CN106866721A - A kind of silicon phthalocyanine derivative and its prepare biotin acceptor target silicon phthalocyanine sensitising agent application - Google Patents
A kind of silicon phthalocyanine derivative and its prepare biotin acceptor target silicon phthalocyanine sensitising agent application Download PDFInfo
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- CN106866721A CN106866721A CN201710141083.XA CN201710141083A CN106866721A CN 106866721 A CN106866721 A CN 106866721A CN 201710141083 A CN201710141083 A CN 201710141083A CN 106866721 A CN106866721 A CN 106866721A
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- China
- Prior art keywords
- biotin
- sipc
- silicon phthalocyanine
- phthalocyanine derivative
- pip
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- 239000011616 biotin Substances 0.000 title claims abstract description 103
- 229960002685 biotin Drugs 0.000 title claims abstract description 102
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 title claims abstract description 100
- 235000020958 biotin Nutrition 0.000 title claims abstract description 51
- JACPFCQFVIAGDN-UHFFFAOYSA-M sipc iv Chemical class [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].C=1C=CC=C(C(N=C2[N-]C(C3=CC=CC=C32)=N2)=N3)C=1C3=CC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 JACPFCQFVIAGDN-UHFFFAOYSA-M 0.000 title claims abstract description 42
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 37
- 230000001235 sensitizing effect Effects 0.000 title claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 61
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- 239000000377 silicon dioxide Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical class OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- YMXHPSHLTSZXKH-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl)pentanoate Chemical compound S1CC2NC(=O)NC2C1CCCCC(=O)ON1C(=O)CCC1=O YMXHPSHLTSZXKH-UHFFFAOYSA-N 0.000 claims description 6
- CACCWEPNYHGKGD-UFLZEWODSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid;n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 CACCWEPNYHGKGD-UFLZEWODSA-N 0.000 claims description 6
- 208000016610 ataxia-hypogonadism-choroidal dystrophy syndrome Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000001179 sorption measurement Methods 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 208000019065 cervical carcinoma Diseases 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- QUTGXAIWZAMYEM-UHFFFAOYSA-N 2-cyclopentyloxyethanamine Chemical compound NCCOC1CCCC1 QUTGXAIWZAMYEM-UHFFFAOYSA-N 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 41
- 230000000694 effects Effects 0.000 abstract description 18
- 231100000419 toxicity Toxicity 0.000 abstract description 15
- 230000001988 toxicity Effects 0.000 abstract description 15
- 238000002428 photodynamic therapy Methods 0.000 abstract description 11
- 230000008685 targeting Effects 0.000 abstract description 11
- 230000014509 gene expression Effects 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- -1 silicon phthalocyanine compound Chemical class 0.000 abstract description 4
- 239000003504 photosensitizing agent Substances 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- 150000001615 biotins Chemical class 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 35
- 238000002474 experimental method Methods 0.000 description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000005286 illumination Methods 0.000 description 7
- 206010034972 Photosensitivity reaction Diseases 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 208000007578 phototoxic dermatitis Diseases 0.000 description 6
- 231100000018 phototoxicity Toxicity 0.000 description 6
- 238000006862 quantum yield reaction Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 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 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000005588 protonation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 2
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000000547 structure data Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 2
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 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 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 108010053098 biotin receptor Proteins 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- BUMGIEFFCMBQDG-UHFFFAOYSA-N dichlorosilicon Chemical compound Cl[Si]Cl BUMGIEFFCMBQDG-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- JKRHDMPWBFBQDZ-UHFFFAOYSA-N n'-hexylmethanediimine Chemical compound CCCCCCN=C=N JKRHDMPWBFBQDZ-UHFFFAOYSA-N 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
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- RWMKKWXZFRMVPB-UHFFFAOYSA-N silicon(4+) Chemical compound [Si+4] RWMKKWXZFRMVPB-UHFFFAOYSA-N 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 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
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to photo-dynamical medicine and sensitising agent technical field, and in particular to a kind of silicon phthalocyanine derivative, and further disclose it and be used to preparing the application that biotin acceptor targets silicon phthalocyanine sensitising agent.Silicon phthalocyanine derivative of the present invention, is on the basis of existing silicon phthalocyanine compound, biotin to be introduced into silicon phthalocyanine axial arrangement by covalent bond, has synthesized a kind of new silicon phthalocyanine analog derivative.The silicon phthalocyanine analog derivative can with target biology element acceptor high expression tumour cell, and be a kind of new biotin acceptor targeting phthalocyanines sensitising agent with excellent photodynamic activity.Meanwhile, the SiPc biotin derivatives will be significantly less than its precursor SiPc pip to the dark toxicity of human normal cell line, be a kind of potential targeting photosensitizer for photodynamic therapy.
Description
Technical field
The invention belongs to photo-dynamical medicine and sensitising agent technical field, and in particular to a kind of silicon phthalocyanine derivative, one is gone forward side by side
Step discloses it to be used to prepare the application that biotin acceptor targets silicon phthalocyanine sensitising agent.
Background technology
Optical dynamic therapy (Photodynamic Therapy, abbreviation PDT), also known as photoradiation therapy
(Photoradiation Therapy, abbreviation PRT) or photochemotherapy (Photochemotherapy), are that one kind is based on
The treatment method of the photochemical reaction principle of particular chemicals, is a kind of tumor therapeuticing method emerging in recent years.Used
Chemical substance is referred to as tumour chemistry diagnosis and treatment medicine (also referred to as sensitising agent, Photosensitizer, abbreviation PS).PDT therapy processes are
Sensitising agent is injected in vivo (can also be applied to affected part for skin) by being injected intravenously, by after certain hour with specific
The light irradiation tumor tissues of wavelength, the sensitising agent for being enriched in tumor tissues is excited by illumination, it is produced active oxygen species
(Reactive oxygen species, ROS), and then reach the purpose for killing tumour.Relative to other oncotherapy sides
Method, PDT has the advantages that the good, toxic and side effect of selectivity is small.Therefore, PDT is acknowledged as clinically except change
The 4th kind of cancer treatment method outside treatment, radiotherapy, operation.Since first photosensitive drugIn 1993~
1997 since the country such as the U.S., Canada, European Union in succession listing, along with continuing to develop for laser technology, PDT
Enter Rapid development stage.At present, PDT has become most active research neck in the disease prevention and cure subject such as tumour
Domain.
ROS has a very strong oxidisability, and its high activity being capable of efficiently oxidative biological molecule, such as nucleic acid, albumen and insatiable hunger
With aliphatic acid etc..Also due to the high activity of ROS also causes its life-span very of short duration, light power effect is set to be concentrated mainly on irradiated region
Domain.But, because the tumor-targeting of sensitising agent traditional at present is poor, sensitising agent is inevitably enriched with health tissues,
This can not only reduce concentration of the sensitising agent in tumor tissues, influence therapeutic effect, and be enriched in the sensitising agent of normal structure
Some side effects can be brought, pain is brought to patient.Therefore, exploitation has the sensitising agent of selectively targeted ability to tumor tissues
It is current PDT problem demanding prompt solution.
Phthalocyanines sensitising agent has a strong absorption due to it in phototherapy window (650-850nm), and dark toxicity is low, creating singlet oxygen
(1O2) quantum yield is high and the characteristics of be easy to modification, becomes most potential sensitising agent in second generation sensitising agent.Silicon phthalocyanine
(silicon (IV) phthalocyanine, SiPc) is obtained as one kind of phthalocyanines sensitising agent in the research of optical dynamic therapy
Extensive concern is arrived.Have been reported and show, by introduce with cancer target ability group or molecule, such as polyamines, carbohydrate,
Polypeptide, monoclonal antibody and vitamin etc., can aid in the tumor-targeting of enhancing sensitising agent.Various bases are had been developed at present
In the novel photosensitive agent of silicon phthalocyanine structure, but there is a problem that targeting is slightly poor to a certain extent.
The content of the invention
Therefore, the technical problems to be solved by the invention are to provide a kind of biotin acceptor targeting silicon phthalocyanine sensitising agent,
To solve the problems, such as that sensitising agent tumor-targeting is not strong in the prior art.
In order to solve the above technical problems, silicon phthalocyanine derivative of the present invention, is the silicon phthalocyanine of biotin axial substituted
Derivative, it has structure shown below：
The invention also discloses a kind of method for preparing the silicon phthalocyanine derivative, comprise the following steps：
(1) synthesis of SiPc-pip
Under inert gas shielding, with SiPcCl2With 4- hydroxy piperidines be raw material, sodium hydride be catalyst in the presence of, it is molten
Back flow reaction is carried out in toluene solvant；After reaction terminates, decompression steams solvent, and rinsing residue, is separated with silica gel column chromatography
Navy blue product is obtained, as required SiPc-pip；
(2) synthesis of SiPc-biotin
With SiPc-pip obtained above as raw material, N-hydroxy-succinamide biotin is added, in the presence of organic amine,
It is dissolved in DMF solvent and is reacted, terminate rear evaporated under reduced pressure solvent, navy blue product is obtained with silica gel column chromatography, it is as required
SiPc-biotin；
In the step (1), the SiPcCl2It is 1-4 with the mol ratio of 4- hydroxy piperidines：10.
In the step (1), what the silica gel column chromatography was separate concretely comprises the following steps：Using 200-300 mesh silica gel, trichlorine is used
Methane fills post；Take sample to be dissolved in DMF solvent, 3 times of silica white adsorption samples of quality are added, after evaporated under reduced pressure DMF, with silica gel
Powder upper prop, is 20 with volume ratio：1 chloroform-methanol solution is eluted for eluant, eluent.
In the step (2), the organic amine is DIPEA or triethylamine.
In the step (2), the mol ratio of the N-hydroxy-succinamide biotin and SiPc-pip is 4-10：1, and
It is preferred that 6：1.
In the step (2), the silica gel column chromatography is concretely comprised the following steps：Using 200-300 mesh silica gel, chloroform is used
Dress post；Take sample to be dissolved in DMF solvent, 3 times of silica white adsorption samples of quality are added, after evaporated under reduced pressure DMF, with silica white
Post, is 30 with volume ratio：1 chloroform-methanol solution is eluted for eluant, eluent.
Further, the preparation method also includes the step of preparing N-hydroxy-succinamide biotin, specifically includes：
Under inert gas shielding, with biotin and N- hydroxysuccinimides as raw material, in N, N'- dicyclohexylcarbodiimides or 1-
In the presence of ethyl-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, it is dissolved in DMF solvent and is reacted, is filtered after terminating
Reaction solution and evaporated under reduced pressure, product ether precipitation obtain final product required BNHS；
The biotin is 1 with the mol ratio of N- hydroxysuccinimides：1-3, and preferably 1：1.25.
The invention also discloses a kind of biotin acceptor targeting silicon phthalocyanine sensitising agent, by described silicon phthalocyanine derivative system
.
It is used to prepare photo-dynamical medicine, photosensitive drug or treating cancer the invention also discloses described silicon phthalocyanine derivative
The purposes of medicine.
The cancer includes cervical carcinoma.
It is the invention also discloses a kind of pharmaceutical composition, including described silicon phthalocyanine derivative and pharmaceutically acceptable
Auxiliary material and/or carrier.
The invention also discloses the clinically-acceptable preparation prepared according to common process by described pharmaceutical composition.
Silicon phthalocyanine derivative of the present invention, is on the basis of existing silicon phthalocyanine compound, by covalent bond by biotin
It is introduced into silicon phthalocyanine axial arrangement, has synthesized a kind of new silicon phthalocyanine analog derivative.According to it has been found that in numerous tumours
In targeted molecular, the growth of cell can be promoted due to biotin, therefore relative to normal cell, tumour cell needs more
Biotin causes biotin acceptor (biotin receptor, BR) in kinds of tumor cells to maintain its fast breeding
Middle overexpression.Herein described derivative, then by means of this advantage of biotin, using biotin as targeting group and as swell
The target spot of knurl specific drug, synthesized silicon phthalocyanine analog derivative can with target biology element acceptor high expression tumour cell, and
It is a kind of new biotin acceptor targeting phthalocyanines sensitising agent with excellent photodynamic activity.Meanwhile, the SiPc-
Biotin derivatives will be significantly less than its precursor SiPc-pip to the dark toxicity of human normal cell line, be a kind of potential targeting light
Dynamic therapy sensitising agent.
Brief description of the drawings
In order that present disclosure is more likely to be clearly understood, below according to specific embodiment of the invention and combine
Accompanying drawing, the present invention is further detailed explanation, wherein,
Fig. 1 is compound SiPc-pip and SiPc-biotin UV-vis absorption spectrums in DMF and 0.5%CEL, wherein
Figure (a) is SiPc-pip, schemes (b) for SiPc-biotin (10 μM)；0.5%CEL:The PBS solution of 0.5%Cremophor EL
(0.5g is dissolved in 100mL PBS)；
Fig. 2 is the fluorescence spectrum of compound SiPc-pip and SiPc-biotin in DMF and 0.5%CEL, wherein figure (a)
For SiPc-pip, figure (b) are SiPc-biotin (5 μM)；0.5%CEL:(0.5g is molten for the PBS solution of 0.5%Cremophor EL
In 100mL PBS)；
Fig. 3 is in 0.5%CEL, the creating singlet oxygen that illumination compound SiPc-pip and SiPc-biotin are produced is inhaled to DPBF
Receive the attenuation of spectrum；
Fig. 4 is the amount of Hela intracellular compounds SiPc-pip and SiPc-biotin；
Fig. 5 is excess biotin (100 μM) to compound SiPc-pip and SiPc-biotin and Hela cell binding abilities
Influence；
Fig. 6 is the fluorescence imaging image of Hela cells；Wherein, figure (a) is (2 μM) culture 1h of SiPc-pip；Scheming (b) is
Hela is pre-processed for (100 μM) first with biotin, then with (2 μM) culture 1h of SiPc-pip；Figure (c) is SiPc-biotin (2 μ
M 1h) is cultivated；Figure (d) is that Hela is pre-processed for (100 μM) first with biotin, then with (2 μM) culture 1h of SiPc-biotin；
Fig. 7 is (λ ≈ 670nm, light intensity 20mWcm under illumination-2, accumulated dose 24Jcm-2), the survival rate of Hela cells；
Fig. 8 is dark and illumination condition (λ ≈ 670nm, light intensity 20mWcm-2, accumulated dose 24Jcm-2) under, compound
Toxicity of the SiPc-pip and SiPc-biotin to Hela；
Fig. 9 is dark toxicity test results of the compound SiPc-pip and SiPc-biotin to LO2.
Specific embodiment
Reagent, instrument and the method being related in following examples include：
Reagent：Phthalocyanine silicon dichloride (SiPcCl2), 4- hydroxy piperidines (4-piperidinol), biotin (biotin), two rings
Hexyl carbodiimide (DCC), N-hydroxy-succinamide (NHS), DIPEA (DIPEA), sodium hydride (NaH),
Emulsifier EL-60 (CEL) is purchased from Sigma-Aldrich, Alfa Aesar and J＆K companies respectively；Dimethylformamide
(DMF) steamed again under a nitrogen with sodium hydride with toluene (toluene)；Cell culture reagent is purchased from Bioind (BI) company；
Instrument and method：
Uv-vis spectra and fluorescence spectrum are in Perkin-Elmer Lambda-25 spectrophotometers and Perkin
Determined on Elmer LS-55 luminoscopes；1H NMR are determined on Bruker DMX 400MHz nuclear magnetic resonance chemical analysers；ESI mass spectrums
Determined on the mass spectrographs of Waters SQ Detector 2；Elementary analysis is surveyed on VarioEL III CHNS elemental analysers
It is fixed；
Fluorescence quantum yield (ΦF) determined in DMF, ZnPc is used as reference (Φ in DMFF=0.28)7；Creating singlet oxygen
(1O2) quantum yield determines in DMF, DPBF conducts1O2Capturing agent, ZnPc is used as reference (Φ in DMF△=0.56)8。
The BNHS used in the following each embodiments of the present invention, can be for existing commercially available prod or according to method in the prior art
Synthesis gained, BNHS synthesizes as follows in following embodiments of the invention：
Under nitrogen protection, biotin (0.50g, 2.05mmol) and NHS (0.29g, 2.56mmol) are dissolved in 20mLDMF
In solvent, and the DMF solution (5mL) containing DCC (0.41g, 2.05mmol) is added, room temperature reaction is overnight.Filtering reacting liquid, and
Evaporated under reduced pressure, product ether precipitation obtains BNHS, and is washed with ether three times.Also DCC can be replaced with 1- ethyls-(3- bis-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate reacted.
Embodiment 1
The method that silicon phthalocyanine derivative is prepared described in the present embodiment, comprises the following steps：
(1) synthesis of SiPc-pip
Under nitrogen protection, by SiPcCl2(0.10g, 0.16mmol), 4- hydroxy piperidines (0.16g, 1.6mmol) and hydrogenation
Sodium (0.03g, 1.28mmol) is dissolved in toluene solvant (50mL), back flow reaction 24 hours；Decompression steams solvent, washes with water residual
Slag；Silica gel column chromatography is separated, and actual conditions is：Using 200-300 mesh silica gel, post is filled with chloroform；Take sample and be dissolved in 20mL
In DMF, add 3 times of silica white adsorption samples of quality, evaporated under reduced pressure DMF solvent, and with silica white upper prop, with chloroform-
Methyl alcohol (volume ratio 20：1) it is eluant, eluent, obtains 0.02g navy blue products, it is 21% to calculate yield；
Detection product structure data are as follows：1H NMR(400MHz,CDCl3),δ(ppm):9.62~9.64 (8H, m, Pc-
Hα), 8.33~8.35 (8H, m, Pc-Hβ), 0.83~0.85 (4H, m, NCH2), 0.64~0.66 (4H, m, NCH2),-1.82
(4H,br,CH2), -2.31~-2.35 (4H, m, CH2), -2.68~-2.71 (2H, m, OCH) .ESI-MS:m/z 763.36
(20%) [M+Na+].Elemental analysis:Found:C,68.2；H,5.1；N, 18.7%；Calc.for
C42H36N10O2Si:C,68.1；H,4.9；N, 18.9%.It can be seen that, product structure is correct.
(2) synthesis of SiPc-biotin
By the BNHS (0.084mmol) and SiPc-pip (0.01g, 0.014mmol) of above-mentioned preparation, and DIPEA (10 μ
L, 0.056mmol) it is dissolved in DMF solvent, in room temperature reaction overnight；After evaporated under reduced pressure solvent, silica gel column chromatography, specific steps bag
Include：Using 200-300 mesh silica gel, post is filled with chloroform, take sample and be dissolved in 20mL DMF solvents, add 3 times of silicon of quality
Rubber powder adsorption sample, evaporated under reduced pressure DMF solvent, and with silica white the upper prop, (volume with chloroform-methanol solution as eluant, eluent
Than 30：1) 0.01g navy blue SiPc-biotin products, are obtained, it is 79% to calculate products collection efficiency；
Detection product structure data are as follows：1H NMR(400MHz,CDCl3),δ(ppm):9.70(8H,br,Pc-Hα),
8.53(8H,br,Pc-Hβ),6.23(2H,s,biotin-NH),6.12(2H,s,biotin-NH),4.13(2H,br,
biotin-CH),3.84(2H,br,biotin-CH),3.09(4H,br,biotin-SCH2),2.72(4H,br,biotin-
SCH),1.99(4H,br,biotin-COCH2), 0.95~0.74 (4H, m, biotin-CH2CH2CH2,CH2NCH2),-1.68
(4H,br,CH2),-2.51(6H,br,CHCH2).ESI-MS:[the M+Na of m/z 1215.78 (87%)+]。Elemental
analysis:Found:C,62.6；H,5.5；N,16.2；S, 5.3%；Calc.for C62H64N14O6S2Si:C,62.4；H,
5.4；N,16.4；S, 5.4%.It can be seen that, product structure is correct.
Embodiment 2
The method that silicon phthalocyanine derivative is prepared described in the present embodiment is same as Example 1, and it is differed only in, the step
(2) in, DIPEA catalyst is replaced with into triethylamine as catalyst.After testing, products therefrom structure is correct.
Experimental example
1st, lipid (log P)
Take the gained compound of a certain amount of embodiment 1 and be dissolved in n-octyl alcohol-water 1:In 1 mixed solvent, ultrasound 30 minutes
It is set to balance between the two phases.After centrifugation, with absorption spectromtry compound concentration between the two phases.The hydrophilic parent of compound
Lipid can be reacted with its lipid (log P), compound thing in the concentration/water of compound in P=n-octyl alcohols
Concentration.Log P are bigger, represent that compound gets over lipophilic, conversely, then more hydrophilic.And the Lipophilicity of compound and its biology
Activity is closely related.
Experimental result shows that the lipophilicity that embodiment 1 is obtained compound SiPc-biotin (log P=1.6) is significantly stronger than
SiPc-pip (log P=-0.9).Existing result of study shows that the Lipophilicity of SiPc depends primarily on axial substituted base
Property.In SiPc-pip, because its axial substituted base is hydrophilic piperidines group, SiPc-pip is set to show significantly
Hydrophily.And in SiPc-biotin compounds, the introducing of hydrophobic biotin causes the lipophilicity of SiPc-biotin big
It is big to increase.
2nd, optical physics and spectrochemical property
The spectral quality in DMF of detection compound SiPc-pip and SiPc-biotin is as shown in table 1 below.Result shows
Show, the fluorescence (Φ of SiPc-biotinF) and creating singlet oxygen (ΦΔ) quantum yield is significantly stronger than SiPc-pip.This result can be with
Explained with intramolecular photo induced electron transfer (PET) effect：There is amine groups in compound SiPc-pip very strong PET to imitate
Should, this can be quenched the singlet excited of SiPc, suppress singlet excited be between pass through (ISC), ultimately result in relatively low fluorescence
With creating singlet oxygen quantum yield.And in compound SiPc-biotin, amine groups are changed into amido link, it is former that this reduces nitrogen
The electron donation of son, therefore reduce the PET effects of amine groups.
The photochemical light physical property of table 1.SiPc-pip and SiPc-biotin.
a610nm is excited.bZnPc as reference (in DMF, ΦF=0.28)cZnPc is used as reference (DMF
In, ΦΔ=0.56).
Because the application of the PDT of SiPc needs to carry out in aqueous, therefore we compare compound
Photochemistry and photophysical property of the SiPc-pip and compound SiPc-biotin in PBS (pH=7.4,10mM) solution.
Result shows that SiPc-pip and SiPc-biotin is respectively provided with the characteristic absorption of monomer silicon phthalocyanine：At 355nm
B bands and positioned at 673nm or so Q band (as shown in Figure 1).In the case where 610nm wavelength light sources are excited, compound SiPc-pip and
The fluorescent emission of SiPc-biotin is respectively 683nm and 686nm (as shown in Figure 2).
As shown in (a) in Fig. 1, in PBS, the Q bands of SiPc-pip have absorbed compared with red shift in DMF about 6nm, this be mainly by
Caused in solvent effect.Importantly, the Q band absorption bands of SiPc-pip are still narrow and strong in PBS, this explanation
There is no obvious aggregation in PBS in SiPc-pip.Meanwhile, hyperfluorescence transmittings of the SiPc-pip in PBS also demonstrates that SiPc-pip
(shown in such as Fig. 2 (a)) substantially existed with monomeric form in PBS.In addition, fluorescence outlines of the SiPc-pip in PBS is strong
In the fluorescence in DMF.This is caused mainly due to the amido of piperidines in the protonation of PBS, and protonation is reduced
The PET effects of amine groups.Different from compound SiPc-pip, the Q bands of compound SiPc-biotin absorb and occur in PBS
Obvious change, absworption peak broadens, and newly occurs in that two absworption peaks of red shift.This shows compound SiPc-biotin in PBS
In have the aggregation of some degree, SiPc-biotin weaker in PBS fluorescence also indicates that SiPc-biotin there occurs aggregation (such as
Shown in Fig. 2 (b)).
Because aggregation can cause sensitising agent to produce the ability of ROSs to decline, and reduce the PDT activity of sensitising agent.Therefore, it is
The comprehensive PDT activity for assessing both sensitising agents, further determines the two efficiency that creating singlet oxygen is produced in PBS.Knot
As shown in figure 3, in PBS solution, the speed of compound SiPc-pip degradeds DPBF is apparently higher than compound SiPc- for fruit
Biotin, illustrates that SiPc-pip has creating singlet oxygen quantum yield higher.This is with the result in DMF conversely, this result
Can be explained in terms of two：First, piperidines group protonation in PBS can strengthen the creating singlet oxygen effect of SiPc-pip
Rate；Secondly, the aggregation of SiPc-biotin causes its creating singlet oxygen efficiency to reduce.
3rd, cellular uptake
In order to the introducing for proving biotin can improve the binding ability of SiPc and biotin acceptor high expression tumour cell,
The application has carried out cell absorption experiment with extraction, i.e., extracted the sensitising agent that cell absorbs using solvent, is determined
Amount analysis.
3.1 cell culture
Biotin acceptor expression Hela cells high, human cervical carcinoma cell Hela and Human normal hepatocyte are employed in experiment
LO2 culture, cultivation temperature in the DMEM (dulbecco's modified eagle medium) containing 10% hyclone
37 DEG C, CO2Concentration is 5%.
First, SiPcs is dissolved in DMF the mother liquor for being configured to that concentration is 1mM.Then (0.5% is contained with DMEM culture mediums
CEL mother liquor) is diluted to 80 μM mother liquors.Secondary mother liquor is diluted to respective concentration further according to requirement of experiment with DMEM.
Hela cells press 1 × 106Concentration kind in 6cm culture dishes.After growth 24h, former culture medium is discarded, addition contains
The culture medium of SiPc (2 μM), continues to cultivate 0.5,1,2 and 4h.After culture terminates, culture medium is discarded, PBS is washed 2 times, pancreatin digestion
Collect.The cell of collection is freezed, the SiPc in FD is extracted with 0.5mL DMF.Determine the UV- of SiPc in extract
Vis absorption values, compare quantitative with standard curve.In competion experiment, cell is co-cultured for (100 μM) first with biotin
2h, is then adding SiPc further to cultivate.
Experimental result is as shown in figure 4, under identical condition of culture, the amount of SiPc-biotin is substantially big in Hela cells
In SiPc-pip, the introducing of this explanation biotin can improve the combination energy of SiPc and biotin acceptor high expression tumour cell
Power.
Targeting abilities of the SiPc-biotin to biotin acceptor is demonstrated using competion experiment.In competition binding reality
In testing, Hela cells carry out the biotin acceptor of saturation Hela cell surfaces with (100 μM) co-cultivations of excess biotin first, then
SiPc is added to enter the step culture of progressive step one.Shown in Fig. 5, excess biotin is added, greatly reduce SiPc- in Hela cells
Biotin amount (>50%).But, SiPc-pip is but influenceed little (≈ 5%).The result shows, SiPc-biotin with
The combination of Hela cells is mainly what is mediated by biotin acceptor, that is to say, that SiPc-biotin can be targetted with reference to biological
The tumour cell of plain acceptor expression high.
3.2 cell fluorescences are imaged
By Hela cells and 1 μM of SiPc co-incubation 1h at 37 DEG C.Before imaging, cell is rinsed three times with PBS.Cell
Acquisition under Olympus Xcellence cell living cells work stations is imaged on, excitation source is 561nm laser.
The fluorescence imaging result of cell further confirms the targeting ability of the biotin acceptor of SiPc-biotin.Such as
Shown in Fig. 6, excess biotin reduces the fluorescence intensity that SiPc-biotin processes cell significantly, and cell is processed to SiPc-pip
Fluorescence intensity have little to no effect.This result demonstrates again that compound SiPc-biotin can be targetted and is enriched in biotin
In the tumour cell of acceptor overexpression.
3.3 Hela cytotoxicity experiments
MTT experiment is used to evaluate the photodynamic activity of SiPc-pip and SiPc-biotin.First, independent light is tested
According to the influence to cell survival rate.
Hela and LO2 cells are taken with 6 × 103Per empty concentration kind in 96 orifice plates, after growth 24h, add and contain difference
Concentration SiPc (10nm-4 μM) culture medium, after continuing to cultivate 2h, discards culture medium containing SiPc, and PBS is washed 2 times, rejoins culture
Base.With LED, (λ ≈ 670nm, light intensity is 20mWcm-2, total radiation dose is 24Jcm-2) irradiating cell.After culture 24h,
MTT (tetrazolium bromide) is added, continues to cultivate 4h.Dark contrast's experiment is carried out simultaneously.Culture medium is discarded, DMSO is added.Selection 490nm
Wavelength, in enzyme linked immunological monitor (Bio-Rad microplate reader ader) reading.
As Fig. 7 shows, the condition of the illumination that this experiment is used will not cause to damage to cell substantially.Eliminate illumination this
After one influence factor, the application has investigated compound SiPc-pip and SiPc-biotin phototoxicity and dark toxicity.As shown in figure 8,
Almost without dark toxicity under test concentrations (10nm~4 μM), compound SiPc-pip has certain to compound SiPc-biotin
Dark toxicity, but dark toxicity is also little.In illumination condition (λ ≈ 670nm, light intensity 20mWcm-2, accumulated dose 24Jcm-2) under, change
Compound SiPc-pip and SiPc-biotin show very strong phototoxicity.
SiPc-biotin is given in table 2 below under illumination condition, to the half lethal concentration (IC of Hela cells50).Can
See, compound SiPc-biotin of the present invention in addition to the binding ability with Hela cells is relatively strong, while having preferable light
Toxicity, is a kind of effective light power sensitising agent.
Phototoxicities of the table 2.SiPc-pip and SiPc-biotin to Hela.
In upper table 2, because the combination of SiPc-biotin and Hela cells is mainly what is mediated by biotin acceptor, because
This is it is considered that SiPc-biotin also should be in the biotin acceptor expression of cell surface to the phototoxicity of Hela cells
Positive correlation.In order to verify us this it is assumed that with reference to the method for competitive experiment, being firstly added excess biotin and being used to satisfy
With the biotin acceptor of cell surface, the detection of photodynamic activity is then carried out.As shown in upper table 2, the presence of excess biotin
Significantly reduce the phototoxicity of SiPc-biotin.This result also indicates that the phototoxicity of SiPc-biotin and the life of cell surface
Thing element receptor expression level correlation, that is to say, that SiPc-biotin can be with the expression high of target killing biotin acceptor
Tumour cell.
3.4 pairs of dark toxicities of normal cell
Dark toxicity size to normal cell is also to evaluate a major criterion of light power sensitising agent, the small meaning of dark toxicity
The damage for sensitising agent normal tissue is small, safer.Therefore, the application has investigated two kinds of SiPc compounds to people's normal hepatocytes
The dark toxicity of cell LO2.Result is as shown in figure 9, compound SiPc-pip is to the dark toxicity of LO2 cells clearly (IC50≈
3.3μM).Relative to SiPc-pip, compound SiPc-biotin is just weak more to the dark toxicity of LO2.In fact, in sensitising agent
When concentration is 4 μM, SiPc-pip causes about 80% cell death, and SiPc-biotin only causes about 20% cell death.
It can be seen that, compound SiPc-biotin of the present invention is used as sensitising agent, with bigger advantage.
Obviously, above-described embodiment is only intended to clearly illustrate example, and not to the restriction of implementation method.It is right
For those of ordinary skill in the art, can also make on the basis of the above description other multi-forms change or
Change.There is no need and unable to be exhaustive to all of implementation method.And the obvious change thus extended out or
Among changing still in the protection domain of the invention.
Claims (13)
1. a kind of silicon phthalocyanine derivative, it is characterised in that the derivative is the silicon phthalocyanine derivative of biotin axial substituted, its
With structure shown below：
2. a kind of method for preparing silicon phthalocyanine derivative described in claim 1, it is characterised in that comprise the following steps：
(1) synthesis of SiPc-pip
Under inert gas shielding, with SiPcCl2With 4- hydroxy piperidines be raw material, sodium hydride be catalyst in the presence of, be dissolved in toluene
Back flow reaction is carried out in solvent；After reaction terminates, decompression steams solvent, and rinsing residue, with the isolated depth of silica gel column chromatography
Blue product, as required SiPc-pip；
(2) synthesis of SiPc-biotin
With SiPc-pip obtained above as raw material, N-hydroxy-succinamide biotin is added, in the presence of organic amine, be dissolved in
Reacted in DMF solvent, terminated rear evaporated under reduced pressure solvent, navy blue product is obtained with silica gel column chromatography, as required SiPc-
biotin；
3. the method for preparing the silicon phthalocyanine derivative according to claim 2, it is characterised in that in the step (1),
The SiPcCl2It is 1-4 with the mol ratio of 4- hydroxy piperidines：10.
4. the method for preparing the silicon phthalocyanine derivative according to Claims 2 or 3, it is characterised in that the step (1)
In, what the silica gel column chromatography was separate concretely comprises the following steps：Using 200-300 mesh silica gel, post is filled with chloroform；Sample is taken to be dissolved in
In DMF solvent, 3 times of silica white adsorption samples of quality are added, after evaporated under reduced pressure DMF, with silica white upper prop, be with volume ratio
20：1 chloroform-methanol solution is eluted for eluant, eluent.
5. the method for preparing the silicon phthalocyanine derivative according to claim any one of 2-4, it is characterised in that the step
Suddenly in (2), the organic amine is DIPEA or triethylamine.
6. the method for preparing the silicon phthalocyanine derivative according to claim any one of 2-5, it is characterised in that the step
Suddenly in (2), the mol ratio of the N-hydroxy-succinamide biotin and SiPc-pip is 4-10：1.
7. the method for preparing the silicon phthalocyanine derivative according to claim any one of 2-6, it is characterised in that the step
Suddenly in (2), the silica gel column chromatography is concretely comprised the following steps：Using 200-300 mesh silica gel, post is filled with chloroform；Take sample molten
In DMF solvent, 3 times of silica white adsorption samples of quality are added, after evaporated under reduced pressure DMF, with silica white upper prop, be with volume ratio
30：1 chloroform-methanol solution is eluted for eluant, eluent.
8. the method for preparing the silicon phthalocyanine derivative according to claim any one of 2-7, it is characterised in that also include
The step of preparing N-hydroxy-succinamide biotin, specifically includes：Under inert gas shielding, with biotin and N- hydroxyl fourths
Imidodicarbonic diamide is raw material, in N, N'- dicyclohexylcarbodiimides or 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt
In the presence of hydrochlorate, it is dissolved in DMF solvent and is reacted, terminate rear filtering reacting liquid and evaporated under reduced pressure, product ether precipitation is obtained final product
Required BNHS；
9. a kind of biotin acceptor targets silicon phthalocyanine sensitising agent, it is characterised in that as the silicon phthalocyanine derivative described in claim 1
It is obtained.
10. the silicon phthalocyanine derivative described in claim 1 is used to prepare photo-dynamical medicine, photosensitive drug or treating cancer medicine
Purposes.
11. purposes according to claim 10, it is characterised in that the cancer includes cervical carcinoma.
12. a kind of pharmaceutical compositions, it is characterised in that including the silicon phthalocyanine derivative described in claim 1, and pharmaceutically may be used
The auxiliary material and/or carrier of receiving.
The 13. clinically-acceptable preparations prepared according to common process as the pharmaceutical composition described in claim 12.
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