CN110964056A - Preparation method and application of fluorine-containing aromatic ring carboxylic acid tetramer compound - Google Patents
Preparation method and application of fluorine-containing aromatic ring carboxylic acid tetramer compound Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- -1 aromatic ring carboxylic acid Chemical class 0.000 title claims abstract description 33
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 29
- 239000011737 fluorine Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 8
- DGOZIZVTANAGCA-UHFFFAOYSA-N 2-amino-4,5-difluorobenzoic acid Chemical compound NC1=CC(F)=C(F)C=C1C(O)=O DGOZIZVTANAGCA-UHFFFAOYSA-N 0.000 claims abstract description 6
- RJGHQTVXGKYATR-UHFFFAOYSA-L dibutyl(dichloro)stannane Chemical compound CCCC[Sn](Cl)(Cl)CCCC RJGHQTVXGKYATR-UHFFFAOYSA-L 0.000 claims abstract description 6
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 6
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- 230000001905 anti-neuroblastoma Effects 0.000 abstract 1
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- 229940041181 antineoplastic drug Drugs 0.000 description 14
- INVGWHRKADIJHF-UHFFFAOYSA-N Sanguinarin Chemical compound C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 INVGWHRKADIJHF-UHFFFAOYSA-N 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- FCEXWTOTHXCQCQ-UHFFFAOYSA-N Ethoxydihydrosanguinarine Natural products C12=CC=C3OCOC3=C2C(OCC)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 FCEXWTOTHXCQCQ-UHFFFAOYSA-N 0.000 description 5
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- 230000001093 anti-cancer Effects 0.000 description 4
- 150000007942 carboxylates Chemical class 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 150000003606 tin compounds Chemical class 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 229910020813 Sn-C Inorganic materials 0.000 description 2
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- 206010067484 Adverse reaction Diseases 0.000 description 1
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- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
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- 231100000002 MTT assay Toxicity 0.000 description 1
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- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
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- XJLXINKUBYWONI-NNYOXOHSSA-O NADP(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-O 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229910020923 Sn-O Inorganic materials 0.000 description 1
- 229910009053 Sn—O—Sn Inorganic materials 0.000 description 1
- JTDNNCYXCFHBGG-UHFFFAOYSA-L Tin(II) iodide Inorganic materials I[Sn]I JTDNNCYXCFHBGG-UHFFFAOYSA-L 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2224—Compounds having one or more tin-oxygen linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A fluorine-containing aromatic ring carboxylic acid tetramer compound and a preparation method and application thereof are disclosed, wherein the structural formula is as follows: adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 20-60 mL of methanol into a reaction vessel, stirring for 5 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow powdery solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the n-hexane is 3: 1-6: 1. The fluorine-containing aromatic ring carboxylic acid tetramer compound has anti-neuroblastoma activity.
Description
Technical Field
The invention relates to a novel fluorine-containing aromatic ring carboxylic acid tetramer compound, a preparation method thereof and application of the compound in preparing anti-cancer drugs, in particular to application in resisting neuroblastoma.
Background
Neuroblastoma (NB) belongs to a neuroendocrine tumor, and can originate from any nerve ridge part of the sympathetic nervous system, and the main metastatic pathway is lymph and blood circulation. Regional lymph node infiltration occurs in about 35% of patients with localized lesions, with hematogenous metastases occurring primarily in the bone marrow, bone, liver and skin, and brain and lung metastases at terminal stage or recurrence. The disease is mostly seen in children under 10 years old, accounting for about 8-10% of tumor occurrence in children, the annual incidence rate is about 1/10 ten thousands, and is only lower than leukemia and central nervous system tumors, neuroblastoma has obvious heterogeneity, and is easy to generate drug resistance to chemotherapy. Neuroblastoma is complex and diverse in clinical manifestations, high in malignancy degree, rapid in disease progression, easy to generate metastasis in early stage, poor in prognosis and low in long-term survival rate, and most of children patients (more than 50%) are in a late-stage high-risk state after diagnosis, and is the most common extracranial solid tumor in childhood. Traditional surgery, chemotherapy and radiotherapy are three main means for treating neuroblastoma, and surgery excision and chemotherapy are generally advocated for localized tumors. The patients who can not be resected after the operation adopt the strategies of firstly chemotherapy, then the operation, then the chemotherapy or the radiotherapy after the diagnosis is confirmed. However, the existing medicines for treating neuroblastoma have poor effects, serious adverse reactions and poor prognosis. Therefore, the development of a pharmaceutical compound effective for the treatment of neuroblastoma is a technical problem to be solved in the art.
Frankland synthesized organotin compound Et for the first time in 18942SnI2This publication discloses the development of the organotin chemistry research, and Crowe proposed and studied in detail the inhibition of leukemic cell activity of halogenated organotin complexes in 1980 (chem. -biol. interactions, 32(1980) 171-. Many new organotin compound structures and associated properties have been studied and discovered. While domestic aboutThe chemical research of organotin started in 1966 and began to rise after 80 s, and reports on organotin chemistry are increasing. To date, in the interdisciplinary science of organic and inorganic chemistry, organic tin compounds have been developed extensively and extensively as important representatives of main group metals, and the fields of research and application thereof are expanding continuously, including industry, agriculture, medical use, ecology, etc. With the development of modern instruments and equipment, people have a continuous and deep understanding of organotin compounds, so that the organotin compounds are industrially produced from laboratories. Organotin carboxylates are an important class of compounds in organotin chemistry. In 1991, Abdelkader Meriem reported organotin carboxylate compounds [ (CH)3CONH-PhCOO)(CH3CH2CH2CH2)2Sn]2O (CAS: 135302-75-9) and [ (CH)3NH-PhCOO)(CH3)2Sn]2O (CAS: 135302-76-0) has higher inhibitory activity on breast and colon cancers than cisplatin (Bulletin des societs Chimiques Belges (1991), 100(5), 367-74). This makes the organotin carboxylate compound a metal anticancer drug which takes the eyeball even after cisplatin is used as an anticancer drug. Since then, there have been more and more researches on the synthesis, structural species, reaction properties, biological activities and mechanisms of organic carboxylic acid esters, and great results have been obtained. It has been found that by changing the type and structure of the carboxylic acid ligand, various organic carboxylic acid esters having a wide variety of structures can be obtained.
The prior art shows that the organotin carboxylate has good treatment effect on malignant tumors. The current research reports that the organic tin carboxylate has inhibition effect on various tumors, but there are only few reports about effective inhibition on neuroblastoma. A series of organic tin carboxylate compounds are reported by the Yang-Yang university college, and pharmacological experiments show that the organic tin compounds have the activity of inhibiting various tumor cells including breast cancer cells, lung cancer cells and colon cancer cells, but the activity of inhibiting neuroblastoma is not disclosed.
Disclosure of Invention
In view of the above problems in the prior art, the first object of the present invention is to provide a novel fluorine-containing aromatic ring carboxylic acid tetramer compound having a significant neuroblastoma inhibitory activity. The structure of the compound and the activity of the compound against neuroblastoma are not reported in documents before the application date.
The second object of the present invention is to provide a process for producing the above-mentioned organotin carboxylate complexes.
The third invention of the present invention is to provide the use of the above organotin carboxylate complexes in the field of anticancer drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
a fluorine-containing aromatic ring carboxylic acid tetramer compound has the following structural formula:
wherein n-Bu represents n-butyl.
The molecular formula of the fluorine-containing aromatic ring carboxylic acid tetramer compound is C60H88F8N4O10Sn4(ii) a The molecular weight is 1652.10.
A method for preparing a fluorine-containing aromatic ring carboxylic acid tetramer compound comprises the following steps:
the preparation method of the fluorine-containing aromatic ring carboxylic acid tetramer compound comprises the following steps: adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 20-60 mL of methanol into a reaction vessel, stirring for 5 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow powdery solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the n-hexane is 3: 1-6: 1.
The reaction formula is as follows:
the application of the fluorine-containing aromatic ring carboxylic acid tetramer compound in preparing a medicament for treating human neuroblastoma cells.
The fluorine-containing aromatic ring carboxylic acid tetramer compound has the advantages of remarkably inhibiting the activity of human neuroblastoma cells, and can be used for preparing medicaments for treating the human neuroblastoma. The fluorine-containing aromatic ring carboxylic acid tetramer compound is prepared by a one-pot method, and has the characteristics of low cost, simple preparation method and the like. Compared with the platinum anticancer drugs commonly used at present, the fluorine-containing aromatic ring carboxylic acid tetramer compound has the advantages of high anticancer activity and good lipid solubility, and provides a new candidate compound for developing anticancer drugs.
Detailed Description
The present invention will be further illustrated by the following examples, which are intended to be merely illustrative and not limitative.
Example 1:
preparation of a fluorine-containing aromatic Ring Carboxylic acid tetramer Compound: adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 20mL of methanol into a standard Schlenk tube, stirring for 5 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow powdery solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the normal hexane is 6: 1. Yield 85%, melting point 112-.
The results of infrared spectroscopic analysis, elemental analysis and X-ray single crystal diffraction are as follows:
infrared Spectrum (KBr, cm)-1)：vas(C＝O)1641，1598；vs(C-O)1387,1290；vas(Sn-C)606，vs(Sn-C)502，v(Sn-O-Sn)686，649，v(Sn-O)479。
Elemental analysis: calculated value C60H88F8N4O10Sn4: c, 43.62; h, 5.37; n, 3.39%; found C, 43.60; h, 5.35; and N, 3.36 percent.
Crystallographic data and structural analysis parameters for the compounds of Table 1
Example 2:
preparation of a fluorine-containing aromatic Ring Carboxylic acid tetramer Compound: adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 40mL of methanol into a flask, stirring for 6 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the normal hexane is 3: 1. Yield 78%, melting point 112-.
Example 3:
preparation of a fluorine-containing aromatic Ring Carboxylic acid tetramer Compound: adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 60mL of methanol into a flask, stirring for 5 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the normal hexane is 4: 1. Yield 82%, melting point 112-.
Example 4:
the determination of the in vitro anticancer activity of the fluorine-containing aromatic ring carboxylic acid tetramer compound is realized by an MTT experimental method, and the principle is as follows: based on the metabolic reduction of exogenous MTT (3- (4, 5-dimethylthiozol-2-yl) -2, 5-diphenylterazolium bromide), NADP-related dehydrogenase was present in mitochondria of living cells, yellow MTT was reduced to insoluble blue-violet crystalline Formazan (Formazan), dead cells were not treated with this enzyme, MTT was not reduced, Formazan was dissolved in dimethyl sulfoxide DMSO, and then optical density at a characteristic wavelength (490nm wavelength) was measured using a microplate reader to process the data. The method can indirectly reflect the number of living cells. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely used for activity detection of some bioactive factors, large-scale screening of anti-tumor drugs, cytotoxicity test, tumor radiosensitivity determination and the like.
Human neuroblastoma IMR-32 cell line was analyzed by MTT assay, and IC thereof was determined50Values, results are shown in table 1, and the conclusion is that: as can be seen from the data in the table, the anticancer drug of the present invention has high in vitro activity on human neuroblastoma IMR-32 cell line, and can be used as a candidate compound of anticancer drugs.
Determination of antitumor activity of compound by MTT method:
the activity screening was performed using sanguinarine hydrate as a positive control, using human neuroblastoma IMR-32 tumor cells at two concentrations, 5. mu. mol/L and 1. mu. mol/L.
(1) And after the superclean bench is subjected to ultraviolet irradiation for 30min, the ultraviolet lamp is turned off, and the illuminating lamp and the fan are turned on.
(2) Discarding the old culture medium, adding PBS to wash for 2-3 times, adding pancreatin, digesting the adherent cells, adding culture medium containing 10% fetal calf serum to stop digestion, collecting the cells, centrifuging at 900rmp/min for 5min, and adding new culture medium to the culture medium before discarding for resuspension.
(3) Cells were counted and adjusted to 5000 cells/well.
(4) Cells were transferred to 96-well plates at 100. mu.l per well and then placed in CO2A constant temperature incubator.
(5) After cell attachment, 100. mu.l of compounds at different concentrations were added, 3 wells each, and 100. mu.l of medium was added to each well as a blank.
(6) After 48h incubation, 20. mu.l MTT was added to each well.
(7) After culturing for 4h, directly throwing the plate, adding 200 mul of dimethyl sulfoxide into each hole, fully dissolving, and measuring the absorbance at 490nm by using an enzyme-labeling instrument, wherein 630nm is used as a reference wavelength. Wherein,
absorbance value of compound 490nm absorbance value-630 nm absorbance value,
inhibition (%) × (1-mean absorbance value of compound/mean absorbance value of blank) × 100%.
(8) Compound IC50Detecting the activity of the screeningPreferred compounds for IC50And (4) measuring. The IC of sanguinarine is known from the literature50Approximately 1. mu. mol/L, so the concentration gradient of the compound was set to 20, 5, 1.25, 0.31, 0.078. mu. mol/L (4-fold dilution) and was used as-is. Human neuroblastoma cells IMR-32 were used for the experiments.
TABLE 2 in vitro Activity test data for anticancer drugs with Compounds
| Human neuroblastoma cell | |
| Sample IC50(ng/mL) | 43 |
| Cell line | IMR-32 |
Comparative example 1:
sanguinarine hydrate and cisplatin were selected for anticancer comparative activity test, and the results are shown in table 3.
TABLE 3 control experiment of tumor inhibitory Activity
| Human neuroblastoma cell inhibitory Activity IC50(ng/mL) | |
| Compounds of the invention | 43 |
| Sanguinarine hydrate | 310 |
| Cis-platinum | 515 |
Through the above IC50The data show that compared with cisplatin and sanguinarine hydrate, the fluorine-containing aromatic ring carboxylic acid tetramer compound provided by the invention has the activity of remarkably inhibiting human neuroblastoma IMR-32, and can be used as a candidate compound of an anti-cancer drug and the research and development application of the anti-cancer drug.
Comparative example 2:
selecting organic tin compound [ (CH) known in the prior art3CONH-PhCOO)(CH3CH2CH2CH2)2Sn]2O and [ (CH)3NH-PhCOO)(CH3)2Sn]2O was tested for anticancer comparative activity and the results are shown in table 4.
TABLE 4 control experiment of tumor inhibitory Activity
| Human neuroblastoma cell inhibitory Activity IC50(ng/mL) | |
| Compounds of the invention | 43 |
| [(CH3CONH-PhCOO)(CH3CH2CH2CH2)2Sn]2O | 616 |
| [(CH3NH-PhCOO)(CH3)2Sn]2O | 589 |
IC by the above three organotin compounds50The data show that the fluorine-containing aromatic ring carboxylic acid tetramer compound provided by the invention has the activity of remarkably inhibiting human neuroblastoma IMR-32, and can be used as a candidate compound of an anticancer drug and the research and development application of the anticancer drug.
Although the present invention has been described with reference to the specific embodiments, it is not intended to limit the scope of the present invention, and various modifications and variations can be made by those skilled in the art without inventive changes based on the technical solution of the present invention.
Claims (3)
1. A fluorine-containing aromatic ring carboxylic acid tetramer compound is characterized in that the structural formula is as follows:
wherein n-Bu represents n-butyl.
2. The method for preparing a tetramer compound containing a fluorine-containing aromatic ring carboxylic acid according to claim 1, comprising the steps of:
adding 1.0mmol of 2-amino-4, 5-difluoro-benzoic acid, 1.0mmol of sodium ethoxide, 1.0mmol of dibutyltin dichloride and 20-60 mL of methanol into a reaction vessel, stirring for 5 hours at 50 ℃, and performing rotary evaporation to obtain a light yellow powdery solid; recrystallizing with dichloromethane-n-hexane to obtain a light yellow transparent crystal, namely a fluorine-containing aromatic ring carboxylic acid tetramer compound; wherein the volume ratio of the dichloromethane to the n-hexane is 3: 1-6: 1.
3. Use of the fluorine-containing aromatic-ring carboxylic acid tetramer compound according to claim 1 in the preparation of a medicament for treating human neuroblastoma cells.
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