CN107198774A - Folic acid targeted lipid-water amphiphilic benzylidene cycloparaffinone photosensitizer, preparation method and application thereof in preparation of photosensitive drugs for photodynamic therapy - Google Patents
Folic acid targeted lipid-water amphiphilic benzylidene cycloparaffinone photosensitizer, preparation method and application thereof in preparation of photosensitive drugs for photodynamic therapy Download PDFInfo
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- CN107198774A CN107198774A CN201610150045.6A CN201610150045A CN107198774A CN 107198774 A CN107198774 A CN 107198774A CN 201610150045 A CN201610150045 A CN 201610150045A CN 107198774 A CN107198774 A CN 107198774A
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound 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 title claims abstract description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 33
- 239000011724 folic acid Substances 0.000 title claims abstract description 33
- 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 title claims abstract description 26
- 229960000304 folic acid Drugs 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims description 6
- 239000003504 photosensitizing agent Substances 0.000 title abstract description 6
- 238000002428 photodynamic therapy Methods 0.000 title abstract description 5
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- 230000008685 targeting Effects 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 126
- 239000003795 chemical substances by application Substances 0.000 claims description 105
- 230000001235 sensitizing effect Effects 0.000 claims description 90
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 71
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 37
- -1 benzal cycloalkane ketone Chemical class 0.000 claims description 36
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 31
- 230000003287 optical effect Effects 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 23
- 238000002560 therapeutic procedure Methods 0.000 claims description 23
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 19
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 16
- 239000012295 chemical reaction liquid Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- 239000013067 intermediate product Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 claims description 11
- 239000000284 extract Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 9
- IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 claims description 9
- 150000003254 radicals Chemical class 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229940064302 folacin Drugs 0.000 claims description 7
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000003929 folic acid group Chemical group 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 2
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- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims 1
- 150000001718 carbodiimides Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 229910001947 lithium oxide Inorganic materials 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
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- 238000003786 synthesis reaction Methods 0.000 abstract description 8
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- 238000001990 intravenous administration Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
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- 239000000835 fiber Substances 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000003303 reheating Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QEDRWEVGKHIPFV-UHFFFAOYSA-N tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate;dichloromethane Chemical compound ClCCl.CC(C)(C)OC(=O)OC(=O)OC(C)(C)C QEDRWEVGKHIPFV-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 206010048828 underweight Diseases 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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- 230000010148 water-pollination Effects 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61K41/008—Two-Photon or Multi-Photon PDT, e.g. with upconverting dyes or photosensitisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- Health & Medical Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a folic acid targeting lipid-water amphiphilic benzylidene naphthenone photosensitizer which has specific targeting property on positive cells of a folic acid receptor, has the characteristics of good lipid-water amphipathy, simple molecular structure and easy synthesis and can realize intravenous administration. The invention also discloses a preparation method of the folic acid targeted lipid-water amphiphilic benzylidene cycloparaffin ketone photosensitizer, which has the characteristics of simple operation, mild reaction, high product purity and quantitative synthesis. The folic acid targeted lipid-water amphiphilic benzylidene cycloparaffin ketone photosensitizer has a targeting effect in photodynamic therapy and has a good application prospect in the aspect of preparing photodynamic medicaments.
Description
Technical field
The present invention relates to field of photodynamic.It is sub- more particularly, to a kind of folate-targeted fat water amphiphilic
Benzyl rings alkane ketone sensitising agent, prepare and its preparing single photon, the photosensitive medicine of double-photon optical dynamic therapy
Application in thing.
Background technology
Optical dynamic therapy (Photodynamic therapy, PDT) is produced by using light and medicine collective effect
Raw curative effect, realizes the high regioselectivity of therapeutic process.With traditional treatment means (operation, radiotherapy
With chemotherapy) compare, PDT largely avoid the damage of normal structure in therapeutic process.According to
The difference of absorbed photons number during sensitising agent induced transition, optical dynamic therapy can be divided into monochromatic light sub-light and move again
Power is treated and double-photon optical dynamic therapy.Because optical source wavelength used in double-photon optical dynamic therapy is usually single
Twice of optical source wavelength used in photon optical dynamic therapy, and it is only occurred at laser spot, therefore double light
Sub-light dynamic therapy can not only improve the spatial selectivity for the treatment of, and can improve the tissue of light source and wear
Saturating depth, the accurate treatment for making it be more beneficial for tumour and nonneoplastic lesion.But, current phototherapy medicine
Thing is all that body is applied to by way of system or local administration, and sensitising agent is being absorbed by pathological tissues
It can also be enriched with the normal tissue simultaneously, this selectively distribution does not cause inevitably to disease
The damage of the normal structure become around tissue；In addition, when sensitising agent in normal skin tissue enriching quantity compared with
When big, patient is likely to trigger serious peak skin dosage under the acute irradiation of daylight or light.Cause
This, improves photosensitive drug very necessary to the selectivity of pathological tissues.
At present, correlative study is mainly attempted in terms of three：1) liposome, micro-capsule, nanometer are utilized
The structures such as particle improve retentivity of the medicine in pathological tissues；2) connection monoclonal antibody, polypeptide, epidermal growth
The factor and other recognizable molecules etc. realize targeting as targeting group；3) PH sensitivities, temperature are prepared
The targeting structure of sensitive or magnetic-field-sensitive, (Chemical Reviews, 2010,110,2795-2838).
Folic acid (Folic acid, FA) is a kind of vitamin that is needed by human but can not synthesizing, participates in a carbon
Unit is metabolized and purine, the de novo formation of thymidine, its merisis and nucleic acid, amino to cell
Acid, the synthesis of protein play an important role.If human body, which lacks folic acid, can cause the exception of red blood cell,
The increase of immature cell, anaemia and white blood cell are reduced；Meanwhile, folic acid be also embryo growth and development not
The nutrient that can lack, pregnant woman lack folic acid be likely to result in occurring during fetal birth under-weight, harelip,
Heart defect etc..Folic acid main endocytic pathway by folacin receptor in human body is ingested cell.Folic acid
Acceptor (Folate receptor, FR) is a kind of after birth glycoprotein connected by glycolsyl-phosphatidylinositol (GPI),
It is tumor related antigen, molecular weight is 38~40kD.Bindu Varghese et al. write articles (Molecular
Pharmaceutics, 2007,4,679-685) to point out, the expression of such a acceptor in the normal tissue is height
It is conservative, and the malignant tumour originated in epithelial tissue for example oophoroma, cervical carcinoma, kidney, breast cancer,
Colon cancer, nasopharyngeal carcinoma etc. tissue in but can altimeter reach.
Research team where inventor has been disclosed for a series of new benzal cycloalkane ketone sensitising agent can
For optical dynamic therapy, such as Chinese invention patent CN102249940A and CN102249939A；With
And article (Journal of Medicinal Chemistry, 2015,58,7949；Organic&Biomolecular
Chemistry,2011,9,4168-4175；Journal of Photochemistry and Photobiology A:
Chemistry,2011,222,228-235).These dyestuffs have that molecular structure is simple, are readily synthesized, can
See that optical band (400~650nm) has strong absorb, near infrared band (650~1000nm) double light
The characteristics of sub- absorption cross-section is big, active oxygen quantum yield is high, has very in two-photon field of photodynamic
Big application potential.However, the characteristics of these sensitising agents do not have active targeting pathological tissues, limits
The maximum performance of its curative effect.Therefore, further it is chemically or physically modified, to improve such light
The quick dose of selectivity to pathological tissues, is very to fully developing them in the potential of field of photodynamic
It is necessary.
The content of the invention
First purpose of the present invention is to provide a kind of folate-targeted fat water amphipathic benzal cycloalkane ketone
Sensitising agent, such sensitising agent has specific target tropism to folate receptor-positive cell, and with fat water
Amphipathic good, molecular structure is simple, molecular structure stabilized and the characteristics of be readily synthesized.
Second object of the present invention is to provide a kind of folate-targeted fat water amphipathic benzal cycloalkane ketone
The synthetic method of sensitising agent；This method has that simple to operate, reaction is gentle, product purity is high, can be high-volume
The characteristics of synthesis.
Third object of the present invention is to provide folate-targeted fat water amphipathic benzal cycloalkane ketone light
The quick dose of application in single photon optical dynamic therapy：Such sensitising agent has in 400~650nm wave-length coverages
Have it is stronger absorb, can quickly be produced under the irradiation of light source in 400~650nm wave-length coverages singlet oxygen,
Superoxide radical isoreactivity oxygen species, can be used in single photon optical dynamic therapy, and can be to folacin receptor
It is identified into positive tumour cell, so as to have targeting to do use in single photon optical dynamic therapy.
Fourth object of the present invention is to provide folate-targeted fat water amphipathic benzal cycloalkane ketone light
The quick dose of application in double-photon optical dynamic therapy；Such sensitising agent has in 650~1000nm wave-length coverages
Larger two photon absorption cross section, list can be quickly produced under 650~1000nm ultrafast laser irradiation
Line state oxygen, superoxide radical isoreactivity oxygen species, can be used in double-photon optical dynamic therapy, and can be right
Folacin receptor is identified into positive tumour cell, so as to have targeting in double-photon optical dynamic therapy
Do use.
To reach above-mentioned first purpose, the present invention uses following technical proposals：
The present invention provides folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent, with following structural formula
M：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4.
To reach above-mentioned second purpose, the present invention uses following technical proposals：
The present invention provides the preparation method of folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent, including
Following steps：
1) C6 is synthesized, reaction equation is as follows：
Wherein：R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
Comprise the following steps that：
0.01~0.2 mole of C3 is dissolved in 50~250 milliliters of ethanol-water solutions, wherein, alcohol-water is molten
The volumn concentration of ethanol is 30%~90% in liquid；Quality is slowly added to for C3 mass to above-mentioned system
1~20 times of alkaline matter, be stirred continuously make its be well mixed；Reaction mixture in a nitrogen atmosphere,
After 50~95 DEG C of stirrings 4~24 hours, using in acidic materials and above-mentioned system, concentration of reaction solution；To
In system after concentration add quality be C3 mass 1~15 times of concentration be 3~10M hydrochloric acid after,
It is heated to reflux 10~48 hours, cools down under nitrogen atmosphere；During end reaction liquid is neutralized to alkaline matter
Property, extracted with dichloromethane, intermediate product C4 is obtained after removing dichloromethane through drying, filtering, revolving；
The quality that 1~5 times of phosphorus pentachloride that mole is reaction substrate amount is added under ice bath be its 2~6
Reaction forms Vilsmeier reagents in 0.5~1 hour in DMF again；The dropwise reaction bottom into above-mentioned system
Thing C4, stirring reaction was recovered to normal temperature and neutralized with alkaline matter after 2~12 hours at 70~140 DEG C
Reaction system；Reaction solution is extracted with dichloromethane, and extract is washed with water, through drying, filtering, revolving
Remove extractant and obtain C5；
Above-mentioned intermediate product C5 is dissolved in into quality in its 2~20 times methanol, to add under agitation mole
Amount is the aqueous solution of intermediate product C5 1-3 times of alkaline matter, is persistently stirred 2~10 hours, is stopped
Reaction, removes methanol by reaction solution revolving, uses dichloromethane aqueous phase extracted, obtained dichloromethane extraction
Liquid is washed with water to neutrality, and removing dichloromethane through drying, filtering, revolving obtains product C6；
2) C7 is synthesized, reaction equation is as follows：
Wherein：R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
By C2 and step 1) gained C6 according to mole 1:1~2 ratio is dissolved in dichloromethane, so
Mole is sequentially added afterwards and is 1~2 times of catalyst, 1~5 times of the acid binding agent of C6 moles, then divides 3
Secondary addition and the condensing agent that C6 mole ratios are 0.8~1.5；Reaction system is reacted 6~24 hours at room temperature
Afterwards, reaction solution is extracted with dichloromethane, and extract is washed with water, and extraction is removed through drying, filtering, revolving
Agent is taken to obtain C7；
3) C12 is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
By step 2) gained C7 and C11 according to mol ratio 1：1~2.5 ratio adds reaction vessel,
Then 10~200 times of the ethanol as solvent that quality is C11 is added, it is C11 moles to add mole
0.01~0.6 times of base catalyst, 25~60 DEG C react 10~40 hours, through revolving remove it is molten
Agent obtains crude product, and C12 is obtained with chromatographic column separating-purifying；
4) C13 is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
10~500 milliliters of dichloromethane are taken to add in reaction vessel, ice bath adds matter thereto to 0~5 DEG C
1~15 times of the trifluoroacetic acid for C12 mass is measured, is stirred；The two of C12 are slowly added dropwise thereto
Chloromethanes solution, reacts 6~24 hours in 0~40 DEG C；The trifluoroacetic acid of solvent and excess is removed through revolving,
Obtain C13；
5) M is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
0.01~0.5 mM of folic acid is weighed, i.e. C14 is added in reaction vessel, according to C14 and diformazan
The mass ratio of base sulfoxide is 1:50~200 ratio mixing, stirring is completely dissolved folic acid；To reaction system
Middle to add 1~1.3 times of the reactant C13 that mole is folic acid mole, then sequentially adding mole is
1~2 times of catalyst, 1~3 times of acid binding agent and 0.8~1.5 times of the condensing agent of folic acid mole；Reaction
It is miscible using chloroform extraction and saturated aqueous common salt after system is reacted 12~48 hours at 25~40 DEG C
Reaction solution, extract is separated through revolving, freeze-drying, efficient liquid phase, obtains target sensitising agent M.
Preferably, the alkaline matter is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, carbonic acid
The mixture of one or both of hydrogen sodium, saleratus any of the above ratio.
Preferably, the acidic materials are one kind or the mixture of its arbitrary proportion in sulfuric acid, hydrochloric acid.
Preferably, the catalyst is I-hydroxybenzotriazole, 1- hydroxyl -7- azos BTA, 4-
The mixture of one or both of dimethylamino naphthyridine, N- hydroxysuccinimides any of the above ratio.
Preferably, the acid binding agent is DIPEA, triethylamine, pyridine, 4- dimethylaminos
The mixture of one or both of pyridine any of the above ratio.
Preferably, the condensing agent is dicyclohexylcarbodiimide, DIC, 1- ethyls
- 3- (3- dimethylamine propyls) carbodiimide hydrochloride, 2- (7- azos BTA)-N, N, N', N'- tetramethylureas
The mixture of one or both of hexafluorophosphoric acid ester any of the above ratio.
Preferably, the base catalyst be lithium hydroxide, sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum,
One or more of combinations in Anhydrous potassium carbonate, pyridine or hexahydropyridine.
Wherein, in preparation method of the invention, C3 can be by commercially available.
In the preparation method of the present invention, C2 synthesis equation is：
Wherein：
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
Reference literature, i.e.,Entitled " the 6-Aminopenicillanic acid (6-APA) of Favre et al.
derivatives equipped with anchoring arms”(Tetrahedron,2012,68,10818-10826)
Synthetic method in article, the dichloromethane of 10~1000 milliliters of addition into a single port bottle, ice bath is cold
But (0~5 DEG C), reactant C1 is added thereto, and adds 1~10 times that mole is C1 moles
Acid binding agent, makes system stir；It is C1 moles 1/3~1/10 that mole is added dropwise into above-mentioned system
Di-tert-butyl dicarbonate dichloromethane solution after, continue react 12~48 hours；By end reaction liquid
Extracted, and be washed with water 3~6 times with dichloromethane, after removing dichloromethane through drying, filtering, revolving
To C2.
In the preparation method of the present invention, C11 synthesis step is：
1. C8 is synthesized, reaction equation is：
Wherein：X=2,3,4,5,6 or 7；R7For methyl, ethyl, propyl group or isopropyl；
Comprise the following steps that：
Entitled " the Conversion of alcohols to thiols via of reference literature, i.e. Arthur Snow et al.
Synthetic method in tosylate intermediates ", Synthesis, 2003, vol.4, pp509-512 articles,
It is its 5~20 times water that NaOH and quality are added into three mouthfuls of reactors, is stirred；Then, press
PEG and NaOH mol ratios 1：1~5 ratio adds PEG and tetrahydrochysene into the above-mentioned NaOH aqueous solution
The mixed solution of furans (THF), the PEG：THF volume ratios are 1：1~10；Ice bath temperature control is used,
Stirred 0.5~2 hour at 0~5 DEG C and logical nitrogen with abundant deoxygenation after, by mole be PEG amounts 0.5~
1 times of paratoluensulfonyl chloride is dissolved in the THF that volume is 1~5 times of PEG volumes, by the THF solution
It is slowly dropped in above-mentioned three mouthfuls of reaction vessels for having added PEG, THF and NaOH aqueous solution；
After being reacted 2~6 hours at 0~10 DEG C, ice bath is removed, continues to react 4~12 hours at room temperature；Reaction
Liquid is extracted with ether, and ether extraction liquid is washed with water to neutrality, and ether is removed through drying, filtering, revolving
Obtain being connected with the p-methyl benzenesulfonic acid ester C8 of PEG group accordingly；
2. C11 is synthesized, reaction equation is：
Wherein：R8For methyl, ethyl or-C2H4OH；
R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
Comprise the following steps that：
Entitled " the Synthesis and of reference literature, i.e. Christian B.Nielsen et al.
characterization of water-soluble phenylene-vinylene-based singlet oxygen
Sensitizers for two-photon excitation ", The Journal of Organice Chemistry, 2005,
Synthetic method in vol.70, pp7065-7079 article, quality is dissolved in for its 10~30 times process by C9
Dry in the tetrahydrofuran (THF) steamed again, it is above-mentioned para aminotenzaldehyde to be then slowly added into mole
The potassium hydroxide and quality that 1~5 times of derivative are 10~30 times of C9 compounds by drying the THF steamed again
In the solution mixed, reaction mixture is stirred after half an hour under N2 atmosphere, is heated to reflux 1~5
Hour, obtain intermediate reaction liquid.The intermediate product C8 that mole is 1~5 times of C9 compounds is slowly dripped
Add in above-mentioned intermediate reaction liquid, continue to be heated to reflux 12~48 hours, cool down, end reaction liquid is used
Acid is neutralized to neutrality, is extracted with dichloromethane, is obtained after removing dichloromethane through drying, filtering, revolving
Crude product, yellow oily liquid, the i.e. benzaldehyde with PEG group are obtained with chromatographic column separating-purifying and is spread out
Biological C10；
Referring to Chinese patent application publication number CN102249939A, by the p-aminophenyl with PEG group
Formaldehyde derivatives C10 andIt is 1 according to mol ratio：1~2 ratio adds reaction vessel, then adds
Quality is that (volumn concentration of wherein ethanol is for 10~30 times of ethanol-water solution of C10 mass
20%~80%), 0.01~0.6 times of the base catalyst that mole is C10 is added, under the conditions of 0 DEG C
Reaction 2~10 hours, removes and is reacted 1~5 hour under ice bath, room temperature condition, through filtering or rotating removing molten
Agent obtains crude product, and C11 is obtained with chromatographic column separating-purifying；
Wherein：For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
The folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent of the present invention can be to folacin receptor Cheng Yang
Property tumour cell be identified so that in optical dynamic therapy have targeting.
The folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent of the present invention all has the property of fat water amphiphilic
Matter, with the increase of PEG group quantity, the hydrophily increase of sensitising agent.
The folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent of the present invention is in 400~650nm wavelength
Scope has stronger Single Photon Absorption.
The amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water of the invention is in 650~1000nm
Wave-length coverage has stronger two-photon absorption.
The amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water of the invention is in 400~650nm
Singlet oxygen, superoxide anion isoreactivity oxygen species can be quickly produced under light source irradiation in wave-length coverage,
There is good application prospect in terms of single photon photo-dynamical medicine is prepared.
The amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water of the invention is in 650~1000nm
Singlet oxygen, superoxide anion isoreactivity oxygen species can be quickly produced under laser irradiation in wave-length coverage,
There is good application prospect in terms of double-photon optical dynamical medicine is prepared.
Beneficial effects of the present invention are as follows：
1. the amphipathic benzal cycloalkane ketone sensitising agent of the folate-targeted fat water of the present invention is in optical dynamic therapy
In have good targeting.
2. the amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water in the present invention is simple in construction,
Molecular weight is small, the chemical constitution with determination, it is easy to prepares, purify and further modifies, and meets clinical
The basic demand of medication.
3. the amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water in the present invention has fat water double
The characteristics of amphiphilic, and its fat moisture proportioning disclosure satisfy that the use requirement of clinical optical dynamic therapy.
4. the synthetic method of the amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water in the present invention
With the characteristics of simple to operate, product yield is high, purity is high.
5. the amphipathic benzal cycloalkane ketone sensitising agent of folate-targeted fat water in the present invention 400~
650nm and 650~1000nm wave-length coverages have higher biological photodynamic activity, are preparing light power
There is good application prospect in terms of medicine.
Brief description of the drawings
The embodiment to the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 shows absorption spectrums of the sensitising agent M-1 in methanol and PBS in embodiment 1.
Fig. 2 shows in embodiment 1 in the presence of sensitising agent M-1 that absorbances of the DPBF in DMF is at any time
Between down ratio.
Fig. 3 shows Two-photon Absorption Spectrums of the sensitising agent M-1 in DMF in embodiment 1.
Fig. 4 shows absorption spectrums of the sensitising agent M-2 in methanol and PBS in embodiment 2.
Fig. 5 shows in embodiment 2 in the presence of sensitising agent M-2 that absorbances of the DPBF in DMF is at any time
Between down ratio.
Fig. 6 shows Two-photon Absorption Spectrums of the sensitising agent M-2 in DMF in embodiment 2.
Fig. 7 shows that sensitising agent M-1 is used for the experiment that monochromatic light sub-light power verifies its targeting in embodiment 1
As a result.
Fig. 8 shows that sensitising agent M-2 is used for the cell survival rate of double-photon optical dynamic experiment in embodiment 2.
Fig. 9 shows that the sensitising agent M-2 in embodiment 2 is used for the reality that monochromatic light sub-light power verifies its targeting
Test result.
Figure 10 shows that the sensitising agent M-1 in embodiment 1 is used for the survival rate of double-photon optical dynamic experiment.
Figure 11 shows that the sensitising agent M-1 in embodiment 1 is used for the result for verifying two-photon excitation process.
Figure 12 shows that the sensitising agent M-2 in embodiment 2 is used for the result for verifying two-photon excitation process.
Embodiment
In order to illustrate more clearly of the present invention, the present invention is done into one with reference to preferred embodiments and drawings
The explanation of step.Similar part is indicated with identical reference in accompanying drawing.Those skilled in the art
It should be appreciated that following specifically described content is illustrative and be not restrictive, it should not be limited with this
Protection scope of the present invention.
Embodiment 1
(I) C2-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
8.0 grams of (54mmol) 2,2'- (ethylene dioxy) double (ethamine) are dissolved in 500 milliliters of dichloromethane,
Ice bath is cooled to 0~5 DEG C；6.0 grams of (60mmol) triethylamines are added thereto, and make system stirring equal
It is even；It is added dropwise into above-mentioned system after the dichloromethane solution of 4.0 grams of (18mmol) di-tert-butyl dicarbonates,
Continue to react 12 hours；End reaction liquid is extracted 3 times with dichloromethane, and is washed with water 3 times, is passed through
Dry, filter, revolving obtains 3.3 grams of C2-1 (yield 75%) after removing dichloromethane.
(II) C6-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
17.3 grams of (0.1mol) C3-1 are dissolved in 50 milliliters of ethanol-water solutions (wherein volume hundred of ethanol
Point content is in 50%)；20 grams of (0.5mol) sodium hydroxides are slowly added to above-mentioned system, are stirred continuously
It is well mixed it；Reaction mixture in a nitrogen atmosphere 60 DEG C stirring 6 hours after, profit is neutralized with hydrochloric acid
Above-mentioned system, concentration of reaction solution；5M 20 grams of hydrochloric acid is added into the system after concentration, in nitrogen gas
It is heated to reflux 12 hours, cools down under atmosphere；End reaction liquid is neutralized to neutrality with sodium carbonate, dichloromethane is used
Alkane is extracted, and 21.6 grams of C4-1 of intermediate product (productions are obtained after removing dichloromethane through drying, filtering, revolving
Rate 98%).
32 grams of (0.15mol) phosphorus pentachlorides are added 1 hour shape is reacted in 80 grams of DMF under ice bath
Into Vilsmeier reagents；21.6 grams of (0.09mol) reaction substrate C4-1 are added dropwise into above-mentioned system,
Stirring reaction is after 2 hours at 140 DEG C, recovers to normal temperature and with sodium acid carbonate neutralization reaction system；Reaction solution
Extracted with dichloromethane, extract is washed with water, removing extractant through drying, filtering, revolving obtains 24.0
Gram C5-1 (yield 99%).
Above-mentioned 24.0 grams of (0.11mol) intermediate products C5-1 is dissolved in 50 grams of methanol, added under agitation
Enter 4.8 grams of (0.12mol) NaOH, persistently stir 10 hours, stop reaction, reaction solution revolving is removed
Methanol is removed, dichloromethane aqueous phase extracted is used, obtained dichloromethane extract is washed with water to neutrality, is passed through
Dry, filter, revolving removes dichloromethane and obtains 20.6 grams of C6-1 (yield 97%) of product.
(III) C7-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
0.50 gram (2mmol) C2-1 and 0.44 gram of (2mmol) C6-1 is dissolved in 15 milliliters of dichloromethanes
Alkane, then sequentially adds 0.28 gram of (2.2mmol) HOBT, 0.20 gram of triethylamine, finally divides 3 times and adds
Enter 0.38 gram of (2mmol) EDCI；Reaction system was reacted after 12 hours at room temperature, and reaction solution uses two
Chloromethanes is extracted, and extract is washed with water, and is obtained C7-1 through drying, filtering, revolving removing extractant and is
0.87 gram.(yield 97%).
(IV) C8-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
8 grams of (0.2mol) NaOH, 80 milliliters of water, stirring are added into 250 milliliters of three-necked flasks
It is uniformly dissolved it；24.9 grams of (0.12mol) tetraethylene glycol monomethyl ethers are added in 50 milliliters of THF and dissolved
Uniformly, then add and be well mixed in above-mentioned three-necked flask with NaOH solution；By 22.7 grams (0.12mol)
Paratoluensulfonyl chloride and 40 milliliters of THF are well mixed, and are then slowly added dropwise in above-mentioned three-necked flask,
Dropwise addition process keeps reacting liquid temperature to be no more than 10 DEG C, after completion of dropping, continues stirring reaction 6 hours,
Stop reaction.Reaction solution is extracted three times with ether, and ether extraction liquid, which is washed with water to neutrality, adds anhydrous sulphur
Sour magnesium is dried, and ether is removed through filtering, revolving, obtains 39.5 grams of corresponding p-methyl benzenesulfonic acid ester C8-1 (productions
Rate：91%)；
(V) C11-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
2.1 grams of (0.01mol) 4- (N, N- bis- (2- hydroxy-ethyls) amino) benzaldehyde C9-1 is dissolved in 50 grams
By drying in the THF steamed again, 1.68 grams (0.03mol) KOH and 50 gram of THF is then slowly added into
The solution mixed, completion of dropping, reaction solution is stirred under N2 atmosphere reheats backflow 1 after half an hour
Hour, obtain intermediate reaction liquid.10.9 grams of (0.03mol) p-methyl benzenesulfonic acid ester C8-1 are dissolved in 50
In gram THF, it is slowly added dropwise in above-mentioned intermediate reaction liquid, continues to be heated to reflux 48 hours, after cooling,
End reaction liquid is neutralized to neutrality with watery hydrochloric acid, extracted with dichloromethane, extract is through anhydrous magnesium sulfate
Dry, filter, revolving obtains crude product after removing dichloromethane, and 4.2 are obtained with chromatographic column separating-purifying
Gram yellow oily liquid C10-1 (yield 71%).
By 3.5 grams of (0.006mol) para aminotenzaldehyde derivative C10-1 and 1 gram (0.012mol)
Cyclopentanone adds reaction vessel, and then adding 40 grams of ethanol-water solutions, (volume basis of wherein ethanol contains
Measure 80%), to add 0.03 gram of (0.75mmol) sodium hydroxide, 4 are reacted under the conditions of 0 DEG C small
When, remove and reacted 1 hour under ice bath, room temperature condition, crude product is obtained through filtering or rotating removing solvent,
1.5 grams of intermediate product C11-1 (yield 38%) are obtained with chromatographic column separating-purifying.
(VI) C12-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
0.45 gram (0.001mol) C7-1 and 0.66 gram of (0.001mol) C11-1 is added into reaction vessel,
Then 20 grams of ethanol as solvent are added, 0.02 gram of (0.5mmol) NaOH is added and makees catalyst,
25 DEG C of 24 hours of reaction, remove solvent through revolving and obtain crude product, 0.5 is obtained with chromatographic column separating-purifying
Gram C12-1 (yield 46%).
(VII) C13-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
15 milliliters of dichloromethane are taken to add in reaction vessel, ice bath adds 0.5 gram thereto to 0~5 DEG C
Trifluoroacetic acid, stirs；0.25 gram of (0.23mmol) C12-1 dichloromethane is slowly added dropwise thereto
Alkane solution, reacts 12 hours in 25 DEG C；The trifluoroacetic acid of solvent and excess is removed through revolving, C13-1 is obtained
For 0.21 gram (yield 95%).
(VIII) target sensitising agent M-1 is synthesized, reaction equation is as follows：
Comprise the following steps that：
Weigh 88 milligrams of (0.2mmol) folic acid C14 to add in reaction vessel, added into reaction bulb
About 6 grams of DMSO, stirring is completely dissolved folic acid；Another reactant is added thereto 0.22 gram (0.22
Mmol) C13-1, then sequentially adds 29 milligrams of (0.25mmol) NHS, 4 milligrams (0.4mmol)
Triethylamine and 42 milligrams of (0.22mmol) EDCI；After reaction system is reacted 12 hours at 40 DEG C,
Using chloroform extraction and the miscible reaction solution of saturated aqueous common salt, extract through revolving, freeze-drying,
Efficient liquid phase is separated, and obtains 0.1 gram of target sensitising agent M-1 (yield 47%).HR-MS(ESI):m/z
[M+H]:Calcd.for[C71H103N11O19]+1412.7348；found 1412.7384.
(IX) with the phosphate buffer (abbreviation of pH value 7.4：PBS) detect that target is photosensitive
Solubility of the agent M-1 in aqueous systems, 25 DEG C of its solubility are more than 2mg/mL；By target sensitising agent M-1
It is dissolved in respectively in methanol and PBS, tests its absorption spectrum, it was demonstrated that sensitising agent M-1 exists
350~650nm wave-length coverages have compared with strong absworption peak, see accompanying drawing 1.
(X) above-mentioned target sensitising agent M-1 is dissolved in DMF, it is 0.1 in 473nm absorbance to make it,
With Rose Bengal (singlet oxygen quantum yield ΦΔ=0.47) be reference, composed as shown in Figure 2
Figure.Illustrate that sensitising agent M-1 generates singlet oxygen under the conditions of 473nm laser excitations.
(XI) sensitising agent is made into 2 × 10-4M DMF solution, uses 1 × 10-4M rhodamine Bs
(Rhodamine B) is reference, and two photon absorption cross section is tested using up-conversion fluorescence method, as a result as attached
Shown in Fig. 3, sensitising agent has larger two photon absorption cross section in 720-880nm wave-length coverages, can make
Photodynamic action is produced with two-photon excitation.
Embodiment 2
(I) embodiment 1 is repeated, its difference is, cyclopentanone in above-mentioned steps (V) is changed into cyclobutanone,
Other conditions are constant, obtain target sensitising agent M-2 (yield 20%).HR-MS(ESI):m/z[M+H]:
Calcd.for[C70H101N11O19]+1398.7191；found 1398.7229.
(II) with reference to the operation of (IX) in embodiment 1, it was demonstrated that M-2 solubility is more than 2mg/mL；And
Have in 350~600nm wave-length coverages compared with strong absworption peak, see accompanying drawing 4.
(III) with reference to the operation of embodiment 1 (X), as a result it has been also demonstrated that target sensitising agent M-2 in 473nm
Reactive oxygen species can be produced under laser irradiation, accompanying drawing 5 is seen.
(IV) with reference to the operation of embodiment 1 (XI), as a result it has been also demonstrated that sensitising agent in 720-880nm
Wave-length coverage has larger two photon absorption cross section, and two-photon excitation can be used to produce photodynamic action.
See accompanying drawing 6.
Embodiment 3
(I) with reference to the operation of (I) in embodiment 1, C2-2 is synthesized, reaction equation is as follows：
Comprise the following steps that：
4.0 grams of (45mmol) C1-2 are dissolved in 100 milliliters of dichloromethane, ice bath is cooled to 0~5 DEG C；
5.8 grams of (45mmol) DIPEAs (DIEA) are added thereto, and stir system
Uniformly；The dichloromethane solution of 0.9 gram of (4.5mmol) di-tert-butyl dicarbonate is added dropwise into above-mentioned system
Afterwards, continue to react 12 hours；End reaction liquid is extracted 3 times with dichloromethane, and is washed with water 3 times,
0.7 gram of C2-2 (yield 80%) is obtained after removing dichloromethane through drying, filtering, revolving.
(II) with reference to the operation of (V) in embodiment 1, using C10-1 and hexamethylene reactive ketone, base catalyst is
Lithium hydroxide, mole is 0.01 times of reactant, prepares intermediate product C11-2.(yield 30%)
(III) other steps in embodiment 1 are repeated, with reference to the operation of (VIII) in embodiment 1, are added successively
Enter the catalyst (I-hydroxybenzotriazole, HOBT) that mole is 2 times of folic acid mole, 3 times are tied up acid
Agent (DMAP, DMAP) and 1.5 times of condensing agent dicyclohexylcarbodiimide (DCC),
Reaction system is reacted 48 hours at 25 DEG C, obtains target sensitising agent M-3 (yield 30%).HR-MS
(ESI):m/z[M+H]:Calcd.for[C70H100N11O17]+1365.7220；found 1365.7221.
Embodiment 4
(I) operation of (II) in embodiment 1 is repeated, makes C3-1 into N- methyl-N- cyanoethyl -4- ammonia
Benzaldehyde, prepares intermediate product C6-2.(yield 97%)
(II) with reference to the operation of (III) in embodiment 1, using C2-1 and C6-2 according to mol ratio 1:2
Ratio feeds intake, and adds the catalyst 1- hydroxyl -7- azo BTAs that mole is 2 times of C6-2 moles
(HOAT), 5 times of acid binding agent pyridine, 1.2 times condensing agent 2- (7- azos BTA)-N, N, N', N'-
Tetramethylurea hexafluorophosphoric acid ester (HATU), reaction is reacted 24 hours at room temperature, obtains compound C7-2.
(yield 98%)
(III) other steps in embodiment 1 are repeated, target sensitising agent M-4, (yield 20%) is obtained.HR-MS
(ESI):m/z[M+H]:Calcd.for[C70H100N11O19]+1397.7119；found 1397.7110.
Embodiment 5
(I) with reference to the operation of (IV) in embodiment 1, pressed using paratoluensulfonyl chloride and five glycol monomethyl ethers
According to mol ratio 0.8:1 ratio feeds intake, and reaction temperature is 0 DEG C, in 3 hours reaction time, prepares middle produce
Thing C8-2, (yield 92%).
(II) with reference to the operation of (V) in embodiment 1, intermediate product C10-2 is prepared.
Comprise the following steps that：
3.6 grams of (0.02mol) N- ethoxy -4- amino-2-methyl benzaldehydes C9-2 are dissolved in 60 grams of processes
Dry in the THF steamed again, be then slowly added into 5.6 grams (0.03mol) KOH and 50 gram of THF and mix
The solution closed, completion of dropping, reaction solution is in N2Reheating backflow 2 after half an hour is stirred under atmosphere small
When, obtain intermediate reaction liquid.24.4 grams of (0.06mol) p-methyl benzenesulfonic acid ester C8-2 are dissolved in 50 grams
In THF, it is slowly added dropwise in above-mentioned intermediate reaction liquid, continues to be heated to reflux 48 hours, after cooling, will
End reaction liquid is neutralized to neutrality with watery hydrochloric acid, is extracted with dichloromethane, and extract is dry through anhydrous magnesium sulfate
Dry, filtering, revolving obtain crude product after removing dichloromethane, and 7.3 grams of Huangs are obtained with chromatographic column separating-purifying
Color oily liquids C10-2 (yield 89%).
(III) repeat other in embodiment 1 to operate, its difference is, by the step of embodiment 1 (V) middle ring
Pentanone is changed to cyclobutanone, obtains target sensitising agent M-5 (yield 15%).HR-MS(ESI):m/z[M+H]:
Calcd.for[C62H84N11O15]+1221.6070；found 1221.6066.
Embodiment 6
(I) operation in embodiment 1 is repeated, its difference is cyclopentanone in the step of embodiment 1 (V)
The quality for being changed to DMSO used in cycloheptanone, step (VIII) is 10 grams, and sequentially adding mole is
The catalyst (DMAP, DMAP) that 1.5 times of folic acid mole, 1.2 times of acid binding agent (three second
The mixture of amine and pyridine) and 0.9 times of condensing agent (DIC, DIC), reaction system
Reacted 36 hours at 35 DEG C, obtain target sensitising agent M-6 (yield 40%).HR-MS(ESI):m/z
[M+H]:Calcd.for[C73H106N11O19]+1439.7588；found 1439.7575.
Embodiment 7
Obtained sensitising agent in embodiment 3 is used for the determination experiment that fat moisture is matched
10 micromolar sensitising agents are dissolved in 2mL PBS, 2mL n-octyl alcohols is then added, will mix
Solution shakes 3min, then is placed in ultrasonic wave and vibrates 5min, then under 5000 turns per minute of speed
5min is centrifuged, makes two-phase laminated flow.The abosrption spectrogram of the sensitising agent in two-phase is determined, passes through Lambert-beer
Law, which is calculated, obtains concentration of the sensitising agent in two-phase, and fat moisture proportioning (Log PC) is that sensitising agent exists
Concentration proportion in two-phase, is shown in Table 1.
Embodiment 8
With reference to the operation in embodiment 7, obtained sensitising agent in embodiment 4 is used for what fat moisture was matched
Determination experiment, is shown in Table 1.
Embodiment 9
With reference to the operation in embodiment 7, obtained sensitising agent in embodiment 5 is used for what fat moisture was matched
Determination experiment, is shown in Table 1.
Embodiment 10
With reference to the operation in embodiment 7, obtained sensitising agent in embodiment 6 is used for what fat moisture was matched
Determination experiment, is shown in Table 1.
Embodiment 11：
Obtained sensitising agent M-1 in embodiment 1 is used for into monochromatic light sub-light dynamic experiment proves its targeting
(I) the MCF-7 cells and the A549 cells of folacin receptor normal expression being overexpressed folic acid,
According to 104The cell density of individual/milliliter is inoculated in 96 porocyte culture plates, and nutrient solution is containing 5% small ox blood
The RPMI 1640 without folic acid component of (FBS) clearly, after being incubated 24 hours at 37 DEG C, adds sensitising agent
M-1, photosensitizer concentration is 2.5 μM, continues to be incubated 8 hours；
(II) 96 orifice plates are taken out, with 515nm LED (half-peak breadth 40nm, power 36mW, work(
Rate density 10mW cm-2) irradiating sample 15 minutes, continue to be incubated 24 hours after irradiation, using CCK-8
Test cell activity.It is the cell being incubated without sensitising agent to compare blank test, as 100% cell
The baseline of survival rate.By killing rate of the test result calculations sensitising agent to two kinds of cells, folic acid target is found
The inactivating efficacy for the tumour cell MCF-7 being overexpressed to sensitising agent to folacin receptor is more excellent, so as to prove it
Targeting.Such as accompanying drawing 7.
Embodiment 12：
Obtained sensitising agent M-2 in embodiment 2 is used for double-photon optical dynamic experiment
(I) the Hela cells of in vitro culture, by 1.0 × 104The cell density of individual/milliliter is inoculated in 96
Porocyte culture plates, nutrient solution is the RPMI 1640 containing 5% calf serum (FBS), is incubated at 37 DEG C
After 24 hours, sensitising agent M-2 is added, photosensitizer concentration is 2.5 μM, continues to be incubated 8 hours；
(II) irradiated 10 minutes using 800nm femtosecond lasers, light source is Ti:Sapphire regenerative amplifications
Device (Spitfire, Spectra-Physics, 1kHz,<130fs, 630mW), spot size about 7mm, often
Secondary one hole of irradiation (bore dia of 96 orifice plates is 6.4mm)；Continue to be incubated 24 hours after irradiation, use
CCK-8 test cells activity.It is the cell being incubated without sensitising agent to compare blank test, as
The baseline of 100% cell survival rate.By killing rate of the test result calculations sensitising agent to two kinds of cells, such as
Accompanying drawing 8.
Embodiment 13
With reference to the operation in embodiment 11, obtained sensitising agent in embodiment 2 is used for monochromatic light sub-light power
Experiment proves its targeting, such as accompanying drawing 9.
Embodiment 14
With reference to the operation in embodiment 12, obtained sensitising agent in embodiment 1 is used for double-photon optical power
Experiment.Such as accompanying drawing 10.
Embodiment 15
Using Molinspiration softwares, the bioactivity of obtained sensitising agent in embodiment 3 is predicted
Chemical constitution obtained by the ChemDraw of sensitising agent is input to the biology of Molinspiration softwares
In the window of Activity Prediction, prediction button is clicked on, the parameters of test result is analyzed, observes its negative electricity
Property degree, is shown in Table 2.
Embodiment 16
With reference to the operation in embodiment 15, obtained sensitising agent in embodiment 4 is used for the pre- of bioactivity
Survey experiment.It is shown in Table 2.
Embodiment 17
With reference to the operation in embodiment 15, obtained sensitising agent in embodiment 5 is used for the pre- of bioactivity
Experiment is surveyed, 2 are shown in Table.
Embodiment 18
With reference to the operation in embodiment 15, obtained sensitising agent in embodiment 6 is used for the pre- of bioactivity
Experiment is surveyed, 2 are shown in Table.
Embodiment 19
The process that obtained sensitising agent in embodiment 1 is used to verify two-photon excitation
(I) light source used in is spectrum physics Tsunami locked modes Ti:Sapphire femto-second lasers (720-880
nm,80MHz,<130fs).Up-conversion fluorescence is by fiber spectrometer (Ocean Optics USB2000
CCD) record.Build light path.
(II) optical maser wavelength is fixed on 800nm, regulation incident intensity is respectively 50mW, 70mW, 90mW,
110mW and 130mW, gathers the up-conversion fluorescence spectrum of sensitising agent under different light intensity.
(III) using the area calculating fluorescence intensity of up-conversion fluorescence spectrum, and pair of this fluorescence intensity is utilized
Several logarithms to incident intensity are mapped, and obtain straight slope, this slope value is close to 2, it was demonstrated that this is one
The process of two-photon absorption.See accompanying drawing 11.
Embodiment 20
With reference to the operation in embodiment 19, obtained sensitising agent in embodiment 2 is used to verify that two-photon swashs
The process experiment of hair.See accompanying drawing 12.
The fat moisture proportioning of the gained sensitising agent of 1 embodiment of table 3,4,5,6
| Sensitising agent title | Log PC |
| M-3 | 0.98 |
| M-4 | -0.66 |
| M-5 | 0.07 |
| M-6 | 0.72 |
The bioactivity prediction index parameter of the gained sensitising agent of 2 embodiment of table 3,4,5,6
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and
It is not the restriction to embodiments of the present invention, for those of ordinary skill in the field,
It can also be made other changes in different forms on the basis of described above, here can not be to all
Embodiment be exhaustive, it is every to belong to the obvious change that technical scheme is extended out
Change or change the row still in protection scope of the present invention.
Claims (10)
1. folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent, it is characterised in that with following knot
Structure formula M：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4.
2. the preparation of folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent as claimed in claim 1
Method, it is characterised in that comprise the following steps：
1) C6 is synthesized, reaction equation is as follows：
Wherein：R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
Comprise the following steps that：
0.01~0.2 mole of C3 is dissolved in 50~250 milliliters of ethanol-water solutions, wherein, alcohol-water is molten
The volumn concentration of ethanol is 30%~90% in liquid；Quality is slowly added to for C3 mass to above-mentioned system
1~20 times of alkaline matter, be stirred continuously make its be well mixed；Reaction mixture in a nitrogen atmosphere,
After 50~95 DEG C of stirrings 4~24 hours, using in acidic materials and above-mentioned system, concentration of reaction solution；To
In system after concentration add quality be C3 mass 1~15 times of concentration be 3~10M hydrochloric acid after,
It is heated to reflux 10~48 hours, cools down under nitrogen atmosphere；During end reaction liquid is neutralized to alkaline matter
Property, extracted with dichloromethane, intermediate product C4 is obtained after removing dichloromethane through drying, filtering, revolving；
The quality that 1~5 times of phosphorus pentachloride that mole is reaction substrate amount is added under ice bath be its 2~6
Reaction forms Vilsmeier reagents in 0.5~1 hour in DMF again；The dropwise reaction bottom into above-mentioned system
Thing C4, stirring reaction was recovered to normal temperature and neutralized with alkaline matter after 2~12 hours at 70~140 DEG C
Reaction system；Reaction solution is extracted with dichloromethane, and extract is washed with water, through drying, filtering, revolving
Remove extractant and obtain C5；
Above-mentioned intermediate product C5 is dissolved in into quality in its 2~20 times methanol, to add under agitation mole
Amount is the aqueous solution of intermediate product C5 1-3 times of alkaline matter, is persistently stirred 2~10 hours, is stopped
Reaction, removes methanol by reaction solution revolving, uses dichloromethane aqueous phase extracted, obtained dichloromethane extraction
Liquid is washed with water to neutrality, and removing dichloromethane through drying, filtering, revolving obtains product C6；
2) C7 is synthesized, reaction equation is as follows：
Wherein：R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
By C2 and step 1) gained C6 according to mole 1:1~2 ratio is dissolved in dichloromethane, so
1~2 times of catalyst, 1~5 times of acid binding agent that mole is C6 moles are sequentially added afterwards, are added
With the condensing agent that C6 mole ratios are 0.8~1.5；Reaction system was reacted after 6~24 hours at room temperature, instead
Answer liquid to be extracted with dichloromethane, extract is washed with water, remove extractant through drying, filtering, revolving and obtain
To C7；
3) C12 is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
By step 2) gained C7 and C11 according to mol ratio 1：1~2.5 ratio adds reaction vessel,
Then 10~200 times of the ethanol as solvent that quality is C11 is added, it is C11 moles to add mole
0.01~0.6 times of base catalyst, 25~60 DEG C react 10~40 hours, through revolving remove it is molten
Agent obtains crude product, and C12 is obtained with chromatographic column separating-purifying；
4) C13 is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
10~500 milliliters of dichloromethane are taken to add in reaction vessel, ice bath adds matter thereto to 0~5 DEG C
1~15 times of the trifluoroacetic acid for C12 mass is measured, is stirred；The two of C12 are slowly added dropwise thereto
Chloromethanes solution, reacts 6~24 hours in 0~40 DEG C；The trifluoroacetic acid of solvent and excess is removed through revolving,
Obtain C13；
5) M is synthesized, reaction equation is as follows：
Wherein：R1For-(C2H4O)m-R5Group；
R2For methyl, ethyl or-(C2H4O)n-R6Group；
R1And R2It can be identical or different substituted radical；
R3For methyl, ethyl, propyl group or isopropyl, it is preferable that R3For methyl or ethyl；
R4For-(CH2)p- group or-CH2CH2(OCH2CH2)q- group；
For cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone；
The m=3,4,5,6,7 or 8, it is preferable that m is 4 or 5；R5For methyl, ethyl,
Propyl group or isopropyl, it is preferable that R5For methyl；
The n=3,4,5,6,7 or 8, it is preferable that n is 4 or 5；R6For methyl, ethyl, third
Base or isopropyl, it is preferable that R6For methyl；
The p=1,2,3,4,5,6,7 or 8, it is preferable that p is 2,3 or 4；
The q=1,2,3 or 4；
Comprise the following steps that：
0.01~0.5 mM of folic acid is weighed, i.e. C14 is added in reaction vessel, according to C14 and diformazan
The mass ratio of base sulfoxide is 1:50~200 ratio mixing, stirring is completely dissolved folic acid；To reaction system
Middle to add 1~1.3 times of the reactant C13 that mole is folic acid mole, then sequentially adding mole is
1~2 times of catalyst, 1~3 times of acid binding agent and 0.8~1.5 times of the condensing agent of folic acid mole；Reaction
It is miscible using chloroform extraction and saturated aqueous common salt after system is reacted 12~48 hours at 25~40 DEG C
Reaction solution, extract is separated through revolving, freeze-drying, efficient liquid phase, obtains target sensitising agent M.
3. preparation method according to claim 2, it is characterised in that the alkaline matter is hydrogen-oxygen
Change sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, one or both of saleratus with
The mixture of upper arbitrary proportion.
4. preparation method according to claim 2, it is characterised in that the acidic materials be sulfuric acid,
The mixture of one kind or its arbitrary proportion in hydrochloric acid.
5. preparation method according to claim 2, it is characterised in that the catalyst is 1- hydroxyls
BTA, 1- hydroxyl -7- azos BTA, DMAP, N- hydroxysuccinimides
One or both of any of the above ratio mixture.
6. preparation method according to claim 2, it is characterised in that the acid binding agent is N, N-
One or both of diisopropylethylamine, triethylamine, pyridine, DMAP any of the above ratio
The mixture of example.
7. preparation method according to claim 2, it is characterised in that the condensing agent is two hexamethylenes
Base carbodiimide, DIC, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride,
One or both of 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester is to take up an official post
The mixture of meaning ratio.
8. preparation method according to claim 2, it is characterised in that the base catalyst is hydrogen
In lithia, sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine
One or more of combinations.
9. it is prepared by folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent as claimed in claim 1
Application in single photon or double-photon optical dynamic therapy photosensitive drug.
10. the benzal cycloalkane ketone sensitising agent of folate-targeted fat water amphiphilic according to claim 9
Application in single photon or double-photon optical dynamic therapy photosensitive drug is prepared, it is characterised in that described
The benzal cycloalkane ketone sensitising agent of folate-targeted fat water amphiphilic can recognize that folacin receptor is thin into positive tumour
Born of the same parents, have targeting in optical dynamic therapy.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102249939A (en) * | 2010-05-19 | 2011-11-23 | 中国科学院理化技术研究所 | Lipid-water amphiphilic benzylidene cyclopentanone dye, preparation method thereof and application thereof in photodynamic therapy |
| CN102249940A (en) * | 2010-05-19 | 2011-11-23 | 中国科学院理化技术研究所 | Lipid-water amphiphilic benzylidene cyclopentanone dye, synthetic method thereof and application thereof in two-photon photodynamic therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102249939A (en) * | 2010-05-19 | 2011-11-23 | 中国科学院理化技术研究所 | Lipid-water amphiphilic benzylidene cyclopentanone dye, preparation method thereof and application thereof in photodynamic therapy |
| CN102249940A (en) * | 2010-05-19 | 2011-11-23 | 中国科学院理化技术研究所 | Lipid-water amphiphilic benzylidene cyclopentanone dye, synthetic method thereof and application thereof in two-photon photodynamic therapy |
Non-Patent Citations (2)
| Title |
|---|
| YANYAN FANG ET AL: "Synthesis of Folate Receptor-targeted Photosensitizers for Photodynamic Therapy", 《PROC. OF SPIE》 * |
| YUXIA ZHAO ET AL: "Polyethylene glycol-functionalized benzylidene cyclopentanone dyes for two-photon excited photodynamic therapy", 《ORG. BIOMOL. CHEM.》 * |
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