CN110016238A - The synthesis and biologic applications of fluorescein derivative photosensitizer with target tumor function - Google Patents
The synthesis and biologic applications of fluorescein derivative photosensitizer with target tumor function Download PDFInfo
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 37
- 239000003504 photosensitizing agent Substances 0.000 title claims description 23
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical class O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 title abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title description 9
- 238000003786 synthesis reaction Methods 0.000 title description 9
- -1 amino folic acid Chemical compound 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000002428 photodynamic therapy Methods 0.000 claims description 7
- SWZVJOLLQTWFCW-UHFFFAOYSA-N 2-chlorobenzene-1,3-diol Chemical class OC1=CC=CC(O)=C1Cl SWZVJOLLQTWFCW-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 4
- 229960004011 methenamine Drugs 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- BOHDZKSQXXJHBO-YRNVUSSQSA-N chembl3208829 Chemical compound C1=CC=CC2=NC(/C=N/O)=CC=C21 BOHDZKSQXXJHBO-YRNVUSSQSA-N 0.000 claims description 3
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims 1
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 claims 1
- 238000004140 cleaning Methods 0.000 claims 1
- 239000012043 crude product Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 7
- 239000000975 dye Substances 0.000 abstract description 7
- 238000003745 diagnosis Methods 0.000 abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 230000005281 excited state Effects 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 abstract 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 abstract 1
- 230000018732 detection of tumor cell Effects 0.000 abstract 1
- 229960000304 folic acid Drugs 0.000 abstract 1
- 235000019152 folic acid Nutrition 0.000 abstract 1
- 239000011724 folic acid Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 11
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 7
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 5
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 229950003776 protoporphyrin Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000006364 Duff aldehyde synthesis reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010040765 Integrin alphaV Proteins 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008004 immune attack Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- LGZXYFMMLRYXLK-UHFFFAOYSA-N mercury(2+);sulfide Chemical compound [S-2].[Hg+2] LGZXYFMMLRYXLK-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K49/0013—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
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
-
- 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
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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
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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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
- 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
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses long-life phosphors element derivative, its synthetic method and the biologic applications with cancer target of a kind of structural formula (I), in formula: L is RGD or amino folic acid；R is the C of symmetrical structure10H8N2O、C8H8O、C6H6OS and C11H9N3O structure.The fluorescein derivative (I) of long-life of the invention can be used for the detection of tumor cell specific, simultaneously because derivative (I) has the longer triplet excited state service life, so that it can produce optical dynamic therapy of the singlet for tumour.This fluorescein derivative based on conventional dyes has the integrated effect of diagnosis and treatment, potential to play a role in biologic applications.
Description
Technical field
The invention belongs to field of medicaments, are related to the preparation of a kind of fluorescein derivative photosensitizer with target tumor function
Method and biologic applications, the compound have relatively good singlet oxygen generative capacity, can be used as excellent photosensitizer and be applied to
The targeting of tumour and photodynamic therapy.
Background technique
Cancer, which has become, threatens one of human life and the principal disease of health, and how effectively to detect is with treating cancer
The important topic that the whole world is paid close attention to always.
Tumour cell is due to having unlimited increment, escape growth inhibition, escape immune attack, infinite copy, resisting cell
The characteristics such as apoptosis make the diagnosing and treating of tumour more intractable, simultaneously because tumour cell has from normal cell, these are different,
So that tumour cell has the marker of some specificity, such as the leaf of membrane glycoprotein, cell surface on tumor neogenetic blood vessels
Specific expressed integrin alpha v beta in acid acceptor and several solid tumor cell surfaces and nearly all tumor neogenetic blood vessels
3 etc., many researchers devise the fluorescence diagnosis point that some receptors based on tumor surface specificity and fluorogen combine
Son, they can have a high degree of specificity selectivity to tumour cell.
After tumour is diagnosed, next considered problem is the treatment method of tumour, ocal resection often companion
With higher recurrence rate, radiotherapy is limited by dose of radiation and damage normal tissue, and chemotherapy easily induces entirely
Body toxic side effect.Photodynamic therapy (PDT) is the nearly 20 years new treatment means occurred, in the presence of oxygen with suitable wavelength
Irradiation sensitising agent can be generated with high activity singlet oxygen, to eliminate the cancer cell of lesion.Singlet oxygen target of attack
Cell causes cell death by direct cellular damage, vessel closure and to target cell stimulation immune response.Photodynamics is controlled
It treats, as a kind of therapy on basis, it is mainly had the advantage that
(1) chief destructive cancer cell, not injuring normal cell；
(2) photosensitizer is non-toxic, and safety will not inhibit the immune function of people, will not inhibit marrow and cause leucocyte,
Red blood cell and decrease of platelet；
(3) it with operation, the radiation and chemotherapy effect of complementing each other, can use simultaneously；
(4) more course for the treatment of administrations can be made, drug resistance will not be generated；
(5) treatment time is short, generates curative effect after 48-72 hours general.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of fluorescein derivative photosensitizers with target tumor function
Synthetic method and biologic applications, this method is that the fluorescein precursor structure for obtaining derivatization is reacted by friedel-craft, basic herein
It is upper then that dye matrix is obtained by Knoevenagel- condensation reaction by aldehyde in Duff reaction, it is then different by link
Tumor marker L obtain have tumour high selectivity long-life phosphors element derivative, have relatively good biologic applications
Prospect.
Technical scheme is as follows:
Present invention firstly provides the fluorescein derivative photosensitizer with target tumor function of a kind of structural formula (I),
The special structure includes that different cancer target marker L links dye matrix, they can efficiently enter peculiar marker
Tumour cell, it is specific that tumour is treated and by photodynamic therapy.The fluorescein derivative has following knot
Structure formula (I):
Wherein:
R0, R0' it is respectively and independently selected from F, Cl, Br, I halogen；
R, R ' it is respectively and independently selected from R1、R2、R3And R4；
L is selected from L1, L2；
The present invention also provides a kind of methods for preparing the compound (I), the described method comprises the following steps:
(1) terephthalaldehydic acid and four chloro resorcinols are dissolved in the organic solvent with acidity, to aldehyde radical benzene first
Acid is 1:2 with four chloro resorcinol molar ratios, is heated to 80-140 DEG C of reflux 8-12h, and reaction solution is cooled to after room temperature slowly
It is added in alkalescent aqueous slkali, filters, washes and dry afterwards three times, obtain formula (II) compound；
(2) under normal temperature state, formula (II) compound and methenamine are dissolved in polar organic solvent, formula (II) is changed
The molar ratio for closing object and methenamine compound is 1:(5~10)；It is heated to 70~90 DEG C of reflux 12-24h, reaction solution
Acid solution is added after being cooled to room temperature, obtains compound (III) after suction filtration, it is dry after washing, it is not purified directly to carry out in next step
Reaction；
(3) in nitrogen atmosphere, in organic solvent by compound (III) dissolution, R intermediate is then added thereto, changes
Object III and intermediate R are closed according to molar ratio 1:(3~5) reaction, then according to molar ratio 1:(2~6 of compound III and piperidines)
Ratio, prepare compound (IV) in reaction system, under nitrogen protection 80-100 DEG C of reflux 12-24h is added in piperidines.Reaction
It is cooled to vacuum distillation after room temperature, obtains compound (IV) after purification；
(4) in nitrogen atmosphere, by compound (IV), L, 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethyl
Urea hexafluorophosphoric acid ester (HATU), n,N-diisopropylethylamine (DIEA) are according to molar ratio 1:(1~5): (1~3): (1~20) adds
It into anhydrous DMF, stirs evenly, after 0 DEG C of holding 10min, is reacted for 24 hours under room temperature (20-25 DEG C), obtain final formula (I)
Product；
Based on above technical scheme, it is preferred that acidic organic solvent described in step (1) is methane sulfonic acid, trifluoroacetic acid
At least one of；
Weakly alkaline solution described in step (1) is saturated sodium carbonate at 0 DEG C, saturated sodium bicarbonate, saturated potassium carbonate, full
At least one of with saleratus.
Based on above technical scheme, it is preferred that step (2) polar organic solvent be selected from trifluoroacetic acid, methylene chloride,
At least one of chloroform, ethyl alcohol, acetonitrile, ethyl acetate, toluene, dimethylbenzene, o-dichlorobenzene；
Acid solution described in step (2) is selected from hydrochloric acid or acetic acid aqueous solution；The acid solutions range is 1.0-
3.0M。
Based on above technical scheme, it is preferred that step (2) polar organic solvent is trifluoroacetic acid, methylene chloride, chlorine
At least one of imitative, ethyl alcohol, acetonitrile, ethyl acetate, toluene, dimethylbenzene, o-dichlorobenzene；
Acid solution described in step (2) is hydrochloric acid or acetic acid aqueous solution；The acid solutions are 1.0-3.0M.
Based on above technical scheme, it is preferred that step (3) organic solvent is selected from methanol, ethyl alcohol, acetonitrile, toluene, two
Toluene, o-dichlorobenzene at least one of.
Based on above technical scheme, it is preferred that R intermediate described in step (3) is R1’(C10H8N2O)、R2’(C8H8O)、
R3’(C6H6OS)、R4’(C11H9N3At least one of O), the R intermediate is above-mentioned R1、R2、R3And R4It is right after removing double bond
The substance answered,
Based on above technical scheme, it is preferred that the step of step (3) described purifying is after vacuum distillation removal solvent, to add
Enter the dissolution reactor product such as a small amount of methanol, DMF, DMSO, is precipitated in a large amount of ether, filters and obtain filter cake, using column chromatography
Method, the mobile phase of liquid chromatogram are the system of methanol and dichloro.
Another aspect of the present invention provides a kind of photosensitizer including above compound.
Further aspect of the present invention provides a kind of fluorescein derivative compound (I) and is preparing excellent tumour
The application of the photosensitizer of targeting and photodynamic therapy.
Beneficial effect
Fluorescein derivative of the present invention is to utilize different tumor markers and have the glimmering of long-life triplet
The link of light element derivative has the effect of target tumor diagnosis and optical dynamic therapy, can be used as a kind of more excellent diagnosis and treatment
Integrated molecular application is in biological testing process.Simultaneously as fluorescein derivative of the invention can pass through intersystem crossing
(ISC) process generates the triplet excited state of long-life, and energy can be transmitted to triplet oxygen molecule from triplet excited state to send out
Raw triplet-triplet energies transmittance process (TTET) process, produces at the singlet oxygen molecular induced cell apoptosis1O2, can
To have wide practical use in the targeting of tumour and photodynamic therapy as excellent photosensitizer.
Detailed description of the invention
Fig. 1 is the mass spectrum table for the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function that embodiment 1 synthesizes
Sign figure.
The nuclear-magnetism that Fig. 2 is the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function that embodiment 1 synthesizes is total
The hydrogen that shakes composes phenogram.
Fig. 3 is wink nanosecond for the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function that embodiment 1 synthesizes
State abosrption spectrogram.
Fig. 4 is the copolymerization of the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function synthesized in embodiment 1
Burnt fluorescence imaging.
Fig. 5 is the single line of the fluorescein derivative FL-RGD photosensitizer with tumor-targeting function synthesized in embodiment 1
State oxygen generates ability.
Specific embodiment
Following non-limiting embodiments can with a person of ordinary skill in the art will more fully understand the present invention, but not with
Any mode limits the present invention.Anyone skilled in the art within the technical scope of the present disclosure, according to
Technical solution of the present invention and its inventive concept, which are equivalently replaced or change, belongs to protection category of the present invention.
In following embodiments, unless otherwise specified, agents useful for same can be bought with drug by commercial sources, wherein intermediate
The synthesized reference literature method of body R synthesizes, R1’(C10H8N2O) bibliography [1] Xiong, X., Song, F., Sun, S., et
al.Red-Emissive Fluorescein Derivatives and Detection of Bovine Serum Albumin
[J] .Asian Journal of Organic Chemistry, 2013,2:145-9. synthesis；R2’(C8H8) and R O3’
(C6H6OS) bibliography [2] Wu, Y., Song, F., Luo, W., et al.Enhanced Thermally Activated
Delayed Fluorescence in New Fluorescein Derivatives By Introducing Aromatic
Carbonyl Groups [J] .ChemPhotoChem, 2017,1:79-83. synthesis；R4’(C11H9N3O) bibliography [3] An,
J.；Wu,Y.；Luo,W.；et al.Long-wavelength chromophores with thermally activated
delayed fluorescence based on fluorescein derivatives[J].Journal of Photonics
For Energy, 2018,8:032103. synthesis.
Embodiment 1
The synthetic route of fluorescein derivative photosensitizer FL-RGD with cancer target:
(1) synthesis of intermediate II
Under room temperature, terephthalaldehydic acid and four chloro resorcinols are dissolved in methane sulfonic acid solvent, terephthalaldehydic acid
It is 1:2 with four chloro resorcinol molar ratios, reaction solution is heated to 90 DEG C of reflux 12h, and cooled reaction solution to room temperature slowly adds
Enter into 0 DEG C of saturated sodium bicarbonate solution, filters, washes and dry afterwards three times, obtain formula (II) compound.
(2) synthesis of intermediate III
Under normal temperature state, II (1.0g, 2.5mmol) and methenamine (1.752g, 12.5mmol) are dissolved in 25mL
In the round-bottomed flask of trifluoroacetic acid.It is heated to 90 DEG C of reflux for 24 hours, 25mL aqueous hydrochloric acid solution (2M) is added after reaction solution is cooling,
Being put into cooling in refrigerator has solid precipitation, and filter cake is filtered in Buchner funnel and obtains compound III, washing is dried afterwards three times, obtained
Chinese red solid, it is not purified directly to carry out next step reaction.
(3) synthesis of intermediate FL
In nitrogen atmosphere, compound III (0.456g, 1mmol) is dissolved in the solvent of 15mL dehydrated alcohol, then to
Intermediate R is wherein added1' (0.688g, 4mmol), mixture is stirring evenly and then adding into piperidines (0.4mL), under nitrogen protection
It is heated to reflux for 24 hours.Reaction system is reduced to vacuum distillation removal solvent after room temperature, and a small amount of methanol dissolution reactor product is added,
It is precipitated in a large amount of ether, is filtered in Buchner funnel and obtain filter cake, using column chromatography (methanol/dichloro system=1/10)
Purifying compound FL.
(4) synthesis of compound FL-RGD
In nitrogen atmosphere, by compound FL (16mg, 0.0209mmol), 2- (7- azo benzotriazole)-N, N, N ',
N '-tetramethylurea hexafluorophosphoric acid ester (HATU, 15.89mg, 0.0418mmol) and N, N- diisopropylethylamine (54.03mg,
It 0.418mmol) is dissolved in 10mL anhydrous DMF with RGD (14.4mg, 0.0209mmol), is reacted at room temperature for 24 hours after 0 DEG C of holding 1h,
Reactor product is put into a large amount of ether and is precipitated, is filtered in Buchner funnel and obtains filter cake, using column chromatography (methanol/bis-
System=1/10 of chlorine) purifying obtains compound FL-RGD, and compound FL-RGD is one of present invention protection compound.
Fig. 1 is the mass spectrum table for the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function that embodiment 1 synthesizes
Sign figure.
The nuclear-magnetism that Fig. 2 is the fluorescein derivative photosensitizer FL-RGD with tumor-targeting function that embodiment 1 synthesizes is total
The hydrogen that shakes composes phenogram.
Fig. 3 is that the nanosecond transient state with fluorescein parent FL (a) and its derivative FL-RGD (b) that embodiment 1 synthesizes is inhaled
It receives.FL-RGD maintains the characteristic of dye matrix delayed fluorescence, the triplet with the long-life.
Embodiment 2
FL-RGD and commercialization photosensitizer protoporphyrin (PpIX) prepared by embodiment 1 carries out the test that singlet produces oxygen,
The specific method is as follows: it chooses 1,3 diphenyl isobenzofuran (DPBF) of singlet oxygen indicator and is used as singlet oxygen indicator, it will
The compound FL, FL-RGD or PpIX of same concentrations are dissolved in the acetonitrile solution containing DPBF, overall solution volume 3mL,
The light source of Photodynamic therapy is the LED light source of 630nm, and reaction solution is constantly in stirring, illumination one in During Illumination
Fixed time, record absorption intensity change with time.
Fig. 4 is the fluorescein derivative FL-RGD that synthesizes is different to integrin alpha v beta 3 expression in embodiment 1 four kinds
The confocal fluorescent of cell is imaged.The channel a is the channel for being commercialized nucleus dyestuff, and the channel b is the channel of FL-RGD dyestuff.By
In RGD can the integrin alpha v beta 3 with tumor surface of specificity combine, the link of RGD so that its to overexpression integrin alpha v beta 3
U87MG cell and SKOV-3 cell have efficient selectivity, so having fluorescence signal in the channel b.And to not expressing integrin alpha
The MCF-7 cell and RAW-264.7 cell of v β 3 not can enter in cell, without selectivity so not having fluorescence letter in the channel b
Number.These are the result shows that FL-RGD has relatively good diagnosis effect to the tumour cell that integrin alpha v beta 3 is overexpressed.
The singlet oxygen that Fig. 5 is the fluorescein derivative FL-RGD synthesized in embodiment 1 generates ability comparison diagram.(a) change
Close object FL in the presence of DPBF attenuation curve, (b) in the presence of dyestuff FL-RGD DPBF attenuation curve, (c) compound FL, FL-
The comparison of RGD and commercialization photosensitizer protoporphyrin (PpIX) singlet oxygen generating rate；Select 1,3 diphenyl isobenzofuran
(DPBF) conduct1O2Agent for capturing, DPBF is because of quilt1O2It aoxidizes and consumes, cause its strong absorption at 410nm to weaken, monitored with this
DPBF at 410nm absorption intensity variation come evaluate fluorescein derivative FL-RGD singlet oxygen generation ability.FL-
RGD has better singlet oxygen to generate ability than commercialized photosensitizer porphyrin (PpIX).
The result shows that: the tumour that there is fluorescein derivative FL-RGD the selection integrin alpha v beta 3 of specificity to be overexpressed is thin
Born of the same parents, while there is relatively good optical dynamic therapy effect, there are the integrated potentiality of diagnosis and treatment.
Claims (9)
1. a kind of general structure (I) compound or its pharmaceutically acceptable salt:
Wherein:
R0, R0' it is respectively and independently selected from F, Cl, Br, I；
R, R ' it is respectively and independently selected from R1、R2、R3And R4；
L is selected from L1, L2；
2. a kind of preparation method of compound described in claim 1, which comprises the following steps:
(1) terephthalaldehydic acid and four chloro resorcinols are dissolved in acidic organic solvent, are heated to 80-140 DEG C of reflux 8-
12h is slowly added into alkalescent aqueous slkali after being cooled to room temperature, is filtered, is dried to obtain formula (II) compound after washing；It is described
The molar ratio of terephthalaldehydic acid and four chloro resorcinols is 1:2；
(2) formula (II) compound and methenamine are dissolved in polar organic solvent, are heated to 70~90 DEG C of reflux 12-24h,
Acid solution is added after reaction is cooling, suction filtration, cleaning and drying obtain formula (III) compound；Formula (II) compound and Wu Luo
The molar ratio of tropine compound is 1:(5~10)；
(3) it in nitrogen atmosphere, in organic solvent by the dissolution of the formula (III) compound, then sequentially adds among R thereto
Body and piperidines, 80-100 DEG C of reflux 12-24h, is evaporated under reduced pressure after cooling, obtains formula (IV) chemical combination after purification under nitrogen protection
Object；The molar ratio of formula (III) compound and intermediate R are 1:(3~5)；The molar ratio of formula (III) compound and piperidines
1:(2~6)；
(4) in nitrogen atmosphere, the formula (IV) compound, L, HATU, DIEA are added in anhydrous DMF, stirred, is protected in 0 DEG C
After holding 10min, room temperature reaction for 24 hours, obtains general structure (I) described compound；Formula (IV) compound, L, HATU, DIEA
Molar ratio be 1:(1~5): (1~3): (1~20)
3. preparation method according to claim 2, which is characterized in that acidic organic solvent described in step (1) is methyl
At least one of sulfonic acid, trifluoroacetic acid；
Alkalescent aqueous slkali described in step (1) is saturated sodium carbonate, saturated sodium bicarbonate, saturated potassium carbonate, saturation at 0 DEG C
At least one of saleratus.
4. preparation method according to claim 2, which is characterized in that step (2) polar organic solvent is trifluoro second
At least one of acid, methylene chloride, chloroform, ethyl alcohol, acetonitrile, ethyl acetate, toluene, dimethylbenzene, o-dichlorobenzene；
Acid solution described in step (2) is hydrochloric acid or acetic acid aqueous solution；The acid solutions are 1.0-3.0M.
5. preparation method according to claim 2, which is characterized in that step (3) organic solvent be methanol, ethyl alcohol,
At least one of acetonitrile, toluene, dimethylbenzene, o-dichlorobenzene.
6. preparation method according to claim 2, which is characterized in that R intermediate described in step (3) is R1’
(C10H8N2O)、R2’(C8H8O)、R3’(C6H6OS)、R4’(C11H9N3At least one of O):
7. preparation method according to claim 2, which is characterized in that step (3) described purification process are as follows: will be evaporated under reduced pressure
It obtains crude product dissolution in a solvent, is then added in ether and is precipitated, suction filtration obtains filter cake, is finally purified using column chromatography, stream
Dynamic is mutually methanol and dichloromethane solution；The solvent is one of methanol, DMF, DMSO.
8. a kind of photosensitizer including compound described in claim 1.
9. compound described in claim 1 is in the photosensitizer that preparation has tumor-targeting function or photodynamic therapy
Using.
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| CN111718320A (en) * | 2020-07-01 | 2020-09-29 | 苏州科技大学 | Halogenated fluorescein weak light up-conversion system and preparation method and application thereof |
| CN113999247A (en) * | 2021-11-03 | 2022-02-01 | 安徽理工大学 | Preparation method of fluorone reagent |
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| CN111718320A (en) * | 2020-07-01 | 2020-09-29 | 苏州科技大学 | Halogenated fluorescein weak light up-conversion system and preparation method and application thereof |
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