CN105670334A - Glycosylation near infrared dye as well as preparation method and application thereof - Google Patents

Glycosylation near infrared dye as well as preparation method and application thereof Download PDF

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CN105670334A
CN105670334A CN201610111482.7A CN201610111482A CN105670334A CN 105670334 A CN105670334 A CN 105670334A CN 201610111482 A CN201610111482 A CN 201610111482A CN 105670334 A CN105670334 A CN 105670334A
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nir dye
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CN105670334B (en
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吕伟
陈世光
方艳芬
章雄文
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East China Normal University
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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
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B57/00—Other synthetic dyes of known constitution
    • A—HUMAN NECESSITIES
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    • A61K49/00—Preparations for testing in vivo
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    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
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    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
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    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
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    • C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom

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Abstract

The invention discloses glycosylation near infrared dye as well as a preparation method and application thereof, in particular relates to dye shown as a general formula I. The dye is finally obtained by respective synthesis of three fragments and substitution and condensation reaction. The dye has the functions of ultraviolet absorption and near-infrared emission, is easy for detection and has a derivatization site which can be used for connecting molecules with different target abilities. In addition, the dye is also provided with a fluorescent switch which can be used for connecting anoxia, pH, enzyme and redox sensitive groups, so that the effect of selectively fluorescing is realized; the dye is applied to visualized target administration (see the description).

Description

A kind of glucosyl nir dye and its preparation method and application
Technical field
The present invention relates to the technical field of fluorescent probe, in particular to a kind of can the dye molecule and its preparation method and application of derivatize.
Background technology
Cancer is the major disease of serious threat human life and social development, is the one of the main reasons of causing death, and its sickness rate is in the trend risen year by year, and serious harm people's is healthy. The prevention and therapy of cancer is the ultimate challenge that current physianthropy health faces. Early stage diagnosis with find it is the key of Therapeutic cancer, but a lot of tumor invasion is concealed, early stage non-evident sympton, and the monitor in real time of tumorigenesis, transfer still lacks the medical means of specificity simultaneously at present. The bioluminescence imaging technique that development in recent years is got up can be implemented in the pathogeny of Molecular level study cancer, real-time follow-up pathologic process, and body is not formed infringement. Imaging-PAM is combined with the activating group of high specific by fluorescence molecule, is activated by tumor tissues specifically after arriving tumor tissues, thus emitting fluorescence. The key of Imaging-PAM is to design the fluorescent probe of high specific, and fluorescence molecule is the crucial part of fluorescent probe. Therefore, find suitable fluorescence molecule and carry out designing probe for significant at Molecular level study tumour cell.
Near-infrared fluorescent refers to the fluorescence of emission wavelength at 650-900nm. Easily being absorbed by biomacromolecule compared to the fluorescence in ultraviolet-visible district, near-infrared fluorescent has without wound, and background interference is little, the feature that penetration power is strong. Therefore near-infrared fluorescent technology is often used to In vivo detection.
In recent years, many molecules with specific recognition effect, such as sugar, peptide, folic acid etc., are attempted being used for the targeted therapy of cancer. Often design a target head, it is necessary to it be connected on a quasi-medicated property dyestuff, to observe its targeting effect visually.
Nir dye research for a long time is maximum is cyanine dyes and rhodamine and derivative thereof. Different from most drug, these two kinds of dyestuffs have a quaternary amine center, and solvability is poor, and complex structure not easily synthesizes. Having document to report the nir dye (DCPO) of a kind of benzopyran structure recently, this dye emission wavelength is simple in about 680nm, fluorescence intensity height, and structure, is easy to synthesis.More importantly, identical with most medicine, such dye structure does not have quaternary ammonium salt center, relative to other dyestuffs, there is better quasi-medicated property, therefore in research, have more cogency at target. But blemish in an otherwise perfect thing, does not have the clear and definite site that can connect target head molecule in this dyestuff, therefore still need to make great efforts research, obtain a new type functional dyestuff.
Summary of the invention
It is an object of the invention to provide a kind of glucosyl nir dye, the problems such as quasi-medicated property in prior art is poor to solve, inconvenient derivatize.
It is a further object of the present invention to provide the preparation method of a kind of glucosyl nir dye.
It is still another object of the present invention to provide the application of a kind of glucosyl nir dye in visual target administration.
The object of the present invention is achieved like this:
A kind of glucosyl nir dye, feature is the structure having shown in general formula I:
In upper formula, R has the sugar of targeting, polypeptide, amino acid or folic acid target head, and hydroxyl exposed on phenyl ring is the switch of this dyestuff, it is possible to connect the group of weary oxygen, pH, enzyme or redox sensitivity, to reach the effect that fluorescence is sent out in control. Above-mentioned group comprises: nitroimidazole, disulfide linkage, thiophenol, acetal, hydrazone, Immuno toxin base. When the hydrophilic radical that target head is sugar or the sugar of PEGization, amino acid, folic acid, polypeptide, when especially size, length are suitable, this molecule can be assembled into micella in water, it is to increase solvability in its water and biological utilisation efficiency.
A preparation method for above-mentioned glucosyl nir dye, the method comprises the steps:
) Compound I I and sodiumazide in solvent DMF, DMSO or water, there is nucleophilic substitution reaction at 40-60 DEG C, after 18-24h, obtain compound III, Compound I I and sodiumazide mol ratio are 1:1.1-1.5;
) compound III and Tosyl chloride be in methylene chloride or DMF, add organic bases triethylamine, pyridine or diisopropylethylamine, reacting 18-24h at 20-40 DEG C and obtain compound IV, the mol ratio of compound III and Tosyl chloride is 1:1.1-1.5;
) compound V and chloromethyl methyl ether in solvent acetone, add mineral alkali salt of wormwood or sodium carbonate, at 20-40 DEG C, anti-18-24h obtains compound VI, and the mol ratio of compound V and chloromethyl methyl ether is 1:1.1-1.5;
) compound VI is reacted with compound IV in solvent DMF or THF, add NaH and do alkali, reacting 18-24h under room temperature and obtain compound VI I, the mol ratio of compound VI and compound IV is the mol ratio of 1:1.1-1.5, compound VI and NaH is 1:1.1-1.5;
) compound VI I is in solvent methanol, under the effect of hydrogen ion exchange resin, 20-40 DEG C of reaction 48-72h deprotection obtains compound VI II, and the consumption of ion exchange resin is 1.2-2 times of compound VI I quality;
Vi) compound VI II and compounds X is made to react in solvent acetonitrile or DCM, system adds acetic acid and piperidines, react 12-24h at 40-70 DEG C and obtain Compound I X, the mol ratio of compound VI II and compounds X is 1:1.0-1.2, acetic acid and piperidines volume ratio are 1:1-5, and acetic acid piperidines mixture and solvent volume are than being 1:20-60;
Vii) in the mixed solvent of water and Virahol, Compound I X carries out click reaction from the different compounds with alkynes base, add the DIPEA of the sodium ascorbate of Compound I X molar weight 1-10% and the copper sulfate of equimolar amount or Compound I X molar weight 1-10% and the cuprous iodide of equimolar amount, reacting 0.5-2h at 40-70 DEG C and obtain final product compound I, Compound I X is (0.8-1) from the mol ratio of the different compounds with alkynes base: 1.
The application of a kind of above-mentioned glucosyl nir dye in visual target administration.
Compared with prior art, the present invention has following useful effect:
A () the present invention provides a kind of functional nir dye newly, having one can the site of derivatize, it is possible to connect the molecule with targeting, it is achieved functional; There is " open-a close " site, fluorescence control can be realized.
B () dyestuff of the present invention, owing to not containing quaternary ammonium salt center in structure, has better quasi-medicated property; The fluorescent emission having near infrared, is more conducive to biological detection.
C glucose is also connected by () the present invention with this dyestuff, it provides several have functional new dye molecule, it is possible to absorb in the way of being different from former dyestuff and enter cell.
Accompanying drawing explanation
Fig. 1 is the uv-visible absorption spectra figure of the embodiment of the present invention 8 obtain solutions;
Fig. 2 is the fluorescence emission spectrums of the embodiment of the present invention 8 obtain solutions under 579nm exciting light;
Fig. 3 is the size distribution DLS figure of the micella obtained by the embodiment of the present invention 9;
Fig. 4 is that community's situation in Hela cell of the compounds X I of the different concns described by the embodiment of the present invention 10 is taken pictures.
Embodiment
The dyestuff of the present invention and preparation method and application describe in the following example more in detail, but embodiment is not construed as limiting the invention.
Embodiment 1
The synthesis of 1.1 compound III
2.0g (16.1mmol) Compound I I is dissolved in 20mLDMSO, adds 1.25g sodiumazide (19.2mmol) wherein, be heated to about 50 DEG C reaction 20h. Being extracted with ethyl acetate, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, and solvent is removed in underpressure distillation. Crude product obtains compound III light yellow liquid 1.54g through column chromatography (ethyl acetate: sherwood oil=1:4), receipts rate 73.3%.
1HNMR(400MHz,CDCl3) δ 3.69 (t, J=4Hz, 2H), 3.63 (t, J=4Hz, 2H), 3.55 (t, J=4Hz, 2H), 3.36 (t, J=6Hz, 2H), 2.67 (s, 1H).
Embodiment 2
The synthesis of 1.2 compound IV
1.0g (8.0mmol) compound III, pyridine 0.97mL (12.05mmol), is dissolved in 20mLDCM, adds TsCl1.8g (9.6mmol), be warming up to room temperature under ice bath, reaction 20h. DCM extracts, and dilute hydrochloric acid is washed, and washing, saturated NaCl washes, anhydrous Na SO4Drying, solvent is removed in underpressure distillation. It is light yellow liquid 1.1g that crude product obtains compound IV through column chromatography (ethyl acetate: sherwood oil=1:4), receipts rate 48.0%.
1HNMR(400MHz,CDCl3) δ 7.80 (d, J=8.0Hz, 2H), 7.35 (d, J=8.0Hz, 2H), 4.17 (t, J=5.4,4.1Hz, 2H), 3.70 (t, J=5.3,4.1Hz, 2H), 3.60 (t, J=5.0Hz, 2H), 3.32 (t, J=5.0Hz, 2H), 2.45 (s, 3H).
Embodiment 3
The preparation of 1.3 compound VI
5.0g (36.2mmol) compound V, is dissolved in 100mL anhydrous propanone, nitrogen protection, adds 6.5g (47.1mmol) potash solid in batches, finishes, and adds 3.3mL (38.7mmol) MOMCl, room temperature reaction 20h in batches. Reaction adds water after terminating, extraction into ethyl acetate, and saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, and solvent is removed in underpressure distillation. It is white solid 4.2g that crude product obtains compound VI through column chromatography (ethyl acetate: sherwood oil=1:4), receipts rate 64.2%.
1HNMR(400MHz,CDCl3) δ 6.12 (s, 2H), 6.08 5.98 (m, 1H), 5.96 (s, 1H), 5.39 (d, J=17.3Hz, 1H), 5.28 (d, J=10.5Hz, 1H), 4.65 (s, 2H), 4.52 (d, J=4.6Hz, 2H), 4.08 (d, J=11.2Hz, 2H), 3.92 (s, 2H), 3.85-3.75 (m, 8H), 2.37-2.29 (m, 4H), 1.67-1.57 (m, 4H), 1.28 (m, 24H), 0.88 (t, J=5.9Hz, 6H).
Embodiment 4
The preparation of 1.4 compound VI I
4.0g (27.4mmol) compound VI, is dissolved in 80mLDMF, nitrogen protection, under ice bath, adds 1.0g (32.9mmol) NaH in batches, finishes, stir 5min under ice bath, add compound IV in batches, room temperature reaction 20h. Reaction adds water, is extracted with ethyl acetate after terminating, and saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying, and solvent is removed in underpressure distillation. It is weak yellow liquid 3.3g that crude product obtains compound VI I through column chromatography (ethyl acetate: sherwood oil=1:8), receipts rate 50.9%.
1HNMR(400MHz,CDCl3) δ 10.35 (s, 1H), 7.80 (d, J=8.6Hz, 1H), 6.69 (d, J=8.7Hz, 1H), 6.62 (s, 1H), 5.22 (s, 2H), 4.28 4.19 (m, 2H), 3.96 3.88 (m, 2H), 3.76 (t, J=4.8Hz, 2H), 3.48 (s, 3H), 3.44 3.37 (m, 2H).
Embodiment 5
The preparation of 1.5 compound VI II
750mg compound VI I is dissolved in 3mL methyl alcohol, adds hydrogen ion exchange resin 1.5g, reaction 30h. Reaction is taken out and is filtered ion exchange resin, washed with methanol after terminating, and solvent is removed in underpressure distillation, and crude product obtains compound VI II weak yellow liquid 140mg through column chromatography (ethyl acetate: sherwood oil=1:2), receipts rate 22.0%.
1HNMR(400MHz,CDCl3) δ 10.29 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 6.95 (d, J=40.8Hz, 1H), 6.51 (dd, J=8.5,2.1Hz, 1H), 6.47 (d, J=2.1Hz, 1H), 4.26 4.18 (m, 2H), 3.95 3.88 (m, 2H), 3.80 3.71 (m, 2H), 3.46 3.36 (m, 2H).
Embodiment 6
The preparation of 1.6 Compound I X
950mg (3.78mmol) compound VI II 12mL acetonitrile dissolves, 790mg (3.78mmol) compounds X is added two-mouth bottle, after changing nitrogen, the acetonitrile solution of compound VI II is added in system, slowly add piperidines 0.6mL, Glacial acetic acid 0.6mL respectively, throw and finish, be warming up to 70 DEG C of reaction 20h. Reaction terminates rear underpressure distillation and removes solvent, adds 2mLDCM, 10mL ether, drips and adds 0.6mL trifluoroacetic acid, precipitates out red solid, takes out filter, and washing, ether are washed, and oil pump is drained, and obtaining product Compound I X is red solid 1.12g, receipts rate 67.1%.
1HNMR (400MHz, DMSO) δ 10.26 (s, 1H), 8.71 (t, J=7.9Hz, 1H), 7.93 7.83 (m, 2H), 7.70 (t, J=9.4Hz, 1H), 7.66 7.54 (m, 2H), 7.29 7.17 (m, 1H), 6.88 6.79 (m, 1H), 6.47 (d, J=6.9Hz, 2H), 4.17 (s, 2H), 3.91 (s, 2H), 3.83 3.75 (m, 2H), 3.51 3.44 (m, 2H).
Embodiment 7
The preparation of 1.7 compounds X I
Compound I X55.9mg (0.13mmol) mixes with compounds X II41.6mg (0.11mmol), add water, each 0.7mL of the trimethyl carbinol, add catalytic amount anhydrous cupric sulfate 1mg (5%), sodium ascorbate 1.3mg (5%), being warming up to 50 DEG C, after 2h, raw material reaction is complete. Solvent is removed in underpressure distillation, and crude product obtains the red waxy substance 57.8mg of compounds X I through column chromatography (methylene dichloride: methyl alcohol=10:1), receipts rate 66.6%.
1HNMR (400MHz, MeOD) δ 8.66 (d, J=8.2Hz, 1H), 7.97 (s, 1H), 7.74 (t, J=7.6Hz, 1H), 7.59 (d, J=16.0Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 7.39 (t, J=7.6Hz, 1H), 7.32 (d, J=8.5Hz, 1H), 6.85 (d, J=16.0Hz, 1H), 6.48 (s, 1H), 6.40 (d, J=8.5Hz, 1H), 6.34 (s, 1H), 4.67 (t, J=4.5Hz, 2H), 4.51 (s, 2H), 4.32 (d, J=7.7Hz, 1H), 4.11 3.97 (m, 5H), 3.88 (s, 3H), 3.77 3.57 (m, 16H), 3.31 (d, J=6.8Hz, 2H), 3.22 (t, J=8.4Hz, 1H).
Embodiment 8
Compounds X I prepared by embodiment 8, detect its absorbing wavelength and the fluorescent emission under this exciting light respectively, get compound 112.0mg, it is dissolved in 1mLTHF, take out 83.3uL, diluting with the mixed solvent (pH7.4) of 4mLDMSO:PBS damping fluid 1:1, VarianCary100 ultraviolet-visible spectrophotometer detects its absorbing wavelength, and result is such as accompanying drawing 1; Under the exciting of maximum absorption wavelength 579nm, by Hitachi's F-4500 spectrophotofluorometer detection fluorescent emission, result is such as accompanying drawing 2.
Embodiment 9
Compounds X I embodiment 8 prepared, is prepared into micella in aqueous phase, detects its particle diameter. Get compounds X I2.0mg, it is dissolved in 1.0mLTHF, get 0.1mL THF and it is diluted to 0.5mL, again with LongerpumpLSP02-18 syringe pump by this solution slowly, be at the uniform velocity injected in 5mL distilled water with 5min, stir 30min, THF is removed in underpressure distillation, use nano-zs dynamic light scattering detection size distribution, obtaining median size is 185nm, PDI=0.081, such as accompanying drawing 3.
Embodiment 10
Being inoculated in 96 orifice plates by the HELA cell being in logarithmic phase, density is 6 × 103Individual cells/well/180uL, 96 orifice plates through cell inoculation are placed on incubator (37 DEG C, 5%CO2The wet environment of concentration) middle cultivation 24h. Adding different concns embodiment 8 after 24h and prepare compounds X I, final concentration is respectively 50uM, 25uM, 12.5uM, 6.25uM, 3.125uM, and each concentration is three multiple holes. And then put into incubator and cultivate after 24h, with shifting liquid rifle sucking-off training liquid, slowly rinse each hole 3 times with PBS, at fluorescent electronic basis of microscopic observation and take pictures. Result shows, and this compound is had good absorption by cell, and fluorescence intensity reduces along with the decline of concentration, such as accompanying drawing 4. In accompanying drawing, taking pictures twice under each concentration, first time, second time was taken pictures (black background) for green glow excites down, is for twice the same visual field, to contrast in order to take pictures (white background) under white light.

Claims (5)

1. a glucosyl nir dye, it is characterised in that there is the structure shown in general formula I:
In upper formula, R has the sugar of targeting, polypeptide, amino acid or folic acid target head, and hydroxyl exposed on phenyl ring is the switch of this dyestuff, it is possible to connect the group of weary oxygen, pH, enzyme or redox sensitivity, to reach the effect that fluorescence is sent out in control.
2. glucosyl nir dye according to claim 1, it is characterised in that the group of described weary oxygen, pH, enzyme or redox sensitivity is nitroimidazole, disulfide linkage, thiophenol, acetal, hydrazone or Immuno toxin base.
3. the preparation method of glucosyl nir dye described in a claim 1, it is characterised in that the method comprises the steps:
) Compound I I and sodiumazide in solvent DMF, DMSO or water, there is nucleophilic substitution reaction at 40-60 DEG C, after 18-24h, obtain compound III, Compound I I and sodiumazide mol ratio are 1:1.1-1.5;
) compound III and Tosyl chloride be in methylene chloride or DMF, add organic bases triethylamine, pyridine or diisopropylethylamine, reacting 18-24h at 20-40 DEG C and obtain compound IV, the mol ratio of compound III and Tosyl chloride is 1:1.1-1.5;
) compound V and chloromethyl methyl ether in solvent acetone, add mineral alkali salt of wormwood or sodium carbonate, at 20-40 DEG C, anti-18-24h obtains compound VI, and the mol ratio of compound V and chloromethyl methyl ether is 1:1.1-1.5;
) compound VI is reacted with compound IV in solvent DMF or THF, add NaH and do alkali, reacting 18-24h under room temperature and obtain compound VI I, the mol ratio of compound VI and compound IV is the mol ratio of 1:1.1-1.5, compound VI and NaH is 1:1.1-1.5;
) compound VI I is in solvent methanol, under the effect of hydrogen ion exchange resin, 20-40 DEG C of reaction 48-72h deprotection obtains compound VI II, and the consumption of ion exchange resin is 1.2-2 times of compound VI I quality;
Vi) compound VI II and compounds X is made to react in solvent acetonitrile or DCM, system adds acetic acid and piperidines, react 12-24h at 40-70 DEG C and obtain Compound I X, the mol ratio of compound VI II and compounds X is 1:1.0-1.2, acetic acid and piperidines volume ratio are 1:1-5, and acetic acid piperidines mixture and solvent volume are than being 1:20-60;
Vii) in the mixed solvent of water and Virahol, Compound I X carries out click reaction from the different compounds with alkynes base, add the DIPEA of the sodium ascorbate of Compound I X molar weight 1-10% and the copper sulfate of equimolar amount or Compound I X molar weight 1-10% and the cuprous iodide of equimolar amount, reacting 0.5-2h at 40-70 DEG C and obtain final product compound I, Compound I X is (0.8-1) from the mol ratio of the different compounds with alkynes base: 1.
4. method according to claim 3, it is characterised in that the described different compound with alkynes base is: with the sugar of alkynes base, polypeptide, amino acid or folic acid target head after modification.
5. glucosyl nir dye described in a claim 1, it is characterised in that, the application of this nir dye in visual target administration.
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