CN109369620B - Pyridine compound, preparation method thereof and application thereof in resisting gastric cancer - Google Patents
Pyridine compound, preparation method thereof and application thereof in resisting gastric cancer Download PDFInfo
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Abstract
The invention provides an RBP2 enzyme activity inhibition method for designing and synthesizing aiming at an enzyme activity siteThe pyridine compound WXSA-051B also provides a preparation method thereof, and experiments prove that the compound can obviously increase the protein level of H3K4me3 in human gastric cancer cell BGC-823, has obvious effect of inhibiting the activity of RBP2 enzyme, and can reduce the migration capacity of human gastric cancer cell BGC-823. The compound can be used as a gastric cancer inhibitor to prepare anti-gastric cancer drugs. The compound has the following structure
。
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a pyridine compound WXSA-051B, a preparation method thereof and application thereof in resisting gastric cancer.
Background
The antineoplastic drugs commonly used in clinic are mainly cytotoxic drugs, and most of the drugs have the defects of poor selectivity, strong toxic and side effects, easy generation of drug resistance and the like which are difficult to avoid. In recent years, with the rapid development of life science research, various basic processes such as signal transduction, cell cycle regulation, apoptosis induction, angiogenesis and interaction between cells and extracellular matrix in malignant tumor cells are gradually elucidated, and the research and development concept of antitumor drugs is greatly changed. Therefore, screening and discovering novel anti-cancer drugs with strong selectivity, high efficiency and low toxicity by taking some key enzymes/proteins related to tumor cell modification as drug targets becomes an important direction for research and development of current anti-tumor drugs. The role of epigenetics in tumor progression is gradually being explored and elucidated, and histone modification, as an epigenetic modification, can regulate chromatin state and gene expression, and plays a role in the development of cancer. Many studies have demonstrated that novel inhibitors of epigenetic enzymes have therapeutic effects on related diseases, and thus many enzymes involved in the regulation of epigenetics have become potential drug targets. This drug development that interferes with epigenetic modification is much in need of further demonstration studies after histone deacetylase inhibitors have been approved for cancer therapy. The structure and function of the substrate of the epigenetic medicine need to be further researched, so that the specificity of the medicine is improved, and the occurrence of adverse reactions is reduced. In general, intervention of epigenetic enzyme activity has promising potential for treatment of many intractable diseases such as cancer and neuropsychiatric disorders.
RBP2, a member of the histone demethylase family, can specifically demethylate H3K4me3/2, and a plurality of studies have proved that RBP2 participates in the development of a plurality of cancers, RBP2 has more and more functions in tumors, RBP2 plays a role in the development of cancers, malignant transformation, metabolism and drug resistance and can be used as a clinical treatment target, RBP2 can promote the up-regulation of CCND1 and CCNE1 so as to promote the development of lung cancer, RBP2 can up-regulate VEGF through an AKT signal pathway in non-small cell lung cancer so as to promote the generation of blood vessels and promote the development of cancers, RBP2 is over-expressed in gastric cancer cells, SP 1-dependent through PI3K/AKT is induced by SP-helicobacter Cag-A, CCND1 is targeted to promote the malignant transformation of helicobacter pylori-induced gastric cancer cells, and is also can be inhibited by TGF-dhE 2, proliferation inhibition of the proliferation of epithelial cells after the tumor growth of digestive cancer, and the tumor proliferation of tumor cells after the tumor growth of tumor cells is promoted by RBP 638, and the tumor growth of tumor cells after the tumor growth of tumor cells is controlled by AKT signal receptor gene expression of RBP 638, and the tumor resistant gene of tumor growth of tumor cells after the tumor growth of tumor resistant gene, and the tumor growth of tumor resistant gene of tumor cells after the tumor growth of tumor cells after the tumor resistant gene of tumor cells after the tumor growth of tumor cells is expressed by the tumor cells after the tumor growth of RBP 638.
There have been many records in recent years relating to the development of KDMs inhibitor synthesis. Since the crystal structure of the catalytic domain of JMJC KDMs shows a funnel-shaped active site, it contains a tight polar binding site for the charged co-substrate 2-OG. Catalytic iron and polar amino acids, conserved across enzyme families, coordinate 2-OG binding, complicating the design of selective KDMs inhibitors. Non-selective metal chelating inhibitors of these enzymes have been generated, such as 2, 2-bipyridine or hydroxyquinoline, some of which lack a clear mechanism of inhibition. The lack of selectivity or poor cell permeability of other molecules that inhibit KDMs, such as oxalylglycine (NOG), 2, 4-pyridinedicarboxylic acid (2, 4-PDA), in a 2-OG competitive manner complicates the interpretation of biological studies using these compounds. There is therefore a need to understand the structural basis of ligand binding, and thus to facilitate the development of selective KDMs inhibitors.
The discovery of the pharmaceutically active lead compound is the source for research and development of new drugs, and the construction of the compound with various structures and high selectivity has important significance for the discovery and optimization of the lead compound. It has been investigated in the literature that heterocyclic compounds containing a caproyl fragment inhibit the enzymatic activity of histone demethylase 5 (KDM 5) family members by binding to their JMJC region. Therefore, according to the active site of the compound, derivative synthesis is carried out, and a compound aiming at the RBP2 enzyme activity is designed and synthesized, and the inhibition effect of the compound in gastric cancer is studied.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a pyridine compound WXSA-051B, a preparation method thereof and an application thereof in resisting gastric cancer.
The invention is realized by the following technical scheme:
the invention provides a pyridine compound WXSA-051B, which has the following structural formula:
the invention also provides a preparation method of the pyridine compound WXSA-051B,
the preparation method of the WXSA-051B comprises the following steps:
step (i), 4-carbomethoxy-2-pyridylmethylamine hydrochloride, 3-bromopropyne and potassium carbonate are used as initial raw materials, and a key intermediate 2 is obtained through one-step nucleophilic substitution reaction;
step (ii), in a mixed solution of DMSO and water, 3-bromo-N-hexyl-N-methylpropionamide and sodium azide firstly undergo one-step nucleophilic substitution, and then undergo Click cyclization reaction with an intermediate 2 to obtain a target compound WXSA-051B;
the synthetic route is as follows:
the reagents and synthesis conditions required for synthesis are as follows:
step (i), 3-bromopropyne, acetonitrile and potassium carbonate, wherein the temperature is 20-30 ℃;
step (ii), 3-bromo-N-hexyl-N-methylpropionamide, sodium azide, cuprous iodide, sodium ascorbate, (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine, dimethyl sulfoxide, water, N2，65-75 ℃。
The preparation method comprises the following specific steps:
(1) taking a 25mL round-bottom flask, weighing 4.9mmol of 4-carbomethoxy-2-pyridinemethylamine hydrochloride and 7.2mmol of potassium carbonate in 10mL of acetonitrile, stirring for 15 minutes at room temperature, dropwise adding a solution of 3-bromopropyne in 2.5mmol of acetonitrile by using a constant-pressure dropping funnel, and continuously stirring at room temperature overnight. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, water is added, ethyl acetate is used for extraction for three times, organic phases are combined, and after washing with saturated salt water, anhydrous sodium sulfate is dried; concentrating and loading, and separating by a rapid preparative chromatographic silica gel column to obtain an intermediate 2.
(2) Taking a 25mL round-bottom flask, weighing 1.07mmol of 3-bromo-N-hexyl-N-methylpropionamide and 1.27mmol of sodium azide in 6mLDMSO and H2Mixed solution of O (DMSO: H)2O = 5: 1), stirring at room temperature; then 0.98mmol of methyl 2- ((prop-2-yne-1-ylamino) methyl) isonicotinate, 0.19mmol of cuprous iodide, 0.39mmol of sodium ascorbate and (1R,2R) - (-) -N, N' -di0.10mmol of methyl-1, 2-cyclohexanediamine, and then 6mLDMSO and H2Mixed solution of O (DMSO: H)2O = 5:1），N2And (4) replacing, stirring and refluxing at 65-75 ℃ for reaction for 6 h. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, water is added, ethyl acetate is used for extraction for three times, organic phases are combined, and after washing with saturated salt water, anhydrous sodium sulfate is dried; concentrating, loading, and separating with flash preparative silica gel column chromatography to obtain compound WXSA-051B.
The room temperature of the invention is 20-25 ℃.
The invention also researches the functions of the provided compound in the process of resisting gastric cancer.
The invention discloses a function verification result of a RBP2 enzyme inhibitor small molecular compound in a gastric cancer resistant generation process. Experiments prove that the RBP2 enzyme inhibitor small molecular compound has good RBP2 histone demethylase activity inhibiting effect, and has obvious cell migration inhibiting capability on human gastric cancer cells BGC-832.
As shown in FIG. 1, the effect of the compound on the substrate H3K4me3 for the RBP2 enzyme was examined. Compound WXSA-051B was prepared as a stock solution in DMSO at a final concentration of 200mM, and was used by dilution in incomplete medium at the time of use, with DMSO at a final concentration of no more than 0.1%. BGC-823 cells were plated in six-well plates for experiments. A blank group, a control group and an additive group are set, and the treatment is carried out when the cell length in the six-hole plate reaches 90 percent. Blank (supplemented with the same volume of medium), control (added DMSO), treated (added compound), incubated for 48h, then digested, and subjected to Histone Extraction with the EpiQuik Total Histone Extraction Kit (OP-0006-®The BCA Protein Assay Kit was used for concentration determination and the Protein quantitative comparison was performed by running a western blot. The result shows that the compound can obviously increase the protein level of H3K4me3 in human gastric cancer cell BGC-823 and has the obvious effect of inhibiting the activity of RBP2 enzyme.
As shown in fig. 2, the effect of the test compound on the ability of gastric cancer cells to migrate was examined. The compound WXSA-051B sample is prepared into mother liquor by DMSO with the final concentration of 200mM, and is diluted by incomplete culture medium when in use, and the final concentration of DMSO does not exceed 0.1%. Taking the human gastric cancer cell BGC-823 with a proportion of more than 90 percentAnd (5) carrying out an experiment. Digesting the cells, counting the cells by 1640 resuspension, taking the concentration of 5X 105The cell suspension (volume should be less than 150. mu.L), 600. mu.L of 20% FBS +80%1640 was added to each well of a 24-well plate, and the chamber was placed in a volume of 5X 10 cells per well5Cells were simultaneously filled in a volume of 150 μ L; the 24-well plate is placed at 37 ℃ and 5% CO2Culturing for 48 hours in an incubator, then washing the inner membrane and the outer membrane of the chamber with PBS for three times, wiping off the inner membrane cells of the chamber with a cotton swab, fixing the chamber cells in a 24-pore plate with 1mL of methanol for 30min, drying in the air, adding 1mL of crystal violet into the 24-pore plate, and dyeing for 30 min. And observing under a mirror and taking a picture. The result shows that the compound can reduce the migration ability of human gastric cancer cell BGC-823.
The compound of the invention has novel structure, can be used as a lead compound for resisting cancers, particularly gastric cancer, and can be applied to the preparation of anticancer drugs.
The compound provided by the invention can be prepared into an anticancer, especially gastric cancer resistant pharmaceutical composition, and comprises the RBP2 enzyme inhibitor small molecule compound and one or more pharmaceutically acceptable carriers or excipients.
The invention has the beneficial effects that: the invention provides a small molecular compound for inhibiting the activity of RBP2 enzyme designed and synthesized aiming at an enzyme activity site, and experiments prove that the level of H3K4me3 in a human gastric cancer cell BGC-823 is obviously increased, the function of obviously inhibiting the activity of RBP2 enzyme is realized, and the migration capability of the human gastric cancer cell BGC-823 is reduced. The RBP2 enzyme inhibitor small molecular compound can be used as a gastric cancer inhibitor to prepare anti-gastric cancer drugs.
Drawings
FIG. 1 is a graph showing the effect of a target compound on the substrate H3K4me3 for RBP2 enzyme action.
FIG. 2 is a graph showing the effect of a compound of interest on migration ability in gastric cancer cells.
Detailed Description
The following examples are provided to aid understanding of the present invention, but are not to be construed as limiting the scope of the present invention.
Example 1 preparation of WXSA-051B
Preparation of intermediate 2
Taking a 25mL round-bottom flask, weighing 4-carbomethoxy-2-pyridinemethanamine hydrochloride (1 g, 4.9 mmol) and potassium carbonate (1 g, 7.2 mmol) in 10mL acetonitrile, and stirring at room temperature for 15 minutes; then, a solution of 3-bromopropyne (0.29 g, 2.5 mmol) in 25mL of acetonitrile was added dropwise to the mixture using a constant pressure addition funnel, and stirring was continued overnight at room temperature (TLC detection reaction with new spot formation). After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, 50mL of water is added into the solvent, 35mL of ethyl acetate is added into the solvent for extraction for three times, the organic phases are combined and washed by saturated salt water, then dried by anhydrous sodium sulfate, filtered, evaporated under reduced pressure and mixed with a sample, and packed into a column by a wet method, and the mixture is mixed with ethyl acetate: petroleum ether: triethylamine = 25: 74: 1 to ethyl acetate: petroleum ether: triethylamine = 49: 50: gradient elution of 1 gave intermediate 2. Yellow solid, yield 21%.
Preparation of II, WXSA-051B
3-bromo-N-hexyl-N-methylpropionamide (291 mg, 1.07 mmol) and sodium azide (83 mg, 1.27 mmol) were weighed out and dissolved in 6mL (DMSO: H)2O = 5: 1) stirring for 6h at room temperature; after this time, methyl 2- ((prop-2-yn-1-ylamino) methyl) isonicotinate (200 mg, 0.98 mmol), cuprous iodide (37 mg, 0.19 mmol), sodium ascorbate (78 mg, 0.39 mmol) and (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (14 mg, 0.10 mmol) were added in succession under nitrogen protection, and 6mL (DMSO: H)2O = 5: 1) and then heated to 70 ℃ and stirred for reflux for 6h (TLC detection is more complete). After the reaction is finished, adding 30mL of water, adding 25mL of ethyl acetate for extraction for three times, combining organic phases, washing the organic phases by using saturated salt water, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, performing reduced pressure rotary evaporation on the samples, filling the samples into a column by a wet method, and adding ethyl acetate: petroleum ether: triethylamine = 66: 33: 1 to dichloromethane: methanol: triethylamine = 90: 1: gradient elution is carried out by 1 to obtain the target compound WXSA-051B. Yellow solid, yield 12%.
Spectral data of WXSA-051B:1H NMR (400 MHz, DMSO) δ 8.71 (d,J= 5.0 Hz,1H), 7.94 (d,J= 13.3 Hz, 1H), 7.88 (d,J= 16.0 Hz, 1H), 7.70 (d,J= 3.9Hz, 1H), 5.40 (s, 2H), 3.92 (s, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.35 (s,3H), 3.31 – 3.25 (m, 2H), 3.03 (s, 2H), 2.84 (s, 1H), 1.54 (d,J= 29.5 Hz,1H), 1.47 – 1.42 (m, 1H), 1.29 (d,J= 12.7 Hz, 3H), 1.24 (s, 3H), 0.86 (dd,J= 13.2, 6.6 Hz, 3H). MS: m/z 417.51. [M + 1]+. C21H32N6O3(416.53).
example 2 examination of the Effect of Compounds on the action of RBP2 enzyme on substrates in gastric cancer cells (Western blot)
Purpose of the experiment:
detecting the effect of the compound on a substrate H3K4me3 acted by RBP2 enzyme
Experimental materials:
RPMI 1640 medium was purchased from Gibco;
fetal bovine serum was purchased from Gibco;
DMSO was purchased from Sigma;
EpiQuik Total Histone Extraction Kit (OP-0006-;
Pierce®BCA Protein Assay Kit available from Thermo fisher scientific
An experimental instrument:
an HF safe biological safety cabinet which comprises a cabinet body,
MCO-15AC carbon dioxide incubator, Sanyo SANYO, Japan,
polyacrylamide gel vertical electrophoresis tank, six instruments factory of Beijing, China
The tested drugs are:
the compound WXSA-051B is prepared into mother liquor with DMSO, the final concentration is 200mM, the compound is diluted by incomplete culture medium when in use, and the final concentration of DMSO does not exceed 0.1%.
Cell lines:
human gastric cancer cell BGC-823, purchased and used in the laboratory before freezing, and cultured in RPMI 1640 medium containing 10% fetal bovine serum;
the experimental scheme is as follows:
western blotting detection of H3K4me3 changes
BGC-823 cells were plated in six-well plates for experiments. A blank group, a control group and an additive group are set, and the treatment is carried out when the cell length in the six-hole plate reaches 90 percent. Blank (supplemented with the same volume of medium), control (added DMSO), treated (added compound), incubated for 48h, then digested, and subjected to Histone Extraction with the EpiQuik Total Histone Extraction Kit (OP-0006-®The BCA Protein Assay Kit was used for concentration determination and the Protein quantitative comparison was performed by running a western blot.
Dose setting:
dose groups: 100 mu M;
the experimental results are as follows:
the experimental result is shown in figure 1, and the compound can obviously increase the protein level of H3K4me3 in human gastric cancer cell BGC-823 and has an obvious effect of inhibiting the activity of RBP2 enzyme.
Example 3 test of the Effect of Compounds on migration Capacity in gastric cancer cells (Transwell)
Purpose of the experiment:
detecting the effect of compounds on gastric cancer cell migration
Experimental materials:
RPMI 1640 medium was purchased from Gibco;
fetal bovine serum was purchased from Gibco;
DMSO was purchased from Sigma;
corning Transwell 3542 cell from Sorbabao Tech Co, Beijing
An experimental instrument:
an HF safe biological safety cabinet which comprises a cabinet body,
MCO-15AC carbon dioxide incubator, Sanyo SANYO, Japan,
olympus CKX53 biomicroscope, shanghai proh optoelectronics, ltd,
the tested drugs are:
the compound WXSA-051B, samples are prepared into mother liquor by DMSO with the final concentration of 200mM, and are used by diluting with incomplete culture medium, and the final concentration of DMSO does not exceed 0.1%.
Cell lines:
human gastric cancer cell BGC-823, purchased and used in the laboratory before freezing, and cultured in RPMI 1640 medium containing 10% fetal bovine serum;
the experimental scheme is as follows:
transwell method for detecting cell migration capacity
The experiment was carried out using cells with a viable cell fraction of more than 90%. Digesting the cells, counting the cells by 1640 resuspension, taking the concentration of 5X 105The cell suspension (volume should be less than 150. mu.L), 600. mu.L of 20% FBS +80%1640 was added to each well of a 24-well plate, and the chamber was placed in a volume of 5X 10 cells per well5Cells were simultaneously filled in a volume of 150 μ L; the 24-well plate is placed at 37 ℃ and 5% CO2Culturing for 48 hours in an incubator, then washing the inner membrane and the outer membrane of the chamber with PBS for three times, wiping off the inner membrane cells of the chamber with a cotton swab, fixing the chamber cells in a 24-pore plate with 1mL of methanol for 30min, drying in the air, adding 1mL of crystal violet into the 24-pore plate, and dyeing for 30 min. And observing under a mirror and taking a picture.
Dose setting:
dose groups: 100 mu M;
the experimental results are as follows:
the experimental result is shown in figure 2, and the compound WXSA-051B can reduce the migration capability of human gastric cancer cell BGC-823.
While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A pyridine compound, designated WXSA-051B, having the structure shown below:
2. the process for the preparation of pyridine compound WXSA-051B according to claim 1, comprising the following steps:
step (i), 4-carbomethoxy-2-pyridylmethylamine hydrochloride, 3-bromopropyne and potassium carbonate are used as initial raw materials, and an intermediate 2 is obtained through one-step nucleophilic substitution reaction;
step (ii), in a mixed solution of DMSO and water, 3-bromo-N-hexyl-N-methylpropionamide and sodium azide firstly undergo one-step nucleophilic substitution, and then undergo Click cyclization reaction with an intermediate 2 to obtain a target compound WXSA-051B;
the synthetic route is as follows:
the reagents and synthesis conditions required for synthesis are as follows:
step (i), 3-bromopropyne, acetonitrile and potassium carbonate, wherein the temperature is 20-30 ℃;
step (ii), 3-bromo-N-hexyl-N-methylpropionamide, sodium azide, cuprous iodide, sodium ascorbate, (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine, dimethyl sulfoxide, water, N2，65-75℃。
3. The process for the preparation of pyridine compound WXSA-051B according to claim 2, comprising the following steps:
(1) taking a 25mL round-bottom flask, weighing 4.9mmol of 4-carbomethoxy-2-pyridinemethylamine hydrochloride and 7.2mmol of potassium carbonate into 10mL of acetonitrile, stirring for 15 minutes at room temperature, dropwise adding a 3-bromopropyne 2.5mmol acetonitrile solution by using a constant-pressure dropping funnel, continuously stirring overnight at room temperature, evaporating the solvent to dryness at reduced pressure after the reaction is finished, adding water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated salt water for three times, and drying with anhydrous sodium sulfate; concentrating, loading by a dry method, and separating by a rapid preparative chromatographic silica gel column to obtain an intermediate 2;
(2) taking a 25mL round-bottom flask, weighing 1.07mmol of 3-bromo-N-hexyl-N-methylpropionamide and 1.27mmol of sodium azide in 6mLDMSO and H2In a mixed solution of O, DMSO and H2Stirring at room temperature, wherein the ratio of O is 5: 1; then 0.98mmol of methyl 2- ((prop-2-yne-1-ylamino) methyl) isonicotinate, 0.19mmol of cuprous iodide, 0.39mmol of sodium ascorbate and (1R,2R) - (-) -N, N' -dimethyl are added in sequence0.10mmol of 1, 2-cyclohexanediamine, 6mL of LDMSO and H2Mixed solution of O, DMSO and H2The ratio of O is 5:1, N2Replacement, stirring and refluxing at 65-75 ℃ for 6h, evaporating the solvent to dryness under reduced pressure after the reaction is finished, adding water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated salt water for three times, and drying with anhydrous sodium sulfate; concentrating, loading by dry method, and separating by flash preparative silica gel column chromatography to obtain compound WXSA-051B.
4. The use of a compound according to claim 1 for the manufacture of a medicament against gastric cancer.
5. An anti-cancer pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
6. An anti-gastric cancer pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
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