CN111228250B - Application of 2-benzenesulfonylamino benzamide compound in preparation of medicine for treating liver cancer - Google Patents

Application of 2-benzenesulfonylamino benzamide compound in preparation of medicine for treating liver cancer Download PDF

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CN111228250B
CN111228250B CN202010139558.3A CN202010139558A CN111228250B CN 111228250 B CN111228250 B CN 111228250B CN 202010139558 A CN202010139558 A CN 202010139558A CN 111228250 B CN111228250 B CN 111228250B
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CN111228250A (en
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何红伟
王玉成
葛茂旭
王菊仙
邵荣光
张娜
李娜仁
刘志锋
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Hebei Maxin Pharmaceutical Technology Co ltd
Institute of Medicinal Biotechnology of CAMS
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Abstract

The invention provides an application of 2-benzenesulfonylamino benzamide compounds in preparation of a medicine for treating liver cancer, and belongs to the technical field of liver cancer prevention and treatment. The 2-benzenesulfonylamino benzamide compound has obvious liver cancer inhibition activity; obviously inhibit the growth of mouse liver cancer H22 oxter transplantation tumor; obviously inhibit the growth of human liver cancer HepG2 nude mouse axillary transplantation tumor; can inhibit the movement of human liver cancer HepG2 cells in a time-dependent and dose-dependent manner; with the increase of the concentration of the compound, the expression levels of fibrinectin, MMP9, vimentin, Slug, Snail, N-Cadherin and MMP2 are reduced, and the EMT process of HepG2 cells is obviously inhibited, so that the compound can be used for preparing a medicament for treating liver cancer.

Description

Application of 2-benzenesulfonylamino benzamide compound in preparation of medicine for treating liver cancer
Technical Field
The invention belongs to the technical field of liver cancer prevention and treatment, and particularly relates to an application of 2-benzene sulfonamide benzamide compounds in preparation of a medicament for treating liver cancer.
Background
Liver cancer is one of common malignant tumors in China, has no obvious symptoms in the early stage of liver cancer, is easy to delay diagnosis, is frequently diagnosed in the later stage when symptoms appear, and has common clinical manifestations of liver region pain, progressive liver swelling, low fever, jaundice, abdominal distension, anorexia, nausea, vomiting, emaciation, hypodynamia, edema, progressive anemia and the like.
The 2-benzenesulfonylamino benzamide compound has activities of anti-inflammation, antibiosis, antitumor, cholesterol resistance and the like, and is mainly used for liver injury protection and liver fibrosis prevention at present.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of a 2-benzenesulfonamido benzamide compound in the preparation of a drug for treating liver cancer, wherein the 2-benzenesulfonamido benzamide compound can significantly inhibit the activity of liver cancer and the growth of liver cancer cells.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an application of 2-benzenesulfonylamino benzamide compounds in preparation of a medicine for treating liver cancer.
Preferably, the structural formula of the 2-benzenesulfonylaminobenzamide compound is shown as the formula I:
Figure GDA0002770008310000011
wherein R1 and R2 are respectively and independently selected from halogen, nitro, trifluoromethyl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C6 cycloalkyl, C1-C6 straight-chain alkoxy, C3-C6 branched-chain alkoxy, C3-C6 cycloalkoxy, primary amino, secondary amino or tertiary amino;
r1 and R2 are respectively and independently 1-5 substituent groups.
Preferably, the 2-benzene sulfonamide benzamide compound comprises N- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzene sulfonamide) benzamide (IMB16-4), N- (2, 4-dichlorophenyl) -2- (3-nitrobenzene sulfonamide) benzamide (IMB16-5) or N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy benzene sulfonamide) benzamide (IMB 17-15).
The invention also provides a medicament for treating liver cancer, which takes the 2-benzene sulfonamide benzamide compound as an active ingredient, and the structural formula of the 2-benzene sulfonamide benzamide compound is shown as the formula I:
Figure GDA0002770008310000021
wherein R1 and R2 are respectively and independently selected from halogen, nitro, trifluoromethyl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C6 cycloalkyl, C1-C6 straight-chain alkoxy, C3-C6 branched-chain alkoxy, C3-C6 cycloalkoxy, primary amino, secondary amino or tertiary amino;
r1 and R2 are respectively and independently 1-5 substituent groups.
Preferably, the effective components of the medicament comprise: a derivative, a pharmaceutically acceptable salt, a solvate, a metabolite, a stereoisomer, a tautomer, a polymorph or a prodrug of N- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide (IMB16-4), N- (2, 4-dichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide (IMB16-5) or N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy benzene sulfonamide) benzamide (IMB 17-15).
Preferably, the medicine also comprises pharmaceutically acceptable auxiliary materials.
The invention provides an application of 2-benzenesulfonylamino benzamide compounds in preparation of a medicine for treating liver cancer. In the present example, half inhibition rate (IC) of 2-benzenesulfonamidobenzamide compounds on human liver cancer HepG2 cells was determined50) It was found that IMB16-4, IMB16-5 and IMB17-15 have significant inhibitory activity against liver cancer, wherein IC of IMB17-1550Can reach 2.768 mu M; the IMB16-4, the IMB16-5 and the IMB17-15 can obviously inhibit the growth of liver cancer HepG2 cells; in an experiment for inhibiting mouse liver cancer H22 axillary transplanted tumors, the 2-benzenesulfonylamino benzamide compound finds that IMB16-4, IMB16-5 and IMB17-15 can obviously inhibit the growth of mouse liver cancer H22 axillary transplanted tumors, wherein the IMB16-4 has the best inhibition effect; the IMB16-4 can obviously inhibit the growth of human hepatoma HepG2 nude mouse axillary transplantation tumor, and the effect is equivalent to 40mg/kg sorafenib; the 2-benzenesulfonylaminobenzamide compound HepG2 found in the cell scratching experimentIMB16-4 was able to inhibit the motility of human hepatoma HepG2 time-and dose-dependently; when Western blot detection is carried out on EMT-related proteins of 2-benzenesulfonylaminobenzamide compounds HepG2 cells, the expression levels of fibrinectin, MMP9, vimentin, Slug, Snail, N-Cadherin and MMP2 are reduced along with the increase of the concentration of the compounds IMB16-4, and the EMT process of HepG2 cells is remarkably inhibited.
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FIG. 1 shows the experimental results of cell growth curves of 2-benzenesulfonamido-benzamide compound HepG 2;
FIG. 2 shows the experimental results of Kunming mouse H22 hepatoma ascites tumor of 2-benzenesulfonamido benzamide compound;
FIG. 3 shows the experimental results of 2-benzenesulfonamido benzamide compound HepG2 cell Balb/c nude mouse transplanted tumor; wherein: a represents a statistical graph of the change of the tumor weight of the 2-benzenesulfonylaminobenzamide compound HepG2 cell transplanted in nude mice; b represents a statistical graph of the volume change of the 2-benzenesulfonylaminobenzamide compound HepG2 cell nude mouse transplanted tumor; c represents a statistical graph of the weight change of 2-benzenesulfonylaminobenzamide compound HepG2 cell nude mice;
FIG. 4 shows the results of cell scratch test for 2-benzenesulfonamido-benzamide compound HepG 2;
FIG. 5 shows the results of Westernblot detection of EMT-associated protein in 2-benzenesulfonamidobenzamide HepG2 cells.
Detailed Description
The invention provides an application of 2-benzenesulfonylamino benzamide compounds in preparation of a medicine for treating liver cancer.
The structural formula of the 2-benzenesulfonylamino benzamide compound disclosed by the invention is preferably shown as a formula I:
Figure GDA0002770008310000031
wherein R1 and R2 are respectively and independently selected from halogen, nitro, trifluoromethyl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C6 cycloalkyl, C1-C6 straight-chain alkoxy, C3-C6 branched-chain alkoxy, C3-C6 cycloalkoxy, primary amino, secondary amino or tertiary amino; r1 and R2 are respectively and independently 1-5 substituent groups.
In the present invention, the 2-benzenesulfonamido-benzamide compound preferably includes N- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzenesulfonamide) benzamide (IMB16-4), N- (2, 4-dichlorophenyl) -2- (3-nitrobenzenesulfonamide) benzamide (IMB16-5) or N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy-benzenesulfonamide) benzamide (IMB17-15), wherein the structural formula of the IMB16-4 is preferably as shown in formula ii:
Figure GDA0002770008310000041
the structural formula of IMB16-5 is preferably as shown in formula III:
Figure GDA0002770008310000042
IMB17-15 is preferably of formula IV:
Figure GDA0002770008310000043
the invention also provides a medicament for treating liver cancer, which takes the 2-benzene sulfonamide benzamide compound as an active ingredient, and the structural formula of the 2-benzene sulfonamide benzamide compound is shown as the formula I:
Figure GDA0002770008310000051
wherein R1 and R2 are respectively and independently selected from halogen, nitro, trifluoromethyl, C1-C6 straight-chain alkyl, C3-C6 branched-chain alkyl, C3-C6 cycloalkyl, C1-C6 straight-chain alkoxy, C3-C6 branched-chain alkoxy, C3-C6 cycloalkoxy, primary amino, secondary amino or tertiary amino; r1 and R2 are each independently 1-5 substituents.
The effective components of the medicament of the invention preferably comprise: a derivative, a pharmaceutically acceptable salt, a solvate, a metabolite, a stereoisomer, a tautomer, a polymorph or a prodrug of N- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide (IMB16-4), N- (2, 4-dichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide (IMB16-5) or N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy benzene sulfonamide) benzamide (IMB 17-15).
The medicine of the invention preferably also comprises pharmaceutically acceptable auxiliary materials. The dosage form of the drug is not particularly limited in the present invention, and conventional dosage forms in the art can be used.
The following examples are provided to illustrate the application of the 2-benzenesulfonamido benzamide compounds of the present invention in the preparation of drugs for treating liver cancer, but they should not be construed as limiting the scope of the present invention.
Example 1
Half inhibition rate (IC) of 2-benzenesulfonylaminobenzamide compounds on human liver cancer HepG2 cells50) Measurement of (2)
HepG2 cells in the logarithmic growth phase were seeded in 96-well plates (cell concentration 8000/well, 200. mu.L/well), cells were allowed to adhere to the wall by culturing for 24 hours, the supernatant was removed, 200. mu.L of fresh medium containing different concentrations of compounds (100. mu.M, 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M) were added (compounds were dissolved in DMSO beforehand, diluted to the desired concentration with complete medium when tested, note that DMSO concentration could not exceed 0.1%. 3 replicate wells were set for each concentration, and blank and negative control wells were set. After further culturing for 48 hours, the supernatant was removed, 200. mu.L of 10% TCA was added to each well, and the mixture was fixed at 4 ℃ for 1 hour. Followed by washing with distilled water 5 times, air-drying, adding 200. mu.l of 4mg/mL SRB solution to each well, staining at room temperature for 30 minutes, discarding the supernatant, and washing with 1% acetic acid 5 times to remove non-specifically bound dye. mu.L of 10mM Tris solution was added to each well, OD was measured at A490 wavelength, and the inhibition rate was calculated. The results are shown in Table 1, and the IMB16-4, IMB16-5 and IMB17-15 have obvious liver cancer inhibition activity, wherein the IC50 of the IMB17-15 can reach 2.768 mu M.
TABLE 12 half-inhibitory Rate of benzenesulfonamidobenzamides on HepG2 cells
Figure GDA0002770008310000061
Example 2
2-benzenesulfonylaminobenzamide compound for inhibiting growth curve of human liver cancer HepG2 cells
HepG2 cells in the logarithmic growth phase were seeded in a 6-well plate (cell concentration: 1000/well, 2 mL/well), cultured for 24 hours to allow the cells to adhere to the wall, the supernatant was removed, 2mL of fresh medium containing 10. mu.M of the compound was added, and cultured for 0, 1, 2, 3, and 4 days, respectively. The absorbance was measured using the method of SRB, and the absorbance for 1-4 days was divided by the absorbance for 0 day to calculate the relative growth multiple. As shown in FIG. 1, IMB16-4, IMB16-5 and IMB17-15 can obviously inhibit the growth of HepG2 cell of liver cancer.
Example 3
2-benzenesulfonylamino benzamide compound for inhibiting mouse liver cancer H22 axillary transplantation tumor
Taking H22 ascites tumor liquid, diluting the H22 ascites tumor liquid with physiological saline, then inoculating the H22 ascites tumor liquid to the armpit of a Kunming mouse of 20-22 g, and then respectively administering IMB 16-4200 mg/kg and 400 mg/kg; IMB 16-5200 mg/kg and 400 mg/kg; IMB 17-15200 mg/kg is injected into abdominal cavity, and the administration is continuously carried out for 28 days. Mice were subsequently sacrificed and dissected and tumor tissue weights were recorded.
The result is shown in figure 2, IMB16-4, IMB16-5 and IMB17-15 can obviously inhibit the growth of mouse liver cancer H22 axillary transplantation tumor, wherein the inhibition effect of IMB16-4 is the best.
Example 4
Experiment of 2-benzenesulfonylaminobenzamide compounds for inhibiting human liver cancer HepG2 cell Balb/c nude mouse transplanted tumor
Inoculating 1000 ten thousand/200 mu L HepG2 cells in logarithmic growth phase to the right axillary subcutaneous part of Balb/c nude mice, cutting off tumor tissue after 3 weeks, and cutting off the tumor tissue into 2mm2The tumor small blocks are aseptically inoculated to the right armpit subcutaneous part of Balb/c nude mice. Tumor of mouseThe size is 100mm2And on the left and right, grouping randomly. The control group was given physiological saline, and the treatment group was given the corresponding compound IMB 16-4400 mg/kg for 28 consecutive days. Measuring tumor size with vernier caliper by length x width2The tumor volume was calculated and the curve was made. After 28 days, tumors were removed weighed and statistically mapped.
The result is shown in figure 3, IMB16-4 can obviously inhibit the growth of human hepatoma HepG2 nude mouse axillary transplantation tumor, and the effect is equivalent to 40mg/kg of sorafenib.
Example 5
2-benzenesulfonylaminobenzamide compound HepG2 cell scratching experiment
Firstly, a marker pen is used at the back of a 6-hole plate, a straight ruler is used for crossing through holes approximately every 0.5-1 cm, and each hole at least penetrates through 5 lines. About 5X 10 additions to the wells5Cells were cultured in 37 ℃ incubator. The next day, a 10 μ L tip was drawn parallel to the straight edge in a direction perpendicular to the marked line, and the tip was vertical and could not be tilted. Cells were washed 3 times with PBS, streaked cells were removed, and serum-free medium was added. Adding IMB 16-41 μ M, 2.5 μ M, 5 μ M, and 10 μ M, respectively, and adding 5% CO at 37 deg.C2Incubators, observed by an inverted microscope for 0, 6 and 12h and photographed. As shown in FIG. 4, IMB16-4 was able to inhibit the motility of human liver cancer HepG2 in a time and dose dependent manner.
Example 6
Western blot detection of EMT (extracellular matrix) related protein of 2-benzenesulfonylaminobenzamide compound HepG2 cells
After 24 hours of incubation of HepG2 in 6-well plates and 24 hours of drug administration treatment, 1ml of Ripa lysate (containing 1% PMSF) was added to each well to extract the protein and the protein concentration was determined by BCA method. The desired protein band was obtained using a ChemiImager 5500imaging system after electrophoresis, membrane transfer, 5% skim milk blocking, and antibody incubation at 25. mu.g/20. mu.l per well.
As shown in FIG. 5, with the increase of the concentration of the compound IMB16-4, the expression levels of Fibronectin, MMP9, vimentin, Slug, Snail, N-Cadherin and MMP2 are reduced, and the EMT process of HepG2 cells is remarkably inhibited.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (1)

  1. The application of 2-benzenesulfonylamino benzamide compounds in preparing medicaments for treating liver cancer;
    the 2-benzene sulfonamide benzamide compound is selected from: n- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide, N- (2, 4-dichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide or N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy benzene sulfonamide) benzamide;
    wherein the structural formula of the N- (3,4, 5-trichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide is shown as a formula II:
    Figure FDA0002770008300000011
    the structural formula of the N- (2, 4-dichlorophenyl) -2- (3-nitrobenzenesulfonamido) benzamide is shown as a formula III:
    Figure FDA0002770008300000012
    the structural formula of the N- (3, 4-dichlorophenyl) -2- (3-trifluoromethoxy benzene sulfonamide) benzamide is shown as a formula IV:
    Figure FDA0002770008300000013
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