CN103497154A - Water-soluble perylene imide compounds, usage as DNA intercalator, and applications thereof in growth inhibition of cancer cells - Google Patents
Water-soluble perylene imide compounds, usage as DNA intercalator, and applications thereof in growth inhibition of cancer cells Download PDFInfo
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- -1 perylene imide compounds Chemical class 0.000 title claims abstract description 86
- 239000012625 DNA intercalator Substances 0.000 title claims abstract description 15
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
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Abstract
The invention discloses water-soluble perylene imide compounds, a usage as a DNA intercalator, and applications thereof in the growth inhibition of cancer cells, and belongs to the technical field of chemical synthesis of biological drugs. Through inducing cation amino functional groups into perylene anhydride derivatives and a perylene mono-anhydride system, the water solubility of the perylene anhydride derivatives and the perylene mono-anhydride system is greatly improved; furthermore, the cation amino functional groups are in a photo-stability combination with perylene derivatives, and thus a series of novel water-soluble perylene imide compounds are obtained. The synthesized water-soluble perylene imide compounds can effectively be embedded between the base pairs of DNA double helix of nucleus and be used as a DNA intercalator. The synthesized water-soluble perylene imide compounds have a planar rigid structure, so that the compounds can be specifically enriched around fixed tissue cell nucleus, the compounds have the advantages of strong fluorescence and easiness in fluorescent imaging, and have a similar effect as the DAPI effect of commercial cell nucleus dye. The synthesized water-soluble perylene imide compounds can effectively inhibit the growth of cancer cells such as U2OS, HTC116, Hela, AGS, etc., and have a very prominent anti-tumor effect.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis of biological medicines, and particularly relates to a water-soluble perylene bisimide compound and application thereof as a DNA intercalator and in inhibition of cancer cell growth.
Background
Perylene and the derivative thereof have good light, heat and chemical stability, almost 100% fluorescence quantum yield, narrow fluorescence emission peak, can be separated from cell background fluorescence (395-479nm) and have excellent dyeing performance, and are widely applied to the fields of organic photoelectric devices, laser dyes and biological fluorescent probes at present.
Intercalators (intercalators) refer to the reversible interaction of small polycyclic aromatic hydrocarbon molecules with DNA. The molecules are small in size, in an electron-deficient state, and have certain plane rigidity, and can be inserted between two stacked base pairs of DNA, and the insertion process causes helical extension and melting of the DNA. As a DNA intercalator, acridines, pyridocarbazoles, benzimidazoles [1,2-C ] quinolines, anthraquinones, and the like have been studied so far, and they are used for antitumor studies. However, perylene derivatives with good planar rigid structure have not been used as DNA intercalators to study their anti-tumor properties.
In recent years, perylene imide compounds have been applied to the biological field, such as cell-specific labeling, however, poor water solubility directly affects the application of the perylene imide compounds in the field, so that the improvement of the water solubility of the perylene imide compounds and the maintenance of high fluorescence quantum yield in aqueous solution are of great significance to the application of the perylene imide compounds in the biological field, especially in the field of DNA intercalators.
Disclosure of Invention
The invention aims to provide a perylene bisimide compound with good light, heat and chemical stability, good water solubility and designable structure, and the perylene bisimide compound is applied to the field of biomedicine, and particularly researches the application of the perylene bisimide compound as a DNA intercalator and in inhibiting the growth of cancer cells.
The technical scheme of the invention is as follows: firstly, perylene anhydride or perylene monoanhydride is selected as a fluorescence emission group and then reacts with a compound containing an amino functional group to prepare perylene imide derivatives and perylene monoimide derivatives modified by the amino functional group; then, preparing perylene imide derivatives and perylene monoimide derivatives with tertiary amine functional group modification through Eschweiler-Clarke reaction; finally reacting to obtain perylene imide derivatives and perylene monoimide derivatives containing different cationization of tertiary amine salt or quaternary ammonium salt and the like. The interaction between the perylene bisimide derivatives and DNA is analyzed through ultraviolet absorption spectrum, fluorescence emission spectrum and Circular Dichroism (CD), and the compounds are confirmed to have excellent DNA intercalation performance and can be used as DNA intercalators to inhibit the growth of tumor cells. Then, the research and the characterization of the cell and tissue level prove that the perylene bisimide derivative synthesized by the invention has the specific enrichment effect of cell nucleus and the effect of inhibiting the growth of cancer cells.
The water-soluble perylene bisimide compound is a polyamine derivative containing a perylene bisimide or perylene monoimide structure, and the structural general formula of the water-soluble perylene bisimide compound is as follows:
or
Or
Or
Wherein,
R2=CH3or CH2CH3，R3= H or CH3Or CH2CH3。
The synthesis method of the water-soluble perylene bisimide compound comprises the following specific preparation steps:
(1) adding 2mmol of perylene anhydride and 6-12mmol of amine compound into 3-6mL of water, uniformly stirring, heating to 120 ℃ for reflux reaction for 12-24h, cooling to room temperature, washing with 1-2wt% of KOH aqueous solution and water, and drying to obtain a product;
(2) reacting 0.6mmol of the product obtained in the step (1) with 5-9mmol of p-toluenesulfonic acid in 3-6mL of water at 50-60 ℃ for 4-8h, filtering, removing the solvent from the filtrate through rotary evaporation, dispersing with acetone, precipitating and washing with diethyl ether, centrifuging, and drying to obtain a tertiary ammonium salt perylene imide compound;
or reacting 0.6mmol of the product obtained in the step (1) with 5-9mmol of methyl p-toluenesulfonate at 50-60 ℃ for 18-24h, adding 3-5mL of methanol into the reaction mixed solution, filtering, concentrating the filtrate through rotary evaporation, then precipitating and washing with diethyl ether, centrifuging, and drying to obtain the quaternary ammonium salt perylene imide compound;
the amine compound in the step (1) is a tertiary amine compound containing a terminal amino group, and the molecular formula of the amine compound is NH2(R1NH)0-5R1N(R2)2Wherein R is1Is an alkyl chain containing 2-6 methylene groups, R2Is methyl or ethyl;
the prepared tertiary ammonium salt perylene imide compound and quaternary ammonium salt perylene imide compound are water-soluble linear perylene imide compounds containing 2-12 amino functionalization.
The amine compound in the step (1) is preferably N, N-dimethylethylenediamine or N, N-diethyldivinyltriamine.
The synthesis method of the water-soluble perylene bisimide compound comprises the following specific preparation steps:
1) adding perylene anhydride and polyamine compounds into a reflux reaction bottle according to the mol ratio of (1: 40) - (1: 60), heating to 98-110 ℃ under the nitrogen atmosphere for reaction for 24-28h, then heating to 170-180 ℃ for continuous reaction for 2-5h, cooling to room temperature, adding a mixed solvent of ethanol and diethyl ether with the volume ratio of (1: 2) - (1: 4), filtering, washing a solid product with toluene and diethyl ether, and drying;
2) adding 138mg of the product obtained in the step 1) into 1-2mL of mixed solution, wherein the mixed solution is prepared by 80-86wt% of formic acid solution and 25-35wt% of formaldehyde solution according to the volume ratio of (1.2:1) - (1.5:1), stirring for 0.5-1.5 hours under nitrogen atmosphere, heating to 90-120 ℃ for reaction for 12-18 hours, cooling to room temperature, precipitating and washing with diethyl ether, and drying to obtain a tertiary amine functionalized perylene imide compound;
3) dissolving 100mg of the tertiary amine functionalized perylene imide compound obtained in the step 2) in 2-4mL of methanol or acetonitrile solvent, then dropwise adding 0.2-0.4mL of methyl iodide or 0.2-0.5mL of ethyl iodide, and heating to 60-80 ℃ under a nitrogen atmosphere to obtain a quaternary ammonium salt perylene imide compound;
the polyamine compound in the step 1) isAmine compound containing three terminal amine groups and having a molecular formula of NH2(R1NH)0-5R1N(R1NH2)2Wherein R is1Is an alkyl chain containing 2 to 6 methylene groups;
the prepared tertiary amine functionalized perylene imide compounds and quaternary ammonium salt perylene imide compounds are water-soluble branched perylene imide compounds containing 6-16 amino groups.
The polyamine compound in the step 1) is preferably tri (2-aminoethyl) amine.
The synthesis method of the water-soluble perylene bisimide compound comprises the following specific preparation steps:
(1) adding 2mmol of perylene monoanhydride and 5-10mmol of amine compound into 3-6mL of water, stirring uniformly, heating to 120 ℃ for reflux reaction for 12-24h, cooling to room temperature, washing with 1-2wt% of KOH aqueous solution and water, and drying to obtain a product;
(2) reacting 0.5mmol of the product obtained in the step (1) with 2.5-5mmol of p-toluenesulfonic acid in 2-4mL of water at 50-60 ℃ for 4-8h, filtering, removing the solvent from the filtrate through rotary evaporation, washing with diethyl ether precipitate, centrifuging, and drying to obtain a tert-ammonium salt perylene monoimide compound;
or reacting 0.5mmol of the product obtained in the step (1) with 2.5-5mmol of methyl p-toluenesulfonate at 50-60 ℃ for 18-24h, filtering, concentrating the filtrate by rotary evaporation, then precipitating and washing with diethyl ether, centrifuging, and drying to obtain the quaternary ammonium salt perylene monoimide compound;
the amine compound in the step (1) is a tertiary amine compound containing a terminal amino group, and the molecular formula of the amine compound is NH2(R1NH)0-5R1N(R2)2Wherein R is1Is an alkyl chain containing 2-6 methylene groups, R2Is methyl or ethyl;
the prepared tertiary ammonium salt perylene monoimide compound and quaternary ammonium salt perylene monoimide compound are water-soluble linear perylene monoimide compounds containing 1-6 amino functionalization.
The amine compound in the step (1) is preferably N, N-dimethylethylenediamine or N, N-diethyldivinyltriamine.
The synthesis method of the water-soluble perylene bisimide compound comprises the following specific preparation steps:
1) adding the perylene monoanhydride and the polyamine compound into a reflux reaction bottle according to the mol ratio of (1: 40) - (1: 60), heating to 98-110 ℃ under the nitrogen atmosphere for reaction for 24-28h, then heating to 170-180 ℃ for continuous reaction for 2-5h, cooling to room temperature, adding a mixed solvent of ethanol and ether with the volume ratio of (1: 2) - (1: 4), filtering, washing a solid product with toluene and ether, and drying;
2) adding 150mg of the product obtained in the step 1) into 1.0-2mL of mixed solution, wherein the mixed solution is prepared from 80-86wt% of formic acid solution and 25-35wt% of formaldehyde solution according to the volume ratio of (1.2:1) - (1.5:1), stirring for 0.5-1.5 hours under nitrogen atmosphere, heating to 90-120 ℃ for reaction for 12-18 hours, cooling to room temperature, precipitating and washing with diethyl ether, and drying to obtain a tertiary amine functionalized perylene monoimide compound;
3) dissolving 100mg of the tertiary amine functionalized perylene monoimide compound obtained in the step 2) in 2-4mL of methanol or acetonitrile solvent, then dropwise adding 0.2-0.4mL of methyl iodide or 0.2-0.5mL of ethyl iodide, and heating to 60-80 ℃ under the nitrogen atmosphere to obtain a quaternary ammonium salt perylene monoimide compound;
the polyamine compound in the step 1) is an amine compound containing three terminal amino groups, and the molecular formula of the polyamine compound is NH2(R1NH)0-5R1N(R1NH2)2Wherein R is1Is an alkyl chain containing 2 to 6 methylene groups;
the prepared tertiary amine functionalized perylene monoimide compound and quaternary ammonium salt perylene monoimide compound are water-soluble branched perylene monoimide compounds containing 3-8 amino groups.
The polyamine compound in the step 1) is preferably tri (2-aminoethyl) amine.
The water-soluble perylene bisimide compound is used as a DNA intercalator.
The water-soluble perylene bisimide compound is applied as a nuclear dye.
The water-soluble perylene bisimide compound is applied to a drug for inhibiting the growth of cancer cells.
The invention has the following beneficial effects:
1. a series of water-soluble perylene imide compounds with different amino functional groups are synthesized by different synthesis methods by taking perylene anhydride derivatives and analogues thereof as fluorescence emitting groups; the compound has the characteristics of good light, heat and chemical stability, high fluorescence quantum yield, good water solubility, designability of structure and the like.
2. The water-soluble perylene bisimide compound synthesized by the invention can be effectively embedded between double helix base pairs of nuclear DNA, can be used as a DNA intercalator, and has good practical application value.
3. The water-soluble perylene imide compound synthesized by the invention has a plane rigid structure, can be specifically enriched in fixed tissue cell nucleus, has strong fluorescence intensity, is easy for fluorescence imaging, and can be compared favorably with the effect of commercial cell nucleus dye DAPI.
4. The water-soluble perylene bisimide compound synthesized by the invention can effectively inhibit the growth of cancer cells such as U2OS, HCT116, Hela, AGS and the like, and has obvious anti-tumor effect; the method has wide application prospect in the fields of scientific research, diagnosis and treatment of biological medicine.
5. The synthetic method is simple, is easy for mass synthesis, and has good application value.
Drawings
FIG. 1 is a molecular model diagram of water-soluble perylene imide compound P2 inserted between DNA base pairs, and a fluorescence imaging diagram applied to specific cell nucleus enrichment and a bar chart for inhibiting HCT116 cell growth.
FIG. 2 is a reaction scheme for synthesizing water-soluble perylene imide compounds in example 1 and example 2.
FIG. 3 is a reaction scheme for the synthesis of water-soluble perylene monoimide compounds in example 3 and example 4.
FIG. 4 shows the UV absorption spectrum (A1-A4) and the fluorescence emission spectrum (B1-B4) of water-soluble perylene imide compounds P2, P3, P5 and P6 (5.0. mu.M) in phosphate buffer (10mM, pH7.4) with the action of Ct-DNA.
FIG. 5 shows a CD spectrum of a blank test (A-D) with a fixed Ct-DNA concentration of 80. mu.M and water-soluble perylene imide compounds P2, P3, P5 and P6 (3. mu.M) added to a phosphate buffer (10mM, pH 7.4).
FIG. 6 fluorescence imaging of drosophila salivary gland fixed tissues under co-staining with water-soluble perylene imide compounds P2, P3 and DAPI. (A-B)10 μm P2, P3 (imide site connecting two amino substituents, P2, P3 have rigid planar framework structure) stained separately to mark drosophila salivary gland, fluorescence imaging at 546nm light channel, and specific enrichment on nucleus. (A '-B') nuclear dye DAPI staining marks drosophila larva salivary gland tissues, and a 405nm light path lower fluorescence imaging picture. The (A '-B') P2, P3 nuclear fluorescence localization imaging effect is completely coincided with the DAPI fluorescence imaging effect.
FIG. 7 fluorescence imaging of Drosophila salivary gland fixed tissues under co-staining with water-soluble perylene imide compounds P5, P6 and DAPI. (A-B)10 μm P5, P6 (imide site connecting four amino substituents, P5, P6 having rigid planar framework structure) stained separately to mark drosophila salivary gland, fluorescence imaging at 546nm light channel, and specific enrichment on nucleus. (A '-B') nuclear dye DAPI staining marks drosophila larva salivary gland tissues, and a 405nm light path lower fluorescence imaging picture. The (A '-B') P5, P6 nuclear fluorescence localization imaging effect is completely coincided with the DAPI fluorescence imaging effect.
Detailed Description
The invention will be further illustrated with reference to specific examples. The present invention is not limited to these specific embodiments.
Characterization of the product structure used: nuclear magnetism1H and13c spectrum (Bruker 400), mass spectrum AXIMA-CFRplus MALDI-TOFMS.
The optical properties of the product were characterized using: ultraviolet visible spectrum (Cintra20, GBC, Australia), fluorescence spectrum (horiba JobinyvonFluoroMax-4NIR, NJ, USA).
The biological experimental characterization of the products used: fluorescence microscope (AMGEVOSf 1 microscope), laser confocal microscope (LeicaTCSSP 2aobsconfocal microscope).
Example 1 was carried out:
1) 0.7846g of perylene anhydride (2.0 mmol) and 0.34mL of N, N-dimethylethylenediamine (6.0 mmol) are suspended in 4mL of water and stirred uniformly, then the temperature is raised to 100 ℃ for reflux reaction for 12 hours, after the temperature is reduced to room temperature, 1wt% of KOH aqueous solution and water are used for washing, and after vacuum drying, a red solid product P1 is obtained, wherein the yield is 75%;
1H-NMR(400MHz,CF3COOD),δppm:8.77(d,J=12.3Hz,8H),4.77(s,4H),3.75(s,4H),3.19(s,12H).13C-NMR(100MHz,CF3COOD),δppm:168.67,138.82,135.64,131.77,128.84,126.85,123.97,60.73,46.42,38.74.MS(MALDI-TOF,m/z):CalcdforC32H28N4O4,532.6;Found,533.6(M+H+).
2) 0.32g of P1 (0.6 mmol) was reacted with 1.02g of P-toluenesulfonic acid (5.4 mmol) in 3.5mL of deionized water at 50 ℃ for 4h, filtered, the filtrate was filtered, the solvent was removed by rotary evaporation, the filtrate was dispersed with acetone, washed with ether precipitate, centrifuged and dried to give the product P2 as a red solid with a yield of 85%.
1H-NMR(400MHz,CF3COOD),δppm:8.76(s,8H),7.77(s,<2H),7.37(d,J=7.7Hz,4H),6.95(d,J=7.7Hz,4H),4.81(s,4H),3.83(s,4H),3.27(d,J=2.9Hz,12H),1.96(s,6H).13C-NMR(100MHz,CF3COOD),δppm:168.73,146.03,138.67,138.52,135.51,131.73,131.41,128.60,127.62,126.62,124.13,60.54,46.50,38.66,21.72.UV-Vis(H2O,c=5.0×10-6M):λmax(ε)=498nm(2.45×104M-1cm-1);Emission(H2O,λex=498nm):λmax=545nm.
P1 (0.32 g, 0.6 mmol) and 2.5mL methyl P-toluenesulfonate (5.4 mmol) were reacted at 50 ℃ for 20 hours, after the temperature was lowered to room temperature, 3mL methanol was added to the reaction mixture solution for filtration, the filtrate was concentrated by rotary evaporation, and then precipitated and washed with ether, centrifuged, and dried to give the product P3 as a red solid in 80% yield.
1H-NMR(400MHz,CF3COOD),δppm:8.99(dt,J=15.1,7.6Hz,8H),7.77(d,J=8.1Hz,4H),7.33(d,J=8.0Hz,4H),4.97(d,J=30.0Hz,4H),3.99(d,J=37.7Hz,4H),3.55(s,12H),3.37(s,6H),2.38(s,6H).UV-Vis(H2O,c=10-5M):λmax=498nm;Emission(H2O,λex=498nm):λmax=545nm。
P2 and P3 are water-soluble linear perylene imide compounds with 2 amino groups.
P2 has the structural formula
P3 has the structural formula
Example 2 was carried out:
1) 0.81g of perylene anhydride (2.1mmol) and 15mL of tris (2-aminoethyl) amine (100.5mmol) were added to a refluxing reaction flask, with tris (2-aminoethyl) amine also being the reaction solvent; heating the solution to 100 ℃ in a nitrogen atmosphere for 28 hours of reaction, then heating to 170 ℃ for continuous reaction for 4 hours, and adding a solvent with a volume ratio of 1: 3, filtering, washing the solid product with toluene and ether, and drying to obtain a red solid product P4 with the yield of 90%.
1H-NMR(400MHz,CF3COOD),δppm:8.82-8.98(m,8H),4.93(m,4H),4.40(m,4H),4.04-4.21(m,16H).UV-Vis(H2O,c=10-5M):λmax=498nm;Emission(H2O,λex=498nm):λmax=545nm.MS(MALDI-TOF,m/z):calcdforC36H40N8O4:648.75.Found:648.3.
2) Adding 138mgP4 into a mixed solution composed of 0.64mL of 85wt% formic acid solution and 0.44mL of 30wt% formaldehyde solution, stirring and reacting for 1 hour at room temperature under a nitrogen atmosphere, then heating to 120 ℃ for reacting for 16 hours, after the temperature is reduced to room temperature, using diethyl ether for precipitation and washing for 3 times, and drying to obtain a red solid product P5 with the yield of 88%; UV-Vis (H)2O,c=10-5M):λmax=498nm;Emission(H2O,λex=498nm):λmax=545nm.MS(MALDI-TOF,m/z):calcdforC44H56N8O4:760.97.Found:761.63.
3) The 100mgP5 is dissolved in 3mL of methanol solvent, then 0.2mL of methyl iodide is added dropwise, and the mixture is heated to 60 ℃ under the nitrogen atmosphere, so that the quaternary ammonium salt perylene imide derivative P6 is obtained.1H-NMR(400MHz,CF3COOD),δppm:8.95(d,J=34.1Hz,8H),5.04(s,4H),4.51(s,20H),4.26(s,6H),3.56(s,36H).UV-Vis(H2O,c=10-5M):λmax=498nm;Emission(H2O,λex=498nm):λmax=545nm.
P5 and P6 are water-soluble branched perylene imide compounds with 6 amino functional groups.
P5 has the structural formula
P6 has the structural formula
Example 3 of implementation:
(1) adding 0.644g of perylene monoanhydride (2.0 mmol) and 0.34mL of N, N-dimethyl ethylenediamine (6.0 mmol) into 3mL of water, uniformly stirring, heating to 110 ℃, carrying out reflux reaction for 15h, cooling to room temperature, washing with 1wt% of KOH aqueous solution and water, and carrying out vacuum drying to obtain a dark red solid product M1 with the yield of 79%;
(2) 0.196g of M1 (0.5 mmol) and 0.51g of p-toluenesulfonic acid (2.7 mmol) react in 2mL of deionized water at 55 ℃ for 5h, the filtrate is filtered, the solvent is removed by rotary evaporation, the filtrate is washed by ether precipitation, and the red solid product M2 is obtained after centrifugation and drying, wherein the yield is 88%;
m1 (0.196 g, 0.5mmol) was reacted with 1.25mL of methyl p-toluenesulfonate (2.7 mmol) at 53 ℃ for 19h, after cooling to room temperature, filtered, the filtrate was concentrated by rotary evaporation, then washed with ether precipitate, centrifuged and dried to give the product M3 as a red solid in 86% yield.
M2 and M3 are water-soluble linear perylene imide compounds with 1 amino group functionalized.
M2 structural formula
M3 structural formula
Example 4 of implementation:
1) 0.644g of perylene monoanhydride (2.0 mmol) and 15mL of tris (2-aminoethyl) amine (100.5mmol) are added to a reflux reaction flask, the solution is heated to 105 ℃ under a nitrogen atmosphere for reaction for 25 hours, then the temperature is raised to 172 ℃ for further reaction for 3 hours, and after the temperature is reduced to room temperature, the solution is added with the volume ratio of 1: 3, filtering, washing the solid product with toluene and ethyl ether, and drying to obtain a red solid product M4 with the yield of 86%.
2) Adding 150mgM4 into a mixed solution composed of 0.72mL of 85wt% formic acid solution and 0.53mL of 30wt% formaldehyde solution, stirring and reacting for 45 minutes at room temperature under a nitrogen atmosphere, then heating to 110 ℃ for reacting for 15 hours, precipitating and washing for 3 times by using diethyl ether after the temperature is reduced to room temperature, and drying to obtain a red solid product M5 with the yield of 93%;
3) the above 100mgM5 was dissolved in 3mL of methanol solvent, and then 0.25mL of methyl iodide was added dropwise, and the mixture was heated to 64 ℃ under a nitrogen atmosphere to obtain quaternary ammonium salt perylene monoimide derivative M6.
M5 and M6 are water-soluble branched perylene imide compounds with 3 amino functional groups.
M5 structural formula
M6 structural formula
The water-soluble perylene imide compounds P2, P3, P5 and P6 prepared in examples 1 and 2 were investigated as DNA intercalators.
1) Ultraviolet absorption spectrum test: the water-soluble perylene imide compounds P2, P3, P5 and P6 prepared in examples 1 and 2 were prepared as solutions with a concentration of 5 μ M using a phosphate buffer (10mM, ph7.4), respectively, in a molar ratio of 1: 0,1: 1,5: 2,1: 3 adding Ct-DNA, standing at room temperature for 12h, and performing ultraviolet absorption spectrum test on the sample. The experimental result shows that the intensity of the ultraviolet absorption spectrum is weakened after Ct-DNA is added into the P2, P3, P5 and P6 samples, and the maximum peak position is accompanied with a red shift phenomenon.
2) Fluorescence emission spectroscopy test: and (2) carrying out fluorescence emission spectrum test on the water-soluble perylene bisimide compound sample solution prepared in the step 1). The experimental results show that the fluorescence emission spectrum intensity is reduced after Ct-DNA is added into the P2, P3, P5 and P6 samples.
3) CD spectrum test: the Ct-DNA concentration was fixed at 80. mu.M, and P2, P3, P5 and P6 and a blank sample were added to a phosphate buffer (10mM, pH7.4) to prepare a solution having a concentration of 3. mu.M, and after leaving at room temperature for 1 hour, the sample was subjected to CD spectroscopic measurement. The experimental results show that the CD peak intensity of the positive signal at 277nm is enhanced and the CD peak intensity of the negative signal at 247nm is weakened after P2, P3, P5 and P6 are added into the Ct-DNA solution.
The experimental results of ultraviolet absorption, fluorescence emission spectrum and CD spectrum show that the water-soluble perylene bisimide compounds P2, P3, P5 and P6 can be inserted between DNA base pairs as DNA intercalators.
The water-soluble perylene imide compounds P2, P3, P5 and P6 prepared in examples 1 and 2 were investigated as nuclear dyes.
After the fixed tissues of drosophila were stained with P2, P3, P5 and P6 (10 μ M) and cultured together for 1 hour, P2, P3, P5 and P6 were able to interact with DNA in the nucleus, thus enriching specifically in the nucleus and being completely consistent with the commercial dye DAPI marker.
The water-soluble perylene imide compounds P2, P3, P5 and P6 prepared in examples 1 and 2 were investigated as drugs for inhibiting the growth of cancer cells.
Studies of P2, P3, P5 and P6 using tetrazolium salt (MTT) reduction assay for in vitro inhibition of cancer cell growth activity on U2OS (human osteosarcoma), HCT116 (colon cancer), Hela (cervical cancer) and AGS (gastric adenocarcinoma) cancer cells. The experimental results are shown in the table below, and show that P2 and P3 have good inhibitory activity on the growth of cancer cells such as U2OS, HCT116, Hela and AGS.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (8)
1. A water-soluble perylene imide compound is characterized in that the compound is a polyamine derivative containing perylene imide or perylene monoimide structure, and the structural general formula of the compound is as follows:
or
Or
Or
Wherein,
R2=CH3or CH2CH3，R3= H or CH3Or CH2CH3。
2. The method for synthesizing the water-soluble perylene bisimide compound according to claim 1, wherein the specific preparation steps are as follows:
(1) adding 2mmol of perylene anhydride and 6-12mmol of amine compound into 3-6mL of water, uniformly stirring, heating to 120 ℃ for reflux reaction for 12-24h, cooling to room temperature, washing with 1-2wt% of KOH aqueous solution and water, and drying to obtain a product;
(2) reacting 0.6mmol of the product obtained in the step (1) with 5-9mmol of p-toluenesulfonic acid in 3-6mL of water at 50-60 ℃ for 4-8h, filtering, removing the solvent from the filtrate through rotary evaporation, dispersing with acetone, precipitating and washing with diethyl ether, centrifuging, and drying to obtain a tertiary ammonium salt perylene imide compound;
or reacting 0.6mmol of the product obtained in the step (1) with 5-9mmol of methyl p-toluenesulfonate at 50-60 ℃ for 18-24h, adding 3-5mL of methanol into the reaction mixed solution, filtering, concentrating the filtrate through rotary evaporation, then precipitating and washing with diethyl ether, centrifuging, and drying to obtain the quaternary ammonium salt perylene imide compound;
amine compound described in step (1)The compound is a tertiary amine compound containing a terminal amino group, and the molecular formula of the compound is NH2(R1NH)0-5R1N(R2)2Wherein R is1Is an alkyl chain containing 2-6 methylene groups, R2Is methyl or ethyl;
the prepared tertiary ammonium salt perylene imide compound and quaternary ammonium salt perylene imide compound are water-soluble linear perylene imide compounds containing 2-12 amino functionalization.
3. The method for synthesizing the water-soluble perylene bisimide compound according to claim 1, wherein the specific preparation steps are as follows:
1) adding perylene anhydride and polyamine compounds into a reflux reaction bottle according to the mol ratio of (1: 40) - (1: 60), heating to 98-110 ℃ under the nitrogen atmosphere for reaction for 24-28h, then heating to 170-180 ℃ for continuous reaction for 2-5h, cooling to room temperature, adding a mixed solvent of ethanol and diethyl ether with the volume ratio of (1: 2) - (1: 4), filtering, washing a solid product with toluene and diethyl ether, and drying;
2) adding 138mg of the product obtained in the step 1) into 1-2mL of mixed solution, wherein the mixed solution is prepared by 80-86wt% of formic acid solution and 25-35wt% of formaldehyde solution according to the volume ratio of (1.2:1) - (1.5:1), stirring for 0.5-1.5 hours under nitrogen atmosphere, heating to 90-120 ℃ for reaction for 12-18 hours, cooling to room temperature, precipitating and washing with diethyl ether, and drying to obtain a tertiary amine functionalized perylene imide compound;
3) dissolving 100mg of the tertiary amine functionalized perylene imide compound obtained in the step 2) in 2-4mL of methanol or acetonitrile solvent, then dropwise adding 0.2-0.4mL of methyl iodide or 0.2-0.5mL of ethyl iodide, and heating to 60-80 ℃ under a nitrogen atmosphere to obtain a quaternary ammonium salt perylene imide compound;
the polyamine compound in the step 1) is an amine compound containing three terminal amino groups, and the molecular formula of the polyamine compound is NH2(R1NH)0-5R1N(R1NH2)2Wherein R is1Is an alkyl chain containing 2 to 6 methylene groups;
the prepared tertiary amine functionalized perylene imide compounds and quaternary ammonium salt perylene imide compounds are water-soluble branched perylene imide compounds containing 6-16 amino groups.
4. The method for synthesizing the water-soluble perylene bisimide compound according to claim 1, wherein the specific preparation steps are as follows:
(1) adding 2mmol of perylene monoanhydride and 5-10mmol of amine compound into 3-6mL of water, stirring uniformly, heating to 120 ℃ for reflux reaction for 12-24h, cooling to room temperature, washing with 1-2wt% of KOH aqueous solution and water, and drying to obtain a product;
(2) reacting 0.5mmol of the product obtained in the step (1) with 2.5-5mmol of p-toluenesulfonic acid in 2-4mL of water at 50-60 ℃ for 4-8h, filtering, removing the solvent from the filtrate through rotary evaporation, washing with diethyl ether precipitate, centrifuging, and drying to obtain a tert-ammonium salt perylene monoimide compound;
or reacting 0.5mmol of the product obtained in the step (1) with 2.5-5mmol of methyl p-toluenesulfonate at 50-60 ℃ for 18-24h, filtering, concentrating the filtrate by rotary evaporation, then precipitating and washing with diethyl ether, centrifuging, and drying to obtain the quaternary ammonium salt perylene monoimide compound;
the amine compound in the step (1) is a tertiary amine compound containing a terminal amino group, and the molecular formula of the amine compound is NH2(R1NH)0-5R1N(R2)2Wherein R is1Is an alkyl chain containing 2-6 methylene groups, R2Is methyl or ethyl;
the prepared tertiary ammonium salt perylene monoimide compound and quaternary ammonium salt perylene monoimide compound are water-soluble linear perylene monoimide compounds containing 1-6 amino functionalization.
5. The method for synthesizing the water-soluble perylene bisimide compound according to claim 1, wherein the specific preparation steps are as follows:
1) adding the perylene monoanhydride and the polyamine compound into a reflux reaction bottle according to the mol ratio of (1: 40) - (1: 60), heating to 98-110 ℃ under the nitrogen atmosphere for reaction for 24-28h, then heating to 170-180 ℃ for continuous reaction for 2-5h, cooling to room temperature, adding a mixed solvent of ethanol and ether with the volume ratio of (1: 2) - (1: 4), filtering, washing a solid product with toluene and ether, and drying;
2) adding 150mg of the product obtained in the step 1) into 1.0-2mL of mixed solution, wherein the mixed solution is prepared from 80-86wt% of formic acid solution and 25-35wt% of formaldehyde solution according to the volume ratio of (1.2:1) - (1.5:1), stirring for 0.5-1.5 hours under nitrogen atmosphere, heating to 90-120 ℃ for reaction for 12-18 hours, cooling to room temperature, precipitating and washing with diethyl ether, and drying to obtain a tertiary amine functionalized perylene monoimide compound;
3) dissolving 100mg of the tertiary amine functionalized perylene monoimide compound obtained in the step 2) in 2-4mL of methanol or acetonitrile solvent, then dropwise adding 0.2-0.4mL of methyl iodide or 0.2-0.5mL of ethyl iodide, and heating to 60-80 ℃ under the nitrogen atmosphere to obtain a quaternary ammonium salt perylene monoimide compound;
the polyamine compound in the step 1) is an amine compound containing three terminal amino groups, and the molecular formula of the polyamine compound is NH2(R1NH)0-5R1N(R1NH2)2Wherein R is1Is an alkyl chain containing 2 to 6 methylene groups;
the prepared tertiary amine functionalized perylene monoimide compound and quaternary ammonium salt perylene monoimide compound are water-soluble branched perylene monoimide compounds containing 3-8 amino groups.
6. The use of the water-soluble perylene imide compound according to claim 1 as a DNA intercalator.
7. The water-soluble perylene imide compound according to claim 1 as a nuclear dye.
8. The use of the water-soluble perylene bisimide compound according to claim 1 as a drug for inhibiting the growth of cancer cells.
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| CN115181065A (en) * | 2022-08-08 | 2022-10-14 | 河南大学 | Perylene bisimide derivative and application thereof |
| CN115181065B (en) * | 2022-08-08 | 2023-07-21 | 河南大学 | Perylene bisimide derivative and application thereof |
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| CN103936731A (en) | 2014-07-23 |
| CN103936731B (en) | 2016-04-27 |
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