CN110105335A - The synthesis and application of the naphthalimide multi-functional compounds of amide key connecting - Google Patents
The synthesis and application of the naphthalimide multi-functional compounds of amide key connecting Download PDFInfo
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Abstract
The present invention provides a kind of naphthalimide multi-functional compounds of amide key connecting.The invention also discloses the preparation methods of the multi-functional compounds.Multi-functional compounds provided by the invention have lower cytotoxicity, act not only as fluorescence probe and efficiently identify copper ion, and can be used as nucleic acid delivery vector, DNA and RNA are transported in cell.In addition, the complex of such multi-functional compounds and copper ion can identify organelle lysosome.The preparation method of the naphthalimide multi-functional compounds of amide key connecting is simple, maturation, is easy to control.
Description
Technical field
The present invention relates to the naphthalimide multi-functional compounds of amide key connecting, and in particular to a kind of sub- containing naphthoyl simultaneously
The synthesis and application of the naphthalimide multi-functional compounds of the amide key connecting of amine, phenyl ring, triazole and Macrocyclic polyamine.
Background technique
Medical means one of of the gene therapy as forefront, in all kinds of major diseases such as cancer and AIDS
Huge power is shown in treatment.During gene therapy, genophore plays highly important role.
Exposed nucleic acid is more open, volume is larger, generally exists with the line style spiral form unfolded, and have negative electricity
Property, therefore itself be difficult cross-film and enter cell, even if there is a small amount of nucleic acid to enter cell, before reaching cell nuclear expression, also very
It is easy to be degraded by intracellular nuclease.These unfavorable factors all make nucleic acid molecules not by other technological means the case where
Under, it is difficult to carry out effectively gene and transfects, therefore developing safely and effectively genophore is the successful precondition of gene therapy.
Copper is the essential trace elements of the human body, in many genetic disorders such as Menkes disease and Wilson disease, mind
Through degenerative disease such as Alzheimer's disease, Parkinson's disease, year general Ang Shi disease and Heng Tingdunshi disease, familial amyotrophic
Lateral schlerosis, metabolic disease is such as fat and diabetes disease in play highly important role.Therefore, to copper ion
Efficient identification plays very important effect to the diagnosing and treating of related disease.
Lysosome is intracellular acidic organelles, and pH value is about 4-6, it can be degraded intracellular big point by catalyzing enzyme
Sub- substance.It participates in many physiology courses, such as cholesterol homeostasis, cell membrane reparation, bone and organization restructuring, and pathogen is anti-
It is imperial, cell death and cell signal.Moreover, lysosome has indispensable energy in terms of carcinogen activation and cancer evolution
Power.Therefore, preparation targets the probe of lysosome and selectively label lysosome is of great significance to.
Summary of the invention
In view of the above-mentioned deficiencies in the prior art, the technical problem to be solved by the present invention is that it is bonded to provide a kind of amide
The synthesis and application of the naphthalimide multi-functional compounds connect.The naphthalimide multi-functional compounds show lower cell toxicant
Property, identification copper ion that not only can be selective in 100% aqueous solution, but also be also used as transgene carrier by DNA and
Rna transport is to target cell.In addition, the complex of the multi-functional compounds and copper ion is capable of the identification lysosome of selectivity, make
For the label lysosome of lysosome probe selectivity.
In order to solve the above technical problems, the technical solution adopted by the present invention is that: a kind of naphthalimide of amide key connecting is more
Functional compounds, the structure formula (I) of the multi-functional naphthalimide compound or (II) are as follows:
Wherein, X and X ' is alkyl diamine.
The naphthalimide multi-functional compounds of above-mentioned amide key connecting, which is characterized in that X is in formula (I)X ' is in formula (II)
In addition, the present invention also provides a kind of sides of naphthalimide multi-functional compounds for preparing above-mentioned amide key connecting
Method, which is characterized in that when X isWhen, the multi-functional chemical combination
The synthetic route of object is as follows:
Method includes: Step 1: weighing 2 compound of formula, formula 3a-3c compound, catalyst, condensing agent and organic in proportion
Solvent dissolution is added in alkali, reacts 8~10 hours, after reaction, is concentrated under reduced pressure, column chromatography for separation obtains under nitrogen atmosphere
Formula 4a-4c compound；
Step 2: the formula 4a-4c compound that step 1 obtains is in the Hydrochloride/ethyl acetate of saturation, at room temperature instead
It answers half an hour, after reaction, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1a-1c compound.
Above-mentioned method, which is characterized in that the ratio between catalyst described in step 1, condensing agent and amount of substance of organic base
For 1:2:3, the catalyst is I-hydroxybenzotriazole, and the condensing agent is 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne
Diimine hydrochloric acid, the organic base are triethylamine, and the eluant, eluent used in column chromatography for separation is petroleum ether and ethyl acetate, petroleum
The volume ratio of ether and ethyl acetate is 4:1.
Further, the present invention provides a kind of naphthalimide multi-functional compounds for preparing above-mentioned amide key connecting
Method, which is characterized in that when X isWhen, the synthetic route of the multi-functional compounds is as follows:
Method includes:
Step 1: weigh 5 compound of formula in proportion and 6 compound of formula be dissolved in tetrahydrofuran solvent tetrahydrofuran is molten
Liquid will be added in the tetrahydrofuran solution, at room temperature reaction 8~10 hours, instead dissolved with copper sulphate and ascorbic aqueous solution
After answering, water, methylene chloride extraction is added, column chromatography for separation obtains formula 7d and 7e compound；
Step 2: formula 7d and the 7e compound that step 1 obtains is in the Hydrochloride/ethyl acetate of saturation, at room temperature
Half an hour is reacted, after reaction, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1d and 1e compound.
Further, the present invention also provides the naphthalimide multi-functional compounds of above-mentioned amide key connecting copper from
Application in son identification, lysosome dyeing and transgene carrier.
Cu-like ion identification probe is additionally provided, a kind of transgene carrier is provided.In addition, additionally providing a kind of lyase
Body probe.
The purpose of the present invention can also further be realized that this method is specifically included by the preparation method of lysosome probe:
The naphthalimide multi-functional compounds for the amide key connecting that molar ratio is 1:5 are mixed to the solution for being made into 1mM with copper ion.
Compared with the prior art, the present invention has the following advantages:
1, more due to containing big ring in the structure of the naphthalimide multi-functional compounds of amide key connecting provided by the invention
Amine, in physiological conditions being capable of Partial protons and the lotus that becomes positively charged, it is thus possible to, and will with electronegative nucleic acid electrostatic interaction
Nucleic acid condensation is the nano particle for being suitble to cell endocytic.
2, it is contaminated due to containing fluorescence in the structure of the naphthalimide multi-functional compounds of amide key connecting provided by the invention
Expect naphthalimide, can be used as unit and fluorescence unit identification copper ion, and the identification of itself and the property of can choose after copper ion coordination
Lysosome organelle.
3, the naphthalimide multi-functional compounds cytotoxicity of amide key connecting of the invention is lower, carrier/DNA compound
70% is all larger than with cell survival rate after cell culture.
4, the preparation method of the naphthalimide multi-functional compounds of amide key connecting of the invention is simple, maturation, is easy to slap
Control.
5, the naphthalimide multi-functional compounds transfection efficiency of amide key connecting of the invention transfects effect in HeLa cell
Rate is higher, is higher than transgene carrier Lipofectamine2000 on sale and 25kD PEI.
Further advantage, target and feature of the invention will be partially reflected by the following instructions, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
With reference to the accompanying drawings and examples, technical scheme of the present invention will be described in further detail.
Detailed description of the invention
Fig. 1 is the naphthalimide multi-functional compounds of amide key connecting of the invention and the fluorescence of different metal ions effect
Spectrum experiment result schematic diagram.
Fig. 2 be amide key connecting of the present invention naphthalimide multi-functional compounds in HeLa cell with copper ion
The fluorescence microscope experimental result schematic diagram of effect.
Fig. 3 is that the naphthalimide multi-functional compounds 1b of amide key connecting of the present invention and DNA and RNA compound scan
Electron microscope experiment result schematic diagram.
Fig. 4 is that the naphthalimide multi-functional compounds 1a-1e of amide key connecting of the present invention and Cy5-RNA compound exist
Cytotoxicity schematic diagram in HeLa cell and HepG2 cell.
Fig. 5 is the naphthalimide multi-functional compounds 1a-1e and Cy5-RNA compound of amide key connecting of the present invention
Transfection schematic diagram in HeLa cell.
Fig. 6 is the naphthalimide multi-functional compounds 1a-1e and Cy5-DNA compound of amide key connecting of the present invention
Transfection schematic diagram in HeLa cell.
Fig. 7 is the naphthalimide multi-functional compounds of the present invention for turning amide key connecting and copper ion complex and business
Change the fluorescence microscope experimental result schematic diagram of lysosome coloring agent Lyso-Tracker Red common location in HeLa cell.
Specific embodiment
It should be appreciated that such as " having ", "comprising" and " comprising " term used herein are not precluded one or more
The presence or addition of a other elements or combinations thereof.
<embodiment 1>
Step 1: weighing 2 compound of formula (1.2mmol), formula 3a compound (1.2mmol), 1- hydroxy benzo three in proportion
Azoles catalyst (1.2mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid condensing agent (2.4mmol) and three
Dichloromethane solvent 50mL dissolution is added, under nitrogen atmosphere reaction 8~10 hours in ethamine (3.6mmol), after reaction,
Decompression evaporates solvent, and 50mL water is added, and methylene chloride (40mL x 2) extraction merges organic phase, and saturated common salt water washing is anhydrous
Sodium sulphate is dry, removes solvent, and silica gel column chromatography separation (petrol ether/ethyl acetate volume ratio=4/1) obtains white solid and obtains
Formula 4a compound, yield: 59%；
Nuclear-magnetism1H NMR(400MHz,CDCl3) δ 8.59 (d, J=7.2Hz, 1H), 8.48 (dd, J=17.1,8.1Hz,
2H), 7.70 (t, J=7.9Hz, 1H), 7.38 (s, 2H), 7.28-7.09 (m, 4H), 5.45 (s, 4H), 4.15 (t, J=
7.2Hz,2H),3.83-3.76(m,8H),3.33(s,16H),3.19(s,3H),2.65(s,3H),2.42(s,8H),1.88-
1.82 (m, 12H), 1.73-1.65 (m, 2H), 1.45 (s, 38H), 0.96 (t, J=7.2Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,CDCl3)δ169.68,164.15,163.76,155.96,143.89,137.52,
136.45,132.15,130.98,130.44,129.94,127.91,126.38,125.16,122.93,115.55,114.88,
79.07,53.01,49.56,46.52,45.30,43.70,41.90,39.85,37.62,30.11,28.36,27.62,
25.96,20.22,13.73；
Infrared IR (KBr, cm-1):3338.86,3127.11,2967.17,2931.93,1690.36,1649.70,
1581.93 1416.57,1359.64,1245.78,1169.88,776.81；
Mass spectrum ESI-MS:m/z=1373.0 ([M+H]+).
Step 2: the formula 4a compound (1.0mmol) that the step 1 obtains is added to the saturation ethyl acetate of hydrogen chloride
In solution, reaction is stirred at room temperature 0.5~1 hour, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1a compound, receive
Rate: 95%.
Nuclear-magnetism1H NMR(400MHz,D2O)δ8.07-7.77(m,4H),7.66-7.49(m,1H),7.31-7.17(m,
1H),7.11-6.98(m,1H),6.81-6.41(m,3H),5.30(s,2H),5.11(s,2H),4.18-4.15(m,4H),
3.73-3.42 (m, 5H), 3.33-2.87 (m, 28H), 2.77 (s, 1H), 2.36-1.91 (m, 14H), 1.31 (d, J=6.9Hz,
1H),1.10(s,3H),0.71-0.66(m,3H)；
Nuclear-magnetism13C NMR(101MHz,D2O)δ176.24,171.88,171.37,164.42,163.66,154.80,
136.46,136.23,135.92,132.44,131.03,129.45,128.75,127.95,126.74,126.52,125.01,
123.96,123.15,121.04,114.39,113.95,113.04,112.66,73.17,60.25,58.07,57.47,
53.26,53.03,48.92,48.24,47.47,45.46,42.35,42.05,41.16,39.98,37.92,33.69,
29.49,20.61,20.19,19.81,17.97,17.04,13.27；
Infrared IR (KBr, cm-1):3428.01,2959.04,2650.00,1684.94,1641.57,1581.93
1451.81,1384.04,1356.93,1234.94,1053.31,790.36；
Mass spectrum ESI-MS:m/z=972.6427 ([M+H]+)。
<embodiment 2>
Step 1: weighing 2 compound of formula (1.2mmol), formula 3b compound (1.2mmol), 1- hydroxy benzo three in proportion
Azoles catalyst (1.2mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid condensing agent (2.4mmol) and three
Dichloromethane solvent 50mL dissolution is added, under nitrogen atmosphere reaction 8~10 hours in ethamine (3.6mmol), after reaction,
Decompression evaporates solvent, and 50mL water is added, and methylene chloride (40mL x 2) extraction merges organic phase, and saturated common salt water washing is anhydrous
Sodium sulphate is dry, removes solvent, and silica gel column chromatography separation (petrol ether/ethyl acetate volume ratio=4/1) obtains white solid and obtains
Formula 4b compound, yield: 78%；
Nuclear-magnetism1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.3Hz, 1H), 8.41 (d, J=8.4Hz, 1H), 8.28
(s, 1H), 7.73 (s, 2H), 7.64 (t, J=7.9Hz, 1H), 7.34 (s, 7H), 7.15 (s, 1H), 6.58 (d, J=8.5Hz,
1H),5.52(s,4H),4.19-4.12(m,2H),3.89(s,2H),3.70(s,4H),3.55(s,2H),3.30-3.24(m,
16H), 2.39 (s, 8H), 1.90-1.66 (m, 14H), 1.42 (d, J=13.1Hz, 38H), 0.96 (t, J=7.3Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,CDCl3)δ168.55,164.39,163.90,156.20,149.97,144.08,
136.55,135.81,134.13,130.72,130.16,129.45,127.07,124.42,122.41,120.11,109.37,
103.27,79.25,53.12,49.65,46.87,45.31,43.90,39.73,39.22,30.21,28.38,25.84,
25.40,20.29,13.78；
Infrared IR (KBr, cm-1):3379.22,2967.17,2923.80,1684.94,1646.99,1584.64,
1413.86,1362.35,1248.49；
Mass spectrum ESI-MS:m/z=1344.9 ([M+H]+).
Step 2: the formula 4b compound (1.0mmol) that the step 1 obtains is added to the saturation ethyl acetate of hydrogen chloride
In solution, reaction is stirred at room temperature 0.5~1 hour, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1b compound, receive
Rate: 93%.
Nuclear-magnetism1H NMR(400MHz,D2O) δ 7.99 (d, J=10.7Hz, 2H), 7.44 (s, 2H), 7.35-6.95 (m,
4H),6.70-6.46(m,1H),5.81-5.78(m,1H),5.40(s,4H),3.94(s,4H),3.53-2.75(m,30H),
2.06 (s, 4H), 1.92 (s, 12H), 1.04 (s, 2H), 0.94-0.82 (m, 2H), 0.56 (t, J=7.1Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,D2O)δ176.38,168.98,164.30,163.40,149.85,136.44,
136.16,134.84,133.60,131.38,130.12,128.04,127.56,127.30,123.44,119.56,118.24,
106.46,103.17,57.48,53.32,48.91,47.49,42.82,42.04,41.14,39.74,38.81,29.56,
20.54,20.16,19.82,17.97,16.95,13.20；
Infrared IR (KBr, cm-1):3425.30,2956.33,2650.00,1682.23,1638.86,1581.93
1546.69,1392.17,1356.93,1234.07,1121.08,1058.73,776.81；
Mass spectrum ESI-MS:m/z=944.6103 ([M+H]+)。
<embodiment 3>
Step 1: weighing 2 compound of formula (1.2mmol), formula 3c compound (1.2mmol), 1- hydroxy benzo three in proportion
Azoles catalyst (1.2mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid condensing agent (2.4mmol) and three
Dichloromethane solvent 50mL dissolution is added, under nitrogen atmosphere reaction 8~10 hours in ethamine (3.6mmol), after reaction,
Decompression evaporates solvent, and 50mL water is added, and methylene chloride (40mL x 2) extraction merges organic phase, and saturated common salt water washing is anhydrous
Sodium sulphate is dry, removes solvent, and silica gel column chromatography separation (petrol ether/ethyl acetate volume ratio=4/1) obtains white solid and obtains
Formula 4c compound, yield: 57%；
Nuclear-magnetism1H NMR(400MHz,CDCl3) δ 8.61 (d, J=7.1Hz, 1H), 8.54 (d, J=8.0Hz, 1H), 8.40
(d, J=8.4Hz, 1H), 7.76-7.72 (m, 1H), 7.41 (s, 2H), 7.31 (s, 2H), 7.24 (d, J=4.0Hz, 2H),
5.56 (s, 4H), 4.31 (t, J=6.7Hz, 1H), 4.20-4.15 (m, 2H), 4.07 (s, 1H), 3.79 (s, 4H), 3.31 (s,
18H),2.44-2.42(m,8H),1.88-1.83(m,12H),1.73-1.67(m,4H),1.44(s,38H),1.28-1.21
(m, 2H), 0.98 (d, J=7.3Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,D2O)δ166.26,165.02,161.60,161.15,153.66,152.17,
141.72,134.54,134.26,129.71,129.66,128.53,128.27,127.13,126.99,126.19,125.60,
124.01,123.59,120.82,120.26,115.24,112.96,76.67,62.88,50.54,50.39,47.10,
44.28,42.82,41.33,37.45,27.93,27.61,25.87,24.75,23.46,17.73,16.54,11.21,
11.08；
Infrared IR (KBr, cm-1):3343.72,3127.11,2969.88,2926.51,1690.36,1657.83,
1590.06 1416.57,1365.06,1229.52,1161.75,784.94；
Mass spectrum ESI-MS:m/z=1370.8 ([M+H]+).
Step 2: the formula 4c compound (1.0mmol) that the step 1 obtains is added to the saturation ethyl acetate of hydrogen chloride
In solution, reaction is stirred at room temperature 0.5~1 hour, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1c compound, receive
Rate: 97%.
Nuclear-magnetism1H NMR(400MHz,D2O)δ8.25(s,2H),7.72-7.39(m,3H),7.43-7.30(m,3H),7.04
(s,1H),6.50(s,1H),5.62(s,4H),4.40(s,4H),3.76(s,2H),3.45-3.25(m,28H),2.88-2.76
(m,4H),2.14-2.12(m,12H),1.18-1.06(m,4H),0.67(s,3H)；
Nuclear-magnetism13C NMR(101MHz,D2O)δ170.32,163.70,163.25,154.49,136.23,136.04,
135.65,129.45,128.20,126.83,124.13,120.87,114.51,53.18,48.97,47.09,41.73,
40.85,29.48,19.89,17.66(s,8H),13.25(s,3H)；
Infrared IR (KBr, cm-1):3428.01,2956.33,2753.01,1693.07,1649.70,1587.35,
1454.52,1386.75,1237.65,1053.31,787.65；
Mass spectrum ESI-MS:m/z=970.6231 ([M+H]+)。
<embodiment 4>
Step 1: weighing 5 compound of formula (1.0mmol) and boc-protected 6 compound of propargylamine formula in proportion
(2.2mmol), which is dissolved in tetrahydrofuran solvent, obtains tetrahydrofuran solution, institute will be added dissolved with copper sulphate and ascorbic aqueous solution
It states in tetrahydrofuran solution, reacts 15~20 hours, after reaction, be concentrated under reduced pressure at room temperature, (eluant, eluent is petroleum to column chromatography
Ether and ethyl acetate, volume ratio 4:1) separate to obtain white solid 7d.Yield: 42%.
Nuclear-magnetism1H NMR(400MHz,CDCl3) δ 8.58 (d, J=7.0Hz, 1H), 8.45 (d, J=8.0Hz, 1H), 8.25
(d, J=8.3Hz, 1H), 7.63-7.59 (m, 3H), 7.38 (s, 2H), 7.32 (s, 1H), 6.71 (d, J=8.1Hz, 1H),
6.61(s,1H),5.76(s,1H),5.52(s,4H),4.16(s,2H),3.74(s,4H),3.58-3.10(m,20H),2.41
(s, 8H), 1.87-1.39 (m, 60H), 0.97 (t, J=6.8Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,CDCl3)δ166.36,164.64,164.06,156.26,149.89,136.84,
136.46,134.41,130.93,129.82,126.77,124.38,122.88,120.33,109.64,104.04,79.31,
53.25,49.85,46.97,45.39,43.95,43.28,39.85,39.71 30.28,29.60,29.38,28.53,
27.88,26.39,26.29,26.04,20.36,13.83；
Infrared IR (KBr, cm-1):3433.43,2929.22,1638.86,1579.22,1384.04,1362.35,
1251.20,1167.17,1104.82,641.2；
Mass spectrum ESI-MS:m/z=1400.6. ([M+H]+).
Step 2: the formula 7d compound (1.0mmol) that the step 1 obtains is added to the saturation ethyl acetate of hydrogen chloride
In solution, reaction is stirred at room temperature 0.5~1 hour, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1d compound.It receives
Rate: 88%.
Nuclear-magnetism1H NMR(400MHz,D2O) δ 7.77 (s, 2H), 7.51 (d, J=6.9Hz, 1H), 7.47 (d, J=7.5Hz,
1H), 7.28 (s, 2H), 7.22 (d, J=8.1Hz, 1H), 7.09 (s, 1H), 6.85 (t, J=7.1Hz, 1H), 5.76 (d, J=
6.9Hz,1H),5.26(s,4H),3.64(s,4H),3.42(s,2H),3.16-2.99(m,18H),2.84(s,2H),2.61
(s, 8H), 2.02 (s, 4H), 1.77 (s, 8H), 1.40 (s, 4H), 1.19 (s, 6H), 1.05-0.98 (m, 2H), 0.62 (t, J=
7.1Hz,3H)；
Nuclear-magnetism13C NMR(101MHz,D2O)δ168.23,164.70,163.71,150.41,138.48,136.03,
135.34,134.07,130.95,130.56,128.19,127.78,126.97,126.96,123.69,119.90,118.71,
106.06,103.34,53.24,48.76,47.31,43.02,42.76,41.77,40.70,39.92,29.76,28.52,
27.67,26.22,26.07,20.00,19.94,19.00,13.30；
Infrared IR (KBr, cm-1):3409.04,2929.22,2853.31,2750.30,1676.81,1638.86,
1579.22,1543.98,1457.23,1432.83,1392.17,1356.93,1245.78,1167.17,1115.66,
1053.31,782.23；
Mass spectrum ESI-MS:m/z=1000.6703 ([M+H]+)。
<embodiment 5>
Step 1: weighing 5 compound of formula (1.0mmol) and boc-protected 6 compound of propargylamine formula in proportion
(1.0mmol), which is dissolved in tetrahydrofuran solvent, obtains tetrahydrofuran solution, institute will be added dissolved with copper sulphate and ascorbic aqueous solution
It states in tetrahydrofuran solution, reacts 15~20 hours, after reaction, be concentrated under reduced pressure at room temperature, (eluant, eluent is petroleum to column chromatography
Ether and ethyl acetate, volume ratio 4:1) separate to obtain white solid formula 7e compound.Yield: 36%.
Nuclear-magnetism1H NMR(400MHz,CDCl3) δ 8.49 (d, J=6.3Hz, 1H), 8.37 (d, J=7.6Hz, 1H), 8.17
(d, J=6.9Hz, 1H), 7.60 (s, 2H), 7.52 (s, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 6.62 (d, J=8.3Hz,
2H),5.65(s,1H),5.48(s,2H),4.31(s,2H),4.08(s,2H),3.67(s,2H),3.39-3.32(m,4H),
3.21-3.16(m,8H),2.33(s,4H),1.73(s,8H),1.61(s,4H),1.47(s,2H),1.37(s,20H),1.18
(s,2H),0.89(s,3H)；
Nuclear-magnetism13C NMR(101MHz,CDCl3)δ166.61,164.67,164.11,156.30,149.72,137.18,
136.56,136.13,134.39,130.97,129.98,129.83,126.41,126.32,126.90,126.41,126.32,
124.48,123.02,120.32,109.92,104.12,79.40,53.94,53.48,49.88,47.22,45.42,44.05,
43.28,39.90,39.69,30.30,29.63,29.47,28.55,28.45,26.36,26.25,20.39,13.83；
Infrared IR (KBr, cm-1):3438.86,2926.51,2099.70,1638.86,1579.22,1549.40,
1384.04,1359.64,1248.49,1164.46,1115.66,779.52；
Mass spectrum ESI-MS:m/z=991.3. ([M+H]+).
Step 2: the formula 7e compound (1.0mmol) that the step 1 obtains is added to the saturation ethyl acetate of hydrogen chloride
In solution, reaction is stirred at room temperature 0.5~1 hour, by solvent concentration, is dried in vacuo 18~24 hours, obtains formula 1e compound.It receives
Rate: 71%.
Nuclear-magnetism1H NMR(400MHz,CD3SOCD3) δ 11.23 (s, 1H), 9.52 (s, 4H), 8.76 (d, J=8.3Hz,
1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.42 (d, J=6.9Hz, 1H), 8.28-8.23 (m, 1H), 7.80 (d, J=
8.7Hz, 2H), 7.66 (t, J=7.6Hz, 1H), 7.46-7.43 (m, 1H), 6.76 (d, J=8.4Hz, 1H), 5.74-5.67
(m,2H),4.53(s,2H),4.42(s,2H),4.20(s,6H),4.04-3.97(m,2H),3.45(s,2H),3.26-3.16
(m, 8H), 2.16-2.14 (m, 4H), 1.87-1.70 (m, 4H), 1.64-1.26 (m, 12H), 0.91 (t, J=7.3Hz, 3H)；
Nuclear-magnetism13C NMR(101MHz,DMSO)δ165.74,164.19,163.35,151.13,137.05,136.09,
134.71,131.06,129.89,129.23,127.24,127.09,124.59,122.24,120.57,107.82,104.15,
53.58,43.19,30.27,29.51,28.22,26.82,26.73,20.27,14.19；
Infrared IR (KBr, cm-1):3400.90,2923.80,2853.31,2099.70,1679.52,1638.86,
1579.22,1546.69,1462.65,1397.59,1384.04,1354.22,1272.89,1237.65,1115.66,
1056.02,782.23；
Mass spectrum ESI-MS:m/z=791.4841 ([M+H]+)。
<embodiment 6>
The preparation of multi-functional compounds 1a-1e in 1-5 containing embodiment
Raw material includes the formula 1a-1e compound of embodiment 1-5 preparation, and formula 1a-1e compound prepared by embodiment 1-5 is molten
In 1.0mL ultrapure water, being made into concentration is 1mM solution, is placed in 4 DEG C of refrigerators and saves backup.
Raw material includes the 1a-1e compound (1mmol) for implementing 1-5 preparation, formula 1a-1e chemical combination prepared by embodiment 1-5
Object and cupric perchlorate (5mmol) are dissolved in the Tis-HCl buffer that 1.0mL pH value is 7.2, are made into the 1-Cu that concentration is 1mM and are matched
Polymer solution is placed in 4 DEG C of refrigerators and saves backup.
<embodiment 7>
The solution of the naphthalimide multi-functional compounds 1a-1e 1mM for the amide key connecting that embodiment 6 is prepared, to it
Carry out the experiment detection of following several aspects:
(1) the effect experiment of the naphthalimide multi-functional compounds 1a-1e of amide key connecting and different metal ions
Taking concentration is the 30 μ L of naphthalimide multi-functional compounds solution of the amide key connecting of 1mM, and the 0.1M of 30 μ L is added
Tris-HCl buffer solution, gently piping and druming mix, add the different metal ions of 5 equivalents, be diluted to ultrapure water
3mL carries out fluorometric investigation after acting on 10min.
As shown in Figure 1, fluorescence is significant after copper ion is added in the naphthalimide multi-functional compounds 1a-1e of amide key connecting
It reduces, and after other metal ions are added, fluorescence does not have significant change.
(2) the cell imaging experiment of the naphthalimide multi-functional compounds 1a-1e and copper ion of amide key connecting
Pancreatin digests the HeLa cell for collecting logarithmic growth phase, will be every about hole 1.0 × 104-3.0×104A cell kind enters
24 porocyte culture plates contain 5%CO in 37 DEG C224 hours of incubator culture, make cell grow to 70%-80% fusion.
Original culture medium in hole is discarded, is washed 1-2 times with PBS buffer solution, the naphthoyl of 20 μM of amide key connecting is separately added into every hole
200 μ L of imines multi-functional compounds solution.After acting on half an hour, PBS buffer solution is washed twice, and 10 times of equivalents are added in every hole
The copper ion of the naphthalimide multi-functional compounds of amide key connecting.Take pictures under fluorescence microscope observation with the time variation
The variation of cell fluorescence intensity.
As shown in Fig. 2, after copper ion is added in the naphthalimide multi-functional compounds 1a-1d of amide key connecting, green fluorescence
It significantly reduces, is held essentially constant after sixty minutes.And after copper ion is added in compound 1e, fluorescence does not have significant change.
(3) the naphthalimide multi-functional compounds 1b of amide key connecting and the partial size of pUC18-DNA or siRNA compound and
The measurement experiment of surface topography
At room temperature, be separately added into PE pipe amide key connecting naphthalimide multi-functional compounds 1b, pUC18-DNA or
The ultrapure water of siRNA and respective volume make the final volume of reaction solution be maintained at 50 μ L, and centrifugation is uniformly mixed, reaction solution transfer
The substance withdrawl syndrome of genophore is 20 μM, and the concentration of pUC18-DNA and siRNA are 9 μ g/mL.Then by be uniformly mixed
After reaction solution room temperature acts on half an hour, it is added drop-wise on silicon wafer.After naturally dry 24 hours, observed in scanning electron microscope
The pattern and size of 1b/DNA and 1b/RNA compound.
As shown in figure 3, the shape of 1b/RNA compound is irregular petal shape, and the shape of 1b/DNA compound is
Rectangle or square, in contrast, the particle of 1b/RNA compound are slightly less than 1b/DNA and are formed by nano particle.
(4) the naphthalimide multi-functional compounds 1a-1e cytotoxicity experiment of amide key connecting
The preparation of the naphthalimide multi-functional compounds and pUC18-DNA compound of amide key connecting
At room temperature, multi-functional compounds are separately added into PE pipe, wherein the naphthalimide multifunction of amide key connecting
The concentration for closing object is respectively 10,15,20,25 μM, and the concentration of DNA is 9 μ g/mL, and the culture medium of respective volume is added, makes reaction solution
Final volume be maintained at 500 μ L.It is put into 37 DEG C of waters bath with thermostatic control, keeps the temperature 0.5 hour.
Cytotoxicity experiment
96 holes will be entered every about 7000, hole cell kind with HeLa the and HepG2 cell that logarithmic growth phase is collected in pancreatin digestion
In plate, contain 5%CO in 37 DEG C224 hours of incubator culture, make the fusion for growing to 70%-80% of cell.Discard hole
Interior original culture medium, is washed 1-2 times with PBS buffer solution, and the multifunction of the above-mentioned various concentration prepared is separately added into every hole
100 μ L of object and pUC18-DNA compound is closed, five parallel holes are arranged in each concentration；Using the DMEM for being free of multi-functional compounds
The cell of culture medium culture only has DMEM as blank control as control without cell.All culture mediums are inhaled after 4 hours
Out, the DMEM that 200 μ L contain 10% fetal calf serum is added in every hole thereto, after cultivating 24 hours in incubator, is added to every hole
10 μ L MTT solution, are sucked out all addition liquid after 4 hours, and 150 μ L dimethyl sulfoxides are added, in shaking after ten minutes on shaking table
Absorbance value of every hole at 490nm is measured with microplate reader.Cell survival rate (%)=[A490test- is calculated as follows
Blank]/[A490control- blank] × 100%.
As shown in figure 4, by the naphthalimide multi-functional compounds for measuring amide key connecting in HeLa and HepG2 cell
Cytotoxicity, it is found that toxicity in these four cells is all relatively low.The survival rate of cell is substantially all 70% or more.
(5) the cross-film experiment of the naphthalimide multi-functional compounds 1a-1e Yu Cy5-RNA compound of amide key connecting
The preparation of the naphthalimide multi-functional compounds and Cy5-RNA compound of amide key connecting
At room temperature, multi-functional compounds are separately added into PE pipe, wherein the naphthalimide multifunction of amide key connecting
The concentration for closing object distinguishes 20 μM, and the concentration of Cy5-RNA is 9 μ g/mL, and the culture medium of respective volume is added, makes the final of reaction solution
Volume is maintained at 500 μ L.Room temperature acts on 0.5 hour.According to above-mentioned method prepare transgenosis carrier Lipofectamine2000
With the compound of Cy5-RNA, PEI and Cy5-RNA.
The HeLa cell that logarithmic growth phase is collected with pancreatin digestion, will be every about hole 7.0 × 104-9.0×104A cell kind
Enter 24 porocyte culture plates, contains 5%CO in 37 DEG C224 hours of incubator culture, so that cell is grown to 70%-80% and melt
It closes.Original culture medium in hole is discarded, is washed 1-2 times with PBS buffer solution, the above-mentioned amide key connecting prepared is separately added into every hole
Naphthalimide and 500 μ L of Cy5-RNA compound.All culture mediums are sucked out after 4 hours, every hole is added 200 μ L and contains thereto
The DMEM of 10% fetal calf serum after cultivating 24 hours in incubator, takes out 24 orifice plates, is washed twice with PBS washing lotion.Fluorescence is aobvious
The fluorescence intensity of micro- microscopic observation Cy5-RNA
As shown in figure 5, being tested by cell transmembrane it follows that in HeLa cell, the naphthalimide of amide key connecting
Cy5-RNA can be deliverrf into cell by 1a-1e.Wherein 1a and 1b delivery efficiency is higher, significantly larger than commercialization transgenosis
Carrier Lipofectamine2000 and PEI.
(6) the cross-film experiment of the naphthalimide multi-functional compounds 1a-1e Yu Cy5-DNA compound of amide key connecting
The preparation of the naphthalimide multi-functional compounds and Cy5-DNA compound of amide key connecting
At room temperature, multi-functional compounds are separately added into PE pipe, wherein the naphthalimide multifunction of amide key connecting
The concentration for closing object distinguishes 20 μM, and the concentration of Cy5-DNA is 9 μ g/mL, and the culture medium of respective volume is added, makes the final of reaction solution
Volume is maintained at 500 μ L.Room temperature acts on 0.5 hour.According to above-mentioned method prepare transgenosis carrier Lipofectamine2000
With the compound of Cy5-DNA, PEI and Cy5-DNA.
The HeLa cell that logarithmic growth phase is collected with pancreatin digestion, will be every about hole 7.0 × 104-9.0×104A cell kind
Enter 24 porocyte culture plates, contains 5%CO in 37 DEG C224 hours of incubator culture, so that cell is grown to 70%-80% and melt
It closes.Original culture medium in hole is discarded, is washed 1-2 times with PBS buffer solution, the above-mentioned carrier and Cy5- prepared is separately added into every hole
500 μ L of DNA compound.All culture mediums are sucked out after 4 hours, 200 μ L are added containing 10% fetal calf serum in every hole thereto
DMEM after cultivating 24 hours in incubator, takes out 24 orifice plates, is washed twice with PBS washing lotion.Fluorescence microscopy microscopic observation Cy5-
The fluorescence intensity of DNA
As shown in fig. 6, being tested by cell transmembrane it follows that in HeLa cell, the naphthalimide of amide key connecting
Cy5-DNA can be deliverrf into cell by multi-functional compounds 1a-1e.Wherein 1c and 1d delivery efficiency is higher, a little higher than quotient
Industry transgene carrier Lipofectamine2000 and PEI.
<embodiment 8>
The 1-Cu complex solution that embodiment 6 is prepared, with commercialization lysosome coloring agent Lyso-Tracker Red
Coloration experiment altogether
Pancreatin digests the HeLa cell for collecting logarithmic growth phase, will be every about hole 1.0 × 104-3.0×104A cell kind enters
24 porocyte culture plates contain 5%CO in 37 DEG C224 hours of incubator culture, make cell grow to 70%-80% fusion.
Original culture medium in hole is discarded, is washed 1-2 times with PBS buffer solution, 20 μM of 1-Cu complex solution 200 is separately added into every hole
μL.After acting on half an hour, Lyso-Tracker Red lysosome coloring agent is added in every hole.Continue after acting on half an hour, it will
All culture mediums are sucked out, and PBS buffer solution washes twice, the 1-Cu for observation transmitting green fluorescence of taking pictures under fluorescence microscope and red
The Lyso-Tracker Red registration of color fluorescence.
As shown in fig. 6, green is the color of 1-Cu complex, it is red for the dyeing of Lyso-Tracker Red lysosome
The color of agent, after red and green superposition, color is essentially coincided, and illustrates the dyeing lyase of the 1-Cu complex property of can choose
Body identifies probe or lysosome dyestuff as lysosome.
In conclusion the cytotoxicity of the multi-functional compounds 1a-1e in the present invention is lower, identification that can be highly selective
Copper ion, while RNA and DNA can be deliverrf into cell, and delivery efficiency with higher.In addition, 1-Cu complex
Lysosome probe, selective identification lysosome can be used as.Such multi-functional compounds preparation method is simple, mature, easy
In control.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With.It can be applied to various suitable the field of the invention completely.It for those skilled in the art, can be easily
Realize other modification.Therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and legend shown and described herein.
Claims (6)
1. a kind of naphthalimide multi-functional compounds of amide key connecting, which is characterized in that the structure of the multi-functional compounds
Formula (I) or (II) are as follows:
Wherein, X and X ' is alkyl diamine.
2. the naphthalimide multi-functional compounds of amide key connecting according to claim 1, which is characterized in that X in formula (I)
For X ' in formula (II)
For
3. a kind of method for the naphthalimide multi-functional compounds for preparing amide key connecting as stated in claim 1 or 2,
It is characterized in that, when X isWhen, the conjunction of the multi-functional compounds
It is as follows at route:
Method includes:
Step 1: weighing 2 compound of formula, formula 3a-3c compound, catalyst, condensing agent and organic base in proportion, it is molten that solvent is added
Solution is reacted 8~10 hours under nitrogen atmosphere, after reaction, is concentrated under reduced pressure, column chromatography for separation obtains formula 4a-4c compound；
Step 2: the formula 4a-4c compound that step 1 obtains in the Hydrochloride/ethyl acetate of saturation, reacts half at room temperature
Hour, after reaction, by solvent concentration, it is dried in vacuo 18~24 hours, obtains formula 1a-1c compound.
4. according to the method described in claim 3, it is characterized in that, catalyst described in step 1, condensing agent and organic base
The ratio between amount of substance is 1:2:3, and the catalyst is I-hydroxybenzotriazole, and the condensing agent is 1- ethyl-(3- dimethylamino
Base propyl) phosphinylidyne diimine hydrochloric acid, the organic base is triethylamine, and the eluant, eluent used in column chromatography for separation is petroleum ether and second
The volume ratio of acetoacetic ester, petroleum ether and ethyl acetate is 4:1.
5. a kind of method for the naphthalimide multi-functional compounds for preparing amide key connecting as stated in claim 1 or 2,
It is characterized in that, when X isWhen, the synthetic route of the multi-functional compounds is as follows:
Method includes:
Step 1: weigh 5 compound of formula in proportion and 6 compound of formula is dissolved in tetrahydrofuran solvent obtaining tetrahydrofuran solution, it will
It is added in the tetrahydrofuran solution dissolved with copper sulphate and ascorbic aqueous solution, reacts 8~10 hours at room temperature, reaction knot
Shu Hou, is added water, methylene chloride extraction, and column chromatography for separation obtains formula 7d and 7e compound；
Step 2: formula 7d and the 7e compound that step 1 obtains react at room temperature in the Hydrochloride/ethyl acetate of saturation
Half an hour by solvent concentration, is dried in vacuo 18~24 hours after reaction, obtains formula 1d and 1e compound.
6. the naphthalimide multi-functional compounds of amide key connecting as described in claim 1 are in copper ion identification, lysosome dye
Application in color and transgene carrier.
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