CN114246851B - Synthesis method and application of histone methyltransferase SMYD3 small molecule inhibitor - Google Patents
Synthesis method and application of histone methyltransferase SMYD3 small molecule inhibitor Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a histone methyltransferase SMYD3 small molecule inhibitor, which belongs to the field of western medicine pharmacy, and mainly relates to the structure, synthesis and application of the histone methyltransferase SMYD3 small molecule inhibitor in treating cancers such as liver cancer and the like. According to the invention, a novel SMYD3 small molecule inhibitor is screened, simulated and synthesized by a computer, and the results of in-vitro and in-vitro experimental model researches show that the histone methyltransferase SMYD3 small molecule inhibitor can be combined with SMYD3 protein in an energy dose-dependent manner in vitro, so that the activity of the SMYD3 enzyme is reduced, and the histone methyltransferase SMYD3 small molecule inhibitor has good drug properties by computer analysis. Can reduce proliferation of various cancer cells at the cellular level in a dose-dependent manner, and has no obvious toxicity to mice. Can inhibit the growth of in-situ liver HepG2 tumor of NTG mice, can reduce the expression level of liver SMYD3 protein of mice with in-situ liver tumor in the mice, and proves that the histone methyltransferase SMYD3 small molecule inhibitor has remarkable therapeutic effect on liver cancer, and is safe and effective.
Description
Technical Field
The invention relates to the technical field of western medicine pharmacy, in particular to a histone methyltransferase SMYD3 small molecule inhibitor, a synthesis method and application thereof.
Background
SMYD3 (SET and MYND domain protein 3) is a protein with histone methylation function discovered in recent years. Can make chromosome histone (H3K 4, etc.) undergo the process of dimethyl or trimethyl treatment, and can result in change of chromosome space structure, change compactness and openness of transcription complex and regulate gene transcription so as to affect downstream oncogene, cell cycle gene and nuclear hormone receptor, adhesion related gene, inhibit tumor cell apoptosis and promote cell proliferation, invasion and metastasis. Several studies have demonstrated that SMYD3 is highly expressed in different types of cancer cells, while its expression levels are low, or even undetectable, in the corresponding normal tissues. Significant tumor cell growth inhibition and increased apoptosis were observed in SMYD3 gene silencing experiments. Therefore, SMYD3 has become a new epigenetic target of antitumor drugs. Most SMYD3 inhibitors reported in the literature are polypeptides, and the phase research of small molecule inhibitors is very lacking. Compared with biological macromolecules, the small molecular inhibitor has the advantages of relatively easy synthesis, oral administration, easy storage and transportation, good tissue permeability, partial passage through blood brain barrier and no immunogenicity due to the simple structure; although several small molecule inhibitors have been reported to inhibit SMYD3 expression to some extent, they have problems such as poor biocompatibility and low inhibition efficiency. No report is made on high-efficiency, safe and selective small molecule targeted anticancer drugs aiming at SMYD3 targets.
Disclosure of Invention
In view of the foregoing, it would be desirable to provide a small molecule inhibitor of histone methyltransferase SMYD 3.
It is also desirable to provide a method for synthesizing small molecule inhibitors of histone methyltransferase SMYD 3.
There is also a need to provide a histone methyltransferase SMYD3 small molecule inhibitor for use.
A small molecule inhibitor of histone methyltransferase SMYD3, the small molecule inhibitor of histone methyltransferase SMYD3 having the formula: c (C) 25 H 24 N 2 O 2 。
Preferably, the histone methyltransferase SMYD3 small molecule inhibitor has the chemical structural formula:
a synthesis method of a histone methyltransferase SMYD3 small molecule inhibitor, which comprises the following steps:
weighing corresponding compound 1, 3-indandione, placing in a flask, adding anhydrous acetonitrile, stirring to dissolve, adding methyl iodide and potassium fluoride, charging nitrogen into a reaction system, reacting at 70deg.C, detecting reaction progress, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with CH 2 Cl 2 Extracting, collecting organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain intermediate 2,2-dimethyl indandione;
weighing and loadingAdding the intermediate 2,2-dimethyl indandione into a flask, adding anhydrous toluene, stirring to dissolve, adding p-anisole and potassium fluoride, slowly dripping 1-2 drops of p-toluenesulfonic acid under stirring, reacting under reflux, detecting the reaction progress, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with CH 2 Cl 2 Extracting, collecting organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain small molecule inhibitor of histone methyltransferase SMYD3, wherein small molecule inhibitor of histone methyltransferase SMYD3 is defined as ZYZ384.
Preferably, in the synthesis method of the histone methyltransferase SMYD3 small molecular inhibitor, 292.2mg of 1, 3-indandione corresponding to 2mmol of compound is weighed by an electronic analytical balance, placed in a 25mL round bottom flask, 2mL of anhydrous acetonitrile is added, stirring is carried out to dissolve the compound, then 6mmol of methyl iodide and 10mmol of potassium fluoride are added, the reaction progress is detected by adopting a thin layer chromatography, after the reaction is completed, the reaction solution is cooled to room temperature, and H is added into the reaction solution 2 O quenching with 3X 20mLCH 2 Cl 2 Extracting;
weighing 174.1mg of the intermediate 1mmol of 2,2-dimethyl indandione by using an electronic analytical balance, placing the mixture in a 25mL round bottom flask, adding 2mL of anhydrous toluene, stirring to dissolve the mixture, then adding 308mg of p-anisole with 2.5mmol and 10mmol of potassium fluoride, slowly dripping 1-2 drops of p-toluenesulfonic acid under stirring, reacting under reflux, detecting the reaction progress by adopting thin layer chromatography TLC, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with 3X 20mLCH 2 Cl 2 And (5) extracting.
The application of a small molecule inhibitor of histone methyltransferase SMYD3 is provided, and the small molecule inhibitor of histone methyltransferase SMYD3 is used for reducing proliferation of cancer cells.
Preferably, the small molecule inhibitor of histone methyltransferase SMYD3 is used as a therapeutic drug for liver cancer.
Preferably, small molecule inhibitors of histone methyltransferase SMYD3 are used to inhibit liver tumor growth in situ.
Preferably, a small molecule inhibitor of histone methyltransferase SMYD3 is used to reduce proliferation of lung cancer cells, human colon cancer cells, human breast cancer cells or human pancreatic adenocarcinoma cells.
According to the invention, virtual screening is performed by Schrodinger software, hundreds of thousands of candidate small molecules are tested to identify SMYD3 inhibitors, and the molecules which are positioned at the front are selected and evaluated for binding activity by BLI (biological-layer interference technology) experiments to screen out lead compounds. The structure of the lead compound is modified, a series of brand-new small molecule inhibitors are synthesized, and the inhibition activity of the small molecule inhibitors is measured by BLI and SMYD3 enzyme activity experiments, wherein the small molecule inhibitors of histone methyltransferase SMYD3 show the best binding force and inhibition efficacy, and after the small molecule inhibitors of histone methyltransferase SMYD3 are analyzed by a computer to prepare medicines, the anti-cancer activity of the small molecule inhibitors of histone methyltransferase SMYD3 on different cancer cell lines in vitro is further tested. After evaluating the safety of the histone methyltransferase SMYD3 small molecule inhibitor by using a C57 mouse, an NTG mouse in-situ HepG2 in-situ tumor model is established, materials are obtained after three weeks of gastric lavage administration, and each group of liver and spleen is collected, observed, counted and analyzed.
The result shows that the small molecule inhibitor of the histone methyltransferase SMYD3 is combined with the SMYD3 protein in a dose-dependent manner, so that the activity of the SMYD3 enzyme is reduced. Inhibitors of histone methyltransferase SMYD3 small molecules significantly reduce proliferation of different cancer cells in a dose-dependent manner: comprises human liver cancer cells HepG2, human non-small cell lung cancer cells A549, human colon cancer cells HTC116, human breast cancer cells MDA-MB-231 and human pancreatic adenocarcinoma cells Miapaca2. Wherein, the histone methyltransferase SMYD3 small molecule inhibitor has obvious inhibition effect on HepG2 proliferation and has the effect of resisting cancer cell proliferation. One time administration of the C57 mice histone methyltransferase SMYD3 small molecule inhibitor was observed for fourteen days after maximum dose intragastric administration, and none of the mice died within fourteen days. The histone methyltransferase SMYD3 small molecule inhibitor can inhibit the growth of NTG (severe combined immunodeficiency) mouse liver HepG2 in-situ tumor, and can reduce the expression level of in-situ tumor model liver SMYD3 protein in vivo. Therefore, the histone methyltransferase SMYD3 small molecule inhibitor provided by the invention has remarkable treatment effect on liver cancer, is safe and effective, and can be used for preparing medicines for treating cancers such as liver cancer.
Drawings
FIG. 1 is a schematic diagram of the chemical structural formula of a small molecule inhibitor of histone methyltransferase SMYD 3;
FIG. 2 is a schematic diagram of a synthetic route for a small molecule inhibitor of histone methyltransferase SMYD 3;
FIG. 3 is a schematic diagram showing the detection of the binding and dissociation of ZYZ384 at different concentrations and SMYD3 proteins using the BLI assay;
in the figure: curve a is a 200 μm binding dissociation curve, curve b is a 100 μm binding dissociation curve, curve c is a 50 μm binding dissociation curve, curve d is a 25 μm binding dissociation curve, curve e is a 12.25 μm binding dissociation curve, and curve f is a 6.25 μm binding dissociation curve;
FIG. 4 is a schematic diagram of a fitted curve for detecting ZYZ384 and SMYD3 proteins using the BLI assay;
in the figure: KD is equilibrium dissociation constant, kon is binding constant, kdis is dissociation constant, R2 is linear regression determination coefficient;
FIG. 5 is a schematic representation of the interaction sites of ZYZ384 and SMYD3 proteins based on molecular docking simulation;
FIG. 6 is a schematic diagram showing the results of in vitro SMYD3 enzyme activity inhibition assay of ZYZ 384;
FIG. 7 is a schematic diagram of a pharmaceutical study analysis of SMYD3 small molecule inhibitor ZYZ384 and its related inhibitors;
FIG. 8 is a schematic representation of the detection of proliferation inhibition of ZYZ384 on different cancer cells using the MTT method;
in the figure: hepG2: human hepatoma cells, miappa 2: human pancreatic adenocarcinoma cells, MDA-MB-231 human breast cancer cells, HTC116 human colon cancer cells, A549: human non-small cell lung cancer cells. * P <0.01; * P <0.001;
FIG. 9 is a schematic diagram showing the results of evaluating the safety of ZYZ384 using a mouse acute toxicity test method;
FIG. 10 is a schematic diagram showing the results of detection of the antitumor effect of ZYZ384 using the NTG mouse in situ tumor model;
wherein: control: normal control group, model: model group, ZYZ384, model+zyz 384.# # # p <0.001vs Control; * P <0.001vs Model; * P <0.01vs Model
FIG. 11 is a schematic diagram showing the results of detecting SMYD3 protein levels in mouse liver tissues by using immunohistochemistry and Westernblot methods;
in the figure, the target gene for data is compared with the corresponding internal reference GAPDH; wherein: control: normal control group, model: model group, ZYZ384, model+zyz 384, p <0.05vs Control; p <0.05vs Model.
Detailed Description
In order to make the technical scheme of the invention easier to understand, the technical scheme of the invention is clearly and completely described by adopting a mode of a specific embodiment with reference to the accompanying drawings.
Example 1 referring to both fig. 1 and 2, a specific route for synthesis of small molecule inhibitors of histone methyltransferase SMYD3 is:
weighing corresponding compound 1, 3-indandione (1, 3-Inranodione, 292.2mg,2 mmol) by using an electronic analytical balance, placing in a 25mL round-bottom flask, adding 2mL anhydrous acetonitrile, stirring to dissolve, then adding methyl iodide (6 mmol)), potassium fluoride (10 mmol), charging nitrogen into a reaction system, reacting at 70 ℃, detecting the reaction progress by using Thin Layer Chromatography (TLC), cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with CH 2 Cl 2 Extraction (3X 20 mL), collection of organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain intermediate 2,2-dimethyl indandione (2, 2-dimethyl indan-1, 3-dione) 313mg in 90% yield. Nuclear magnetic resonance spectroscopy: 1 H NMR(600MHz DMSO)δ7.99-8.03(m,4H),1.18(s,6H)； 13 C NMR(150MHz,DMSO)δ203.24,139.23,135.92,122.84,48.63,19.47。
the intermediate 2, 2-dimethylindandione (174.1 mg,1 mmol) was weighed out by an electronic analytical balance and placed in a 25mL round bottom flask, 2mL of anhydrous toluene was added and stirred to dissolve it, then p-anisole (308 mg,2.5 mmol)), potassium fluoride (10 mmol) was added under stirringSlowly dripping 1-2 drops of p-toluenesulfonic acid, reacting under reflux, detecting reaction progress by Thin Layer Chromatography (TLC), cooling to room temperature after the reaction is completed, adding H into the reaction solution 2 O quenching with CH 2 Cl 2 Extraction (3X 20 mL), collection of organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain 238mg of histone methyltransferase SMYD3 small molecule inhibitor with the yield of 62%. Nuclear magnetic resonance spectroscopy: 1 H NMR(600MHz,DMSO)δ8.08(dd,J＝1.6,7.6Hz,2H),7.74(dd,J＝1.6,7.6Hz,2H),7.38(d,J＝7.6Hz,4H,6.96(d,J＝7.6Hz,4H),3.79(s,6H),1.03(s,6H)； 13 C NMR(150MHz,DMSO)δ165.4,158.2,144.5,132.8,131.4,131.0,122.9,114.9,56.0,44.1,26.2。
the histone methyltransferase SMYD3 small molecule inhibitor has a molecular formula of: c (C) 25 H 24 N 2 O 2 。
The chemical structural formula of the histone methyltransferase SMYD3 small molecular inhibitor is shown in figure 1, the synthetic route is shown in figure 2, and the naming mode of the histone methyltransferase SMYD3 small molecular inhibitor adopts the research and development subject group name abbreviation ZYZ and molecular weight naming of the histone methyltransferase SMYD3 small molecular inhibitor, and the histone methyltransferase SMYD3 small molecular inhibitor is named as ZYZ384.
Example 2 experiments on binding of ZYZ384 to SMYD3 protein
The method comprises the following steps: SMYD3-GST tag protein was immobilized on glutathione S-transferase (GST) biosensor (Fortebio). ZYZ384 was diluted to different concentrations ranging from 6.25 μm to 200 μm. After baseline with PBS, the biosensor tips were immersed in wells containing ZYZ384 serial dilutions for 180 seconds to bind and 180 seconds to dissociate. Saving data, calculating KD values using a 1:1 binding model in data analysis software 9.0 (Fortebio), monitoring binding and dissociation curves in real-time mode, please refer to FIG. 3, curve a being 200 μM binding and dissociation curve, curve b being 100 μM binding and dissociation curve, curve c being 50 μM binding and dissociation curve, curve d being 25 μM binding and dissociation curve, curve e being 12.25 μM binding and dissociation curve, curve f being 6.25 μM binding and dissociation curve; the computer calculates the result display, linear regression decision, as shown in FIG. 4, based on the combined dissociation curve analysis of FIG. 3Coefficient R 2 = 0.9563 the equilibrium dissociation constant (KD) of the interaction between SMYD3 and ZYZ384 was 79.9 μm according to a simple 1:1 binding pattern, and the binding and dissociation of ZYZ384 to SMYD3 was dose dependent.
Example 3 molecular docking of ZYZ-384 with SMYD3 protein
The ZYZ-384 and SMYD3 proteins were analyzed for molecular docking by cdOCker of Discovery studio 0 (2021) software. The best binding mode and interactions were analyzed by Discovery Studio software and Pymol (Version 2.5.2) software. The binding energy of ZYZ-384 to SMYD3 is-8.73 kcal/mol, the binding pocket is reasonable, the stable conformation of ZYZ-384 to SMYD3 is favorably maintained, as shown in FIG. 5, the binding region comprises a plurality of amino acid residues such as SER-182, PHE-183, CYS-186, MET-190, ILE-214, TYR-257, LYS-297, HIS-366 and VAL-368, and the like, a plurality of interactions such as hydrogen bonds, van der Waals forces and Pi-Pi conjugation can be formed, wherein methoxy groups on ZYZ-384 form hydrogen bond interactions with TYR-257, SER-182, ASP-332 and LYS-297 of Smyd3 proteins, and conjugated interactions with the presence of the various amino acid residues such as PHE-182, ILE-214, HIS-366, VAL-368 and MET-190 of ZYZ-384 have significance for maintaining the stability of the ZYZ-384 and SMYD3 complex, and the key sites of these interactions may be key sites of physiological roles of ZYZ-384.
Example 4 experiments on the enzyme Activity of ZYZ384 against SMYD3
The method comprises the following steps: methyltransferase activity was detected using SMYD3 homogeneous assay kit (BPS bioscience, USA) in three simple steps on microtiter plates. First, samples containing SMYD3 enzyme were incubated with substrate and different concentrations of inhibitor (ZYZ 384) for three hours. Next, acceptor beads and primary antibodies were added, and finally donor beads were added, followed by reading Alpha counts.
The experimental results are shown in fig. 6, where ZYZ384 can reduce SMYD3 enzyme activity in a dose-dependent manner.
Example 5 ADMET prediction of Smyd3 inhibitor ZYZ-384 and related inhibitors
The method comprises the following steps: ADMET (Absorption of drug) was calculated using Discovery Studio software
Distribution, metabolic Metabolism, excretion and Toxicity) properties: 25 degrees celsius water solubility (aqueous solubility); blood brain barrier permeability (Blood brain barrier penetration, BBB); cytochrome P4502D6 inhibitory (Cytochrome P4502D6 inhibitory), hepatotoxicity (hepatotoxicity); the human intestinal tract absorbability (human intestinal absorption, HIA), plasma protein binding rate (plasma protein binding), small Molecules | Calculate Molecular Properties | ADMET Descriptors in the Discovery Studio, the default settings selected by parameters will calculate the ADMET properties of ZYZ-384 and its related inhibitors, the results of which are shown in FIGS. 3 and 4, the ADMET plot is a two-dimensional plot of ADMET_PSA_2D vs ADMET_AlogP98 showing confidence intervals of 95% and 99% for the blood brain barrier permeability (BBB) model, and 95% and 99% for the human intestinal tract absorbability (HIA) model, and ZYZ-384 has better ADMET properties, as shown in FIG. 7 by analysis, for good patentability.
Example 6ZYZ384 cytotoxicity assay.
The method comprises the following steps: cells in 100mL of medium (1×104/well) were seeded in 96-well plates and treated with ZYZ384. After 24 hours of treatment, cell viability was determined by adding 1mg/ml of MTT-containing medium for 4 hours and then adding 100ml of DMSO to dissolve formazan. Absorbance at 570nm, and cell proliferation were recorded using a microplate UV/VIS spectrophotometer (Tecan, mannedorf, switzerland), and the results are shown in fig. 8, which demonstrate that ZYZ384 significantly reduced proliferation of different cancer cells in a dose-dependent manner: including human hepatoma cells HepG2, adenocarcinoma human alveolar basal epithelial cells a549, human colon cancer cells HTC116, human breast cancer cells MDA-MB-231 and human pancreatic adenocarcinoma cells Miapaca2, wherein ZYZ384 exhibits a significant inhibitory effect on HepG2 proliferation (ic50=5.23 μm).
Experimental results prove that the ZYZ384 has obvious proliferation inhibition effect on various cancer cells.
EXAMPLE 7ZYZ384 animal toxicity test
C57 mice group: seven (6) weeks of age, 20C 57 male mice weighing 22-26g and in good condition, 18-22 g were randomly selected and randomly divided into a blank group and a dosing group (n=10). A maximum of 2 g/kg/time was administered once by gavage and observed continuously for 14 days. As shown in fig. 9, the experimental results showed that none of the 14 days after administration died, and that the mice were not abnormal in feeding, water intake, spontaneous activities, etc. LD50 of ZYZ384 >2g/kg.
Example 8ZYZ384 experiments on inhibition of liver in situ tumor growth in NTG mice
NTG mice group: 30 male NTG mice weighing 22-26g and having good status were randomly selected for 6 weeks of week age and randomly divided into 3 groups (n=10), namely: (1) CON is a normal control group; (2) MODEL is a MODEL group; (3) ZYZ384 is model group plus ZYZ384 group; (2) group 3 mice were anesthetized by intraperitoneal injection of 0.8% sodium pentobarbital (75 mg/kg), fixed in supine position, shaved off the abdominal hair, cut the skin about 1cm upward along the midline of the abdomen at 2cm of the lower sternum, split and cut off the peritoneum, expose the liver, gently press the abdomen, squeeze out the left lobe of the liver, slowly inject 100 μl (1×106/100 μl) of HepG2 cell suspension into the liver parenchyma under the liver capsule with a syringe, needle at about 30 ° angle to the liver surface, penetration depth 1cm, see whitening of liver tissue at the injection site, demonstrate successful injection, slowly dial out the needle, gently press the injection site with hemostatic cotton to prevent bleeding and cell extravasation. The liver was returned to its natural position and the peritoneum and skin incision were sutured with 6.0 absorbable surgical suture. At week 3 post inoculation, the appearance of gray nodules at the liver surface inoculation sites indicated successful model. Administration: (3) the group was given ZYZ384100mg/kg/day by intragastric administration daily. Mice were sacrificed after 3 weeks and livers and spleens were isolated for later analytical detection. Experimental data were analyzed for one-way variance with p < 0.05.
Please refer to fig. 10 and 11 simultaneously: after the NTG mouse liver is obtained, the liver in a blank group is normal in morphology, the liver in a model group is seriously adhered and shrunken, the shape is irregular, and diffuse lumps are protruded; the administration group has relatively normal morphology and little tumor. The liver and spleen weights of the model group are increased compared with that of the blank group, the weight is reduced after administration, and the statistical results are shown in figure 10. HE staining results show that the blank liver cells are complete in morphology, the blue color of the intracellular staining is nucleus, the nucleus is large and round, the cytoplasm is rich, and the cells are most eosinophilic. The model group has the advantages of lacking liver cell morphology, obvious nucleus atypical property, deep cytoplasmic staining and obvious alkalophilicity. Normal cells and abnormal cells coexist in the administration group, the cell nucleus is different in size, the cytoplasm is slightly deeply stained, and the cell morphology is different in many ways. The liver tissue immunohistochemistry and immunoblotting results show that SMYD3 is highly expressed in the model group, the blank and administration groups have low expression level, and the statistical results are shown in figure 11. Proved by the demonstration, the ZYZ384 has the effect of obviously inhibiting the growth of the liver in-situ tumor.
It should be noted that the embodiments described herein are only some embodiments of the present invention, not all the implementation manners of the present invention, and the embodiments are only exemplary, and are only used for providing a more visual and clear way of understanding the present disclosure, not limiting the technical solution described in the present invention. All other embodiments, and other simple alternatives and variations of the inventive solution, which would occur to those skilled in the art without departing from the inventive concept, are intended to be protected by the invention.
Claims (6)
1. A histone methyltransferase SMYD3 small molecule inhibitor, characterized by: the histone methyltransferase SMYD3 small molecule inhibitor has a molecular formula of: c (C) 25 H 24 N 2 O 2 ；
The chemical structural formula of the histone methyltransferase SMYD3 small molecule inhibitor is as follows:
2. the method of synthesizing a small molecule inhibitor of histone methyltransferase SMYD3 according to claim 1, wherein: the synthesis method of the histone methyltransferase SMYD3 small molecule inhibitor comprises the following steps:
weighing corresponding compound 1, 3-indandione, placing in a flask, adding anhydrous acetonitrile, stirring to dissolve, adding methyl iodide and potassium fluoride, charging nitrogen into a reaction system, reacting at 70deg.C, detecting reaction progress, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O advancesRun-quench with CH 2 Cl 2 Extracting, collecting organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain intermediate 2,2-dimethyl indandione;
weighing the intermediate 2,2-dimethyl indandione, placing in a flask, adding anhydrous toluene, stirring to dissolve, adding p-anisole and potassium fluoride, slowly dripping 1-2 drops of p-toluenesulfonic acid under stirring, reacting under reflux, detecting the reaction progress, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with CH 2 Cl 2 Extracting, collecting organic phase, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating by column chromatography to obtain small molecule inhibitor of histone methyltransferase SMYD 3.
3. A method of synthesizing a histone methyltransferase SMYD3 small molecule inhibitor according to claim 2, wherein: in the synthesis method of the histone methyltransferase SMYD3 small molecular inhibitor, 292.2mg of 1, 3-indandione of the corresponding compound, which is 2mmol, is weighed by an electronic analytical balance, is placed in a 25mL round bottom flask, 2mL of anhydrous acetonitrile is added, stirring is carried out to dissolve the corresponding compound, then 6mmol of methyl iodide and 10mmol of potassium fluoride are added, the reaction progress is detected by adopting a thin layer chromatography, after the reaction is completed, the reaction solution is cooled to room temperature, and H is added into the reaction solution 2 O quenching with 3X 20mLCH 2 Cl 2 Extracting;
weighing 174.1mg of the intermediate 1mmol of 2,2-dimethyl indandione by using an electronic analytical balance, placing the mixture in a 25mL round bottom flask, adding 2mL of anhydrous toluene, stirring to dissolve the mixture, then adding 308mg of p-anisole with 2.5mmol and 10mmol of potassium fluoride, slowly dripping 1-2 drops of p-toluenesulfonic acid under stirring, reacting under reflux, detecting the reaction progress by adopting thin layer chromatography TLC, cooling to room temperature after the reaction is completed, and adding H into the reaction solution 2 O quenching with 3X 20mLCH 2 Cl 2 And (5) extracting.
4. Use of a histone methyltransferase SMYD3 small molecule inhibitor according to claim 1, characterized in that: the histone methyltransferase SMYD3 small molecule inhibitor is used for preparing a therapeutic drug for liver cancer.
5. Use of a histone methyltransferase SMYD3 small molecule inhibitor according to claim 1, characterized in that: the histone methyltransferase SMYD3 small molecule inhibitor is used for preparing a proliferation medicament for reducing lung cancer cells, human colon cancer cells, human breast cancer cells or human pancreatic adenocarcinoma cells.
6. The method of claim 1, wherein the small molecule inhibitor of histone methyltransferase SMYD3 is used to prepare a medicament for inhibiting liver tumor growth.
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