CN114890965B - Small molecular compound of selective targeting vimentin, preparation method and application thereof - Google Patents

Small molecular compound of selective targeting vimentin, preparation method and application thereof Download PDF

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CN114890965B
CN114890965B CN202210536404.7A CN202210536404A CN114890965B CN 114890965 B CN114890965 B CN 114890965B CN 202210536404 A CN202210536404 A CN 202210536404A CN 114890965 B CN114890965 B CN 114890965B
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vimentin
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CN114890965A (en
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欧田苗
汪晓娜
陈玥如
苏晓萱
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Sun Yat Sen University
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Abstract

The invention discloses a small molecular compound of selective targeting vimentin, a preparation method and application thereof, wherein the structural formula of the small molecular compound is shown as the formula

Description

Small molecular compound of selective targeting vimentin, preparation method and application thereof
The invention relates to a small molecular compound with the name of selective targeting vimentin, a preparation method and application thereof, which are classified application of the invention patent application with the application date of 2021.01.27 and the application number of 202110110479.4.
Technical Field
The invention belongs to the technical field of medicines and chemical industry, and particularly relates to a small molecular compound of a selective targeting vimentin, a preparation method and application thereof.
Background
Cancer is one of the major diseases threatening human life health, where invasion and metastasis of cancer are more of the major causes of death in solid tumor patients and poor prognosis. The existing anti-tumor migration drugs are very deficient, and many problems and challenges still exist in the development of the anti-tumor migration drugs, so that the development of good anti-tumor drugs is an important research direction in pharmacology.
Vimentin (vimentin) is the component with the highest expression level in the intermediate silk skeleton protein. Related studies have shown that vimentin plays a very important role in the mobility deformation of tumors and tumor-related signal pathways, and that vimentin has abnormal expression and modification in various malignant tumors, including prostate cancer, melanoma, hepatocellular carcinoma, breast cancer, endometrial cancer, and the like. However, currently well known chemotherapeutic drug targets are also only cytoskeletal proteins (e.g., tubulin). Therefore, there is a need to develop a drug capable of targeting the proliferation and migration of the tumor of vimentin.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a small molecular compound which has stable chemical property, can target vimentin and has the functions of resisting tumor proliferation and migration.
In a first aspect of the invention, there is provided:
the structure of the small molecular compound is shown as a formula (II):
wherein in the formula (II), X is selected from carbon, oxygen, nitrogen, sulfur, ester group, carbonyl or amide;
r is selected from any open-chain compound, carbocycle, heterocycle, halogen, nitro, cyano, amino, hydroxyl or mercapto;
n is any integer from 1 to 4.
According to one embodiment of the invention, it has at least the following advantages: the small molecular compound prepared by the method has small molecular weight, is favorable for quick absorption, and has small steric hindrance, thereby being favorable for the combination with protein; secondly, the small molecular compound prepared by the invention has a certain linear structure and hydrophobicity, and promotes the efficient combination of the small molecular compound and the vimentin also containing hydrophobic amino acid; in addition, the small molecular compound prepared by the invention contains a two-branched chain structure on the same side, which is helpful for the alpha helix combination with vimentin.
Moreover, in contrast to the conventional vimentin-binding molecule PQ7 (polyquaternium-7, CAS: 26590-05-6), which also has anti-tumor activity, it is unsuitable for rapid absorption as a drug and also unfavorable for binding to proteins due to its large molecular weight and large steric hindrance. And PQ7 has poor water solubility, so that the drug property is reduced. Under the condition of overcoming the problems, the small molecular compound prepared by the invention has the advantages of more stable chemical property, more obvious drug effect (combining vimentin and anti-tumor activity), proper molecular size, good water solubility, strong patentability and the like.
Preferably, according to the first aspect of the present invention, the small molecule compound does not comprise:
(1) R is bromine;
(2) n is 2 and R is a structure of formula 29;
(3) n is 3 and R is a structure of formula 30;
wherein the structure of formula 29 is:
the structure of formula 30 is:
preferably, according to the first aspect of the present invention, the small molecule compound includes a compound having a structure shown in formulae 6 to 18;
of course, the compounds of the structures shown in the above formulas 6 to 18 are only preferable compounds of the present invention, and the compounds of the present invention include, but are not limited to, the compounds of the structures shown in the above formulas 6 to 18.
In a second aspect of the invention, there is provided:
a composition comprising a small molecule compound according to the first aspect of the invention.
In a third aspect of the invention, there is provided:
the method for producing a small molecule compound according to the first aspect, comprising:
carrying out demethylation treatment on anisoyl in an acid solution, adding a dibromoalkane chain, adjusting the pH to be alkaline, and adding a cyclic compound or a nitrogen-containing open-chain compound to obtain a small molecular compound with a structural formula shown in a formula (II);
the secondary structure of vimentin is mainly an alpha helix structure, and hydrophobic amino acids in these structures can cause two vimentin monomers to intertwine to form a dimer. According to the preparation method provided by the third aspect of the invention, anisoyl can be used as a raw material to synthesize a small molecular compound with small molecular weight and linear and hydrophobic structures, and the small molecular compound can be combined with alpha helix of vimentin through two branched structures on the same side, so that dimerization of vimentin monomers is inhibited.
According to a third aspect of the present invention, the cyclic compound includes an aromatic compound or a heterocyclic compound.
In some preferred embodiments of the present invention, the aromatic compound comprises: an aromatic compound containing a dimethylamino group, an aromatic compound containing a diethylamino group, an aromatic compound containing a piperidyl group, an aromatic compound containing a piperazinyl group, and benzene.
In some preferred embodiments of the present invention, the heterocyclic compound includes: piperidinyl-containing heterocyclic compounds, piperazinyl-containing heterocyclic compounds, thiophenes, furans, tetrahydropyrroles, and morpholines.
The nitrogen-containing open-chain compounds include dimethylamino open-chain compounds and diethylamino open-chain compounds.
In some preferred embodiments of the present invention, the dibromoalkane chain includes 1, 2-dibromoethane, 1, 3-dibromoethane, and 1, 4-dibromoethane.
In some preferred embodiments of the invention, the demethylating agent of the demethylating treatment is hydrobromic acid and the acidity regulator is acetic acid.
In a fourth aspect of the invention, there is provided:
a medicament comprising a small molecule compound according to the first aspect of the invention or a pharmaceutically acceptable salt thereof.
Of course, the person skilled in the art can reasonably further process the small molecule compound according to the first aspect of the present invention to obtain its stereoisomers or prodrug molecules thereof according to the actual circumstances.
According to a fourth aspect of the invention, the medicament further comprises pharmaceutically acceptable excipients.
According to a fourth aspect of the invention, the dosage form of the medicament comprises an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
In a fifth aspect of the invention, there is provided:
the application of the small molecule compound in preparing a vimentin detection preparation is provided.
In a sixth aspect of the invention, there is provided:
the application of the small molecular compound in preparing antitumor drugs is provided.
According to a sixth aspect of the invention, the tumour comprises one or more of ovarian cancer, cervical cancer, breast cancer, lung adenocarcinoma, colon cancer, liver cancer, leukaemia, non-small cell lung cancer, skin cancer, epithelial cell cancer, prostate cancer, nasopharyngeal carcinoma, glioblastoma, lymphoma or melanoma.
In some embodiments of the invention, the tumor is lung cancer, liver cancer, breast cancer, and colorectal cancer.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a diagram showing the synthetic routes of compounds represented by the general formulae (II) and (I);
FIG. 2 shows the response of the interaction (SPR) of the compound prepared in the examples of the present invention with vimentin;
FIG. 3 is a Western blot illustration of the compound prepared in the embodiment of the invention for promoting autophagy of MDA-MB-231 tumor cells.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
The term "anisoyl" in the following embodiments includes structurally identical compounds under different names as will be understood by the person skilled in the art, including: 4,4 '-dimethoxyphenol ester and 4,4' -dimethoxybenzil.
Process for producing compounds of the general formulae (II) and (I)
The synthetic route for the compounds of the examples of the present invention is shown in figure 1.
As shown in fig. 1, anisoyl (compound 1) undergoes demethylation reaction in the environment of 40% hydrobromic acid acetic acid solution to obtain compound 2 (structural formula is shown in formula 2); the compound 2 reacts with dibromoalkane chains with different lengths to obtain an intermediate 3 (the structural formula is shown as the formula 3), an intermediate 4 (the structural formula is shown as the formula 4) and an intermediate 5 (the structural formula is shown as the formula 5); intermediate 3, intermediate 4 and intermediate 5 are each substituted with a different nitrogen-containing aliphatic heterocycle or nitrogen-containing non-heterocyclic substituent compound under basic conditions (using K 2 CO 3 Adjusting pH) to obtain the compound shown in the general formula (II).
And mixing the compound shown in the general formula (II) with sodium acetate, and reacting with 1, 2-phenylenediamine by taking acetic acid as a reaction solvent to obtain the compound shown in the general formula (I).
Wherein, the structural formula of the compound 2 in the above embodiment is:
the structural formula of the intermediate 3 is as follows:
the structural formula of the intermediate 4 is as follows:
the structural formula of the intermediate 5 is as follows:
the structural formula of the compound shown in the general formula (II) is as follows:
the structural formula of the compound shown in the general formula (I) is as follows:
example 1 preparation of Compound 2
4,4' -dimethoxy benzil (anisoyl, 18.50 mmol) was mixed with 50mL40% hydrobromic acid acetic acid solution, stirred at 120℃for 36 hours, and after the TLC plate monitored the reaction was complete, the majority of the acid solution in the solution was removed by rotary evaporation, wherein the acid solution was removed by an acid absorption device. After rotary evaporation until a small amount of solution remains, stirring in ice water until a yellow solid is separated out, filtering, and vacuum drying to obtain a yellow solid, namely the compound 2.
The yield of compound 2 in this example is: 95.98%.
The hydrogen spectrum of compound 2 in this example is:
1 H NMR(400MHz,DMSO)δ10.82(s,2H),7.76–7.72(m,4H),6.95–6.90(m,4H)。
example 2 preparation of intermediate 3
5.00g of the compound 2 (20.64 mmol) obtained in example 1 above were taken together with 23.27g of 1, 2-dibromoethane (123.85 mmol) and 17.12g K 2 CO 3 (123.85 mmol) and adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80deg.C for 16 hr, monitoring the reaction by TLC plate, filtering to remove solid precipitate, and performing column chromatographySeparating and purifying, wherein the mobile phase is petroleum ether: dichloromethane = 1:1, to finally obtain intermediate 3 as a pale yellow solid.
The yields of intermediate 3 in this example were: 40.53%.
The hydrogen spectrum of intermediate 3 in this example is:
1 H NMR(400MHz,CDCl3)δ7.93(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.08(t,J＝5.9Hz,4H),3.48(t,J＝6.4Hz,4H),2.11–2.04(m,4H),2.02–1.94(m,4H)。
example 3 preparation of intermediate 4
5.00g of compound 2 (20.64 mmol) prepared in example 1 above were taken together with 25.00g of 1, 3-dibromopropane (123.85 mmol) and 17.12g K 2 CO 3 (123.85 mmol) and adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80deg.C for reaction for about 16 hr, monitoring the reaction by TLC plate, filtering to remove solid precipitate, and separating and purifying by column chromatography, wherein the mobile phase is petroleum ether: dichloromethane = 1:1, to finally obtain intermediate 4 as a pale yellow solid.
The yields of intermediate 4 in this example were: 41.53%.
The hydrogen spectrum of intermediate 4 in this example is:
1 H NMR(400MHz,CDCl3)δ7.94(d,J＝8.9Hz,4H),6.97(d,J＝8.9Hz,4H),4.19(t,J＝5.8Hz,4H),3.60(t,J＝6.3Hz,4H),2.34(p,J＝6.1Hz,4H)。
example 4 preparation of intermediate 5
5.00g of the compound 2 (20.64 mmol) obtained in example 1 above were taken together with 26.74g of 1, 4-dibromobutane (123.85 mmol) and 17.12g K 2 CO 3 (123.85 mmol) and adding appropriate amount of acetone or acetonitrile as solvent, stirring at 80deg.C for reaction for about 16 hr, monitoring the reaction by TLC plate, filtering to remove solid precipitate, and separating and purifying by column chromatography, wherein the mobile phase is petroleum ether: dichloromethane = 1:1, to finally obtain intermediate 5 as a pale yellow solid.
The yields of intermediate 5 in this example were: 20.22%.
The hydrogen spectrum of intermediate 5 in this example is:
1 H NMR(400MHz,CDCl3)δ7.95(d,J＝9.0Hz,4H),6.98(d,J＝9.0Hz,4H),4.37(t,J＝6.2Hz,4H),3.66(t,J＝6.2Hz,4H)。
EXAMPLE 5 preparation of Compound C-1
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 3 (2.19 mmol) obtained in example 2 was taken, and 448.03mg of piperidine (5.26 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase condition is methanol: dichloromethane = 2:25, and a small amount of aqueous ammonia was added to give compound C-1 as a pale yellow solid.
The structural formula of the compound C-1 in the embodiment is shown in the formula 6:
the yield of compound C-1 in this example was: 74.66%.
The hydrogen spectrum of compound C-1 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.96(d,J＝8.9Hz,4H),4.21(t,J＝5.9Hz,4H),2.83(t,J＝5.9Hz,4H),2.55(s,8H),1.67–1.59(m,8H),1.51–1.41(m,8H)。
the carbon spectrum of compound C-1 in this example is:
13 C NMR(126MHz,CDCl3)δ193.58,164.19,132.42,126.35,114.91,66.44,57.64,55.11,25.90,24.15.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-1 in this example was:
[M+H] + m/z＝465.2748,calcd for 464.2675。
the purity of compound C-1 in this example was 95.1% by HPLC.
EXAMPLE 6 preparation of Compound C-2
According to the general formulaPreparation of Compounds represented by (II) and (I) 1g of intermediate 3 (2.19 mmol) obtained in example 2 was taken and 237.22mg of dimonium chloride (5.26 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase is methanol: dichloromethane = 2:25 to give compound C-2 as a pale yellow solid.
The structural formula of the compound C-2 in the embodiment is shown in the formula 7:
the yield of compound C-2 in this example was: 53.22%.
The hydrogen spectrum of compound C-2 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.97(d,J＝8.9Hz,4H),4.14(t,J＝5.6Hz,4H),2.76(t,J＝5.6Hz,4H),2.34(s,12H)。
the carbon spectrum of compound C-2 in this example is:
13 C NMR(101MHz,CDCl3)δ193.49,164.09,132.36,126.34,114.82,66.34,57.96,45.85.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-2 in this example was:
[M+H] + m/z＝385.2122,calcd for 384.2049。
the purity of compound C-2 in this example was 95.6% by HPLC.
EXAMPLE 7 preparation of Compound C-3
According to the preparation method of the compounds shown in the general formulas (II) and (I), 1g of intermediate 3 (2.19 mmol) prepared in example 2 is taken, and tetrahydropyrrole (5.26 mmol) and a proper amount of K are added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase condition is methanol: dichloromethane = 1:20 to give a pale yellow solidCompound C-3.
The hydrogen spectrum of compound C-3 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.8Hz,1H),6.98(d,J＝8.9Hz,1H),4.19(t,J＝5.8Hz,1H),2.94(t,J＝5.8Hz,1H),2.65(s,2H),1.82(s,2H)。
the carbon spectrum of compound C-3 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-3 in this example was:
[M+H] + m/z＝437.2435,calcd for 436.2362。
the purity of compound C-3 in this example was 98.3% by HPLC.
EXAMPLE 8 preparation of Compound C-4
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 3 (2.19 mmol) obtained in example 2 was taken, and 458.41mg of morpholine ring (5.26 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase condition is methanol: dichloromethane = 1:20 to give Compound C-4 as a pale yellow solid.
The structural formula of the compound C-4 in the embodiment is shown in the formula 9:
the yield of compound C-4 in this example was: 75.65%.
The hydrogen spectrum of compound C-4 in this example is:
1 H NMR(400MHz,CDCl3)δ7.95(d,J＝8.9Hz,1H),6.98(d,J＝8.9Hz,1H),4.21(t,J＝5.6Hz,1H),3.79–3.67(m,2H),2.85(t,J＝5.6Hz,1H),2.65–2.54(m,2H)。
the carbon spectrum of compound C-4 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-4 in this example was:
[M+H] + m/z＝469.2333,calcd for 486.2260。
the purity of compound C-4 in this example was 94.2% by HPLC.
EXAMPLE 9 preparation of Compound C-5
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 3 (2.19 mmol) obtained in example 2 was taken, and 453.23mg of pyridine (5.26 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase is methanol: dichloromethane = 2:25 to give compound C-5 as a pale yellow solid.
The structural formula of the compound C-5 in the embodiment is shown in the formula 10:
the yield of compound C-5 in this example was: 30.26%.
The hydrogen spectrum of compound C-5 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,1H),6.96(d,J＝8.9Hz,1H),4.17(t,J＝5.8Hz,1H),2.99–2.87(m,2H),2.81(t,J＝5.8Hz,1H),2.55(s,2H),2.55(s,2H),2.05(s,1H)。
the carbon spectrum of compound C-5 in this example is:
13 C NMR(101MHz,CDCl3)δ193.56,164.15,132.49,126.45,114.93,66.38,57.58,54.87,46.01.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-5 in this example was:
[M+H] + m/z＝467.2653,calcd for 466.2580。
the purity of compound C-5 in this example was 96.2% by HPLC.
EXAMPLE 10 preparation of Compound C-6
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 4 (2.07 mmol) obtained in example 2 was taken, and 233.48mg of piperidine (4.96 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the flow phenomenon is methanol: dichloromethane = 1:100 to give compound C-5 as a pale yellow solid.
The structural formula of the compound C-6 in the embodiment is shown in the formula 11:
the yield of compound C-6 in this example was: 43.83%.
The hydrogen spectrum of compound C-6 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.95(d,J＝9.0Hz,4H),4.11(t,J＝6.2Hz,4H),2.57(t,J＝25.5Hz,12H),2.13–2.04(m,4H),1.68(s,8H),1.53–1.44(m,4H)。
the carbon spectrum of compound C-6 in this example is:
13 C NMR(126MHz,CDCl3)193.42,164.29,132.35,126.07,114.73,77.41,77.09,76.77,66.75,66.45,55.24,53.61,25.99.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-6 in this example was:
[M+H] + m/z＝493.3061,calcd for 492.2988。
the purity of compound C-6 in this example was 95.1% by HPLC.
EXAMPLE 11 preparation of Compound C-7
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 4 (2.07 mmol) obtained in example 2 was taken, and 233.48mg of dimethylamine (4.96 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the flow phenomenon is methanol: dichloromethane = 1:100 to give compound C-7 as a pale yellow solid.
The structural formula of the compound C-7 in the embodiment is shown in the formula 12:
the yield of compound C-7 in this example was: 43.83%.
The hydrogen spectrum of compound C-7 in this example is:
1 H NMR(400MHz,CDCl3)δ7.91(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.08(t,J＝6.4Hz,4H),2.45(t,J＝7.2Hz,4H),2.25(s,12H),1.97(dt,J＝13.4,6.6Hz,4H)。
the carbon spectrum of compound C-7 in this example is:
13 C NMR(126MHz,CDCl3)δ193.67,164.43,132.48,126.32,114.86,66.65,56.18,45.43,27.19.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-7 in this example was:
[M+H] + m/z＝413.2435,calcd for 412.2362。
the purity of compound C-7 in this example was 94.7% by HPLC.
EXAMPLE 12 preparation of Compound C-8
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 4 (2.07 mmol) obtained in example 2 was taken, and 352.54mg of tetrahydropyrrole (4.96 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the completion of the reaction, which was monitored by TLC plate, the reaction was removed by filtrationRemoving solid precipitate, and performing column chromatography separation and purification under the following conditions: dichloromethane = 2:25 to give compound C-8 as a pale yellow solid.
The structural formula of the compound C-8 in the embodiment is shown in the formula 13:
the yield of compound C-8 in this example was: 73.54%.
The hydrogen spectrum of compound C-8 in this example is:
1 H NMR(400MHz,CDCl3)δ7.91(d,J＝8.9Hz,4H),6.95(d,J＝8.9Hz,4H),4.11(t,J＝6.4Hz,4H),2.68–2.60(m,4H),2.56(t,J＝5.8Hz,8H),2.09–1.99(m,4H),1.82–1.75(m,8H)。
the carbon spectrum of compound C-8 in this example is:
13 C NMR(126MHz,CDCl3)δ193.65,164.34,132.49,126.35,114.86,66.66,54.27,53.01,28.16,23.56.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-8 in this example was:
[M+H] + m/z＝465.2748,calcd for464.2675。
the purity of compound C-8 in this example was 93.6% by HPLC.
EXAMPLE 13 preparation of Compound C-9
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 4 (2.07 mmol) obtained in example 2 was taken, and 431.85mg of morpholine (4.96 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, and column chromatography separation and purification are carried out under the following separation conditions: dichloromethane = 1:20 to give Compound C-9 as a pale yellow solid.
The structural formula of the compound C-9 in the embodiment is shown in the formula 14:
the yield of compound C-9 in this example was: 75.22%.
The hydrogen spectrum of compound C-9 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.8Hz,4H),6.95(d,J＝8.8Hz,4H),4.10(t,J＝6.3Hz,4H),3.75–3.67(m,8H),2.52(t,J＝7.2Hz,4H),2.46(s,8H),2.04–1.94(m,4H)。
the carbon spectrum of compound C-9 in this example is:
13 C NMR(126MHz,CDCl3)δ193.60,164.40,132.50,126.36,114.85,66.88,66.57,55.39,53.75,26.14.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-9 in this example was:
[M+H] + m/z＝465.2748,calcd for 496.2573。
the purity of compound C-9 in this example was 96.4% by HPLC.
EXAMPLE 14 preparation of Compound C-10
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 4 (2.07 mmol) obtained in example 2 was taken, and 426.97mg of pyridine (4.96 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the reaction was completely performed by TLC plate, solid precipitate was removed by filtration, and column chromatography was performed under the mobile phase condition of 2:25, and a small amount of aqueous ammonia was added to give compound C-10 as a pale yellow solid.
The structural formula of the compound C-10 in the embodiment is shown in the formula 15:
the yield of compound C-10 in this example was: 21.52%.
The hydrogen spectrum of compound C-10 in this example is:
1 H NMR(500MHz,CDCl3)δ7.92(d,J＝8.4Hz,1H),6.96(d,J＝8.9Hz,1H),4.09(t,J＝4.8Hz,1H),2.91(s,2H),2.63–2.47(m,2H),2.05–1.93(m,1H)。
the carbon spectrum of compound C-10 in this example is:
13 C NMR(101MHz,CDCl3)δ193.60,163.84,132.27,126.22,114.83,66.66,54.58,54.42,50.01,23.28.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-10 in this example was:
[M+H] + m/z＝495.2966,calcd for 494.2893。
the purity of compound C-10 in this example was 94.1% by HPLC.
EXAMPLE 15 preparation of Compound C-11
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 5 (1.95 mmol) obtained in example 2 was taken, and 398.96mg of piperidine (4.69 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase is methanol: dichloromethane = 2:25 to give compound C-11 as a pale yellow solid.
The structural formula of the compound C-11 in the embodiment is shown in the formula 16:
the yield of compound C-11 in this example was: 72.44%.
The hydrogen spectrum of compound C-11 in this example is:
1 H NMR(400MHz,DMSO)δ7.84(d,J＝8.9Hz,4H),7.12(d,J＝8.9Hz,4H),4.11(t,J＝6.5Hz,4H),2.37–2.23(m,12H),1.79–1.69(m,4H),1.60–1.51(m,4H),1.50–1.43(m,4H),1.41–1.33(m,4H)。
the carbon spectrum of compound C-11 in this example is:
13 C NMR(126MHz,CDCl3)δ193.68,164.47,132.46,126.23,114.82,68.27,58.82,54.53,27.21,25.75,24.35,23.19.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-11 in this example was:
[M+H] + m/z＝521.3374,calcd for520.3301。
the purity of compound C-11 in this example was 93.8% by HPLC.
EXAMPLE 16 preparation of Compound C-12
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 5 (1.95 mmol) obtained in example 2 was taken, and 333.23mg of tetrahydropyrrole (4.69 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase condition is methanol: dichloromethane = 2:25 to give compound C-12 as a pale yellow solid.
The structural formula of the compound C-12 in the embodiment is shown in the formula 17:
the yield of compound C-12 in this example was: 48.13%.
The hydrogen spectrum of compound C-12 in this example is:
1 H NMR(400MHz,CDCl3)δ7.89(d,J＝8.7Hz,4H),6.92(d,J＝8.7Hz,4H),4.04(t,J＝6.3Hz,4H),2.61–2.47(m,12H),1.86–1.65(m,16H)。
the carbon spectrum of compound C-12 in this example is:
13 C NMR(126MHz,CDCl3)δ193.57,164.36,132.34,126.11,114.71,68.14,55.95,54.12,27.08,25.24,23.39.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-12 in this example is:
[M+H] + m/z＝493.3061,calcd for 492.2988。
the purity of compound C-12 in this example was 96.8% by HPLC.
EXAMPLE 17 preparation of Compound C-13
According to the preparation method of the compounds represented by the general formulae (II) and (I), 1g of intermediate 5 (1.95 mmol) obtained in example 2 was taken, and 408.19mg of morpholine (4.69 mmol) and an appropriate amount of K were added 2 CO 3 Acetonitrile is used as a solvent, and the reaction is stirred at normal temperature. After the TLC plate monitors that the reaction is completely carried out, solid precipitate is removed by filtration, column chromatography separation and purification are carried out, and the mobile phase condition is methanol: dichloromethane = 1:20 to give Compound C-13 as a pale yellow solid.
The structural formula of the compound C-13 in the embodiment is shown in the formula 18:
the yield of compound C-13 in this example was: 66.52%.
The hydrogen spectrum of compound C-13 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.94(d,J＝8.9Hz,4H),4.06(t,J＝6.3Hz,4H),3.76–3.66(m,8H),2.52–2.36(m,12H),1.89–1.79(m,4H),1.74–1.63(m,4H)。
the carbon spectrum of compound C-13 in this example is:
13 C NMR(101MHz,CDCl3)δ193.61,164.38,132.45,126.14,114.79,68.11,66.65,58.42,53.55,26.94,22.72.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound C-13 in this example was:
[M+H] + m/z＝525.2934,calcd for 524.2886。
the purity of compound C-13 in this example was 96.8% by HPLC.
EXAMPLE 18 preparation of Compound B-1
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C-1 (452.38 mmol) prepared in the above example 5 was taken, 49.54mg of 1, 2-phenylenediamine (458.14 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the reaction was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-1 as a yellow solid having blue fluorescence.
The structural formula of the compound B-1 in the embodiment is shown in the formula 19:
the yield of compound B-1 in this example was: 52.25%.
The hydrogen spectrum of the compound B-1 in this example is:
1 H NMR(400MHz,CDCl3)δ8.10(dd,J＝6.3,3.4Hz,2H),7.69(dd,J＝6.4,3.4Hz,2H),7.46(d,J＝8.7Hz,4H),6.86(d,J＝8.7Hz,4H),4.12(t,J＝6.0Hz,4H),2.77(t,J＝6.0Hz,4H),2.50(s,8H),1.60(dt,J＝11.0,5.6Hz,8H),1.48–1.38(m,4H)。
the carbon spectrum of compound B-1 in this example is:
13 C NMR(101MHz,CDCl3)δ159.16,152.99,141.08,131.91,131.27,129.59,129.02,114.46,57.65,54.97,25.42,23.82.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-1 in this example is:
[M+H] + m/z＝537.3224,calcd for 536.3151。
the purity of compound B-1 in this example was 94.7% by HPLC.
EXAMPLE 19 preparation of Compound B-2
According to the preparation method of the compounds represented by the general formulas (II) and (I), 200mg of the compound C3 prepared in the above example 7 (458.46 mmol) was taken, 59.49mg of 1, 2-phenylenediamine (550.16 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25, obtaining crude product, purifying by thin layer chromatography (large plate), and adopting the conditions of methanol as developing solvent: ammonia water: dichloromethane = 10:1:300, to give compound B-2 as a yellow solid having blue fluorescence.
The structural formula of the compound B-2 in this example is shown in formula 20:
the yield of compound B-2 in this example was: 48.75%.
The hydrogen spectrum of compound B-2 in this example is:
1 H NMR(400MHz,CDCl3)δ8.14(dd,J＝6.4,3.4Hz,1H),7.73(dd,J＝6.4,3.4Hz,1H),7.49(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),4.17(t,J＝5.9Hz,2H),2.95(t,J＝5.9Hz,2H),2.68(t,J＝6.0Hz,4H),1.84(t,J＝5.1Hz,4H)。
the carbon spectrum of compound B-2 in this example is:
13 C NMR(126MHz,CDCl3)δ159.46,153.15,141.17,131.89,131.34,129.64,129.11,114.55,67.02,55.07,54.87,23.59.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-2 in this example is:
[M+H] + m/z＝509.2911,calcd for 508.2838。
the purity of compound B-2 in this example was 93.3% by HPLC.
EXAMPLE 20 preparation of Compound B-3
According to the preparation method of the compounds represented by the general formulas (II) and (I), 200mg of the compound C6 (405.96 mmol) prepared in the above example 10 was taken, 52.68mg of 1, 2-phenylenediamine (487.15 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-3 as a yellow solid having blue fluorescence.
The structural formula of the compound B-3 in this example is shown in formula 21:
the yield of compound B-3 in this example was: 45.24%.
The hydrogen spectrum of compound B-3 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.3,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.88(t,J＝9.1Hz,4H),4.15(t,J＝5.9Hz,4H),2.81(t,J＝5.9Hz,4H),2.58(d,J＝17.9Hz,8H),1.68–1.60(m,8H),1.49–1.43(m,4H),1.25(s,4H)。
the carbon spectrum of compound B-3 in this example is:
13 C NMR(126MHz,CDCl3)δ159.39,153.14,141.21,131.98,131.38,129.69,129.15,122.34,114.59,65.84,57.83,55.13,29.84,25.72,24.07.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-3 in this example is:
[M+H] + m/z＝509.2911,calcd for 508.2838。
the purity of compound B-3 in this example was 95.5% by HPLC.
EXAMPLE 21 preparation of Compound B-4
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C7 (484.81 mmol) prepared in the above example 11 was taken, 62.91mg of 1, 2-phenylenediamine (581.78 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-4 as a yellow solid having blue fluorescence.
The structural formula of the compound B-4 in this example is shown in formula 22:
the yield of compound B-4 in this example was: 45.68%.
The hydrogen spectrum of compound B-4 in this example is:
1 H NMR(400MHz,CDCl3)δ8.11(dd,J＝6.4,3.4Hz,2H),7.71(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.8Hz,4H),6.86(d,J＝8.8Hz,4H),4.04(t,J＝6.4Hz,4H),2.52–2.45(m,4H),2.28(s,12H),1.98(dt,J＝13.5,6.5Hz,4H)。
the carbon spectrum of compound B-4 in this example is:
13 C NMR(101MHz,CDCl3)δ159.62,153.11,141.07,131.63,131.27,129.56,129.02,114.36,66.23,56.38,45.49,27.42.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-4 in this example is:
[M+H] + m/z＝485.2911,calcd for 484.2838。
the purity of compound B-4 in this example was 96.1% by HPLC.
EXAMPLE 22 preparation of Compound B-5
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C8 (430.47 mmol) prepared in the above example 12 was taken, 55.86mg of 1, 2-phenylenediamine (516.56 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-5 as a yellow solid having blue fluorescence.
The structural formula of the compound B-5 in this example is shown in formula 23:
the yield of compound B-5 in this example was: 38.25%.
The hydrogen spectrum of compound B-5 in this example is:
1 H NMR(400MHz,CDCl3)δ8.11(dd,J＝6.3,3.4Hz,2H),7.71(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.86(d,J＝8.7Hz,4H),4.05(t,J＝6.4Hz,4H),2.74–2.61(m,4H),2.56(s,8H),2.09–1.96(m,4H),1.80(s,8H)。
the carbon spectrum of compound B-5 in this example is:
13 C NMR(101MHz,CDCl3)δ159.55,152.99,140.97,131.51,131.18,129.44,128.92,114.27,66.33,54.19,53.08,28.66,23.41.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-5 in this example is:
[M+H] + m/z＝537.3209,calcd for 536.3151。
the purity of compound B-5 in this example was 95.8% by HPLC.
EXAMPLE 23 preparation of Compound B-6
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C9 (402.74 mmol) prepared in the above example 13 was taken, 52.26mg of 1, 2-phenylenediamine (483.29 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-6 as a yellow solid having blue fluorescence.
The structural formula of the compound B-6 in the embodiment is shown in the formula 24:
the yield of compound B-6 in this example was: 52.81%.
The hydrogen spectrum of compound B-6 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.48(d,J＝8.7Hz,4H),6.86(d,J＝8.8Hz,4H),4.06(t,J＝6.3Hz,4H),3.79–3.72(m,8H),2.61–2.55(m,4H),2.52(s,8H),2.02(dt,J＝13.5,6.6Hz,8H)。
the carbon spectrum of compound B-6 in this example is:
13 C NMR(126MHz,CDCl3)δ159.56,153.01,141.07,131.72,131.25,129.56,129.00,66.91,66.14,55.54,53.73,26.34.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-6 in this example is:
[M+H] + m/z＝569.3122,calcd for 568.3050。
the purity of compound B-6 in this example was 94.0% by HPLC.
EXAMPLE 24 preparation of Compound B-7
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C11 (384.09 mmol) prepared in the above example 15 was taken, 49.84mg of 1, 2-phenylenediamine (460.91 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the reaction was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-7 as a yellow solid having blue fluorescence.
The structural formula of the compound B-7 in this example is shown in formula 25:
the yield of compound B-7 in this example was: 33.26%.
The hydrogen spectrum of compound B-7 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.47(d,J＝8.7Hz,4H),6.85(d,J＝8.7Hz,4H),4.00(t,J＝6.2Hz,4H),2.55–2.38(m,12H),1.86–1.77(m,4H),1.75–1.69(m,4H),1.67–1.59(m,4H),1.49–1.42(m,4H)。
the carbon spectrum of compound B-7 in this example is:
13 C NMR(126MHz,CDCl3)δ159.68,153.08,141.05,131.54,131.23,129.46,128.99,114.32,67.82,59.07,54.60,27.40,25.97,24.48,23.47.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-7 in this example is:
[M+H] + m/z＝593.3848,calcd for 592.3777。
the purity of compound B-7 in this example was 98.1% by HPLC.
EXAMPLE 25 preparation of Compound B-8
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C12 (453.95 mmol) prepared in the above example 16 was taken, 58.91mg of 1, 2-phenylenediamine (544.74 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the mixture was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-8 as a yellow solid having blue fluorescence.
The structural formula of the compound B-8 in this example is shown in formula 26:
the yield of compound B-8 in this example was: 28.55%.
The hydrogen spectrum of compound B-8 in this example is:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝8.9Hz,4H),6.94(d,J＝8.9Hz,4H),4.06(t,J＝6.3Hz,4H),3.76–3.66(m,8H),2.52–2.36(m,12H),1.89–1.79(m,4H),1.74–1.63(m,4H)。
the carbon spectrum of compound B-8 in this example is:
13 C NMR(126MHz,CDCl3)δ159.77,153.21,141.19,131.73,131.35,129.61,129.12,114.46,67.86,59.46,45.47,27.21,24.24.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-8 in this example is:
[M+H] + m/z＝513.3224,calcd for 512.3151。
the purity of compound B-8 in this example was 96.2% by HPLC.
EXAMPLE 26 preparation of Compound B-9
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C13 (405.95 mmol) prepared in the above example 17 was taken, 52.68mg of 1, 2-phenylenediamine (487.14 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the reaction was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-9 as a yellow solid having blue fluorescence.
The structural formula of the compound B-9 in this example is shown in formula 27:
the yield of compound B-9 in this example was: 40.68%.
The hydrogen spectrum of compound B-9 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.4Hz,2H),7.72(dd,J＝6.4,3.4Hz,2H),7.50–7.45(m,4H),6.85(d,J＝8.8Hz,4H),4.00(t,J＝6.3Hz,4H),3.76–3.70(m,8H),2.50–2.40(m,12H),1.87–1.78(m,4H),1.75–1.65(m,4H)。
the carbon spectrum of compound B-9 in this example is:
13 C NMR(126MHz,CDCl3)δ159.69,153.10,141.13,131.70,131.32,129.59,129.07,114.37,67.78,67.05,58.70,53.80,27.24,23.14.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-9 in this example is:
[M+H] + m/z＝597.3435,calcd for 564.3463。
the purity of compound B-9 in this example was 96.5% by HPLC.
EXAMPLE 27 preparation of Compound B-10
According to the preparation method of the compounds represented by the general formulae (II) and (I), 200mg of the compound C14 (381.20 mmol) prepared in the above example 18 was taken, 49.47mg of 1, 2-phenylenediamine (457.44 mmol) and an appropriate amount of sodium acetate were added, acetic acid was used as a solvent, and the reaction was stirred at 120℃for 24 hours. After the TLC plate monitoring reaction is completely carried out, the TLC plate monitoring reaction is diluted by ice water, then the pH value of the solution is regulated to be neutral by sodium bicarbonate, dichloromethane is used for extraction, and the extract is subjected to column chromatography separation and purification after being washed for 2-3 times, wherein the condition of a mobile phase is 1:25 to give compound B-10 as a yellow solid having blue fluorescence.
The structural formula of the compound B-10 in the embodiment is shown in the formula 28:
the yield of compound B-10 in this example was: 15.28%.
The hydrogen spectrum of compound B-10 in this example is:
1 H NMR(400MHz,CDCl3)δ8.12(dd,J＝6.4,3.5Hz,2H),7.72(dd,J＝6.3,3.4Hz,2H),7.47(d,J＝8.6Hz,4H),6.85(d,J＝8.7Hz,4H),4.00(t,J＝6.1Hz,4H),3.13–3.06(m,4H),2.69–2.63(m,4H),2.52–2.46(m,4H),2.31(s,10H),1.87–1.77(m,4H),1.75–1.63(m,4H)。
the carbon spectrum of compound B-10 in this example is:
13 C NMR(101MHz,CDCl3)δ159.73,153.19,141.16,131.69,131.35,129.65,129.09,114.42,67.85,58.87,54.21,45.91,27.33,23.29.11.10。
the electrospray mass spectrum (ESI-HRMS) of compound B-10 in this example is:
[M+H] + m/z＝595.3755,calcd for 596.3363。
the purity of the compound B-10 in this example was 95.1% by HPLC.
Detection of vimentin-binding Effect of Compounds prepared in the above examples
The binding of the compounds prepared in examples 1 to 28 to vimentin was tested using surface plasmon resonance, comprising the following steps:
1. diluting vimentin with sodium acetate solution (pH 5.5) to a final concentration of 100mM, and labeling on NTA chip;
2. diluting a compound to be tested to 50mM by using an SPR buffer solution, setting a program, enabling the compound to be tested to flow through an NTA chip, and flushing the NTA chip by using the SPR buffer solution after the compound to be tested is combined with the vimentin to dissociate the compound to be tested;
3. and fitting the equilibrium dissociation constant KD value of the compound to be tested and the vimentin.
Among them, PQ7 (Polyquaternium-7, CAS: 26590-05-6) was used as a control. PQ7 is a small molecule that specifically binds vimentin.
The equilibrium dissociation constant KD values of the test compounds and vimentin are shown in Table 1.
TABLE 1 equilibrium dissociation constant KD values for test compounds and vimentins
Meanwhile, the response value of the compound to be tested and the vimentin is calculated, and the binding capacity and the binding mode of the compound to be tested and the vimentin are preliminarily judged according to the response value and the dissociation curve, and the result is shown in figure 2.
From the results, the compounds prepared in the examples have strong binding capacity to vimentin and are mostly better than PQ7.
Inhibition detection of tumor cell growth by the Compounds prepared in the examples above
The compound with stronger binding effect on vimentin in the above example is selected, and the MTT method is used for detecting in vitro cytotoxicity of various tumor cell strains.
Wherein the tumor cell lines used are: a549 human non-small cell lung cancer cells, HEK293T human embryonic kidney epithelial cells, hepG2 human liver cancer cells, MDA-MB-231 human breast cancer cells, HUVEC human umbilical vein vascular endothelial cells, SW480 human colon cancer cells, DLD-1 human colorectal adenocarcinoma epithelial cells.
The method comprises the following specific steps: and respectively adding the compounds to be tested with different concentrations into cells in the logarithmic growth phase, incubating for 24 hours, adding MTT, and measuring the absorbance. The concentration of the compound (IC 50 value) at which the growth of the cells was inhibited by 50% was calculated, and the results are shown in Table 2.
TABLE 2 inhibition of growth of various tumor cell lines by test compounds (IC 50 Value/. Mu.M)
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From the results, the IC50 of the various compounds prepared in the above examples was lower than that of PQ7, indicating that the compounds prepared in the above examples have a stronger inhibitory ability against various tumor cells.
Test of the effect of the Compounds prepared in the examples above on autophagy of tumors
The effect of the compound prepared in the above example on autophagy of tumor is detected by Western blot, and the specific steps are as follows:
culturing cells (MDA-MB-231 tumor cells are taken as an experimental object), adding cell lysate, and extracting the total protein of the supernatant. The BCA method was used to measure total protein concentration and then the protein was denatured. Proteins of the same mass were loaded and protein bands were separated by SDS-PAGE electrophoresis. And (3) calculating the molecular weight according to the target protein, cutting off the electrophoresis adhesive tape at the corresponding position, and transferring the protein tape onto the PVDF film by a wet transfer method.
A5% skim milk powder solution (w/v) was dissolved in TBST buffer (25 mM NaCl, 100mM Tris, 0.2% Tween-20, pH 7.4), the PVDF membrane was blocked, primary and secondary antibodies were added for incubation, then rinsed in TBST buffer, and developed using SuperECL Plus super luminescent kit.
As shown in FIG. 3, the Western Blot results prove that the compound prepared in the embodiment can induce tumor cell autophagy to cause death of tumor cells, and the capability of promoting tumor autophagy is far better than that of PQ7 of a control group.
In summary, the compound in the embodiment of the present invention has much better binding ability to vimentin, autophagy promoting effect on tumor cells, and inhibitory ability to tumor cells (including lung cancer, liver cancer, breast cancer, colorectal cancer cells, etc.) than PQ7, wherein the chemical structure of the B-series compound (examples 18 to 27) is simpler than PQ7, and the activity in all aspects is stronger; whereas C-series compounds (examples 5 to 17) have a linear structure similar to PQ7, but exhibit a stronger vimentin binding capacity than PQ7.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.

Claims (5)

1. The small molecular compound is characterized by comprising compounds with structures shown in formulas 6-7, 9-10 and 13-18;
2. a composition comprising the small molecule compound of claim 1.
3. The method for producing a small molecule compound according to claim 1, comprising:
carrying out demethylation treatment on anisoyl in an acid solution, adding dibromoalkane chains, adjusting pH to be alkaline, and adding a nitrogen-containing compound to obtain the micromolecular compound; wherein the nitrogen-containing compound is selected from piperidine, dimethylamine, tetrahydropyrrole, morpholine or piperazine.
4. A process according to claim 3, wherein the dibromoalkane chain is selected from the group consisting of 1, 2-dibromoethane, 1, 3-dibromopropane, 1, 4-dibromobutane.
5. The application of a small molecular compound in preparing a vimentin detection preparation comprises the compounds with structures shown in formulas 6-18;
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