CN114426470A - Application of human PCID2 protein in preparation or screening of antitumor drugs and compound with antitumor activity - Google Patents
Application of human PCID2 protein in preparation or screening of antitumor drugs and compound with antitumor activity Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
The invention belongs to the technical field of biotechnology and gene therapy, and particularly relates to application of human PCID2 protein in preparation or screening of antitumor drugs and an antitumor compound. The PCID2 gene is found to promote the proliferation of tumor cells and regulate the cell cycle, is a key molecule for regulating the occurrence and development of tumors, and can be used as a target protein for preparing or screening antitumor drugs; meanwhile, the human PCID2 protein is used as a target protein, and a class of anti-tumor compounds targeting the PCID2 protein are screened out by a molecular docking technology, and the compounds can obviously inhibit the proliferation of tumor cells and promote the apoptosis of the tumor cells.
Description
The present case is the divisional application of former application, former patent number: 2021103641290, respectively; the original patent name is as follows: the application of human PCID2 protein in preparing or screening antitumor drugs and compounds with antitumor activity; the original application date: 2021, 4 months and 3 days.
Technical Field
The invention belongs to the technical field of new accurate cancer medical targets and medicines, and particularly relates to application of human PCID2 protein in preparation or screening of antitumor medicines and a compound with antitumor activity.
Background
The tumor is a disease of cell damage or malignant and unlimited proliferation, wherein liver cancer is one of common malignant tumors, and accounts for the sixth place and the fourth place of the global tumor morbidity. The new liver cancer of our country accounts for more than 50% of the whole world every year. Liver cancer is occult, early symptoms are not obvious, the intrahepatic and extrahepatic metastasis rate is high, and the prognosis is very poor. Tumor chemotherapy is currently the primary means of treating malignant tumors. However, drug resistance, especially acquired multidrug resistance, has become a major obstacle to current tumor chemotherapy. Most of tumor chemotherapy drugs applied to clinical application generate therapeutic effects by inducing apoptosis of tumor cells, and thus, an anti-apoptosis pathway is a main mechanism for drug resistance of tumor cells.
Active replication of cellular DNA and rapid cycle of mitosis are the basis for maintaining abnormal proliferation of tumors, and cell cycle-specific targeted therapy is therefore also considered to be the most promising anti-cancer strategy. However, the currently clinically approved drugs have strong toxic and side effects and poor target specificity, so that the application effect of the cell cycle-directed inhibitor in the clinical treatment of tumors is unsatisfactory. In normal cells, DNA synthesis replication occurs at G0/G1 and S phase, but the intense DNA replication stress of tumor cells can abnormally activate Chromosome Fragile Sites (CFSs), causing DNA replication to occur at various nodes of the cell cycle, especially M phase, to maintain genome stability and quality, which is a unique feature and defect of tumor cell DNA replication. If a key target point for coordinating the DNA replication pressure can be found, the stability of the tumor cell DNA can be thoroughly destroyed, and then the cell proliferation is fundamentally inhibited. Dynamic new therapies based on specific targeting of tumor cell DNA synthesis hold promise to improve the therapeutic outcome of tumors, and the development of corresponding cell cycle specific multi-target natural small molecule inhibitors has created promise for clinical treatment of tumors.
The existing antitumor chemotherapeutic drugs still have defects in treatment due to strong toxic and side effects and poor specificity and targeting. In the field of liver cancer treatment, although sorafenib, sovitinib and regorafenib have certain curative effects on the treatment of advanced liver cancer, each has defects. In the future, the development of the antagonist of the multifunctional molecule/pathway targeting the growth specificity of cells such as HIF-1 alpha, RAAS and the like is of great significance for improving the curative effect of liver cancer and prolonging the prognosis.
The natural medicine and the derivatives thereof have broad-spectrum biological characteristics in the treatment of serious diseases such as tumor and the like, have low toxic and side effects, and have obvious advantages in the research and development of tumor-specific target antagonists. Therefore, the development of multi-target natural small molecule inhibitors is a promising direction for the targeting treatment of tumor molecules, but the structural optimization of the high-efficiency antagonist is not started due to the lack of specific functional targets.
PCID2 is a key transporter that regulates cell cycle checkpoints. The PCID2 gene is found to promote the proliferation of tumor cells and regulate the cell cycle, is a key molecule for regulating the occurrence and development of tumors, can be used as a target protein for screening antitumor drugs, and is used for screening the antitumor drugs; meanwhile, the invention screens out a kind of anti-tumor compounds targeting PCID2 molecules by a molecular docking technology, and the anti-tumor compounds can obviously inhibit tumor cell proliferation and promote tumor cell apoptosis and have obvious anti-tumor activity.
Disclosure of Invention
The invention provides a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof,
wherein, R is1Hydrogen and hydroxyl; r2Hydrogen, methyl, methoxy, halogen and nitro.
Preferably, the halogen is chlorine.
In a fifth aspect, the invention provides an application of a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament.
Preferably, the tumor is a tumor of the digestive system.
Preferably, the tumor is liver cancer.
Preferably, the compound or the pharmaceutically acceptable salt thereof is added with a pharmaceutically acceptable carrier and/or auxiliary materials, and can be prepared into any one dosage form of tablets, capsules, granules, powder, pills, tinctures, vinum, soft extracts and mixtures.
The invention has the beneficial effects that: the invention screens out a kind of antitumor drugs targeting human PCID2 protein by molecular docking technology, and the drugs can obviously inhibit liver cancer cell proliferation, promote liver cancer cell apoptosis and have the activity of obviously inhibiting liver cancer.
Drawings
FIG. 1 is a schematic representation of the PCID2 domain and PCID2-DSS1 crystal structure; wherein, A is a schematic diagram of a PCID2 structural domain, and B is a schematic diagram of a crystal structure of PCID2-DSS 1;
FIG. 2 shows the binding between chalcone compound 11 and PCID2 protein obtained by molecular docking;
FIG. 3 shows the inhibition of hepatoma cells by Compound 11 and Compound 1;
FIG. 4 shows the results of detecting the PCID2 protein expression levels in the liver cancer cells SMCC7721, MHCC97H, Huh7 and normal liver cell L02 after the drug intervention of the compound 11; wherein the DMCC is compound 11;
FIG. 5 shows the real-time unmarked results of the pharmacodynamic analysis anaplerosis experiment RTCA before and after 24h of the compound 11 in the liver cancer cell Huh7 cell; wherein OE represents PCID2 overexpression.
Detailed Description
The invention provides an application of a PCID2 gene and/or a PCID2 protein in preparing a medicament for treating tumors. In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments. The scope of the invention is not limited to the examples described below.
The sources of reagents, vectors, cells described in the following examples are as follows:
liver cancer cells SMCC7721, Huh7, MHCC97H, HCCLM3, Hep3B, PLC, Bel-7404, Bel-7402 and HEK-293T cells were from Shanghai institute of bioscience for Biological Sciences Cell Resource Center; the vectors Ubi-MCS-3FLAG-SV40-EGFP-IRES-puromycin, hU6-MCS-CMV-EGFP, plas-043-pBiFC-YC-hGdown1, plas-044-pBiFC-VN-hGdown1 were from Shanghai Genechem Co., Ltd. Other reagents not described are of conventional origin.
Example 1 antitumor Compounds and tumor inhibition experiments
1. Screening for anti-tumor Compounds
(1) Determination of the Crystal Structure of the PCID2 Domain and the PCID2-DSS1 Complex
Human PCID2 binds to disordered protein DSS1(26S proteosome complex subunit, 26S proteasome complex subunit) (PCID 2-DSS1 complex for short) to maintain the PCID2 protein structure stable. The crystal structures of the PCID2 domain and the PCID2-DSS1 complex were determined in this example, and the results are shown in FIG. 1, in which the WH (wired helix) domain is the main interaction site and is one of the important functional regions of the PCID2 protein.
(2) Preparation of virtual Compound libraries
The chalcone derivative is designed by a biological electronic isostere, a similarity structure transition technology and other methods at three substitution positions of a chalcone matrix by using a shape similarity method (such as ROCS) and a fingerprint similarity method and screening from an existing small molecule database (such as SPECS, Chemdiv, TCMD and the like). In order to ensure the druggability of the target compound, the drug-like property evaluation is carried out on the analog molecule library.
(3) Virtual screening based on molecular docking:
first adopt
Glide molds in softwareThe block was subjected to a molecular docking method to analyze the interaction of compound 11 with PCID2, including hydrogen bonding, van der waals interactions, electrostatic interactions, etc., to obtain a binding mode of the two interactions. Then, compounds in the analogue molecule library are butted to an active site of PCID2, and screening is carried out by sequentially carrying out butting methods with different accuracies. And finally, performing cluster analysis on the result of the virtual screening, and selecting target molecules (compounds 1-12) which have stronger binding effect with the PCID2 theoretically according to the joint score value and the experience.
2. Chemical synthesis of target molecules
(1) Synthesis method
The target compound was synthesized in the references (J Med Chem,2015,58, 1795-: firstly, 2, 4-dihydroxyacetophenone (a) or 2,4, 6-trihydroxyacetophenone is taken as a raw material, an intermediate 2, 4-dimethoxyacetophenone (b) or 2-hydroxy-4, 6-dimethoxyacetophenone is obtained through methylation, and secondly, the target molecules and the analogues thereof are obtained through condensation reaction of the 2, 4-dimethoxyacetophenone or 2-hydroxy-4, 6-dimethoxyacetophenone and different substituted benzaldehydes.
(2) Structural characterization of drug molecules
After obtaining the target molecule, characterizing and identifying the structure and purity of all drug molecules by using Nuclear Magnetism (NMR), Mass Spectrum (MS), High Performance Liquid Chromatography (HPLC), and the like, wherein the nuclear magnetism data are shown as follows:
compound 1
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.43(s,1H),8.19(d,J＝16Hz,1H),8.01(d,J＝15.6Hz,1H),7.65(dd,J＝8,1.6Hz,1H),7.40(m,1H),7.03(t,1H),6.97(d,J＝8.4Hz,1H),6.14(d,J＝2.4Hz,1H),5.99(d,J＝2.4Hz,1H),3.94(s,3H),3.94(s,3H),3.86(s,3H)；13C NMR(100MHz,CDCl3)δ193.00,168.30,166.00,162.47,158.59,37.77,131.29,128.71,127.82,124.50,120.63,111.14,106.38,93.74,91.11,55.68,55.47,55.42。
Compound 2
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.27(s,1H),7.90(d,J＝15.6Hz,1H),7.76(d,J＝15.6Hz,1H),7.35(t,1H),7.22(d,J＝7.6Hz,1H),7.13(d,J＝2Hz,1H),6.95(dd,J＝5.6,2Hz,1H),6.12(d,J＝2.4Hz,1H),5.97(d,J＝2Hz,1H),3.92(s,3H),3.86(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3)δ192.49,168.33,,166.20,162.44,159.80,142.04,136.90,129.76,127.80,120.81,115.51,113.56,106.24,93.75,91.16,55.74,55.47,55.18。
Compound 3
(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.41(s,1H),7.84(d,J＝16Hz,1H),7.80(d,J＝16Hz,1H),7.58(dd,J＝6.8,1.6Hz,2H),6.94(d,J＝8.8Hz,2H),6.13(d,J＝1.2Hz,1H),5.97(d,J＝2Hz,1H),,3.92(s,3H),3.85(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3)δ192.51,168.31,165.96,162.40,161.30,142.38,130.04,128.23,125.05,114.29,106.27,93.76,91.13,55.75,55.48,55.31。
Compound 4
(E)-3-(2-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.20(s,1H),8.17(d,J＝15.6Hz,1H),7.90(d,J＝15.6Hz,1H),7.71(t,1H),7.45(m,1H),7.32(dd,J＝4.4,2.4Hz,2H),6.12(d,J＝2.4Hz,1H),5.97(d,J＝2.4Hz,1H),3.91(s,3H),3.85(s,3H)；13C NMR(100MHz,CDCl3)δ192.34,168.48,166.42,162.49,137.89,135.39,133.84,130.71,130.27,130.03,127.81,127.01,126.92,93.80,91.31,55.90,55.65。
Compound 5
(E)-3-(3-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.18(s,1H),7.89(d,J＝15.6Hz,1H),7.70(d,J＝15.6Hz,1H),7.57(s,1H),7.31(m,1H),7.20(dd,J＝4,0.8Hz,2H),6.12(d,J＝2.4Hz,1H),5.97(d,J＝2.4Hz,1H),3.93(s,3H),3.85(s,3H)；13C NMR(100MHz,CDCl3)δ192.21,168.42,166.42,162.47,140.37,137.44,134.80,130.06,129.77,128.85,127.83,126.55,106.25,93.79,91.29,55.89,55.58。
Compound 6
(E)-3-(4-chlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ14.22(s,1H),7.88(d,J＝15.6Hz,1H),7.36(d,J＝15.6Hz,1H),7.54(d,J＝8.4Hz,2H),7.39(d,J＝8Hz,2H),6.12(d,J＝2.4Hz,1H),5.97(d,J＝2.4Hz,1H),3.92(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3)δ192.28,168.42,166.34,162.44,140.71,135.81,134.06,129.42,129.10,128.01,106.25,93.80,91.28,55.84,55.57。
Compound 7
(E)-1-(2,4-dimethoxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ8.03(d,J＝16Hz,1H),7.76(d,J＝8.8Hz,1H),7.61(dd,J＝7.6,1.2Hz,1H),7.57(d,J＝16Hz,1H),7.37(m,1H),6.99(d,J＝7.2Hz,1H),6.95(t,1H),6.57(dd,J＝8.8,2.4Hz,1H),6.50(d,J＝2.4Hz,1H),3.90(s,3H),3.89(s,3H),3.87(s,3H)；13C NMR(100MHz,CDCl3)δ190.93,163.88,160.23,158.5,137.41,132.68,131.09,128.55,127.63,124.38,122.42,120.55,111.07,105.06,98.55,55.60,55.41,55.37。
Compound 8
(E)-1-(2,4-dimethoxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.8Hz,1H),7.66(d,J＝15.6Hz,1H),7.51(d,J＝15.6,1H),7.33(t,1H),7.21(d,J＝7.6Hz,1H),7.12(t,1H),6.94(m,1H),6.58(dd,J＝8.8,2.4Hz,1H),6.50(d,J＝2.4Hz,1H),3.90(s,3H),3.87(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3)δ190.12,164.07,160.26,159.65,141.57,136.66,132.63,129.60,127.32,121.86,120.66,115.35,113.26,105.13,98.37,55.50,55.30,55.03。
Compound 9
(E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.4Hz,1H),7.68(d,J＝15.6Hz,1H),7.57(d,J＝8.4,2H),7.41(d,J＝15.6Hz,1H),6.39(d,J＝8.8Hz,2H),6.59(dd,J＝8.8,2.4Hz,1H),6.51(d,J＝2Hz,1H),3.91(s,3H),3.88(s,3H),3.85(s,3H)；13C NMR(100MHz,CDCl3)δ190.56,163.90,161.17,160.19,141.97,132.63,129.90,128.09,124.95,122.39,114.22,105.06,98.6,55.67,55.45,55.29。
Compound 10
(E)-3-(2-chlorophenyl)-1-(2,4-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ8.06(d,J＝15.6Hz,1H),7.79(d,J＝8.4Hz,1H),7.71(m,1H),7.51(d,J＝16Hz,1H),7.43(m,1H),7.30(m,2H),6.59(dd,J＝8.8,2.4Hz,1H),6.50(d,J＝2.4Hz,1H),3.91(s,3H),3.88(s,3H)；13C NMR(100MHz,CDCl3)δ190.09,164.31,160.43,137.60,135.21,133.74,132.97,130.53,130.09,129.61,127.67,126.90,121.85,105.27,98.54,55.67,55.49。
(E)-3-(3-chlorophenyl)-1-(2,4-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.8Hz,1H),7.62(t,2H),7.53(d,J＝16Hz,1H),7.47(dd,J＝8,1.6Hz,1H),7.34(t,2H),6.59(dd,J＝8.8,2.4Hz,1H),6.51(d,J＝2.4Hz,1H),3.92(s,3H),3.88(s,3H)；13CNMR(100MHz,CDCl3)δ189.77,164.35,160.45,139.89,137.28,134.63,132.87,129.94,129.58,128.30,127.69,126.41,121.72,105.29,98.45,55.65,55.43。
Compound 12
(E)-3-(4-chlorophenyl)-1-(2,4-dimethoxyphenyl)prop-2-en-1-one：1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.8Hz,1H),7.64(d,J＝15.6Hz,1H),7.54(t,3H),7.37(d,J＝8.8Hz,2H),6.59(dd,J＝8.4,2Hz,1H),6.50(d,J＝2.4Hz,1H),3.91(s,3H),3.88(s,3H)；13C NMR(100MHz,CDCl3)δ189.92,164.29,160.41,140.22,135.6,133.95,132.88,129.33,128.98,127.58,121.90,105.26,98.53,55.67,55.46。
The structural formula of the obtained compound is shown as the following formula 1-12:
3. cell viability assay
Cell viability was measured using a Cell Counting Kit (CCK-8) (Dojindo). Cells in the log phase were trypsinized and counted according to the instructions provided with the kit, and cells were seeded in 96-well plates (150 μ L/well) at the appropriate concentration, with 6 duplicate wells per group. After conventional culture is carried out for 24h, 48h, 72h and 96h respectively, the original culture medium is sucked dry, and 110 mu L/hole CCK-8 solution detection mixed solution is added into the culture plate (10 mu L CCK-8 solution is added into each 100 mu L complete culture medium); and (3) after the culture plate is incubated in a cell temperature incubator for 2h, detecting the OD value at 450nm by using an enzyme-labeling instrument, and drawing a cell proliferation curve according to the detection result. The compound is used for intervening liver cancer cells, and the cell activity is detected through a CCK8 cell activity experiment; and detecting the expression level of PCID2 in the liver cancer cells after the intervention of the compounds by Western blot.
Cell activity experiments show that the compounds 1-12 have half of fatality rate IC to liver cancer cells50As shown in table 1 below; wherein the compound 11(3- (3-chlorphenyl) -1- (2, 4-dimethoxyphenyl) -2-propylene-1-ketone, ((E) -3- (3-chlorophenyl) -1- (2, 4-dimethoxyphenyl) prop-2-en-1-one)) has the strongest effect on liver cancer cells and half of fatality rate IC (integrated circuit) on the liver cancer cells50It was 9.286. mu. mol/L. And its interaction with PCID2 is strongest as shown in fig. 2.
TABLE 1 half-lethality of Compounds 1-12 to hepatoma cells
| Compound numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| IC50(μmol/L) | ND | 39.34 | 450.9 | ND | 30.49 | 39.42 |
| Compound numbering | 7 | 8 | 9 | 10 | 11 | 12 |
| IC50(μmol/L) | ND | 10.73 | ND | ND | 9.286 | ND |
Note: ND means not detected
The screened compounds 1-12 can inhibit the proliferation of liver cancer cells, wherein the inhibition activity of the compound 1 on the proliferation of the liver cancer cells is weaker, and the compound 11 has the strongest inhibition activity on the proliferation of the liver cancer cells. The results of the cell proliferation experiments are shown in fig. 3, which provides a result graph of the inhibitory activity of only compounds 1 and 11 on the proliferation of liver cancer cells.
4. Effect of Compound 11 drug intervention on hepatoma cell proliferation
(1) Influence of compound 11 drug intervention on expression level of PCID2 in hepatoma cells
Performing compound 11 drug-stem prognosis on liver cancer cells SMCC7721, MHCC97H, Huh7 cell lines and normal liver cells L02, and detecting the expression level of the PCID2 protein of the liver cancer cells by Western blot.
The experimental result is shown in fig. 4, compared with the solvent control group (DMSO), the expression level of the PCID2 protein of the liver cancer cell is significantly reduced after the compound 11 drug is dried, and the expression of the PCID2 of the normal liver cell line L02 cell is not significantly affected. The result shows that the compound 11 can obviously inhibit the expression of the gene PCID2 in the liver cancer cell and has an influence on the gene PCID2 of a normal liver cell.
(2) After gene PCID2 is over-expressed, compound 11 medicine intervenes the influence on liver cancer cell proliferation
The liver cancer Huh7 cell line was divided into a blank group (Huh7-NC), a compound 11 drug intervention group (Huh7-11#), a solvent control group (Huh7-DMSO) and a PCID2 overexpression compound 11 drug intervention group (Huh7-OE-11 #). RTCA real-time label-free detection of the growth of the liver cancer Huh7 cell line.
The results of the RTCA real-time unmarked experiment are shown in FIG. 5, and before drug intervention (before 24 h), the PCID2 overexpression can remarkably promote the growth of liver cancer cells; after drug intervention (after 24 h), the proliferation capacity of liver cancer cells in the compound 11 drug intervention group (Huh7-11#) and the PCID2 overexpression compound 11 drug intervention group (Huh7-OE-11#) was significantly inhibited. The result shows that the compound 11 can obviously inhibit the proliferation of normal liver cancer cells and also can obviously inhibit the proliferation of the liver cancer cells over-expressed by PCID2, which indicates that the compound 11 inhibits the proliferation of the liver cancer cells by inhibiting PCID 2.
The above description is only for details of a specific exemplary embodiment of the present invention, and it is obvious to those skilled in the art that various modifications and changes may be made in the present invention in the practical application process according to specific preparation conditions, and the present invention is not limited thereto. All that comes within the spirit and principle of the invention is to be understood as being within the scope of the invention.
Claims (5)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein, R is1Hydrogen and hydroxyl; r2Hydrogen, methyl, methoxy, halogen and nitro.
2. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor medicament.
3. The use of claim 2, wherein the tumor is a tumor of the digestive system.
4. The use of claim 3, wherein the tumor is liver cancer.
5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is added with a pharmaceutically acceptable carrier and/or an auxiliary material, and can be prepared into any dosage form of tablets, capsules, granules, powder, pills, tinctures, vinum, soft extracts and mixtures.
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