CN112500331A - Nicotinic acid derivative VIII with hypoglycemic, anti-tumor, anti-platelet aggregation and immunosuppressive activities and application thereof - Google Patents
Nicotinic acid derivative VIII with hypoglycemic, anti-tumor, anti-platelet aggregation and immunosuppressive activities and application thereof Download PDFInfo
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Abstract
The invention provides a nicotinic acid derivative VIII with immunosuppressive activity, which has a structural general formula as follows:
wherein R is1Is H+、OH‑、CH3 ‑、SH、CH2CH3 ‑、CONH2 ‑Or NH2 ‑One of (1), R2Is H+、OH‑、CH3 ‑、SH、CH2CH3 ‑、CONH2 ‑Or NH2 ‑One of (1), R1And R2The substitution site(s) of (a), may be simultaneously substituted with the substituent group(s). The nicotinic acid compound provided by the invention has good immunosuppressive activity and anti-inflammatory activity, strong selectivity and good clinical application value.
Description
Technical Field
The invention relates to a compound, in particular to a nicotinic acid compound separated from the extraction of tripterygium medicinal materials 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 tripterygium wilfordii is about 0.07-0.29%, and the components have important function in the aspect of immune suppression. Sesquiterpene alkaloid structure is characterized by dihydrofuran type sesquiterpene, and the reported structure mainly comprises 71 types including wilfordate/evosonate, hydroxy-wilfordate/evosonate and iso-wilfordate/evosonate. Tripterygium wilfordii sesquiterpenoid alkaloids are sesquiterpenoids with high oxygen content, and are structurally characterized by containing a special macrocyclic dilactone framework structure, wherein the macrocyclic dilactone framework structure comprises two parts, namely 2- (carboxyalkyl) nicotinic acid (2- (carboxyakyl) nicotinic acid) and polyhydroxy-dihydro-beta-agarofuran sesquiterpene (polyoxygenated dihydro-beita-agarofuran sespropeptide). 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, 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 thereof is significantly manifested. 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 nicotinic acid derivative VIII with immunosuppressive activity, which has a structural general formula as follows:
wherein R is1Is H+、OH-、CH3 -、SH、CH2CH3 -、CONH2 -Or NH2 -One of (1), R2Is H+、OH-、 CH3 -、SH、CH2CH3 -、CONH2 -Or NH2 -One of (1), R1And R2The substitution site(s) of (a), may be simultaneously substituted with the substituent group(s).
The structure is as follows:
the structure is as follows:
the structure is as follows:
the application of the nicotinic acid derivative VIII with immunosuppressive activity in the tripterygium preparation for treating autoimmune diseases such as rheumatoid arthritis, psoriasis and the like.
The application of the nicotinic acid derivative VIII with anticancer activity in tripterygium genus in preparing the medicine for treating liver tumor is provided.
The application of the nicotinic acid derivative VIII with hypoglycemic activity of Tripterygium in preparing the medicine for treating the type II diabetes is provided.
The nicotinic acid derivative VIII with the activity of resisting platelet aggregation in tripterygium is applied to the preparation of diseases such as 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 and anti-inflammatory activity, strong selectivity and good clinical application value.
Drawings
FIG. 1 ESI-MS profile of nicotinic acid derivative VIII-1;
FIG. 2 Process for preparing nicotinic acid derivative VIII-11An H-NMR spectrum;
FIG. 3 ESI-MS profile of nicotinic acid derivative VIII-2;
FIG. 4 Process for preparing nicotinic acid derivative VIII-21An H-NMR spectrum;
FIG. 5 ESI-MS profile of nicotinic acid derivative VIII-3;
FIG. 6 Process for preparing nicotinic acid derivative VIII-31An H-NMR spectrum;
FIG. 7 anti-RA activity of nicotinic acid derivative VIII;
FIG. 8 anti-hepatoma cell activity of nicotinic acid derivative VIII;
FIG. 9 the hypoglycemic activity of nicotinic acid derivative VIII;
FIG. 10 examination of anti-platelet aggregation activity of nicotinic acid derivative VIII;
FIG. 11 shows the docking results of nicotinic acid derivative VIII with 5 LYW;
FIG. 12 the docking results of nicotinic acid derivative VIII with 6 IIV;
FIG. 13 docking results of nicotinic acid derivative VIII with 3 KVJ;
figure 14 results of docking nicotinic acid derivative VIII with 2 UZQ.
Detailed Description
EXAMPLE 1 preparation of nicotinic acid derivative VIII
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 volume 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 nicotinic acid derivative VIII
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 monomer is obtained by adopting a preparation liquid phase.
The nicotinic acid derivative compound obtained by the synthesis is carried out1H-NMR chemical structure analysis and ESI-MS chemical structure analysis, and specific results are shown in the appendix.
Example 3 examination of anti-RA Activity of nicotinic acid derivative VIII
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 continuing 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 of the experiment are shown in FIG. 7.
Example 4 examination of anti-hepatoma cell Activity of nicotinic acid derivative VIII
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 molecular group to be detected, a molecule to be detected and a PBS group, adding medicines, culturing for 12 hours, 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 regulation factors (PPAR gamma) in the cells of each experimental group. The results of the experiment are shown in FIG. 8.
Example 5 examination of hypoglycemic Activity of nicotinic acid derivative VIII
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 of the experiment are shown in FIG. 9.
Example 6 examination of anti-platelet aggregation Activity of nicotinic acid derivative VIII
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 LPRP and 10. mu.L of test compound at different concentrations (1000, 500, 200, 100, 10. mu. mol/L), 10. mu.L ADP (final concentration 10. mu. mol/L) was added as inducer, and the maximal platelet aggregation rate over 5min was recorded by observation, each concentration being measured in parallel. The experimental results are shown in fig. 10.
Example 7 molecular docking analysis of nicotinic acid derivative VIII
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 March11, 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 shown 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 proteins 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 proteins. 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 of the experiments are shown in FIGS. 11, 12, 13 and 14.
TABLE 1 reverse docking analysis of nicotinic acid derivatives VIII
Claims (8)
1. Nicotinic acid derivative VIII having immunosuppressive activity, characterized in that: the general structural formula is as follows:
wherein R is1Is H+、OH-、CH3 -、SH、CH2CH3 -、CONH2 -Or NH2 -One of (1), R2Is H+、OH-、CH3 -、SH、CH2CH3 -、CONH2 -Or NH2 -One kind of (1).
2. The nicotinic acid derivative VIII having immunosuppressive activity according to claim 1, wherein: the structure is as follows:
3. the nicotinic acid derivative VIII having immunosuppressive activity according to claim 1, wherein: the structure is as follows:
4. the nicotinic acid derivative VIII having immunosuppressive activity according to claim 1, wherein: the structure is as follows:
5. use of the nicotinic acid derivative VIII with immunosuppressive activity of Tripterygium species according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and the like.
6. The use of the nicotinic acid derivative VIII with anticancer activity of Tripterygium species according to claim 1 in the preparation of a medicament for treating liver tumor.
7. The use of the nicotinic acid derivative VIII with hypoglycemic activity of Tripterygium species according to claim 1 in the preparation of a medicament for treating type II diabetes.
8. The use of the nicotinic acid derivative VIII with platelet aggregation inhibiting activity of Tripterygium in claim 1 in the preparation of platelet aggregation inhibiting diseases.
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