、R3each independently selected from the group consisting of: H. glucose group, glucose group,
R4、R5Each independently selected from:
R6selected from: H. OH, ═ O, or absent;
R7selected from: h or is absent;
or, R6、R7An epoxy structure is formed.
Preferably, R8、R10Each independently selected from: substituted or unsubstituted C1-10Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C3-10Cycloalkyl groups of (a);
R9independently selected from: substituted or unsubstituted C1-10Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or a salt thereofSubstituted or unsubstituted aryl, substituted or unsubstituted C3-10A cycloalkyl group of,
Or
R11、R12Each independently selected from: H. substituted or unsubstituted C1-10A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted C3-10Cycloalkyl groups of (a);
R13、R14each independently selected from: H. substituted or unsubstituted C1-10A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted C3-10Cycloalkyl groups of (a);
when R is8、R9、R10、R11、R12、R13Or R14Is substituted C1-10When the alkyl group is a straight or branched chain alkyl group of (1), C1-10The substituent of the linear chain or branched chain alkyl is one of amido, substituted or unsubstituted aryl and cyano, and the substituent of the aryl is one or more of halogen, amido, alkyl, nitro, hydroxyl or alkoxy;
when R is8、R9、R10、R11、R12、R13Or R14When the aryl is substituted alkenyl, the substituent of the alkenyl is one of amido, substituted or unsubstituted aryl and cyano, and the substituent of the aryl is one or more of halogen, amido, alkyl, nitro, hydroxyl or alkoxy;
when R is8、R9、R10、R11、R12、R13Or R14When the substituent is substituted alkynyl, the substituent of the alkynyl is one of amino, substituted or unsubstituted aryl and cyano, and the substituent of the aryl is halogen,One or more of amino, alkyl, nitro, hydroxyl or alkoxy;
when R is8、R9、R10、R11、R12、R13Or R14Is substituted C3-10Cycloalkyl of, C3-10The substituent of the naphthenic base is one of amido, substituted or unsubstituted aryl and cyano, and the substituent of the aryl is one or more of halogen, amido, alkyl, nitryl, hydroxyl or alkoxy;
when R is8、R9、R10、R11、R12、R13Or R14When the aryl is substituted, the substituent of the aryl is one or more of halogen, amino, alkyl, nitro, hydroxyl or alkoxy.
As used herein, "a" or "an" or "a class" means at least one or more than one.
As used herein, "alkyl" means any saturated straight, pendant, or cyclic hydrocarbon group, and specifically includes small alkyl groups containing ten or less carbons.
As used herein, "aryl" is a cyclic conjugated aromatic system and may contain one or more non-carbon atoms (other than carbon, such as nitrogen) in the ring, such as phenyl, pyridyl, pyrazinyl.
It is specifically further noted that the various substituents defined above also include those groups which they form by further substitution, wherein these novel substituents may also contain other groups. For example, the substitution of hydrogen atoms on alkyl and aryl groups by amino, halogen or other groups is a group falling within the definitions set forth above.
The invention also provides a pharmaceutical composition which is mainly characterized by comprising the derivative modified by the structure of the polygala tenuifolia sapogenin or the pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier.
The invention provides application of the polygala tenuifolia sapogenin structure modified derivative in preparing a medicine for treating oxidative stress related diseases, in particular neurodegenerative diseases, inflammation, cancer, diabetic nephropathy and the like.
By adopting the polygala tenuifolia sapogenin derivative, the pharmaceutical composition and the application thereof, the lead compound is systematically subjected to structural modification aiming at 3 hydroxyls for the first time, a series of new compounds are synthesized, and many of the new compounds show good activity through activity tests of related targets, so that the polygala tenuifolia sapogenin derivative is very valuable for treating oxidative stress related diseases. Makes up the defects of the polygala tenuifolia sapogenin derivative in the prior art and is very significant.
Detailed Description
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.
All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.
To further illustrate the present invention, the polygalasaponin derivative provided by the present invention is described in detail below with reference to examples, and the scope of the present invention is not limited by the following examples.
Example 1
Preparation of tenuifolin derivative Y2-Y5
Preparation of Compounds Y2-Y5
Polygalaxolide Y1(6.80g,10mmol) was dissolved in N, N-dimethylformamide (40mL), potassium carbonate (1.66g,12mmol) and various iodoalkanes (12mmol) were added, and the reaction was carried out at 65 ℃ for 3 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, water was added to quench (50mL), and the mixture was extracted with dichloromethane (100 mL. times.3), and the organic layers were combined, washed successively with saturated sodium bicarbonate solution (100mL), water and saturated brine (100mL), collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give Y2-Y5 (85-95%).
Compound Y2, white solid.1H NMR(400MHz,CDCl3)δ5.86(1H,m),5.30(1H,m),3.70(3H,s),3.65(6H,s),3.28(1H,d,J＝12Hz),3.18(1H,d,J＝12Hz),1.26(3H,s),1.20(3H,s),0.96(3H,s),0.91(3H,s),0.66(3H,s).MS(ESI):m/z 709.42[M+H]+。
Compound Y3, white solid.1H NMR(400MHz,CDCl3)δ5.86(1H,m),5.30(1H,m),4.02(4H,m),3.28(1H,d,J＝12Hz),3.18(1H,d,J＝12Hz),1.63(4H,m),1.35(8H,m),1.25(3H,s),1.20(3H,s),0.96(3H,s),0.91(6H,m),0.90(3H,s),0.67(3H,s).MS(ESI):m/z 821.54[M+H]+。
Compound Y4, white solid.1H NMR(400MHz,CDCl3)δ5.87(1H,m),5.30(1H,m),3.95(4H,m),3.30(1H,d,J＝12Hz),3.18(1H,d,J＝12Hz),1.97(4H,m),1.25(3H,s),1.21(3H,s),0.96(3H,s),0.94(12H,m),0.90(3H,s),0.67(3H,s).MS(ESI):m/z 793.51[M+H]+。
Compound Y5, white solid.1H NMR(400MHz,CDCl3)δ5.86(1H,m),5.30(1H,m),4.00(4H,m),3.27(1H,d,J＝12Hz),3.18(1H,d,J＝12Hz),1.66(4H,m),1.25(3H,s),1.20(3H,s),0.96(6H,m),0.94(3H,s),0.90(3H,s),0.67(3H,s).MS(ESI):m/z 765.48[M+H]+。
Example 2
Preparation of senegenin carbamate derivative SA1-SA16
When R is2When H, R1Is composed of
When R is1When H, R2Is composed of
Preparation of Y2
Polygala tenuifolia saponin Y1(6.80g,10mmol) was dissolved in N, N-dimethylformamide (40mL), methyl iodide (1.70g,12mmol) and potassium carbonate (1.66g,12mmol) were added, the mixture was reacted at 65 ℃ for 3 hours, and the progress of the reaction was monitored by TLC. After completion of the reaction, water was added to quench (50mL), dichloromethane was extracted (100 mL. times.3), and the organic layers were combined, washed successively with a saturated sodium bicarbonate solution (100mL), water and a saturated brine (100mL), and the organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give Y2 (95%).
Preparation of SQ
Y2(708mg,1mmol) was weighed accurately and dissolved in 0.2mol/L sodium dihydrogen phosphate buffer (pH 5.0), placed in an erlenmeyer flask, 3.54g snailase was weighed accurately and added to the erlenmeyer flask and mixed well. Culturing in a constant temperature shaker at 37 deg.C for 8 h. After the reaction, 8 times the amount of methanol was added to inactivate the enzyme, and the mixture was left overnight. Methanol was removed under reduced pressure, aglycone was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give SQ (70%).
Preparation of Compound SA1-16
SQ (5.5g,10mmol) and p-nitrobenzoate (12mmol) were dissolved in 40mL of anhydrous dichloromethane under nitrogen, anhydrous pyridine (0.5mL) was added in ice bath, the reaction was continued at room temperature for 3h, and the progress of the reaction was monitored by TLC. After completion of the reaction, ice water (100mL) was added, methylene chloride was extracted (100 mL. times.3), the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an intermediate, which was then used in the next reaction without further purification.
The intermediate (10mmol) and triethylamine (0.1mL) were dissolved in 40mL of anhydrous dichloromethane under nitrogen, the corresponding amine (12mmol) was added and the reaction was allowed to proceed for 3h at room temperature and monitored by TLC for the progress of the reaction. After completion of the reaction, ice water (100mL) was added, methylene chloride was extracted (100 mL. times.3), the organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain differently substituted SA1-16 (35% -45%).
Compound SA1, white solid.1H NMR(400MHz,CDCl3)δ7.28(5H,m),5.53(1H,s),5.38(1H,m),4.29(2H,d,J＝8Hz),3.64(6H,s),1.26(3H,s),1.14(3H,s),0.92(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 680.42[M+H]+。
Compound SA2, white solid.1H NMR(400MHz,CDCl3)δ5.55(1H,s),5.29(1H,m),3.68(3H,s),3.63(3H,s),2.97(2H,m),2.12(1H,m),1.26(3H,s),1.16(3H,s),0.91(3H,s),0.88(6H,d,J＝8Hz),0.86(3H,s),0.68(3H,s).MS(ESI):m/z 646.43[M+H]+。
Compound SA3, white solid.1H NMR(400MHz,CDCl3)δ5.53(1H,s),5.29(1H,m),3.66(3H,s),3.64(3H,s),3.52(1H,m),1.24(3H,s),1.13(3H,s),0.90(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 672.45[M+H]+。
Compound SA4, white solid.1H NMR(400MHz,CDCl3)δ5.56(1H,s),5.33(1H,m),3.68(3H,s),3.63(3H,s),3.32-3.40(10H,m),1.26(3H,s),1.16(3H,s),0.92(3H,s),0.86(3H,s),0.71(3H,s).MS(ESI):m/z 658.43[M+H]+。
Compound SA5, white solid.1H NMR(400MHz,CDCl3)δ5.55(1H,s),5.32(1H,m),3.68(3H,s),3.64(3H,s),3.30-3.38(8H,m),1.26(3H,s),1.19(3H,s),0.91(3H,s),0.85(3H,s),0.70(3H,s).MS(ESI):m/z 644.42[M+H]+。
Compound SA6, white solid.1H NMR(400MHz,CDCl3)δ5.55(1H,s),5.35(1H,m),3.91(1H,m),3.69(3H,s),3.63(3H,s),1.25(3H,s),1.15(3H,s),0.92(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 658.43[M+H]+。
Compound SA7, white solid.1H NMR(400MHz,CDCl3)δ7.30-7.35(5H,m),5.55(1H,s),5.33(1H,m),3.66(3H,s),3.62(3H,s),1.22(3H,s),1.13(3H,s),0.90(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 666.40[M+H]+。
Compound SA8, white solid.1H NMR(400MHz,CDCl3)δ5.54(1H,s),5.30(1H,m),3.69(3H,s),3.63(3H,s),3.22(5H,m),1.26(3H,s),1.16(3H,s),0.92(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 618.40[M+H]+。
Compound SA9, white solid.1H NMR(400MHz,CDCl3)δ7.30(5H,m),5.83(1H,d,J＝8Hz),5.43(1H,m),4.27(2H,d,J＝8Hz),3.65(3H,s),3.63(3H,s),1.22(3H,s),1.13(3H,s),0.91(3H,s),0.88(3H,s),0.66(3H,s).MS(ESI):m/z 680.42[M+H]+。
Compound SA10, white solid.1H NMR(400MHz,CDCl3)δ5.82(1H,d,J＝8Hz),5.34(1H,m),3.66(3H,s),3.62(3H,s),2.67(2H,m),2.23(1H,m),1.26(3H,s),1.15(3H,s),0.91(3H,s),0.88(3H,s),0.86(6H,d,J＝8Hz),0.67(3H,s).MS(ESI):m/z 646.43[M+H]+。
Compound SA11, white solid.1H NMR(400MHz,CDCl3)δ5.81(1H,d,J＝8Hz),5.28(1H,m),3.68(3H,s),3.63(3H,s),3.46(1H,m),1.26(3H,s),1.14(3H,s),0.92(3H,s),0.87(3H,s),0.68(3H,s).MS(ESI):m/z 672.45[M+H]+。
Compound SA12, white solid.1H NMR(400MHz,CDCl3)δ5.80(1H,d,J＝8Hz),5.34(1H,m),3.67(3H,s),3.62(3H,s),3.31-3.40(10H,m),1.28(3H,s),1.13(3H,s),0.94(3H,s),0.91(3H,s),0.66(3H,s).MS(ESI):m/z 658.43[M+H]+。
Compound SA13, white solid.1H NMR(400MHz,CDCl3)δ5.84(1H,d,J＝8Hz),5.31(1H,m),3.69(3H,s),3.64(3H,s),3.31-3.37(8H,m),1.25(3H,s),1.17(3H,s),0.96(3H,s),0.91(3H,s),0.67(3H,s).MS(ESI):m/z 644.42[M+H]+。
Compound SA14, white solid.1H NMR(400MHz,CDCl3)δ5.83(1H,d,J＝8Hz),5.35(1H,m),3.93(1H,m),3.69(3H,s),3.64(3H,s),1.26(3H,s),1.12(3H,s),0.96(3H,s),0.90(3H,s),0.67(3H,s).MS(ESI):m/z 658.43[M+H]+。
Compound SA15, white solid.1H NMR(400MHz,CDCl3)δ7.29-7.36(5H,m),5.83(1H,d,J＝8Hz)5.35(1H,m),3.66(3H,s),3.64(3H,s),1.25(3H,s),1.10(3H,s),0.92(3H,s),0.88(3H,s),0.72(3H,s).MS(ESI):m/z 666.40[M+H]+。
Compound SA16, white solid.1H NMR(400MHz,CDCl3)δ5.81(1H,d,J＝8Hz),5.35(1H,m),3.67(3H,s),3.62(3H,s),3.21(5H,m),1.26(3H,s),1.14(3H,s),0.94(3H,s),0.91(3H,s),0.66(3H,s).MS(ESI):m/z 618.40[M+H]+。
Example 3
Preparation of polygala tenuifolia sapogenin ester Q1-2
When R is2When H, R1Is composed of
When R is1＝R2And is a
Preparation of Compound Q1-2
SQ (5.5g,10mmol) was dissolved in dichloromethane (40mL) under nitrogen and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI,3.84g,20mmol) and 4-dimethylaminopyridine (DMAP,2.44g,20mmol) were added and the various carboxylic acids (15mmol) were added and reacted at room temperature for 3h and the progress of the reaction was monitored by TLC. After completion of the reaction, water was added to quench (50mL), and the mixture was extracted with dichloromethane (100 mL. times.3), and the organic layers were combined, washed successively with a saturated sodium bicarbonate solution (100mL) and a saturated brine (100mL), collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give Q1-Q2 (75% -85%).
Compound Q1, white solid.1H NMR(400MHz,CDCl3)δ5.27(1H,m),3.66(3H,s),3.64(6H,s),2.31(2H,m),1.67(2H,m),1.26(3H,s),1.20(3H,s),0.96(3H,m),0.93(3H,s),0.91(3H,s),0.68(3H,s).MS(ESI):m/z 617.41[M+H]+。
Compound Q2, white solid.1H NMR(400MHz,CDCl3)δ8.11(2H,d,J＝8Hz),8.02(2H,d,J＝8Hz),7.60(2H,m),7.45(4H,m),5.50(1H,m),3.65(3H,s),3.63(3H,s),1.26(3H,s),1.12(3H,s),0.97(3H,s),0.91(3H,s),0.70(3H,s).MS(ESI):m/z 755.42[M+H]+。
Example 4
Polygala tenuifolia sapogenin derivative pair H2O2Effect of injury-inducing PC12 cell Activity
(1) Reagent material
PC12 murine adrenal medulla chromaffin cells were purchased from American Type Culture Collection; DMEM medium, fetal bovine serum FBS, penicillin/streptomycin, pancreatin purchased from Gibco; 30% hydrogen peroxide was purchased from national reagents.
(2) Laboratory apparatus
Pipettes were purchased from Thermo Scientific fluorescence microscope from Nikon Ti-S, Nikon; carbon dioxide incubator purchased from Thermo Scientific; the 96-well plate was purchased from Jet Biofil electrothermal constant temperature air drying oven from Shanghai-Hengscientific instruments & meters Co.
(3) MTT method for detecting cell survival rate
Murine adrenal medulla chromaffin PC12 cells, the culture medium is DMEM medium containing 10% fetal bovine serum, 100IU/mL penicillin and 100. mu.g/mL streptomycin. PC12 cells were cultured in 6cm petri dish, and placed in cell incubator at 37 deg.C and 5% CO2And culturing under saturated humidity condition. The cells grow to logarithmic growth phase at 1X 105Perml was seeded in 96-well plates at 100. mu.L per well. Zero setting wells, blank control, injury group and drug experiment group were set.
H2O2And (3) damage model: PC12 cells were cultured at 1X 105The concentration of the suspension/mL, 100. mu.L per well, was plated in a 96-well plate, with 3 wells per set. After 24 hours, the compound was diluted to 10. mu.M from 10mM stock in serum-free medium, replacing the original medium. After incubation in an incubator for 2H, H was added at a concentration of 2mM2O2mu.L was added to each well to give a final concentration of 200. mu.M. After incubation in an incubator for 24 hours, 11. mu.L of MTT was added to each well, and after 4 hours, all the liquid was aspirated, dissolved in 150. mu.L of DMSO to each well, and the OD at 490nm was measured using a microplate reader.
Protection rate ═ aExperimental group-ANegative control group)/(ABlank group-ANegative control group)×100％
(4) Results of the experiment
| Compound (I) | Percent protection (10 mu M) | Compound (I) | Percent protection (10 mu M) |
| Y2 | 25.3±1.1 | SA8 | 24.6±0.8 |
| Y3 | 21.0±1.2 | SA9 | 73.3±3.4 |
| Y4 | 21.1±1.1 | SA10 | 34.7±2.5 |
| Y5 | 22.1±1.4 | SA11 | 30.2±1.3 |
| SA1 | 37.1±1.2 | SA12 | 87.7±5.2 |
| SA2 | 21.2±0.3 | SA13 | 21.1±0.1 |
| SA3 | 21.3±0.2 | SA14 | 22.3±0.5 |
| SA4 | 21.5±0.5 | SA15 | 51.3±2.1 |
| SA5 | 22.3±0.6 | SA16 | 21.5±0.2 |
| SA6 | 79.8±3.4 | Q1 | 21.1±1.2 |
| SA7 | 21.5±0.2 | Q2 | 31.6±2.1 |
| NAC(1mM) | 36.1±2.5 |
NAC: aminoguanidine, positive control compound.
Example 5
Effect of Polygala tenuifolia sapogenin derivatives on NO inhibitory activity of RAW264.7 cells induced by LPS-induced injury
(1) Reagent material
RAW264.7 cell line (Shanghai institute of cell biology, Chinese academy of sciences); DMEM medium (containing 10% fetal bovine serum, 100IU/mL penicillin and 100. mu.g/mL streptomycin); griess reagent (containing 1% sulfanilamide, 0.1% N-1-naphthyl ethylenediamine hydrochloride, 2.5% phosphoric acid), other reagents as above. The inducer is Lipopolysaccharide (LPS), and the positive control is indomethacin.
(2) Experimental methods
Cell survival rate detection by MTT method:
RAW264.7 cells grown to confluent state at 2X 10 per well4The number of individual cells was plated in 96-well plates. After overnight, compounds were diluted from 10mM stock to 10. mu.M in serum-free medium, replacing the original medium, with three wells per group. After 24 hours incubation in the incubator, 10. mu.L of MTT solution was added to each well to a final concentration of 5 mg/mL. After incubation for 4 hours at 37 ℃, the liquid in the 96-well plate was removed and 130 μ L DMSO was added, and after shaking to be uniform, the OD at 490nm was measured with a microplate reader. The experiment was repeated three times.
NO test:
mouse macrophage RAW264.7 in DMEM medium at 37 deg.C, 5% CO2Culturing in an incubator under the environment. The concentration of 100 μ L is 1X 106The cell suspension/mL was plated on 96-well plates and incubation continued for 5-6 hours. Then, the positive control drug and the prepared compound at the corresponding concentrations were added to the suspensions, respectively. The experiment is divided into three groups of blank control group, LPS group and experimental group. Half an hour later, 10. mu.L of LPS was added to the LPS group and the experimental group to make the final concentration of LPS 1. mu.g/mL. After 20 hours of culture, the content of nitrite in the cell supernatant was measured by the Griess methodReflecting the generation amount of NO; and (3) adding an equivalent amount of Griess reagent into 50 mu L of cell culture solution, measuring absorbance at the wavelength of 540nm, drawing a standard curve by using a nitrite standard solution, and calculating the concentration of the nitrite.
Inhibition rate (negative control group NO production-experimental group NO production)/negative control group NO production × 100%
(3) Results of the experiment
| Compound (I) | NO inhibition% (10. mu.M) | Compound (I) | NO inhibition% (10. mu.M) |
| Y2 | 21.1±1.1 | SA8 | 24.9±0.8 |
| Y3 | 25.5±1.5 | SA9 | 14.2±0.4 |
| Y4 | 30.7±1.8 | SA10 | 34.7±1.9 |
| Y5 | 22.0±1.1 | SA11 | 29.9±0.8 |
| SA1 | 45.9±1.2 | SA12 | 33.6±1.2 |
| SA2 | 46.3±1.3 | SA13 | 51.9±4.1 |
| SA3 | 33.5±1.7 | SA14 | 49.9±1.5 |
| SA4 | 40.7±1.5 | SA15 | 42.2±1.1 |
| SA5 | 38.5±1.6 | SA16 | 54.9±2.2 |
| SA6 | 59.4±1.4 | Q1 | 31.7±1.9 |
| SA7 | 22.6±0.2 | Q2 | 28.4±1.1 |
| Indo | 34.5±2.5 |
Indo: indomethacin, positive control compound.
Example 6
Protection effect of polygala tenuifolia sapogenin derivative on SH-SY5Y cell oxygen sugar deficiency
(1) Reagent material
SH-SY5Y cells (Shanghai institute of cell biology, Chinese academy of sciences); high-sugar serum-free DMEM medium and deoxidized sugar-free serum-free DMEM medium are purchased from Gibco; the other reagents are the same as above, and the positive control is aminoguanidine.
(2) Experimental methods
SH-SY5Y cells grown to a confluent state at 1X 10 per well5The number of individual cells was plated in 96-well plates. After overnight, compounds were diluted from 10mM stock to 10. mu.M in high-sugar serum-free medium, replacing the original medium, with three wells per group. After 24 hours incubation in the incubator, the plates were gently washed 1 time with pre-warmed PBS, and the compounds were diluted from 10mM stock solution to 10 μ M with deoxygenated sugar-free serum-free DMEM, replacing the original medium, 100 μ L/well, three wells per group. Placing in a three-gas incubator (37 deg.C, 94% N)2、5％CO2、1％O2) OGD culture was performed for 5.5 h. To each well was added 10. mu.L of MTT solution at a final concentration of 5 mg/mL. After incubation for 4 hours at 37 ℃, the liquid in the 96-well plate was removed and 150 μ L DMSO was added, and after shaking to be uniform, the OD at 490nm was measured with a microplate reader.
Protection rate ═ aExperimental group-ANegative control group)/(ABlank group-ANegative control group)×100％
(3) Results of the experiment
| Compound (I) | Percent protection (10 mu M) | Compound (I) | Percent protection (10 mu M) |
| Y2 | 23.1±1.6 | SA8 | 20.2±1.1 |
| Y3 | 21.4±1.2 | SA9 | 45.8±2.5 |
| Y4 | 21.7±1.3 | SA10 | 29.8±1.8 |
| Y5 | 21.2±1.1 | SA11 | 47.4±2.8 |
| SA1 | 36.8±1.8 | SA12 | 46.7±3.2 |
| SA2 | 31.6±1.3 | SA13 | 10.3±0.3 |
| SA3 | 25.4±1.9 | SA14 | 26.5±1.4 |
| SA4 | 35.9±1.5 | SA15 | 89.5±5.2 |
| SA5 | 11.3±0.2 | SA16 | 22.5±0.3 |
| SA6 | 50.0±3.4 | Q1 | 21.0±1.2 |
| SA7 | 27.8±0.9 | Q2 | 32.9±2.1 |
| NAC(1mM) | 83.9±6.5 |
NAC: aminoguanidine, positive control compound.
In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.
Claims (7)
1. The polygala tenuifolia sapogenin derivative is characterized in that the structural formula of the polygala tenuifolia sapogenin derivative is shown as a general formula (1):
wherein the content of the first and second substances,
R1、R2、R3each independently selected from: H. glucose group, glucose group,
R4、R5Each independently selected from:
R6selected from: H. OH, ═ O, or absent;
R7selected from: h or is absent;
or, R6、R7An epoxy structure is formed.
2. The modified polygalacturgenin structure derivative according to claim 1,
R8、R10each independently selected from: substituted or unsubstituted C1-10Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C3-10Cycloalkyl groups of (a);
R9independently selected from: substituted or unsubstitutedC1-10Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C3-10A cycloalkyl group of,
R11、R12Each independently selected from: H. substituted or unsubstituted C1-10A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted C3-10Cycloalkyl groups of (a);
R13、R14each independently selected from: H. substituted or unsubstituted C1-10A substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted C3-10A cycloalkyl group of (a).
3. The modified polygalacturgenin structure derivative according to claim 2,
when R is8、R9、R10、R11、R12、R13Or R14Is substituted C1-10When the alkyl group is a straight or branched chain alkyl group of (1), C1-10The substituent of the linear chain or branched chain alkyl is one of amido, substituted or unsubstituted aryl and cyano;
when R is8、R9、R10、R11、R12、R13Or R14When the substituted alkenyl is adopted, the substituent of the alkenyl is one of amino, substituted or unsubstituted aryl and cyano;
when R is8、R9、R10、R11、R12、R13Or R14When substituted alkynyl, substitution of alkynylThe group is one of amido, substituted or unsubstituted aryl and cyano;
when R is8、R9、R10、R11、R12、R13Or R14Is substituted C3-10Cycloalkyl of, C3-10The substituent of the naphthenic base is one of amino, substituted or unsubstituted aryl and cyano;
when R is8、R9、R10、R11、R12、R13Or R14When the aryl is substituted, the substituent of the aryl is one or more of halogen, amino, alkyl, nitro, hydroxyl or alkoxy.
4. The polygala root sapogenin structure modified derivative according to claim 1, wherein the polygala root sapogenin structure modified derivative is one of the following compounds,
5. a pharmaceutical combination, comprising a pregangliogenin structurally modified derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
6. Use of the pharmaceutical composition of claim 5 for the manufacture of a medicament for the treatment of a condition associated with oxidative stress.
7. The use according to claim 6, wherein the oxidative stress-related disease is a neurodegenerative disease, inflammation, cancer, or diabetic nephropathy.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1709903A (en) * | 2005-06-17 | 2005-12-21 | 中国人民解放军第二军医大学 | Saponin compound and use of its glucoside in preparing medicine for treating neure injure |
| US20080280890A1 (en) * | 2007-02-22 | 2008-11-13 | Ghanshyam Patil | Hydroxylamine compounds and methods of their use |
| CN102304164A (en) * | 2011-07-18 | 2012-01-04 | 山西大学 | Senegenin derivative, as well as preparation method and application thereof |
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2020
- 2020-10-23 CN CN202011143471.XA patent/CN112209989A/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1709903A (en) * | 2005-06-17 | 2005-12-21 | 中国人民解放军第二军医大学 | Saponin compound and use of its glucoside in preparing medicine for treating neure injure |
| US20080280890A1 (en) * | 2007-02-22 | 2008-11-13 | Ghanshyam Patil | Hydroxylamine compounds and methods of their use |
| CN102304164A (en) * | 2011-07-18 | 2012-01-04 | 山西大学 | Senegenin derivative, as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
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| S. W. PELLETIER ET AL.: "A PROSAPOGENIN FROM POLYGALA SENEGA AND POLYGALA TENUIFOLIA", 《TETRAHEDRON LETTERS》 * |
| SHUOQI CHEN ET AL.: "Tenuifolin Attenuates Amyloid-β42-Induced Neuroinflammation in Microglia Through the NF-κB Signaling Pathway", 《JOURNAL OF ALZHEIMER"S DISEASE》 * |
| 张晶 等: "远志皂苷元对H2O2大鼠海马神经元损伤的影响及其机制", 《中国病理生理杂志》 * |
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