CN112341381A - Pyridine-2-formic acid derivative VII and application thereof in platelet aggregation resistance, tumor resistance and immunosuppressant development - Google Patents
Pyridine-2-formic acid derivative VII and application thereof in platelet aggregation resistance, tumor resistance and immunosuppressant development Download PDFInfo
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Abstract
The invention provides a pyridine-2-formic acid derivative VII esterified substance with immunosuppressive activity, which has a structural general formula as follows:
the nicotinic acid compound provided by the invention has good immunosuppressive activity, anti-liver tumor activity and anti-type II diabetes activity, and has strong selectivity and good clinical application value.
Description
Technical Field
The invention relates to a compound, in particular to VII esters and isomers of pyridine-2-formic acid derivatives with immunosuppressive activity and application thereof.
Technical Field
In the process of clinical long-term symptom differentiation and treatment, the traditional Chinese medicine finds that the plant of the genus Tripterygium of Celastraceae has a long history of being used for treating the rheumatism, is bitter, cold and toxic in nature and taste, has the effects of dispelling wind and removing dampness, relaxing tendons and activating collaterals and clearing heat and toxic materials, is a clinically important immunosuppressant, and has an important role in treating autoimmune diseases such as rheumatoid arthritis, primary nephrotic syndrome, systemic lupus erythematosus and the like.
Tripterygium plant mainly comprises Tripterygium hypoglaucum Hutch, Tripterygium regelii Sprague et Takeda and Tripterygium wilfordii hook. According to the statistical data of official websites of the State drug administration, currently, 45 tripterygium medicinal materials related to preparations are on the market in 43 pharmaceutical production enterprises in China. The chemical components of Tripterygium plant mainly comprise sesquiterpene alkaloids, diterpenes and triterpenes. Wherein, the content of the total alkaloids of the tripterygium wilfordii is about 0.07-0.29 percent, and the components have important function in the aspect of immunosuppression. Sesquiterpene alkaloids are characterized by dihydrofuran type sesquiterpenes, and the reported structure mainly comprises 71 types including wilfordate/evoninate, hydroxy-wilfordate/evoninate and iso-wilfordate/evoninate. Tripterygium wilfordii sesquiterpene alkaloids are sesquiterpene compounds with high oxygen content, and have structural characteristics of containing a special macrocyclic dilactone framework structure, and comprise two parts of 2- (carboxyalkyl) nicotinic acid (2- (carboxyyalky) nicotinic acid) and polyhydroxy-dihydro-beta-agarofuran sesquiterpene (polyoxygenated dihydro-beita-agarofuran sesterpentaid). The hydroxyl group of the sesquiterpene moiety is usually esterified with various organic acids including acetic acid, benzoic acid, furan acid, nicotinic acid and fatty acids; the 2- (carboxyalkyl) nicotinic acid part is mainly derived from acetylenic acid, vitamin acid, hydroxy vitamin acid or homologues thereof, and the difference of the 2- (carboxyalkyl) nicotinic acid part is the core of the difference of the macrocyclic dilactone skeleton structure and the core of the structural diversity of the chemical components of the tripterygium wilfordii alkaloid.
The traditional Chinese medicine finds that the plant of the genus Leptospermum of the family Celastraceae has exact curative effect on treating the rheumatism arthralgia syndrome in the process of clinical long-term symptom differentiation treatment, is bitter, cold and toxic in nature and taste, has the effects of dispelling wind and removing dampness, relaxing tendons and activating collaterals and clearing heat and toxic materials, and has important effect on treating autoimmune diseases such as rheumatoid arthritis and the like. The mechanism of tripterygium wilfordii for treating rheumatoid arthritis is closely related to key targets of inflammation generation and T cell immune regulation. After the tripterygium hypoglaucum hutch is given to the rheumatoid arthritis for one week, the tripterygium hypoglaucum hutch has obvious inhibiting effect on the secondary foot swelling degree and the arthritis index of an adjuvant arthritis model rat; the concentration of proinflammatory factors IL-1 alpha and IL-1 beta and functional protein MMP3 in serum is obviously reduced, and the concentration of inflammation-inhibiting factors IL-4 and IL-10 in serum is obviously increased; after three weeks of administration, the proportion of regulatory T cells (Tregs) occupying T lymphocytes is significantly higher than that of the model group, and the therapeutic effect is significantly shown. Aiming at the research of immunosuppressive active ingredients in the Tripterygium wilfordii Chinese medicinal materials, the applicant carries out deep and systematic research, and the research successively invests more than 1500 ten thousand yuan through national provincial scientific research projects; the related subjects are respectively: the special item of the technology for creating the national great new medicine of the department of science and technology: research on a new medicine of the artemisia stem wind-dispelling capsule for treating rheumatoid diseases (the project number is 2017ZX 09101002-002-004); chongqing city health bureau project: "the research of promoting the technology of large variety of Ficus L.root pieces and expanding the adaptive symptoms (project number: cstc2013jcsf 10011)", the project of Chongqing City science and technology bureau: "the industrialization of the large variety of the Ficus L.var.major L.slice is popularized and promoted" (project number: cstc2014jcsf10001), and project of science and technology bureau of Chongqing city: "study on the action mechanism of application of Huobaoshua root tablet based on metabonomics of traditional Chinese medicine to immunosuppression of rheumatoid arthritis" (item number: 2015 cstc-jbky-01913); chongqing City science and technology office project: the metabolism dynamics research of tripterygium wilfordii alkaloid in Beagle dogs (project number: cstc2018jxjl 130055).
Disclosure of Invention
On the basis of the prior art, the invention provides a pyridine-2-formic acid derivative VII esterified substance with immunosuppressive activity, which has a structural general formula as follows:
the structure is as follows:
on the basis of the prior art, the invention provides an isomer of VII esterified pyridine-2-formic acid derivative with immunosuppressive activity, which has the following structure:
the pyridine-2-formic acid derivative VII esterified substance and isomer with immunosuppressive activity of Tripterygium have application in preparing medicines for treating autoimmune diseases such as rheumatoid arthritis and psoriasis.
The pyridine-2-formic acid derivative VII esterified substance and isomer with anticancer activity of Tripterygium have application in preparing medicine for treating liver tumor.
The pyridine-2-formic acid derivative VII esterified substance and isomer of Tripterygium have hypoglycemic activity and can be used for preparing medicines for treating type II diabetes.
The pyridine-2-formic acid derivative VII esterified substance and isomer with anti-platelet aggregation activity of Tripterygium have application in preparation of anti-platelet aggregation and other diseases.
The beneficial technical effects of the invention are as follows: the nicotinic acid compound provided by the invention has good immunosuppressive activity, anti-liver tumor activity and anti-type II diabetes activity, and has strong selectivity and good clinical application value.
Drawings
FIG. 1 shows esterification of VII pyridine-2-carboxylic acid derivatives1An H-NMR spectrum;
FIG. 2 ESI-MS spectrum of esterified VII pyridine-2-carboxylic acid derivative;
FIG. 3 isomer of VII-esterified pyridine-2-carboxylic acid derivative1An H-NMR spectrum;
FIG. 4 ESI-MS spectra of isomers of esterified VII pyridine-2-carboxylic acid derivatives;
FIG. 5 anti-RA activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives;
FIG. 6 shows the anti-hepatoma cell activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives;
FIG. 7 shows the hypoglycemic activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives;
FIG. 8 shows the platelet aggregation inhibition activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives.
Detailed Description
EXAMPLE 1 preparation of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Crushing root bark of tripterygium hypoglaucum, weighing 1Kg of medicinal powder, placing the powder into a 5000mL round-bottom flask, adding 3000mL and 2000mL of water respectively, performing reflux extraction, soaking for 60min before each extraction, and performing reflux extraction for 60min respectively; mixing the two extractive solutions, concentrating into paste, diluting the extract with a small amount of water, and extracting with 1.5 times, 1 time, and 0.5 time of ethyl acetate respectively. Combining ethyl acetate layers and recovering an organic phase; evaporating the extract to dryness to obtain 5g, dissolving 7.5mL of pure methanol, adding 2.5mL of 0.4mol/L NaOH methanol solution, reacting in a water bath at constant temperature of 60 ℃ for 4h, evaporating the methanol from the reaction solution, diluting with 10mL of water, extracting with 2 times of ethyl acetate for 3 times, and evaporating the water layer to dryness. Wet loading the water layer on C18 column, eluting with 5% methanol water at natural flow rate, intercepting eluate by stages, and monitoring eluate components by LC-MS. ② concentrating the water layer to extractum, dissolving a little water, and passing through a polyamide column. Eluting with 5 times of column with water, collecting eluate, evaporating to dryness, re-dissolving with a small amount of water, adding 3 times of 95% ethanol, stirring for 30min, centrifuging to obtain supernatant, evaporating to dryness, dissolving with 5% methanol to prepare liquid phase, eluting with 15% methanol water as mobile phase, collecting eluate by stages, and monitoring eluate components with LC-MS.
EXAMPLE 2 preparation of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Crushing root bark of tripterygium hypoglaucum, weighing 1Kg of medicinal material powder, placing the powder into a 5000mL round-bottom flask, taking 80% ethanol solution to perform reflux extraction respectively according to the volume of 3000mL and 2000mL, soaking for 60min before each extraction, performing reflux extraction respectively for 60min, and adjusting the pH to 4.0; mixing the two extractive solutions, recovering ethanol, diluting the extract with small amount of water, extracting with 1.5 times, 1 time, and 0.5 time of ethyl acetate respectively, mixing ethyl acetate layers, and recovering organic phase; evaporating the extract to dryness to obtain 5g, dissolving 7.5mL of pure methanol, adding 2.5mL of 0.4mol/L NaOH methanol solution, reacting in a water bath at constant temperature of 60 ℃ for 4h, evaporating the methanol from the reaction solution, diluting with 10mL of water, extracting with 2 times of ethyl acetate for 3 times, and evaporating the water layer to dryness. Wet loading the water layer on C18 column, eluting with 5% methanol water at natural flow rate, intercepting eluate by stages, and monitoring eluate components by LC-MS.
The pyridine-2-formic acid derivative obtained by the synthesis is subjected to1The specific results of H-NMR chemical structure analysis and ESI-MS chemical structure analysis are shown in figures 1,2, 3 and 4.
EXAMPLE 3 examination of anti-RA Activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Firstly, performing drug concentration toxicity test, namely culturing RA-FLSs cells (fibroblast-like synoviocytes) in a DMEM culture medium containing 10% FBS and 1% double antibody in an incubator at 37 ℃ and 5% CO2, collecting logarithmic phase cells, adjusting the concentration of cell suspension, and dividing the cells into 96-well plates with 150 mu L per well; after culturing for 24h, adding 200 mu L of samples to be tested with different concentrations, and continuously culturing for the required time; discarding the supernatant, adding 80 μ L of fresh culture solution, adding 20 μ L of LMTT solution, and culturing for 3 hr; the supernatant was discarded, 100. mu.L of DMSO was added to each well, and the mixture was shaken on a shaker at a low speed for 10min, and then the absorbance of each well was measured at 570 to calculate the cell viability. And secondly, carrying out anti-RA activity detection, namely, subculturing RA-FLSs cells on a six-well plate, dividing the cells into 3 groups, contrasting a PBS group, a molecule group to be detected and a PBS group to be detected, adding medicines, culturing for 12h, extracting cell RNA, carrying out reverse transcription, carrying out RT-PCR analysis, and detecting the change of the transcription expression level of inflammatory factors (IL-6, IL-8, MCP-1 and TNF-alpha) and transcription regulatory factors (PPAR gamma) in the cells of each experimental group. The results are shown in FIG. 5.
Example 4 examination of anti-hepatoma cell Activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Firstly, a drug concentration toxicity test is carried out, culturing HepG2 cells in a DMEM culture medium containing 10% FBS and 1% double antibody at 37 ℃ in a 5% CO2 incubator, collecting logarithmic phase cells, adjusting the concentration of cell suspension, and distributing the cells in a 96-well plate with 150 mu L per well; after culturing for 24h, adding 200 mu L of samples to be tested with different concentrations, and continuously culturing for the required time; discarding the supernatant, adding 80 μ L of fresh culture solution, adding 20 μ L of MTT solution, and continuing culturing for 3 h; the supernatant was discarded, 100. mu.L of DMSO was added to each well, and the mixture was shaken on a shaker at a low speed for 10min, and then the absorbance of each well was measured at 570 to calculate the cell viability. And secondly, carrying out anti-liver cancer activity detection, namely, subculturing HepG2 cells on a six-hole plate, dividing the cells into 3 groups, contrasting a PBS group, a molecule group to be detected and a PBS group to be detected, adding medicines, culturing for 12h, extracting cell RNA, carrying out reverse transcription, carrying out RT-PCR analysis, and detecting the change of the transcription expression level of inflammatory factors (IL-6, IL-8, MCP-1 and TNF-alpha) and transcription regulatory factors (PPAR gamma) in the cells of each experimental group. The results are shown in FIG. 6.
EXAMPLE 5 examination of hypoglycemic Activity of VII esters and isomers of pyridine-2-carboxylic acid derivatives
And (2) subculturing HepG2 cells on a six-well plate, dividing the cells into 4 groups, contrasting a PBS group, a high-sugar model + to-be-detected molecule group and a to-be-detected molecule + PBS group, adding medicines, culturing for 12h, extracting cell RNA, performing reverse transcription, performing RT-PCR analysis, and detecting the change of the transcription expression level of inflammatory factors (IL-6, IL-8, MCP-1 and TNF-alpha) and transcription regulatory factors (PPAR gamma) in the cells of each experimental group. The results are shown in FIG. 7.
EXAMPLE 6 examination of anti-platelet aggregation Activity of VII-esterified pyridine-2-carboxylic acid derivative and isomer
The inhibitory activity of 7 target compounds on Adenosine Diphosphate (ADP) -induced platelet aggregation in rabbits was tested by the Born turbidimetric method. Collecting blood from heart of rabbit, anticoagulating with 3.8 vol% sodium citrate 1: 9, centrifuging at 1000r/min for 10min to obtain Platelet Rich Plasma (PRP), centrifuging the rest at 3000r/min for 15min to obtain Platelet Poor Plasma (PPP), and testing platelet aggregation activity by turbidimetry. The tubes were incubated for 5min with 280. mu.L of PRP and 10. mu.L of test compound at different concentrations (1000, 500, 200, 100, 10. mu. mol/L), followed by 10. mu.L of LADP (final concentration 10. mu. mol/L) as inducer, and the maximal platelet aggregation rate over 5min was recorded by observation, and each concentration was measured in parallel. The results are shown in FIG. 8.
EXAMPLE 7 molecular Butt assay of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Reverse docking targets were collected from three sources: DisGeNET database (https:// www.disgenet.org/, v6), Online Mendelian initiative in Man (OMIM) database (http:// www.omim.org/, updated on June 26,2020), and GeneCards database (https:// www.genecards.org/, updated on March 11,2020).
To verify the binding affinity of candidate targets to compounds, mock molecular docking was achieved in the LibDock program using Discovery Studio 16.1(DS 16.1). As described in Table 1, all crystal structures of candidate targets (http:// www.pdb.org/, updated on June2020) were directly downloaded from RCSB protein database and checked for resolution, each protein was defined as receptor, except for co-crystallized ligand and structural water molecules, and active sites of the protein were found in the receptor cavity using Discovery Studio tool, followed by performing docking protocol using LibDock to show the interaction between the components in Discovery Studio and the difference protein. Since LibDock can provide 10-100 predicted LibDock scores and the location of each binding protein within the protein binding pocket is different, we only considered the best LibDock score. The protein with the highest score was considered as the putative composite target.
TABLE 1 reverse target docking analysis of VII esters and isomers of pyridine-2-carboxylic acid derivatives
Claims (7)
1. A pyridine-2-carboxylic acid derivative vii, characterized in that: the general structural formula is as follows:
2. The pyridine-2-carboxylic acid derivative vii according to claim 1, wherein: the structure is as follows:
3. the pyridine-2-carboxylic acid derivative vii according to claim 1, wherein: the structure is as follows:
4. use of the pyridine-2-carboxylic acid derivative VII having immunosuppressive activity according to any of claims 1-3 for the preparation of a medicament for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and the like.
5. Use of the pyridine-2-carboxylic acid derivative VII having immunosuppressive activity according to any of claims 1-3 for the preparation of a medicament for the treatment of hepatoma.
6. Use of a pyridine-2-carboxylic acid derivative VII having immunosuppressive activity according to any of claims 1-3 for the manufacture of a medicament for the treatment of anti-type II diabetes.
7. Use of the pyridine-2-carboxylic acid derivative VII having immunosuppressive activity according to any one of claims 1 to 3 for the preparation of an anti-platelet aggregation disease or the like.
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Application publication date: 20210209 |