CN105566938A - Mitochondrion-targeted heptamethine indocyanine dye, preparation method and application - Google Patents
Mitochondrion-targeted heptamethine indocyanine dye, preparation method and application Download PDFInfo
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- CN105566938A CN105566938A CN201610074422.2A CN201610074422A CN105566938A CN 105566938 A CN105566938 A CN 105566938A CN 201610074422 A CN201610074422 A CN 201610074422A CN 105566938 A CN105566938 A CN 105566938A
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- compound
- alkyl
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- indoles
- hydroxyl
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- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
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- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 56
- -1 methoxyl group Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 239000000975 dye Substances 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 150000002475 indoles Chemical class 0.000 claims description 24
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000001246 bromo group Chemical group Br* 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 14
- 241000370738 Chlorion Species 0.000 claims description 14
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 14
- 229940006461 iodide ion Drugs 0.000 claims description 14
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 14
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 14
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- 150000005840 aryl radicals Chemical class 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- AJZDHLHTTJRNQJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(tetrazol-1-yl)ethyl]benzamide Chemical compound N1(N=NN=C1)CCNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O AJZDHLHTTJRNQJ-UHFFFAOYSA-N 0.000 claims description 10
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
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- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 7
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- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 claims description 4
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- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 claims description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0016—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a halogen atom
-
- 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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
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Abstract
The invention relates to a mitochondrion-targeted heptamethine indocyanine dye, a preparation method and application. The mitochondrion-targeted heptamethine indocyanine dye is composed of a mitochondrion-targeted indoheptamethine chain and N-alkyl side chains of different lengths. The mitochondrion-targeted heptamethine indocyanine dye is multifunctional small organic molecules which are guided by near infrared fluorescence imaging to synchronously achieve the precise and efficient photothermal and photodynamic anti-tumor effect by taking a tumor mitochondrion as a target. The mitochondrion-targeted heptamethine indocyanine dye provides feasibility for thorough inhibition on tumor growth and prevention on drug resistance and relapse. A photosensitizer prepared from the mitochondrion-targeted heptamethine indocyanine dye better has the application and conversion prospect compared with an existing relying nanomaterail photosensitizer which is expensive and complex in preparation.
Description
Technical field
The present invention relates to biological field, particularly seven methine indoles cyanine dye and preparation method and application of a chondrioid target.
Background technology
Malignant tumour is the major disease of serious harm human health and life, has become China's population first cause of death.Resistance and the recurrence of tumour are the major reasons that tumour is difficult to capture.Think at present, improve the targeting of medicine and combine the important channel that multiple treatment means is reduction tumor drug resistance and recurrence.Tumour optical therapeutic, be considered to always a kind of local, the means of noninvasive treatment tumour.Because it only has therapeutic action to the part of photo-irradiation treatment, be expected the selectivity and the reduction toxic side effect that increase treatment.Tumour optical therapeutic, mainly comprises optical dynamic therapy (PDT) and photo-thermal therapy (PTT) two kinds of major ways.No matter be PDT, or PTT, its key all needs to depend on photosensitizers.Light energy conversion is become a large amount of active oxygens or high heat respectively by photosensitizers after absorbing luminous energy, and then causes death of neoplastic cells (Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z.Chem.Rev.2014,114,10869).A desirable photosensitizers should have efficient Phototherapy and less toxic side effect, and such photosensitizers needs to possess efficient light sensitive characteristic and the high specific to tumour cell simultaneously.In order to strengthen light sensitive characteristic, much the well-designed nano material with preparing, fits together light power photosensitizers and photo-thermal photosensitizers, synchronously realizes therapeutic action (Wang, the S. of PDT and PTT; Riedinger, A.; Li, H.; Fu, C.; Liu, H.; Li, L.; Liu, T.; Tan, L.; Barthel, M.J.; Pugliese, G.; Donato, F.D.; Abbusco, M.S.D.; Meng, X.; Manna, L.; Meng, H.; Pellegrino, T.ACSNano2015,9,1788); In order to improve the tumour-specific of photosensitizers, strategy the most frequently used at present photosensitizers and cancer target part is linked together by chemical connection process, thus utilize target part with enabling photosensitizers specificity and high efficiency on tumor cell membrane the biomarker of high expression level be combined and take in (Zhang, S.; Jia, N.; Shao, P.; Tong, Q.; Xie, X.; Bai, M.Chem.Biol.2014,21,338).Based on these two kinds of strategies, the photosensitizers of newly-developed not only incorporates PDT/PTT bimodal optical therapeutic, also has good targeting, is the hope that oncotherapy brings.But, the multi-functional photosensitizers of nano material class will face a difficult problem for a lot of essence, such as be difficult to repeatability and large-scale preparation, most of worry etc. being absorbed and be trapped in reticuloendothelial organ, long term toxicity, the multi-functional photosensitizers of most of nano material class is caused also to rest on early development stage (Chen, F.; Cai, W.Nanomedicine (Lond) 2015,10,1).Meanwhile, develop multi-functional photosensitizers by chemical connection process and may change the structure of target part, extra synthesis step and cost, these can hinder their practical application (Cheng, Z. equally; Al, Z.A.; Hui, J.Z.; Muzykantov, V.R.; Tsourkas, A.Science2012,338,903).
Plastosome is the important organelle of cells survival, and it plays central role in energy manufacture and apoptosis path.Therefore, plastosome is considered to ubcellular target spot (Thomas, the A.P. of applicable cancer therapy for a long time; Bae, B.; Kim, N.D.; Kim, S.H.; Suh, P.G.; Ryu, J.H.; Kang, B.H.J.Am.Chem.Soc.2015,137,4358).Especially because plastosome is very responsive to a large amount of active oxygens (as singlet oxygen, free radical), the mitochondrial photosensitizers of some targets is proved to be and significantly improves optical dynamic therapy effect.In addition, nearest report finds magnetic nanoparticle one being comprised lipophilic triphenylphosphine positively charged ion (TPP) group, first by tumour EPR effect, specific accumulation is in tumor tissues, and then the TPP of lipophilic cation makes it be accumulated in efficiently in the plastosome of tumour cell.But Mitochondrially targeted PDT and PTT Synergistic treatment has no relevant report.
Summary of the invention
The object of this invention is to provide seven methine indoles cyanine dyes of a chondrioid target and preparation method and application.Described seven methine indoles cyanine dyes are with tumour plastosome for target, under near-infrared fluorescence imaging guides, and the synchronous multi-functional organic molecule realizing accurately light light and heat power antitumor action efficiently.Seven methine indoles cyanine dyes of the present invention, for thorough Tumor suppression growth, prevent resistance and recurrence from providing feasibility.Adopt photosensitizers prepared by seven methine indoles cyanine dyes of the present invention, prepare compared with complicated nano material class photosensitizers with must costliness be depended at present, have more conversion and application prospect.
Realizing technical scheme of the present invention is:
One class seven methine indoles cyanine dye, it is made up of the N-alkyl group side chain of Mitochondrially targeted indoles seven methine chain and different lengths, has following general structure:
Wherein, n=1-5, R are any one in hydrogen, methyl, methoxyl group, carboxyl, carboxylate salt, sulfonic group, sulfonate, hydroxyl, aromatic base; X
-for arbitrary a kind of in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate.
An above-mentioned class seven methine indoles cyanine dye:
1) n=1 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 1;
2) n=2 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 2-3;
3) n=3 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 4-5;
4) n=4 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 6;
5) work as n=5, R is acid amides or ester derivative, and its general formula is-COXY-; Work as X=O, Y is any one in hydrogen, various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, when X is any one in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate, its structural formula is compound 7-9;
6) X=N is worked as, Y is any one in hydrogen, various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, when X is any one in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate, its structural formula is compound 10-15;
The structural formula of compound 1-15 is
The synthetic method of an above-mentioned class seven methine indoles cyanine dye, has following steps:
1) DMF is reaction reagent and solvent, pimelinketone and POCl
3there is Vilsmeimer-Haack formylation reaction, react 4 hours, synthetic compound A0 (its structure is as in reactions steps, lower same); Its cyclohexanone: POCl
3: the mol ratio of DMF is 1:5:15; Compound A-40 obtains sterling through re-crystallizing in ethyl acetate;
2) toluene is solvent, 2,3, the derivative of 3-trimethylammonium 3H indoles and bromo is under argon gas and lucifuge are protected, and the synthesis of backflow 10-20 hour, N-alkylated reaction contains 2 of different chain length or different functional end-group, 3,3-trimethylammonium 3H indoles quaternary ammonium bromine salt A1-A6; Wherein 2,3,3-trimethylammonium 3H indoles: the mol ratio of N-alkylating reagent is 1:1.2, and compd A 1-A6 obtains sterling through recrystallisation from isopropanol;
3) dehydrated alcohol is organic solvent, and under sodium acetate, anhydrous base catalysis, A0 and A1-A6, in 70 DEG C, condensation reaction occurs, and contains the compound 1-6 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis;
4) 6-bromocaproic acid is raw material, and sulfur oxychloride is acyl chlorides activating reagent and reaction solvent, and reaction 4-6 hour, after reduction vaporization removes excessive sulfur oxychloride, obtains 6-bromine caproyl chloride; Methylene dichloride is solvent, and triethylamine is acid binding agent, and 6-bromine caproyl chloride becomes ester or amides B7-B12 with the derivative (X-Y) containing hydroxyl or amino respectively; 2,3,3-trimethylammonium 3H indoles respectively with B7-B12 under argon gas and lucifuge are protected, reflux after 10-20 hour, be organic solvent again with dehydrated alcohol, under sodium acetate, anhydrous base catalysis, there is condensation reaction with A0 in 70 DEG C respectively, contain the compound 7-12 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis;
5) step 4) B7-B9 that obtains is reaction raw materials, in tetrahydrofuran aqueous solution, lithium hydroxide is alkaline hydrolysis reagent, hydrolysis methyl esters, respectively synthesis of carboxylic acid derivative B13-B15; 2; 3; 3-trimethylammonium 3H indoles respectively with B13-B15 under argon gas and lucifuge are protected; reflux after 10-20 hour; be organic solvent again with dehydrated alcohol; under sodium acetate, anhydrous base catalysis, there is condensation reaction with A0 in 70 DEG C respectively, contain seven methine indoles cyanine dye representation compound 13-15 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis.
Step 2) described bromo derivative is as in structural formula as described in n=1-4.
Step 2)-3) described different chain length or different functional end-group, refer to as n=1-4, R can be in hydrogen, various alkyl, carboxyl, carboxylate salt, sulfonic group, sulfonate, hydroxyl, aromatic base any one.
Step 4) structure of the described derivative (X-Y) containing hydroxyl or amino is, as n=5, X=O or N, Y be in structural formula compound 7-15 separately corresponding N-alkyl group side chain become the structure before ester or acid amides.
In above-mentioned 15 representation compounds, compound 5,7,8,9,10,11,12,13,14,15 be showed no synthesis report, adopt above-mentioned preparation method's step 1)-5) method synthesis above-mentioned seven methine indoles cyanine dyes.
An above-mentioned class seven methine indoles cyanine dye is in the application preparing photosensitizers in optical therapeutic tumour.
Above-mentioned photosensitizers, refers to that such seven methines indoles cyanine dye molecule has near-infrared fluorescence imaging, the Mitochondrially targeted accumulation of tumour and photosensitive antitumor action.
Seven methine indoles cyanine dyes are the structure of different chain length or different functional end-group, have mitochondrial target.
Described optical therapeutic tumour, refers to tumour cell plastosome for target, near-infrared fluorescence imaging guide and 650-900nm single light source laser radiation under, realize accurately location and synchronously realize photo-thermal and Photodynamic therapy tumour cell.
Seven methine indoles cyanine dyes of the present invention are small molecules of the N-alkyl group side chain containing different chain length, different functional end-group, have near-infrared fluorescent, a multifunction activity such as the Mitochondrially targeted accumulation of tumour, light light and heat power Synergistic treatment kill and wound.The experimental result of applicant shows, seven prepared methine indoles cyanine dyes, can be used for tumour PDT and PTT Synergistic treatment.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.
Accompanying drawing explanation
Fig. 1 is the external photoinduction ramp case of 1-15 compound in the embodiment of the present invention 9;
Fig. 2 is that in the embodiment of the present invention 10,1-15 compound generates situation at the postradiation singlet oxygen of near-infrared laser;
Fig. 3 is the living imaging of animal-transplanted tumor model;
In the 1-15 compound of Fig. 4 embodiment of the present invention 12, representation compound 1,2,5,6,7, No. 10 compounds accumulate the plastosome in tumour cell;
Fig. 5 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 1 (n=1);
Fig. 6 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 2 (n=2);
Fig. 7 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 5 (n=3);
Fig. 8 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 6 (n=4);
Fig. 9 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 7 (n=5);
Figure 10 is the photoinduction cell killing effect that in the embodiment of the present invention 13, CCK-8 detects representation compound 10 (n=5).
Specific embodiment
The reagent adopted in embodiment and instrument:
Except reagent methylene dichloride, methyl alcohol, DMF, POCl
3, triethylamine need beyond distillation purifying and drying treatment, the chemical reagent involved by other and solvent are bought in the Reagent Company such as sigma-aldrich or Aladdin and are directly used;
Institute carries out under responding and being all in argon gas and lucifuge protective condition, and silica gel thin-layer chromatography monitoring is to reacting end.
The High Performance Thin Layer Chromatography silica-gel plate (model C F-254) that silica gel thin-layer chromatography uses Yantai City's Zhifu Huang business silica gel development experiments factory to produce, under adopting 254nm fluorescence, functional group's developer such as direct-detection or employing phospho-molybdic acid, triketohydrindene hydrate, tetrabromo-mcresolsulfonphthalein, iodine colour developing detects.
Column chromatography is used for the final purifying of dye molecule, adopts the chromatographic silica gel (10-40 μ) that Yantai City's Zhifu Huang business silica gel development experiments factory produces.Chromatography organic solvent is analytical pure, and through the dry process of overweight evaporate to dryness.
All compounds
1hNMR and
13the MercuryPlus-400 nuclear magnetic resonance spectrometer that CNMR is produced by Varian company of the U.S. measures, and mark in TMS does, without specified otherwise, all uses CDCl
3make solvent, δ value unit is ppm.
Mass spectrum is measured by HP5989A type mass spectrograph, and IR is measured by TestscanSchimadzuFTIR8000series.
Near-infrared fluorescence imaging adopts Kodak imaging system In-VivoFXProfessionalImagingSystem (NewHaven, CT).
Embodiment 1
The synthesis of compound A-40
By in 35mL dry methylene chloride and the solution instillation 80mL dry methylene chloride of 37mL phosphorus oxychloride and the mixed solution of N, N-dimethyl formyl (1:1, v/v) under ice bath.At maintaining 0 DEG C, 10g (0.10mol) pimelinketone is dropwise added to reaction solution, is then slowly warming up to back flow reaction 3h.Stopped reaction, ice-water bath cools, and is poured in 200g trash ice by reaction solution in batches.A large amount of red solid is separated out.Filtration under diminished pressure, washing is to yellow on a small quantity in batches with freezing acetone for solid, and vacuum drains to obtain crude product, obtains yellow solid (compound A-40) 12.86g, yield: 73%, fusing point: 130-132 DEG C with acetone recrystallization.
Embodiment 2
The preparation of compd A 1-A6:
Get 3.84g (2.41 × 10
-2mol) 2,3,3-trimethylammonium-3H-indoles are in 100ml single neck round bottom bottle, add 2.89 × 10
-2the each bromo organism of mol, add 30ml toluene, 12h is reacted at 110 DEG C, sampling TLC monitoring reaction (methylene dichloride: methyl alcohol=15:1), display raw material reaction is complete, revolve and steam except toluene, obtain reddish-brown thick liquid, obtain reddish-brown thick liquid A1-A6 with the rough recrystallization of dichloromethane-ether.Product is not purified directly carries out next step reaction.
Embodiment 3
The preparation of compound 1-6:
Get 7.75 × 10
-3molA1-A6 adds in 100ml single neck round bottom bottle, adds 0.67g (3.87 × 10
-3mol) A0, adds 0.66g (7.75 × 10
-3mol) sodium acetate, adds 40ml diacetyl oxide, stirs, react 1h at 70 DEG C, sampling TLC monitoring reaction (methylene dichloride: methyl alcohol=15:1), display raw material reaction is complete, reaction solution is transferred in separating funnel, washs by saturated NaCl solution, anhydrous Na SO
4drying, filter, concentrating under reduced pressure obtains reddish-brown liquid, obtains red brown solid with the rough recrystallization of dichloromethane-ether, and column chromatography obtains dark green solid compound 1-6:
1(11％):
1HNMR(400Hz,DMSO-d
6)δ:8.26(d,J＝14.4Hz,2H),7.94(d,J＝8.0Hz,4H),7.69(d,J＝7.6Hz,2H),7.40(t,J＝7.2Hz,8H),7.33-7.28(m,2H),6.38(d,J＝14.0Hz,2H),5.63(s,4H),2.53-2.50(m,4H),1.73(s,14H)；HRMS[M-Br]
+:calc.723.2984,measured723.2882.
2(82％):
1HNMR(400Hz,DMSO-d
6)δ:8.26(d,J＝14.0Hz,2H),7.65(d,J＝7.2Hz,2H),7.49-7.41(m,4H),7.29(t,J＝7.2Hz,2H),6.35(d,J＝14.0Hz,2H),4.21(t,J＝6.4Hz,4H),2.72(t,J＝5.2Hz,4H),1.87-1.84(m,2H),1.80-1.75(m,4H),1.67(s,12H),0.97(t,J＝7.6Hz,6H)；HRMS[M-Br]:calc.539.3188,measured539.3172.
3(25％):
1HNMR(400Hz,DMSO-d
6)δ:12.60(s,2H),8.25(d,J＝14.0Hz,2H),7.63(d,J＝6.4Hz,2H),7.46-7.40(m,4H),7.30-7.26(m,2H),6.43(d,J＝14.0Hz,2H),4.44(t,J＝6.4Hz,4H),2.81-2.72(m,8H),1.85(s,2H),1.66(s,12H)；HRMS[M-Br]
+:calc.599.2671,measured599.2587.
4(21％):
1HNMR(400Hz,DMSO-d
6)δ:12.36(s,2H),8.27(d,J＝14.0Hz,2H),7.64(d,J＝7.2Hz,2H),7.50(d,J＝8.0Hz,2H),7.29(t,J＝7.4Hz,2H),6.43(d,J＝14.0Hz,2H),4.21(t,J＝6.4Hz,4H),2.73(s,4H)，2.46(t,J＝6.8Hz,4H),1.94-1.84(m,6H),1.68(s,12H)；HRMS[M-Br]
+:calc.627.2984,measured627.3036.
5(22％):
1HNMR(400Hz,DMSO-d
6)δ:8.18(d,J＝14.0Hz,2H),7.92-7.87(m,4H),7.64(d,J＝7.2Hz,2H),7.48(d,J＝8.0Hz,2H),7.41(t,J＝7.6Hz,2H),7.29(t,J＝7.6Hz,2H),6.98-6.93(m,4H),6.25(d,J＝14.0Hz,2H),4.37(s,4H),4.12(d,J＝4.8Hz,4H),2.32(s,4H),2.22(s,4H),1.66(s,12H),1.55-1.45(m,4H)；HRMS[M-Br]
+:calc.811.3508,measured811.3359.
6(10％):
1HNMR(400Hz,DMSO-d
6)δ:8.27(d,J＝14.0Hz,2H),7.63(d,J＝7.2Hz,2H),7.47-7.41(m,4H),7.29(t,J＝7.0Hz,2H),6.33(d,J＝14.0Hz,2H),4.23(t,J＝6.4Hz,4H),2.71(d,J＝5.6Hz,4H),2.29(t,J＝7.2Hz,4H),1.88-1.84(m,2H),1.80-1.72(m,4H),1.67-1.57(m,16H)；HRMS[M-Br]
+:calc.655.3297,measured655.3312.
Embodiment 4
The preparation of compd B 7-B12:
1g (5.13 × 10 is added in 50ml single neck round bottom bottle
-3mol) 6-bromocaproic acid, 1ml thionyl chloride, at 50 DEG C, reacting by heating is emerged to bubble-free, boils off excessive thionyl chloride, obtains yellowish brown liquid 1.05g.Separately be dissolved in anhydrous methylene chloride by the arene compound containing hydroxyl or amino, add triethylamine, under external ice bath, in controlling, temperature is less than-5 DEG C, drips 6-bromine caproyl chloride, and temperature 0 DEG C in controlling, drips and finish, and stirring at room temperature reaction is spent the night, and TLC monitors reaction.After having reacted, washed by reaction solution saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains brown viscous liquid, and column chromatography obtains B7-B12:
B7(34％)：1HNMR(400MHz,CDCl3)δ:8.07(d,J＝8.5Hz,3H),7.17(d,J＝8.5Hz,2H),3.92(s,3H),3.44(t,J＝6.7Hz,2H),2.61(t,J＝7.4Hz,2H),2.01–1.87(m,2H),1.86–1.72(m,2H),1.68–1.46(m,2H).\
B8(45％)：
1HNMR(400MHz,CDCL
3)δ:7.99(d,J＝8.7Hz,2H),7.18(d,J＝8.7Hz,2H),3.44(t,J＝6.7Hz,2H),2.71-2.55(m,5H),2.13-1.86(m,2H),1.86-1.74(m,2H),1.58(m,,2H).
B9(21％)：
1HNMR(400MHz,CDCL
3)δ:7.61(d,J＝8.8Hz,2H),7.61(d,J＝8.8Hz,2H),7.30(d,J＝8.8Hz,2H),7.13(s,1H),3.44(t,J＝6.8Hz,2H),2.36(t,J＝7.2Hz,2H),1.94-1.87(m,2H),1.60-1.49(m,2H).
B10(33％)：
1HNMR(400MHz,CDCl
3)δ:6.08(d,J＝5.5Hz,1H),4.61(t,J＝7.2Hz,1H),3.76(s,3H),3.41(t,J＝6.7Hz,2H),2.24(t,J＝7.5Hz,2H),1.96-1.81(m,2H),1.76-1.56(m,2H),1.56-1.36(m,5H).
B11(37％)：
1HNMR(400MHz,CDCL
3)δ:6.07(s,1H),3.71(s,3H),3.52(dd,J＝11.6,5.8Hz,2H),3.41(t,J＝6.7Hz,2H),2.60(t,J＝5.8Hz,2H),2.20(t,J＝7.5Hz,2H),1.99-1.57(m,4H),1.46(m,2H).
B12(28％)：
1HNMR(400MHz,CDCl3)δ:6.03(d,J＝8.2Hz,1H),4.62(dd,J＝8.6,5.0Hz,1H),3.74(s,3H),3.41(t,J＝6.7Hz,2H),2.26(t,J＝7.4Hz,2H),1.97-1.79(m,3H),1.76-1.55(m,2H),1.55-1.42(m,3H),1.42-1.09(m,1H),0.92(dd,J＝12.1,7.1Hz,6H).
Embodiment 5
The preparation of compound B-11 3-B15:
10mLTHF/H is added in reaction flask
2o (V/V=4/1), the 1mMLiOH aqueous solution, under then reaction flask being placed in ice bath, in controlling, temperature is at 0 DEG C, adds 1mM compound B-11 0-B12, insulated and stirred reaction 3h, TLC monitoring reaction.Add 1MHCl after having reacted and reaction solution is adjusted to PH=1, be extracted with ethyl acetate, concentrating under reduced pressure obtains crude pale yellow liquid, obtains B13-B15 with Diethyl ether recrystallization:
B13(25％)：
1HNMR(400MHz,CDCl
3)δ:9.35(s,1H),6.22(d,J＝6.9Hz,1H),4.59(p,J＝7.1Hz,1H),3.41(t,J＝6.7Hz,2H),2.28(t,J＝7.5Hz,2H),1.85(m,2H),1.68(m,2H),1.49(m,5H).
B14(28％)：
1HNMR(400MHz,CDCL
3)δ:6.25(s,1H),3.53(dd,J＝11.6,5.8Hz,2H),3.40(t,J＝6.7Hz,2H),2.60(t,J＝5.8Hz,2H),2.20(t,J＝7.5Hz,2H),1.98-1.79(m,2H),1.77-1.58(m,2H),1.58-1.38(m,2H).
B15(16％)：
1HNMR(400MHz,CDCL
3)δ:6.25(s,1H),3.53(dd,J＝11.6,5.8Hz,2H),3.40(t,J＝6.7Hz,2H),2.60(t,J＝5.8Hz,2H),2.20(t,J＝7.5Hz,2H),1.98-1.79(m,2H),1.77-1.58(m,2H),1.58-1.38(m,2H).
Embodiment 6
The preparation of compound 7-12:
Method with reference to synthesis A1-A6: get 24mM2,3,3-trimethylammonium-3H-indoles, in 100ml single neck round bottom bottle, adds 24mM each bromo organism B7-B12, adds 30ml toluene, 12h is reacted at 110 DEG C, sampling TLC monitoring reaction (methylene dichloride: methyl alcohol=15:1), display raw material reaction is complete, revolves and steams except toluene, obtain reddish-brown thick liquid, obtain each indoles quaternary ammonium salt intermediate with the rough recrystallization of dichloromethane-ether.Not purified, get respective indoles quaternary ammonium salt intermediate (about 1mM) and add in 100ml single neck round bottom bottle, add 0.5mMA0, add 1mM sodium acetate, add 15ml diacetyl oxide, stir, react 4-6h at 70 DEG C, display raw material reaction is complete.Reaction solution is transferred in separating funnel, washs by saturated NaCl solution, anhydrous Na SO
4drying, filter, concentrating under reduced pressure obtains reddish-brown liquid, obtains red brown solid with the rough recrystallization of dichloromethane-ether, and column chromatography obtains dark green solid compound 7-12:
7(10％):
1HNMR(400MHz,CDCl
3)δ:8.05(d,J＝8.8Hz,2H),7.42-7.10(m,16H),6.28(d,J＝8.8Hz,2H),4.28(m,4H),3.91(s,6H),2.70(m,4H),2.63(m,4H),1.92(m,6H),1.86(m,4H),1.66(s,12H),1.63(m,4H)；HRMS[M-Br]
+:calc.951.4346,measured951.4190.
8(9％):
1HNMR(400MHz,CDCl
3)δ:8.33(d,J＝14.0Hz,2H),7.98-7.08(m,16H),6.35(d,J＝14.0Hz,2H),4.32(t,J＝14Hz,4H),2.76(t,J＝15.6Hz,4H),2.65(t,J＝14.4Hz,4H),2.60(s,6H),1.92(m,6H),1.86(m,4H),1.71(s,12H),1.66(m,4H)；HRMS[M-Br]
+:calc.919.4447,measured919.4434.
9(15％):
1HNMR(400Hz,DMSO-d
6)δ：8.25(d,J＝14.0Hz,2H),8.20(s,4H),7.64(d,J＝7.2Hz,2H),7.48-7.41(m,4H),7.29(t,J＝7.2Hz,2H),6.33(d,J＝14.0Hz,2H),4.25(s,4H),2.67(t,J＝7.0Hz,8H),1.80-1.76(m,10H),1.67(s,12H),1.56(s,4H)；HRMS[M-Br]
+:calc.1590.8035,measured1590.8727.
10(19％):
1HNMR(400MHz,CDCl
3)δ:8.33(d,J＝14.0Hz,2H),7.41-7.04(m,10H),6.72(d,J＝7.2Hz,2H),6.20(d,J＝13.9Hz,2H),4.50(m,2H),4.14(m,4H),3.71(s,6H),2.72(m,4H),2.50(t,4H),2.00(m,2H),1.84(m,4H),1.88(m,4H),1.78(m,4H),1.72(s,12H),1.52(m,6H),1.46(m,4H)；HRMS[M-Br]
+:calc.853.4665,measured853.4528.
11(30％):
1HNMR(400MHz,CDCl
3)δ:8.44(d,J＝14.0Hz,2H),7.42–7.16(m,10H),6.18(s,J＝14.0Hz,2H),4.11(m,4H),3.67(s,6H),3.50(m,4H),2.72(m,4H),2.60(t,J＝6.7Hz,4H),2.32(t,J＝7.2Hz,4H),1.99(m,2H),1.93(m,4H),1.80(m,4H),1.72(s,12H),1.52(m,4H)；HRMS[M-Br]
+:calc.853.4665,measured853.4522.
12(19％):
1HNMR(400MHz,CDCl
3)δ:8.34(d,J＝14.0Hz,2H),7.39-7.14(m,8H),6.60(d,2H),6.23(d,J＝14.0Hz,2H),4.54(s,2H),4.18(t,J＝6.9Hz,4H),3.72(s,6H),2.74(m,4H),2.39(m,4H),2.10(m,2H),1.84(m,4H),1.79(s,12H),1.62(m,4H),1.51(m,4H),1.44(m,4H),1.27(m,2H),0.92(m,12H)；HRMS[M-Br]
+:calc.937.5604,measured937.5485.
Embodiment 7
The preparation of compound 13-15:
Method with reference to synthesis 7-12: get 10mM2,3,3-trimethylammonium-3H-indoles, in 100ml single neck round bottom bottle, adds 10mM each bromo organism B13-B15, adds 30ml toluene, 12h is reacted at 110 DEG C, sampling TLC monitoring reaction (methylene dichloride: methyl alcohol=15:1), display raw material reaction is complete, revolves and steams except toluene, obtain reddish-brown thick liquid, obtain each indoles quaternary ammonium salt intermediate with the rough recrystallization of dichloromethane-ether.Not purified, get respective indoles quaternary ammonium salt intermediate (about 2mM) and add in 100ml single neck round bottom bottle, add 1mMA0, add 2mM sodium acetate, add 30ml diacetyl oxide, stir, at 70 DEG C, react 4-6h.Reaction solution is transferred in separating funnel, washs by saturated NaCl solution, anhydrous Na SO
4drying, filtration under diminished pressure concentrates, and column chromatography obtains dark green solid compound 13-15:
13(8％):
1HNMR(400MHz,CDCl
3)δ:8.25(d,J＝13.2Hz,2H),7.75(d,2H),7.65-7.37(m,8H),6.33(d,J＝13.8Hz,2H),4.15(m,4H),4.00(s,2H),2.61(m,4H),2.11(m,4H),1.85(s,2H),1.70(s,12H),1.54(s,6H),1.45(m,4H),1.21(m,8H)；HRMS[M-Br]
+:calc.825.4352,measured825.4265.
14(37％):
1HNMR(400MHz,CDCl
3)δ:8.34(d,2H),7.37-6.99(m,10H),6.16(d,2H),4.03(m,4H),3.86(m,4H),3.48(m,4H),2.69(m,4H),2.48(m,4H),2.21(m,2H),1.96(m,4H),1.82(m,4H),1.72(s,12H),1.47(m,4H)；HRMS[M-Br]
+:calc.825.4352,measured825.4289.
15(7％):
1HNMR(400MHz,CDCl
3)δ:10.26(s,2H),8.22(d,J＝13.4Hz,2H),7.75-7.28(m,10H),6.32(d,J＝13.4Hz,2H),4.22(m,4H),4.14(m,2H),2.84(m,4H),2.13(m,4H),1.74(m,4H),1.64(s,12H),1.54(m,4H),1.34(m,4H),1.24(m,4H),1.19(m,2H),0.99(m,2H),0.86(m,12H)；HRMS[M-Br]
+:calc.909.5291,measured909.5220.
Embodiment 8
The near-infrared fluorescent characteristic of compound 1-15
On ten thousand/balance, accurate weighing compound 1-15 sample, is made into the DMSO solution of 10mM, for subsequent use.During test, first get 2 these solution of μ L in the brown volumetric flask of 10mL with accurate liquid-transfering gun, then use methyl alcohol and serum-dilution to scale respectively, namely obtain the dye solution of 2 μMs.Maximum absorption spectrum and emmission spectrum measure by ShimadzuUV-3600 ultraviolet infrared spectrophotometer and VarianCaryEclipseFluorometer fluorescence spectrophotometer respectively.With the molar absorptivity of Law of Lambert-Beer computerized compound.Calculation formula is A=ε ab, and in formula, A represents absorption intensity, and ε represents molar extinction coefficient, and a is the concentration (unit is mol/L) of compound, and b is the thickness (unit is cm) of quartz cell.Test result shows, the maximum absorption wavelength of all compounds and emission wavelength are all at near-infrared region (780-820nm), and molar absorptivity, at 99000-300000, has more excellent near-infrared fluorescent characteristic.
Embodiment 9
Calorigenic effect under compound 1-15 illumination:
Each for compound 1-15 personal dimethyl sulfoxide (DMSO) (DMSO) is mixed with the storage liquid of 10mM concentration, is placed in-20 DEG C and keeps in Dark Place.From the storage liquid of the 1-15 compound of above configuration each draw 2 μ l be dissolved in 2ml containing in the DMEM substratum of 10%FBS (with the DMEM substratum of blank 10%FBS in contrast), be mixed with the detection liquid of 10 μMs, add respectively in 24 porocyte culture plates.Culture plate is placed in 808nm, 1.5W/cm
2near-infrared laser under each hole illuminated 5 minutes respectively, per minute is monitored and records the change of temperature simultaneously, the results are shown in Figure 1.Found that 1-15 compound is in the intensification effect (Δ T=5-28 DEG C) accepting all to show after near-infrared laser irradiates in various degree.Particularly, the intensification effect of 2 and 5 these two compounds is remarkable especially: be subject to after according to 1-2 minute, solution temperature is (and being significantly higher than the temperature that the Indocyanine Green (ICG) of non-tumor-targeting that clinical approval uses produces) more than 50 DEG C, shows that this compounds synthesized by us has more excellent photo-thermal antitumor properties.
Embodiment 10
The generation of singlet oxygen under compound 1-15 illumination:
In 2ml, the various cyanine dye aqueous solution of 10 μMs, add the SOSG probe (this probe is prepared with 100% methanol solution) that concentration is 1.5 μMs, the methanol content in whole solution is 2%.Then, after fully being mixed by above-mentioned solution, their (808nm, 1.5W/cm are given
2) near-infrared laser, irradiate 5 minutes.After irradiation terminates immediately by solution collection in cuvette, then on near-infrared fluorescent spectrophotometer, promptly detect the fluorescent emission POP of solution at 500-600nm.(be that the light source activation SOSG of 494nm can obtain its maximum emission peak at 530nm place with wavelength, quantize the generation of singlet oxygen with the fluorescence intensity at this emission peak place.As Fig. 2 display, found that with blank water for contrasting, 1-15 chemical combination, accepting all can produce a large amount of singlet oxygens after near-infrared laser irradiates, provides feasibility for realizing photodynamic therapy.
Embodiment 11
The preferential Accumulation of compound 1-15 tumour:
Utilize rat dermal stem cell vicious transformation and come sarcoma cell strain (rTDMC, early stage is set up acquisition in this laboratory; Biomaterials2010,31,9535; Biomaterials2012,33,2230) establish SD subcutaneous rat lotus knurl model.These tumor-bearing rats are given the 1-15 compound (often kind of a compound adopts 3 tumor-bearing rats) of 0.4mg/kg respectively through tail vein, utilize small animal living body imaging system (Kodak, New after 24h
Haven, CT) carry out near-infrared fluorescence imaging.By the living imaging (Fig. 3) to animal-transplanted tumor model, after experimental result shows tail intravenously administrable 24h, compound 1,2,5,6,7,8,10,11,13 shows the preferential Accumulation of good tumour.Fluorescence intensity ratio (the contrastindex obtaining tumour and adjacent tissue is calculated further by imaging software (KodakMIsoftware5.0.1), signal to noise ratio), as table 1. result shows, fluorescence intensity ratio (contrastindex) is all greater than 2.5.(P.Natl.Acad.Sci.USA2007,104,7893-7898) is when the fluorescence contrast value (contrastindex) of tumour and surrounding tissue is more than 2.5 according to the literature, is namely considered to have cancer target accumulation.Therefore, compound 1,2,5,6,7,8,10,11,13 has the preferred Accumulation of tumour, and for tumour animal scanning, border are distinguished, and the precise optical treatment etc. under imaging guiding has great importance.
The target evaluation of table 1 compound 1-15 in subcutaneous transplantation knurl rat (the fluorescence intensity ratio of tumor locus and adjacent tissue)
| Compounds | 1 | 2 | 3 | 4 | 5 |
| Contrast index | 8.73±2.34 | 5.44±0.79 | 2.06±0.21 | 1.43±0.43 | 9.17±1.54 |
| Compounds | 6 | 7 | 8 | 9 | 10 |
| Contrast index | 2.74±0.27 | 2.88±0.29 | 2.92±0.44 | 1.38±0.36 | 6.44±1.23 |
| Compounds | 11 | 12 | 13 | 14 | 15 |
| Contrast index | 2.74±0.31 | 1.07±0.10 | 6.33±1.89 | 2.15±0.19 | 2.41±0.71 |
Embodiment 12
Tumour plastosome is located:
Tumor cell line selects human lung carcinoma cell line A549 (purchased from American ATCC company), cultivates based on 37 DEG C, 5%CO with the DMEM containing 10% foetal calf serum
2cultivate under condition, change a nutrient solution every other day.Get well-grown, reach 70-80% merge cell, digest centrifugal after be inoculated in the culture dish of 35mm confocal microscopy, overnight incubation.Next day discards substratum, adds the 1-15 compound that concentration is 5 μMs, volume is 1ml in culture dish respectively, in 37 DEG C, and 5%CO
220 minutes are hatched under condition.Discard dye liquor, with PBS damping fluid rinsing three times, take concentration as the mitochondrial probe Mito-traker incubated cell of 1:6000, act on 15 minutes.Discard dye liquor, to observe the overlapping cases of the fluorescent signal of 1-27 compound and the fluorescent signal of Mito-traker after PBS damping fluid rinsing three times under Laser Scanning Confocal Microscope.Result shows, in n=1-5,1-15 compound, respective representation compound 1,2,5,6,7,10 efficiently can be absorbed by tumour cell under culture condition in vitro, demonstrates very strong red fluorescent; Red fluorescent can overlap completely with from mitochondrial green florescent signal, after confirming that compound enters cell, is mainly distributed in cell mitochondrial (Fig. 4).Embodiment 13
External photoinduction cell toxicity test
By A549 cell with every hole 3x10
3quantity is inoculated into overnight incubation in 96 orifice plates.Then in cell, add the compound 1-15 of different concns respectively and act on 24 hours.Following cell is given or does not give near-infrared laser (808nm, 1.5W/cm
2) irradiate, continue 5 minutes.Through the cultivation of 24 hours after having irradiated, the relative reactivity of cell has been obtained by by CCK-8 testing inspection.From 15 compounds, as n=1-5, every group selection 1-2 representative structure 1,2,5,6,7,10 does result to be shown.Their CCK-8 detected result respectively as shown in fig. 5-10.Result shows, the fluorescent small molecule of our this chondrioid target has the optics lethal effect of significant concentration dependent.
The foregoing is only preferred embodiment of the present invention, and be not used to limit substantial technological context of the present invention, substantial technological content of the present invention is broadly defined in the right of application, any technology entities that other people complete or method, if with application right define identical, also or a kind of change of equivalence, be all covered by being regarded as among this right.
Claims (9)
1. a class seven methine indoles cyanine dye, is characterized in that being, it is made up of the N-alkyl group side chain of Mitochondrially targeted indoles seven methine chain and different lengths, has following general structure:
Wherein, n=1-5, R are any one in hydrogen, methyl, methoxyl group, carboxyl, carboxylate salt, sulfonic group, sulfonate, hydroxyl, aromatic base; X
-for arbitrary a kind of in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate.
2. a class seven methine indoles cyanine dye according to claim 1, is characterized in that:
1) n=1 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 1;
2) n=2 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 2-3;
3) n=3 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 4-5;
4) n=4 is worked as, R is hydrogen, any one in various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, X be in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate arbitrary a kind of time, its structural formula is compound 6;
5) work as n=5, R is acid amides or ester derivative, and its general formula is-COXY-; Work as X=O, Y is any one in hydrogen, various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, when X is any one in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate, its structural formula is compound 7-9;
6) X=N is worked as, Y is any one in hydrogen, various alkyl, carboxyl, sulfonic group, hydroxyl, amino, aryl radical, when X is any one in iodide ion, chlorion, bromide anion, alkyl azochlorosulfonate, tetrafluoroborate, perchlorate, its structural formula is compound 10-15;
The structural formula of compound 1-15 is
3. the synthetic method of the class seven methine indoles cyanine dye described in claim 1 or 2, is characterized in that there are following steps:
1) DMF is reaction reagent and solvent, pimelinketone and POCl
3there is Vilsmeimer-Haack formylation reaction, react 4 hours, synthetic compound A0 (its structure is as in reactions steps, lower same); Its cyclohexanone: POCl
3: the mol ratio of DMF is 1:5:15; Compound A-40 obtains sterling through re-crystallizing in ethyl acetate;
2) toluene is solvent, 2,3, the derivative of 3-trimethylammonium 3H indoles and bromo is under argon gas and lucifuge are protected, and the synthesis of backflow 10-20 hour, N-alkylated reaction contains 2 of different chain length or different functional end-group, 3,3-trimethylammonium 3H indoles quaternary ammonium bromine salt A1-A6; Wherein 2,3,3-trimethylammonium 3H indoles: the mol ratio of N-alkylating reagent is 1:1.2, and compd A 1-A6 obtains sterling through recrystallisation from isopropanol;
3) dehydrated alcohol is solvent, and under sodium acetate, anhydrous base catalysis, A0 and A1-A6, in 70 DEG C, condensation reaction occurs, and contains the compound 1-6 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis;
4) 6-bromocaproic acid is raw material, and sulfur oxychloride is acyl chlorides activating reagent and reaction solvent, and reaction 4-6 hour, after reduction vaporization removes excessive sulfur oxychloride, obtains 6-bromine caproyl chloride; Methylene dichloride is solvent, and triethylamine is acid binding agent, and 6-bromine caproyl chloride becomes ester or amides B7-B12 with the derivative (X-Y) containing hydroxyl or amino respectively; 2,3,3-trimethylammonium 3H indoles respectively with B7-B12 under argon gas and lucifuge are protected, reflux after 10-20 hour, be organic solvent again with dehydrated alcohol, under sodium acetate, anhydrous base catalysis, there is condensation reaction with A0 in 70 DEG C respectively, contain the compound 7-12 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis;
5) step 4) B7-B9 that obtains is reaction raw materials, in tetrahydrofuran aqueous solution, lithium hydroxide is alkaline hydrolysis reagent, hydrolysis methyl esters, respectively synthesis of carboxylic acid derivative B13-B15; 2; 3; 3-trimethylammonium 3H indoles respectively with B13-B15 under argon gas and lucifuge are protected; reflux after 10-20 hour; be organic solvent again with dehydrated alcohol; under sodium acetate, anhydrous base catalysis, there is condensation reaction with A0 in 70 DEG C respectively, contain seven methine indoles cyanine dye representation compound 13-15 of the N-alkyl group side chain of different chain length or different functional end-group through silica gel column chromatography synthesis.
4. method according to claim 3, is characterized in that: step 2) described bromo derivative is as in structural formula as described in n=1-4.
5. method according to claim 3, it is characterized in that: step 2)-3) described different chain length or different functional end-group, refer to as n=1-4, R can be in hydrogen, various alkyl, carboxyl, carboxylate salt, sulfonic group, sulfonate, hydroxyl, aromatic base any one.
6. method according to claim 3, it is characterized in that: step 4) structure of the described derivative (X-Y) containing hydroxyl or amino is, as n=5, X=O or N, Y be in structural formula compound 7-15 separately corresponding N-alkyl group side chain become the structure before ester or acid amides.
7. the class seven methine indoles cyanine dye described in claim 1 or 2 is preparing the photosensitive application in optical therapeutic tumour.
8. application according to claim 7, is characterized in that: the different chain length of seven methine indoles cyanine dyes or the structure of different functional end-group, have mitochondrial target.
9. application according to claim 7, it is characterized in that: described optical therapeutic tumour, refer to tumour cell plastosome as target, near-infrared fluorescence imaging guide and 650-900nm single light source laser radiation under, realize accurately location and synchronously realize photo-thermal and Photodynamic therapy tumour cell.
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| CN109054428A (en) * | 2018-11-01 | 2018-12-21 | 北京天罡助剂有限责任公司 | A kind of preparation method of near-infrared cyanine dye |
| CN110357899A (en) * | 2019-09-06 | 2019-10-22 | 中国科学院兰州化学物理研究所 | A kind of traceable antitumor podophyllotoxin derivative and its preparation and application |
| CN111592482A (en) * | 2020-05-15 | 2020-08-28 | 江南大学 | PH reversible activation type photo-thermal/photodynamic/fluorescent integrated probe molecule |
| CN111592482B (en) * | 2020-05-15 | 2021-06-25 | 江南大学 | PH reversible activation type photo-thermal/photodynamic/fluorescent integrated probe molecule |
| CN113304261A (en) * | 2021-05-28 | 2021-08-27 | 江南大学 | Construction and application of charge reversal type intelligent light diagnosis and treatment platform |
| CN113304261B (en) * | 2021-05-28 | 2022-07-22 | 江南大学 | Construction and application of charge reversal type intelligent light diagnosis and treatment platform |
| CN113350336A (en) * | 2021-07-01 | 2021-09-07 | 中国人民解放军陆军军医大学 | Application of heptamethine indocyanine or derivative thereof |
| CN114668842A (en) * | 2022-04-20 | 2022-06-28 | 中国人民解放军陆军军医大学 | Application of heptamethine indocyanine micromolecules with different chain length N-alkyl side chains in preparation of photosensitizer for treating tumors |
| CN118615444A (en) * | 2024-07-25 | 2024-09-10 | 山东第二医科大学 | Nanometer immunoregulator F@PDA@I and application thereof in tumor immunotherapy |
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