CN111233695B - Chlor Liu Anhuan propyl derivative, preparation method and application thereof - Google Patents

Chlor Liu Anhuan propyl derivative, preparation method and application thereof Download PDF

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CN111233695B
CN111233695B CN202010176865.9A CN202010176865A CN111233695B CN 111233695 B CN111233695 B CN 111233695B CN 202010176865 A CN202010176865 A CN 202010176865A CN 111233695 B CN111233695 B CN 111233695B
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compound
fibroblast
preparation
anhuan
liu
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CN111233695A (en
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黄晴菲
王启卫
韩英蕾
叶庭洪
谭醉
张雪玲
范挺
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Chengdu Organic Chemicals Co Ltd of CAS
University of Chinese Academy of Sciences
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Chengdu Organic Chemicals Co Ltd of CAS
University of Chinese Academy of Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Abstract

The invention provides a chloronitro Liu Anhuan propyl derivative shown in the formula I, which has better anti-fibrosis activity than that of niclosamide, has good anti-tumor activity, and can be better used for patients with fibrosis and tumor diseases. The invention also provides a preparation method of the chloronitrate Liu Anhuan propyl derivative, and the chloronitrate Liu Anhuan propyl derivative can be safely and conveniently prepared.

Description

Chlor Liu Anhuan propyl derivative, preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a chloronitrate Liu Anhuan propyl derivative, a preparation method and application thereof.
Background
Fibrosis refers to the pathological process of parenchymal cytopenia or necrosis of a patient's organ, increased extracellular matrix in tissue and diffuse excessive deposition caused by various pathogenic factors, and continued progression can lead to destruction of organ structure, hypofunction, and until failure. Fibrosis can occur in a variety of organs, with the most common clinically fibrosis being predominantly: (1) pulmonary fibrosis; (2) liver fibrosis; (3) cardiac fibrosis; (4) kidney fibrosis and (5) pancreatic fibrosis; furthermore, fibrosis may also occur in the eyes, blood vessels, nervous system.
Pulmonary fibrosis (Pulmonary fibrosis, PF) is a common outcome for a variety of pulmonary diseases of different etiology (e.g. SARS, idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis, allergic pneumonitis, drug and radiation induced pulmonary fibrosis, and fibrosing alveolitis associated with collagen vascular disease, etc.). It has a potentially enormous pathogenesis, and many common underlying diseases are likely to cause pulmonary fibrosis, and should be of great concern in the medical pharmaceutical field.
Niclosamide is an approved small molecule formulation for use in the past clinically against intestinal parasitic infections. In recent years, research has found that the small molecular compound has good anti-fibrosis effect, the application number CN201210158802.6, and the patent name of the invention of the application of niclosamide or the salt thereof in preparing medicines for preventing and treating pulmonary fibrosis disclose the curative effect of niclosamide on inhibiting pulmonary fibrosis, and provide a good direction for treating pulmonary fibrosis.
In addition, niclosamide or a drug taking niclosamide as an active center has a certain research on other common fibrosis, for example, the application number is CN201810496062.4, and the invention patent named as application of niclosamide and structural modification thereof in heart protection, pulmonary hypertension resistance and tumor resistance discloses that niclosamide has good curative effect on heart fibrosis resistance; the invention patent with the application number of CN201510916996.5 and the patent name of 'the application of niclosamide phosphate to preparing medicines for inhibiting kidney tissue fibrosis' discloses that niclosamide has the effect of inhibiting kidney tissue fibrosis.
The disclosure of the above patent shows that niclosamide has a certain curative effect in inhibiting fibrosis, however, the effect is also quite large, and the improvement on niclosamide is needed to develop a new compound with better anti-fibrosis activity in order to better serve patients with fibrosis diseases.
Disclosure of Invention
One of the purposes of the invention is to provide a chloronitro Liu Anhuan propyl derivative which has better anti-fibrosis activity than that of niclosamide, has better anti-tumor activity and can be better used for patients with fibrosis and tumor diseases.
Another object of the present invention is to provide a method for preparing the above-mentioned chloronitrate Liu Anhuan propyl derivative, which can safely and conveniently prepare the chloronitrate Liu Anhuan propyl derivative of the present invention.
Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned chloronitrate Liu Anhuan propyl derivative as an active ingredient and use of the chloronitrate Liu Anhuan propyl derivative of the present invention.
For this purpose, the inventors provided the following technical solution:
first, the inventors provide a chloronitrate Liu Anhuan propyl derivative represented by formula I or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof,
wherein: m=1 to 6; preferably, m=1 to 5, further preferably, m=1, 2,3 or 4; still further preferred is that: m=1, 2 or 3; most preferably, m=1 or 2.
When m=1, the structural formula of the compound i is:
the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof is a compound which has a good synergistic effect on the anti-fibrosis of niclosamide and is researched and developed based on the application knowledge of niclosamide in the anti-fibrosis effect, cyclopropyl is creatively introduced into niclosamide molecules to form niclosamide Liu Anhuan propyl derivatives, and under the synergistic effect of cyclopropyl, the anti-fibrosis activity of the compound is obviously superior to that of niclosamide, so that the compound has a good therapeutic effect on fibrotic patients, especially pulmonary fibrotic patients; in addition, the compound shown in the formula I has an anti-tumor effect equivalent to that of niclosamide.
The invention also provides a preparation method of the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, which comprises the following steps:
step 1: reacting cyclopropylamine with bromoacyl bromide IV in a solvent under the action of alkali to obtain a compound III;
step 2: and adding alkali into the compound III and niclosamide in a solvent to react to obtain a compound I.
Wherein: m=1 to 6.
In the reactions in the step 1 and the step 2, the alkali is one or more selected from potassium carbonate, sodium carbonate and triethylamine; the solvent is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 4-dioxane.
Step 2 is a key step of the preparation method of the compound I, and a new compound is formed by reacting the compound III with niclosamide, loading cyclopropyl on the niclosamide molecule and introducing an acyl bromide group: the preparation method has the advantages that the reaction process of the chlor Liu Anhuan propyl derivative is simple and safe, and industrialization is easy to realize; in addition, the reaction between bromoacyl bromide and cyclopropyl is a conventional chemical combination reaction, and compound III can be prepared in high yield, so as to provide a simple and easily obtained raw material for the reaction of the step 2.
Based on the above summary of the invention, the present invention also provides a pharmaceutical composition, which is a preparation prepared by using a compound shown in formula I or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof as an active ingredient, and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Specifically, the pharmaceutical composition of the present invention may be a tablet, capsule, granule, injection, suspension, etc.; the auxiliary materials can be any one or more selected from excipient (including solid carrier, pasty carrier and liquid solvent), preservative, lubricant, antioxidant, emulsifier, suspending agent, adhesive, stabilizer, cosolvent, dispersing agent, buffer, pH regulator, antifreezing agent, correctant, disintegrating agent, filler and colorant.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof in preparing anti-fibrosis drugs and/or anti-tumor drugs.
Specifically, the anti-fibrosis drug is a drug for inhibiting fibroblast proliferation; more specifically, the fibroblast is one or more of embryonic fibroblast, lung fibroblast, liver fibroblast, heart fibroblast, kidney fibroblast, pancreas fibroblast, eye fibroblast and vascular fibroblast; still more particularly, the fibroblast is a lung fibroblast.
The anti-tumor drug is a drug for inhibiting proliferation of tumor cells; specifically, the tumor cells are any one or more of breast tumor cells, colorectal tumor cells, lung tumor cells, stomach tumor cells and lymphatic tumor cells; further specifically, the tumor cell is a breast tumor cell or a colorectal tumor cell.
The beneficial effects of the invention are as follows:
1. the anti-fibrosis activity of the chloronitro Liu Anhuan propyl derivative is better than that of the chlorosalix amide, and the derivative has better treatment effect on fibrotic diseases than that of the chlorosalix amide; experiments prove that the inhibition rate of the chloranil-chloranil compound on the proliferation of lung fiber cells can reach more than 85%, and has obvious synergy relative to the inhibition rate of the chloranil-chloranil which can reach 77%, so that the chloranil-Liu Anhuan propyl derivative has good industrialization prospect.
2. The chloronitrate Liu Anhuan propyl derivative has good anti-tumor activity.
3. The preparation method of the chloronitrate Liu Anhuan propyl derivative has the advantages of simple and safe reaction process and easy realization of industrialization.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The following examples will provide those skilled in the art with a more complete understanding of the present invention and are not intended to limit the invention in any way.
Example 1
This example provides compound IIIa and a method of preparation thereof:
the specific preparation process of the compound IIIa comprises the following steps:
under ice water bath conditionCyclopropylamine (1.47 mmol) was dissolved in dichloromethane (2 mL), triethylamine 0.21mL (1.47 mmol) was added, compound Iva bromoacetyl bromide (1.47 mmol) was slowly added dropwise, stirring was carried out for 15min, the reaction was completed, water (6 mL) was added to the reaction solution, dichloromethane (3X 3 mL) was extracted, the organic phases were combined, washed with saturated brine (1X 3 mL), dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was chromatographed on a silica gel column to give compound IIIa. Compound IIIa 1 H NMR(300MHz,CDCl 3 )δ:6.66(s,1H),3.83(d,J＝2.2Hz,2H),2.71(tq,J＝7.2,3.8Hz,1H),0.91～0.67(m,2H),0.55(ddd,J＝6.9,5.3,3.8Hz,2H)。
Example 2
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85 mmol) produced in example 1 was dissolved in acetonitrile (15 mL), 235mg (1.70 mmol) of potassium carbonate, 277mg (0.85 mmol) of niclosamide was added, the reaction was completed for 3h, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product Ia. Of compound Ia 1 H NMR(300MHz,DMSO-d 6 )δ:10.86(s,1H),8.63(d,J＝9.2Hz,1H),8.43(d,J＝2.6Hz,1H),8.37(s,1H),8.29(dd,J＝9.2,2.6Hz,1H),7.93(d,J＝2.8Hz,1H),7.66(dd,J＝9.0,2.8Hz,1H),7.19(d,J＝9.0Hz,1H),4.88(s,2H),2.63(dq,J＝7.1,3.5Hz,1H),0.61(dd,J＝7.1,2.3Hz,2H),0.47～0.24(m,2H).HR-MS(ESI)m/z:Calcd for C 18 H 15 Cl 2 N 3 O 5 Na{[M+Na] + }446.0286,found 446.0278。
Example 3
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85 mmol) produced in example 1 was dissolved in dichloromethane (15 mL), 172mg (1.70 mmol) of triethylamine, 277mg (0.85 mmol) of niclosamide was added, the reaction was completed for 3h, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product Ia.
Example 4
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85 mmol) produced in example 1 was dissolved in tetrahydrofuran (15 mL), 180mg (1.70 mmol) of sodium carbonate was added, niclosamide 277mg (0.85 mmol) was reacted for 3h, the reaction was completed, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the product Ia.
Example 5
This example provides compound IIIb and a method of preparation thereof:
the specific preparation process of the compound IIIb comprises the following steps:
under ice water bath, cyclopropylamine (1.47 mmol) is dissolved in dichloromethane (2 mL), triethylamine (0.21 mL) (1.47 mmol) is added, compound IVb bromopropionyl bromide (1.47 mmol) is slowly added dropwise, stirring is carried out for 15min, water (6 mL) is added to the reaction solution, dichloromethane (3X 3 mL) is added for extraction, the organic phases are combined, saturated saline (1X 3 mL) is used for washing, anhydrous sodium sulfate is used for drying, solvent is distilled off, the residue is subjected to silica gel column chromatography to obtain compound IIIb, compound IIIb is obtained 1 H NMR(300MHz,CDCl 3 )δ:6.68(s,1H),3.59(t,J＝2.2Hz,2H),2.71(m,1H),2.68(t,J＝2.2Hz,2H),0.91～0.67(m,2H),0.55(m,2H)。
Example 6
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ib and a preparation method thereof:
the specific preparation process of the compound Ib comprises the following steps:
the compound IIIb (0.85 mmol) produced in example 5 was dissolved in acetonitrile (15 mL), 235mg (1.70 mmol) of potassium carbonate, 277mg (0.85 mmol) of niclosamide was added, the reaction was completed for 3h, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product Ib, compound Ib 1 H NMR(300MHz,DMSO-d 6 )δ:10.88(s,1H),8.64(d,J＝9.2Hz,1H),8.45(d,J＝2.6Hz,1H),8.37(s,1H),8.29(m,1H),7.93(d,J＝2.8Hz,1H),7.66(m,1H),7.19(d,J＝9.0Hz,1H),4.86(t,J＝2.5Hz,2H),2.68(t,J＝2.5Hz,2H),2.63(m,1H),0.61(m,2H),0.47～0.24(m,2H).
Example 7
This example provides compound IIIc and a method of preparation thereof:
the specific preparation process of the compound IIIc comprises the following steps:
cyclopropylamine (1.47 mmol) was dissolved in dichloromethane (2 mL), triethylamine (0.21 mL) (1.47 mmol) was added thereto, bromobutyryl bromide (1.47 mmol) was slowly added dropwise, stirring was carried out for 15min, water (6 mL) was added to the reaction solution after the reaction was completed, dichloromethane (3X 3 mL) was extracted, the organic phases were combined, washed with saturated brine (1X 3 mL), dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was chromatographed on a silica gel column to give compound IIIc. 1 H NMR(300MHz,CDCl 3 )δ:6.68(s,1H),3.51(t,J＝2.3Hz,2H),2.71(m,1H),2.34(m,2H),2.07(t,J＝2.5Hz,2H),0.91～0.67(m,2H),0.55(m,2H)。
Example 8
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ic and a preparation method thereof:
the specific preparation process of the compound Ic is as follows:
the compound IIIc (0.85 mmol) produced in example 7 was dissolved in acetonitrile (15 mL), 235mg (1.70 mmol) of potassium carbonate, 277mg (0.85 mmol) of niclosamide was added, the reaction was completed for 3h, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the product Ic, compound Ic 1 H NMR(300MHz,DMSO-d 6 )δ:10.87(s,1H),8.64(d,J＝9.2Hz,1H),8.46(d,J＝2.6Hz,1H),8.37(s,1H),8.29(m,1H),7.94(d,J＝2.8Hz,1H),7.66(m,1H),7.19(d,J＝9.0Hz,1H),4.84(t,J＝2.7Hz,2H),2.63(m,3.5Hz,1H),2.34(m,2H),2.09(t,J＝2.5Hz,2H),0.63(m,2H),0.47～0.24(m,2H).
Example 9
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Id (m=4) and a preparation method thereof, and the chloronitrate Liu Anhuan propyl derivative Id comprises the following steps:
step 1:
step 2:
the preparation method of the compound IIId is different from that of the example 7 in that the compound IVc (bromobutyryl bromide) is replaced by the compound IVd (bromovaleryl bromide);
the preparation of compound Id differs from that of example 8 in that compound IIIc is replaced by compound IIId.
Example 10
The embodiment provides a chloronitrate Liu Anhuan propyl derivative Ie (m=5) and a preparation method thereof, and the chloronitrate Liu Anhuan propyl derivative Ie comprises the following steps:
step 1:
step 2:
the preparation of compound IIIe differs from example 7 in that compound IVc (bromobutyryl bromide) is replaced by compound IVe (bromohexanoyl bromide);
the preparation of compound Ie differs from example 8 in that compound IIIc is replaced by compound IIIe.
Example 11
The embodiment provides a chloronitrate Liu Anhuan propyl derivative If (m=6) and a preparation method thereof, and the chloronitrate Liu Anhuan propyl derivative If comprises the following steps:
step 1:
step 2:
the preparation of the above compound IIIf differs from example 7 in that compound IVc (bromobutyryl bromide) is replaced with compound IVf (bromoheptanoyl bromide);
the preparation of the above compound If differs from example 8 in that the compound IIIc is replaced by the compound IIIf.
Experimental example 1
In vitro anti-fibrotic Activity Studies
The experimental example verifies the inhibition of the niclosamide derivative Ia prepared in example 2 to fibroblasts, and compares it with the inhibition of niclosamide to fibroblasts. The specific experimental process is as follows:
inoculating 3T3 cells in logarithmic growth phase into 96-well culture plate, 1300 cells per well, 100 μl/well, placing at 37deg.C and 5% CO 2 Incubate in incubator for 24 hours. Setting blank control group (culture medium without drug) and positive drug group, with compound concentration of 10 μmol/L, setting 5 multiple holes, and adding into CO 2 Incubator (37 ℃,5% CO) 2 ) Is cultured for 72 hours. Adding 20 mu L of MTT solution of 5mg/mL into each hole, continuously culturing for 3 hours, discarding supernatant, adding 150 mu L of DMSO into each hole, oscillating for 5 minutes to dissolve formazan particles, measuring a light absorption value at 492nm wavelength by an enzyme-labeling instrument, and calculating the inhibition rate of the control group and the experimental group on fibroblasts according to the absorbance OD value.
Inhibition% = (control well OD value-dosing well OD value)/control well OD value x 100%.
After 48h and 72h, the MTT method detects the evaluation results of the proliferation inhibition rate of the compound of the invention on the 3T3 cells of the mice at the concentration of 10 mu M and 30 mu M, and the evaluation results are shown in Table 1.
TABLE 1 inhibition of fibroblast proliferation by the compounds of the invention
Description: the higher the inhibition rate, the better the anti-fibrosis activity; the inhibition activity of the blank control was 0, and niclosamide was used as a positive control.
The above results indicate that: compared with niclosamide, the compound has obvious synergistic effect on inhibiting the proliferation of the fiber cells, and the 48h inhibition rate and the 72h inhibition rate of the compound on the proliferation of the 3T3 cells of the mice are obviously improved.
Experimental example 2
In vitro anti-tumor Activity study
The experimental example verifies the inhibition effect of the niclosamide derivative Ia prepared in the example 2 on tumor and compares with the inhibition effect of niclosamide on tumor cells. The specific experimental process is as follows:
taking fine tumor in logarithmic growth phaseCells were inoculated in 96-well plates with 1300 cells per well, 100. Mu.L/well, 37℃and 5% CO 2 Incubate in incubator for 24 hours. Setting blank control group (culture medium without drug) and positive drug group (culture medium containing niclosamide) with compound concentration of 10 μmol/L, setting 5 multiple holes, and adding into CO 2 Incubator (37 ℃,5% CO) 2 ) Is cultured for 72 hours. Adding 20 mu L of MTT solution of 5mg/mL into each hole, continuously culturing for 3 hours, discarding supernatant, adding 150 mu L of DMSO into each hole, oscillating for 5 minutes to dissolve formazan particles, measuring light absorption value at 492nm wavelength by using a microplate reader, and calculating IC of a control group and an experimental group according to absorbance OD value 50 As a result.
The test results are shown in table 2:
TABLE 2 IC of the compounds of the invention for proliferation of tumor cells 50 Results (unit is. Mu.M)
Description: IC (integrated circuit) 50 The smaller the number of half inhibition concentration, the better the anti-tumor activity, and the positive control is niclosamide. 4T1 is mouse breast cancer cell, MDA-MB-231, MCF-7 is human breast cancer cell, CT26 is mouse colorectal cancer cell, HCT116 is human colorectal cancer cell.
The above results indicate that: compared with niclosamide, the compound has basically equivalent IC50 for 72h of tumor cell proliferation and good anti-tumor cell proliferation effect.
In conclusion, the chloronitro Liu Anhuan propyl derivative has better effect of resisting fibroblast growth than that of the niclosamide, has excellent effect of resisting tumor cell proliferation, and can be well used for patients with fibrosis and tumor diseases.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein: m=1 to 6.
2. A process for the preparation of a compound of formula i according to claim 1, comprising the steps of:
step 2: adding alkali into the compound III and niclosamide in a solvent to react to obtain a compound I;
wherein: m=1 to 6.
3. The preparation method according to claim 2, wherein the base in the step 2 is one or more selected from potassium carbonate, sodium carbonate and triethylamine; the solvent in the step 2 is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 4-dioxane.
4. A pharmaceutical composition, characterized in that it is a preparation prepared by taking a compound shown in the formula i as defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
5. The use of a compound of formula i as defined in claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an anti-fibrotic and/or anti-tumour agent.
6. The use according to claim 5, wherein the anti-fibrotic drug is a drug that inhibits fibroblast proliferation; the antitumor drug is a drug for inhibiting proliferation of tumor cells.
7. The use according to claim 6, wherein the fibroblast is any one or more of embryonic fibroblast, lung fibroblast, liver fibroblast, heart fibroblast, kidney fibroblast, pancreatic fibroblast, ocular fibroblast, vascular fibroblast.
8. The use according to claim 7, wherein the tumour cells are any one or more of breast tumour cells, colorectal tumour cells, lung tumour cells, stomach tumour cells, lymphoid tumour cells.
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