CN112375034A - Isonicotinic acid derivative IX with platelet aggregation resistance, anti-tumor and immunosuppressive activities and application thereof - Google Patents
Isonicotinic acid derivative IX with platelet aggregation resistance, anti-tumor and immunosuppressive activities and application thereof Download PDFInfo
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- CN112375034A CN112375034A CN202011236035.7A CN202011236035A CN112375034A CN 112375034 A CN112375034 A CN 112375034A CN 202011236035 A CN202011236035 A CN 202011236035A CN 112375034 A CN112375034 A CN 112375034A
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Abstract
The invention provides an isonicotinic acid derivative IX 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 an isonicotinic acid derivative IX 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 di-hydrogen-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.
Disclosure of Invention
On the basis of the prior art, the invention provides an isonicotinic acid derivative IX with immunosuppressive activity, which has a structural general formula as follows:
the structural formula is as follows:
the structural formula is as follows:
the application of the isonicotinic acid derivative IX with the immunosuppressive activity of the tripterygium in preparing medicines for treating autoimmune diseases such as rheumatoid arthritis, psoriasis and the like.
The isonicotinic acid derivative IX with anticancer activity of Tripterygium is applied to the preparation of the medicine for treating liver tumor.
The application of the isonicotinic acid derivative IX with hypoglycemic activity of Tripterygium in preparing the medicine for treating the anti-II type diabetes mellitus is provided.
The isonicotinic acid derivative IX with anti-platelet aggregation activity of Tripterygium is applied to preparation of diseases such as anti-platelet aggregation and the like.
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 of isonicotinic acid derivatives IX-11An H-NMR spectrum;
FIG. 2 is an ESI-MS spectrum of an isonicotinic acid derivative IX-1;
FIG. 3 is a 1H-NMR spectrum of an isonicotinic acid derivative IX-2;
FIG. 4 is an ESI-MS spectrum of an isonicotinic acid derivative IX-2;
FIG. 5 anti-RA activity of isonicotinic acid derivative IX;
FIG. 6 anti-hepatoma cell activity of isonicotinic acid derivative IX;
FIG. 7 the hypoglycemic activity of isonicotinic acid derivatives IX;
FIG. 8 is the anti-platelet aggregation activity of isonicotinic acid derivative IX;
FIG. 9 docking of isonicotinic acid derivative IX with 5 LYW;
FIG. 10 the docking results of isonicotinic acid derivatives IX with 6 IIV.
Detailed Description
EXAMPLE 1 Process for the preparation of isonicotinic acid derivatives IX
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 Process for the preparation of isonicotinic acid derivatives IX
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 isonicotinic acid derivative compound obtained by the synthesis is carried out1H-NMR chemical structure analysis and ESI-MS chemical structure analysis, concrete structureThe results are shown in FIGS. 1,2, 3, and 4.
EXAMPLE 3 examination of anti-RA Activity of Isonicotinic acid derivative IX
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 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-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 Isonicotinic acid derivative IX
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 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-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 blood sugar-lowering Activity of Isonicotinic acid derivative IX
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 platelet aggregation inhibitory Activity of Isonicotinic acid derivative IX
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 docking analysis of isonicotinic acid derivatives IX
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 June 2020) 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. The results are shown in FIGS. 9 and 10.
TABLE 1 inverse target docking analysis of isonicotinic acid derivatives IX
Claims (7)
1. Isonicotinic acid derivatives IX having immunosuppressive activity, characterized in that: the general structural formula is as follows:
the side chain substituent is hydrogen, methyl or hydroxyl.
2. An isonicotinic acid derivative ix having immunosuppressive activity according to claim 1, characterized in that: the structural formula is as follows:
3. an isonicotinic acid derivative ix having immunosuppressive activity according to claim 1, characterized in that: the structural formula is as follows:
4. use of the isonicotinic acid derivative IX according to any one of claims 1 to 3 with immunosuppressive activity for the manufacture of a medicament for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and the like.
5. Use of the isonicotinic acid derivative IX according to any one of claims 1 to 3 with anticancer activity for the manufacture of a medicament for the treatment of liver tumors.
6. Use of the isonicotinic acid derivative IX of Tripterygium with hypoglycemic activity according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of type II diabetes.
7. Use of isonicotinic acid derivative IX according to any one of claims 1 to 3 having activity of inhibiting platelet aggregation in the preparation of a medicament for inhibiting platelet aggregation.
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Application publication date: 20210219 |