CN108409656A - Application of the small molecule containing naphthalimide as fluorescence probe in terms of RNA detections and imaging - Google Patents

Application of the small molecule containing naphthalimide as fluorescence probe in terms of RNA detections and imaging Download PDF

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CN108409656A
CN108409656A CN201810280056.5A CN201810280056A CN108409656A CN 108409656 A CN108409656 A CN 108409656A CN 201810280056 A CN201810280056 A CN 201810280056A CN 108409656 A CN108409656 A CN 108409656A
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rna
probe
cell
fluorescence
naphthalimide
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易涛
曹春艳
魏鹏
李想
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Fudan University
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Fudan University
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Priority to CN201810943851.8A priority patent/CN108949154B/en
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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
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Biochemistry (AREA)
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  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials Engineering (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

The invention belongs to cell imaging technical field, application of specially a kind of small molecule containing naphthalimide as fluorescence probe in terms of RNA detections and imaging.The micromolecular compound containing naphthalimide, the response of Fluorescence Increasing is combined with RNA, but it is very weak to the response of DNA under the same conditions, show that it has selectivity well in solution state, the probe for differentiating RNA and DNA is can be used as, DNA interference Selective recognitions RNA is excluded under solution state and in active somatic cell；And the micromolecular compound can pass rapidly through the cell membrane and nuclear membrane of active somatic cell in two minutes, realize the fluorescence imaging to cytoplasm and cell nuclear RNA, and have good bio-compatibility.

Description

Small molecule containing naphthalimide is as fluorescence probe in terms of RNA detections and imaging Using
Technical field
The invention belongs to fluorescent probe technique fields, and in particular to a kind of fluorescence probe containing naphthalimide is detected in RNA With the application in terms of imaging.The probe can exclude DNA interference Selective recognitions RNA in phosphate buffer and cell；In work In cell, compound can pass rapidly through the fluorescence imaging of cell membrane and nuclear membrane realization to all RNA in cytoplasm and nucleus.
Background technology
RNA is using a chain of DNA as masterplate, and using base pair complementarity as principle, one for transcribing and being formed is single-stranded, main It is the expression for realizing hereditary information on protein to want function, is bridge of the hereditary information to expression conversion, and in addition RNA is also assisted in The adjusting and catalysis of intracellular chemistry reaction.The variation of rna expression amount and the change of expression position are that organism generation metabolism is different Normal important symbol.Therefore RNA is imaged in living cells to not only facilitate the essence for understanding vital movement and disease can be improved The accuracy of detection.
Currently, the probe of imaging cells endogenous RNA can be mainly divided into four classes：(1) in situ hybridization of fluorescent marker is visited Needle（FISH）, it is one section of nucleic acid sequence with fluorogen label, the different piece complementation of sequence and targeted rna.They are A kind of imaging technique of mature, but this method background is higher, and can only be imaged in fixed cell.(2) molecular beacon （MBs）, molecular beacon is in unidentified RNA, without fluorescence；After RNA, fluorescence restores.They solve in situ hybridization The high problem of probe background signal, but such material hardly enters living cells.(3) nano molecular beacon refers to load nanometer The molecular beacon of particle.Nano particle can reduce synthesis cost as quencher and carrier simultaneously.(4) small-molecule fluorescent probe, Organic molecule class compound.Its advantage is that synthesis is simple, fluorescent spectroscopic properties are adjustable, have prodigious development potentiality.
Existing microRNA fluorescence probe includes mainly cyanine type dye and organometallic complex two major classes.It is being imaged In living cells when RNA, two problems of generally existing：（1）Selectivity is not high, comes in particular for the DNA similar with RNA structures It says.It is difficult to which the two can be distinguished well by finding fluorescent probe；（2）Permeable membrane is poor, i.e., these probes are difficult across cell Film and nuclear membrane carry out quick RNA imagings, need longer incubation time in imaging, which limits chased after to RNA is dynamic (dynamical) Track.The features such as cyanine type dye is due to the design feature of itself simultaneously, and there are stoke shift is smaller and easy photobleaching.Organic gold Metal complex is because of the design feature per se with positive charge, it is difficult to distinguish electronegative RNA and DNA.Therefore develop other classes Other organic molecule rna probe is in demand.
For naphthoyl imide compounds due to good light stability, stoke shift is larger, is always that a kind of good fluorescence is visited Needle.But existing naphthoyl imide compounds are not yet to the report of RNA responses.We have found a kind of RNA fluorescence probes, this One probe can have the response of Fluorescence Increasing with RNA, and weaker with the response of DNA.Meanwhile this probe can be rapidly entered and be lived carefully Born of the same parents realize the fluorescence imaging to intracellular rna.
Invention content
The purpose of the present invention is to provide a kind of micromolecular compounds containing naphthalimide, are examined in RNA as fluorescence probe Application in terms of survey and imaging.
Micromolecular compound of the present invention containing naphthalimide, using naphthalimide as fluorescent parent, 4 progress amine Base is modified, and the nitrogen-atoms on naphthalimide parent is covalently attached with free amino-compound；Its structural formula is：
General molecular formula is：[R1R2N-C12NO2-R3-NH2]；In formula, R1, R2, R3For the alkyl chain containing 1-8 carbon, halogen substitution Alkyl chain or ether oxygen chain.
Experiment shows the micromolecular compound containing naphthalimide, is combined with the response of Fluorescence Increasing with RNA, but It is very weak to the response of DNA under the same terms, show that it has selectivity well in solution state, can be used as and differentiate RNA and DNA Probe, DNA interference Selective recognition RNA is excluded under solution state and in active somatic cell.
Experiment shows the micromolecular compound containing naphthalimide, in living cells, can quickly be worn in two minutes The cell membrane and nuclear membrane of active somatic cell are crossed, realizes the fluorescence imaging to cytoplasm and cell nuclear RNA, and there is good biology Compatibility.
First, the fluorescence spectrum that the micromolecular compound titrates in phosphate buffer with Bake saccharomycete RNA is investigated, is seen Fig. 1.It was found that addition of the compound with Bake saccharomycete RNA, fluorescence intensity have duration enhancing, finally it is enhanced to original 34 times, while maximum emission wavelength is blue shifted to 532 nanometers by 545 nanometers, illustrates that this compound has RNA the sound of Fluorescence Increasing It answers, and maximum emission wavelength blue shift.Fig. 2 is under the same terms, and the fluorescence titration spectrum of the compound and DNA, Fig. 2 show fluorescence Intensity also has enhancing with the addition of calf thymus DNA, but finally there was only 5 times or so of increase, and maximum emission wavelength It is not subjected to displacement with the addition of DNA.Complex chart 1 and Fig. 2 explanations：Relative to DNA, which has RNA better The difference of fluorescence response characteristic, maximum emission wavelength shows that compound interacts in different combinations with DNA and RNA.
Then, living cells imaging test is carried out, referring to Fig. 3.Experiments have shown that：The compound can pass through thin in 30 seconds After birth and nucleopore realize the dyeing to kernel, and kernel fluorescence reaches saturation, over time, cytoplasm in 60 seconds Interior dotted fluorescence gradually increases, and reaches saturation in 120 seconds.This description of test, this compound are a kind of fast short-term trainings The probe of picture.
Fig. 4 is that RNA enzyme verifies the Choice tests result of probe in the cell.Display co-cultures thin with RNA enzyme on Fig. 4 The integral fluorescence intensity of born of the same parents, cell have more obvious reduction；And the cell co-cultured with DNA enzymatic, fluorescence intensity reduce smaller.Figure 4 times display RNA living cells commercialization probe Syto and this probe tendentiousness having the same.This result is explainable, and probe more holds Easily degraded by RNA enzyme.Syto is the rna probe of commercialization, higher to the selectivity of RNA in cell.The probe of the present invention also exists There is similar selectivity in cell.
Fig. 5 is to test cell toxicity test result of the probe in cervical cancer cell with mtt assay.Cell is in experimental concentration It is incubated altogether with cervical cancer cell 6 hours, the survival rate of cell is all in 90 % or more.This illustrates that probe does not have cervical cancer cell substantially It is toxic, it was confirmed that the bio-compatibility of probe.
It is an advantage of the invention that：The micromolecular compound has the advantage that RNA is specifically responded, and can distinguish RNA and DNA. Probe can be responded selectively with RNA, Fluorescence Increasing is to original 34 times, and to DNA under the same terms in phosphate buffer Only 5 times of enhancing can distinguish RNA and DNA in solution.In living cells imaging research, this probe can be in 2 minutes quickly Into living cells, RNA rapid fluorescences imaging in living cells is realized.RNA enzyme degradation experiment demonstrates probe not only in aqueous solution With preferable selectivity, still there is preferable selectivity when cell imaging.Meanwhile this probe has HeLa cells There is higher cell survival rate, illustrates the bio-compatibility of this probe.
Description of the drawings
Fig. 1 is fluorescence titration spectrum of the probe molecule to RNA.The excitation wavelength of fluorescence spectrum is 450 nanometers, launch wavelength Capture range be 470 nanometers to 650 nanometers, a concentration of 10 micromole of probe, test condition be pH 7.2 20 mmoles The concentration of that phosphate buffer, RNA is measured with 25000 dalton of average molecular weight.
Fig. 2 is selectivity of the probe molecule to RNA.Illustrate probe under the same conditions with the fluorescence titration spectrum of DNA. The excitation wavelength of fluorescence spectrum is 450 nanometers, and the capture range of launch wavelength is 470 nanometers to 650 nanometers, the concentration of probe For 10 micromoles, test condition is 20 mMs of phosphate buffers of pH 7.2, and the concentration of DNA is with average molecular weight 25000 Er Dun is measured.
Fig. 3 is the probe living cells imaging intracellular in HeLa.Concentration and probe concentration is 5 micromoles, adds DMEM high glucose mediums It is co-cultured at 37 DEG C with HeLa cells after dissolving.488 nanometers of laser is selected, it is 515 to 565 nanometers to collect wave band.Photo To add probe and HeLa cells to co-culture 0 second, 30 seconds, 60 seconds, 90 seconds, 120 seconds fluorescence photos and photograph via bright field.
Fig. 4 is RNA enzyme degradation experiment.HeLa cells are laid on 6 orifice plates, 5 μM of probes is added to co-culture after five minutes, with ice first Alcohol fixes cell, uses RNA enzyme or DNA enzymatic to be co-cultured 4 hours with cell respectively.It shoots respectively untreated, adds DNA enzymatic to handle, add The fluorescence photo of RNA enzyme processing.488 nanometers of laser is selected, it is 515 to 565 nanometers to collect wave band.
Fig. 5 is to test cytotoxicity of the probe in cervical cancer cell with mtt assay.It is 0,1 to have separately verified concentration and probe concentration, 2.5,5,7.5,10,15,20 and 30 micromoles are incubated 6 hours cell survival rates with HeLa cells altogether.
Specific implementation mode
Below by example, the present invention is described further.
Embodiment 1：Micromolecular compound containing naphthalimide, wherein R1 = R2 = CH3, R3 = CH2CH2, R4 = Boc is denoted as probe molecule C.It is investigated in the solution to the response of RNA.
Probe molecule C is dissolved to 10 μM with the phosphate buffer of 20 mM, and Bake saccharomycete RNA solution, observation is gradually added dropwise Fluorescence spectrum be added dropwise with RNA after change.When experiment, the excitation wavelength of fluorescence spectrum is 450 nanometers, the collection model of launch wavelength Enclose is 470 nanometers to 650 nanometers.
Embodiment 2：Probe molecule C is in the solution to the selectivity of RNA
Probe molecule C is dissolved to 10 μM with the phosphate buffer of 20 mM, and calf thymus DNA solution is gradually added dropwise, and observes fluorescence Spectrum be gradually added dropwise with DNA after change.When test, the excitation wavelength of fluorescence spectrum is 450 nanometers, the collection model of launch wavelength Enclose is 470 nanometers to 650 nanometers.
Embodiment 3：Cell imagings of the probe molecule C in HeLa living cells
HeLa cell inoculations are incubated overnight in 6 orifice plates, keep it completely adherent.It is dissolved and is visited with the DMEM high glucose mediums of serum-free Needle configures the solution that ultimate density is 5 μM, and 6 orifice plates are then added and are co-cultured at 37 degree with HeLa cells, aobvious with laser co-focusing Micro mirror observe probe molecule C to HeLa cells different time staining conditions.When experiment, 488 nanometers of laser is selected.It receives The wave band of collection is 515-565 nanometers.
Embodiment 4：RNA enzyme degradation experiment verifies selectivity of the probe molecule C in cell
RNA enzyme be can special degradation of rna without degradation of dna protease, opposite DNA enzymatic can only degradation of dna and cannot degrade RNA.In this experiment, first by HeLa cell inoculations in 6 orifice plates, overnight incubation causes cell completely adherent for we.Then by 2 Milliliter ice methanol is added 6 orifice plates and is incubated altogether 5 minutes, and cell is made to fix.1 μM of 5 μM of probe or Syto are separately added into difference again Hole culture.Laser co-focusing shoots the cell of staining fluorescent probe and Syto.Then with serum free medium by RNA enzyme or DNA enzymatic is diluted to 100 μ g/ml, is separately added into different 6 orifice plates, is incubated 4 hours in 37 degree of incubators.Laser is total again Shooting is focused through RNA enzyme degradation and the fluorescent images after DNA enzymatic degradation.As a result it proves：Our fluorescence probe and commercialization RNA live cell dyes Syto have similar phenomenon.That is fluorescence signal intracellular HeLa is after RNA enzyme is incubated, than passing through DNA enzymatic incubation has more obvious fluorescence to reduce.This proves that two kinds of probes all have preferable selectivity in cell.
Embodiment 5：Cytotoxicities of the probe molecule C in cervical cancer cell
6 hours cytotoxicities in being incubated altogether with HeLa cells with mtt assay test probe molecule C.Concentration and probe concentration is tested respectively For 0,1,2.5,5,7.5,10,15,20 and 30 micromolar cell survival rate.
By the fluorescence probe that embodiment synthesizes there is the special responses of RNA, probe can be selected in phosphate buffer Property with RNA respond, Fluorescence Increasing is to original 34 times.But only has 5 times of Fluorescence Increasing to DNA under the same conditions.And this One probe can pass rapidly through RNA in cell membrane and nucleopore staining cell kernel and cytoplasm in 2 minutes, realize in living cells The rapid fluorescence of RNA is imaged, RNA enzyme degradation experiment verify this probe in the cell selective dyeing RNA the characteristics of.Together When, this fluorescence probe has preferable bio-compatibility.
Above-described embodiment is the preference of the present invention, is not intended to limit the present invention, all within the principle of the present invention, institute Any modification, variation, accommodation or the alternative made, within protection scope of the present invention.

Claims (3)

1. application of the small molecule containing naphthalimide as fluorescence probe in terms of RNA detections and imaging, this contains naphthalimide Micromolecular compound, using naphthalimide as fluorescent parent, 4 progress amido modifications, nitrogen-atoms on naphthalimide parent with Free amino-compound is covalently attached；Its structural formula is：
General molecular formula is：[R1R2N-C12NO2-R3-NH2]；In formula, R1, R2, R3Replace for alkyl chain, halogen containing 1-8 carbon Alkyl chain or ether oxygen chain.
2. application according to claim 1, which is characterized in that the micromolecular compound containing naphthalimide is tied with RNA Closing has the response of Fluorescence Increasing, but very weak to the response of DNA under the same conditions, shows that it has choosing well in solution state Selecting property can be used as the probe for differentiating RNA and DNA, and excluding DNA under solution state and in active somatic cell interferes Selective recognition RNA。
3. application according to claim 1, which is characterized in that the micromolecular compound containing naphthalimide, Neng Gou The cell membrane and nuclear membrane of active somatic cell are passed rapidly through in two minutes, realize the fluorescence imaging to cytoplasm and cell nuclear RNA, and With good bio-compatibility.
CN201810280056.5A 2018-04-01 2018-04-01 Application of the small molecule containing naphthalimide as fluorescence probe in terms of RNA detections and imaging Pending CN108409656A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110954515A (en) * 2019-12-03 2020-04-03 山西大学 1, 8-naphthalimide derivative and application thereof

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CN103113284B (en) * 2013-01-18 2015-04-22 大连理工大学 Half cyanine dye compound, preparation method and application of half cyanine dye compound
CN103265947B (en) * 2013-06-03 2016-01-20 山东大学 A kind of indolepyridinium salt fluorescent probe for RNA in viable cell and kernel imaging
CN103710021B (en) * 2013-12-12 2015-06-03 大连理工大学 Fluorescent dye with nitrobenzimidazole as RNA (ribonucleic acid) recognition group as well as preparation method and application of fluorescent dye
CN105777637B (en) * 2014-12-22 2018-10-09 中国科学院化学研究所 A kind of Mitochondrially targeted image probe of water solubility and preparation method thereof
WO2017125462A1 (en) * 2016-01-19 2017-07-27 Universiteit Gent Methods for obtaining colored or chromic substrates
CN106634964B (en) * 2016-11-09 2019-04-09 大连理工大学 Oxazine compound is preparing the application near infrared fluorescent probe

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110954515A (en) * 2019-12-03 2020-04-03 山西大学 1, 8-naphthalimide derivative and application thereof

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