CN103864833B - A kind of axial end hydroxyl replaces silicon phthalocyanine and self-assembly thereof - Google Patents
A kind of axial end hydroxyl replaces silicon phthalocyanine and self-assembly thereof Download PDFInfo
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- CN103864833B CN103864833B CN201410108985.XA CN201410108985A CN103864833B CN 103864833 B CN103864833 B CN 103864833B CN 201410108985 A CN201410108985 A CN 201410108985A CN 103864833 B CN103864833 B CN 103864833B
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Abstract
The invention discloses a kind of axial end hydroxyl and replace silicon phthalocyanine and self-assembly thereof, and their preparation method and application, belong to photo-dynamical medicine or photosensitizer preparation field.The axial end hydroxyl that the present invention provides replaces silicon phthalocyanine and self-assembly can have high photodynamic activity as photosensitizer for optical dynamic therapy, light power diagnosis or photodynamic disinfection.
Description
Technical field
The invention belongs to photo-dynamical medicine or photosensitizer preparation field, be specifically related to a kind of axial end hydroxyl and replace silicon phthalocyanine
And self-assembly, and their preparation method and application.
Background technology
Phthalocyanine compound is the functional material that a class is important, can develop into different purposes by different structural modifications
Functional material.Phthalocyanine ring introduces suitable substituent and central ion, it is possible to develop as oxidation catalyst, desulfurization catalyst
Agent, nonlinear optical material, photosensitive drug, liquid crystal material, optical recording material or light-guide material, but how to regulate and control substituent group and
Central ion obtains objective function compound, is but to need creative work.
Phthalocyanine compound draws as photosensitizer application prospect in optical dynamic therapy (Photodynamic Therapy)
People attractes attention.So-called optical dynamic therapy (or claiming photodynamic therapy), substantially, is the photosensitization of photosensitizer (or claiming photosensitive drug)
React the application at medical domain.Its mechanism is first photosensitizer to be injected body, after a period of time (when this section waits
Between be allow medicine in target body relatively enrichment), shooting at the target body with the illumination of specific wavelength (can be by optical fiber etc. to endoceliac target
Interventional technique imports light source), the photosensitizer being enriched in target body, under light excites, has inspired a series of optical physics photochemistry anti-
Should, produce active oxygen, and then destroy target body (such as cancerous cell and cancerous tissue).
In some developed countries, optical dynamic therapy has become the 4th kind of conventional method for the treatment of cancer.With traditional therapy,
As surgical operation, chemotherapy, radiotherapy are compared, the advantage of photodynamic therapy maximum is cancerous tissue to be carried out selective destruction
Without performing surgical operation, and side effect is little, thus gets most of the attention.
Meanwhile, research in recent years is it is also shown that photodynamic therapy also can effectively treat antibacterial infection, oral disease, Huang
The non-Cancerous diseases such as speckle degeneration oculopathy, arteriosclerosis, traumatic infection and dermatosis.Photosensitizer can be also used for light power and disappears
Poison, most importantly for water body, blood and the sterilization of blood derivatives.Meanwhile, the photoluminescent property utilizing photosensitizer enters
Row light power diagnosis, is also an important use of photosensitive drug.
Optical dynamic therapy it is critical only that photosensitizer, light power curative effect depends on the quality of photosensitizer.Control based on light power
Treating the potentiality in terms for the treatment of tumor and Other diseases, scientific circles are it is believed that optical dynamic therapy will become the important of 21 century
Therapy, then, the photosensitizer as optical dynamic therapy core will become an important and tempting new high-tech industry.
So far, it is approved the formal photosensitizer used clinically and is mainly hematoporphyrin derivative.In the U.S., Canada, moral
The state such as state, Japan, uses Photofrin(U.S. FDA in nineteen ninety-five official approval Photofrin for clinical treatment cancer
Disease), it is the mixture of the hemoporphyrin oligomer extracting and carrying out chemical modification from cow blood.Hematoporphyrin derivative shows
Show certain curative effect, but also exposed critical defect: maximum absorption wavelength (380-420nm) is not to tissue transmitance
Preferably red light district (650-800nm), skin phototoxicity is big, is mixture, composition instability etc., thus clinical practice is limited
System, so exploitation New Generation Optical dynamical medicine (photosensitizer) is international study hotspot.
It is positioned at easily through features such as the red light region of tissue and photosensitization ability are strong owing to having maximum absorption wavelength,
Phthalocyanine compound draws attention as the application of photosensitizer.In various phthalocyanine compounds, due to the fact that silicon phthalocyanine is made
Application for novel photosensitive agent is highly valued: (1) silicon phthalocyanine can be axially introduced into two substituent groups, it is thus possible to more effectively
Ground stops phthalocyanine ring to be assembled, it is ensured that the performance of phthalocyanine photosensitization ability；(2) biocompatibility of silicon is higher, without dark toxicity.The U.S.
The axial substituted phthalocyanine silicon (Pc4) that Case Western Reserve university develops shows high light photodynamic activity, has been enter into
Clinical trial.But, the complex synthetic route of Pc4, preparation cost is high, poor stability.Therefore, new photosensitive in the urgent need to screening
Activity is high, preparation is easy, the axial of low cost modifies silicon phthalocyanine photosensitizer.It addition, the photosensitizer of clinical trial at present (includes phthalein
Cyanines class photosensitizer) also lack the selectivity to tumor tissues and cancerous cell, also it is to be currently needed for the problem that emphasis overcomes.
Patent ZL200410013289.7 and ZL200610200598.4 describe a series of axial substituted silicon phthalocyanine chemical combination
Thing, its preparation and application in optical dynamic therapy (this invention and the application are same inventor) thereof.But, due to photosensitive
Agent and the potential tremendous economic social value of optical dynamic therapy, great range of application and the refinement for the treatment of focus, prepare
More axial substituted silicon phthalocyanine compounds with photosensitive activity are the most necessary as drug candidate.
Owing to having EPR effect, nano anti-cancer medicine has the relative selectivity to tumor tissues, but, receiving of phthalocyanine
Rice self-assembly application potential in optical dynamic therapy is not also exploited.
Summary of the invention
It is an object of the invention to provide a kind of axial end hydroxyl and replace silicon phthalocyanine and self-assembly thereof, and their system
Preparation Method and application, belong to photo-dynamical medicine or photosensitizer preparation field.The axial end hydroxyl that the present invention provides replaces silicon phthalocyanine
And self-assembly can have high light power as photosensitizer for optical dynamic therapy, light power diagnosis or photodynamic disinfection
Activity.
For achieving the above object, the present invention adopts the following technical scheme that
The structural formula that a kind of axial end hydroxyl replaces silicon phthalocyanine is as follows:
、、、Or。
It is axially symmetric two replacements and the silicon phthalocyanine of Asymmetrical substitute that described axial end hydroxyl replaces silicon phthalocyanine, axially takes
Dai Ji is connected with silicon by oxygen atom；Silicon phthalocyanine or claim silicon phthalocyanine, be central ion be the phthalocyanine compound of silicon.Phthalocyanine, English
Title phthalocyanine, is the abbreviation of four benzo tetraazatetradecane porphyrins.The knot of the described substituted silicon phthalocyanine of axial end hydroxyl
Structure feature is: the end group of substituent group is hydroxyl.
Preparation method comprises the following steps:
(1) with the one in phthalocyanine silicon dichloride and triethylene glycol, TEG, PEG400, PEG600 as reactant, both
Molar ratio be 1:1 ~ 20, with toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, at 100 ~ 130 DEG C
React 1 ~ 20 hour, removed raw material and the impurity of excess by column chromatography for separation, obtain axial polyethyleneglycol modified silicon phthalocyanine.
(2) with phthalocyanine silicon dichloride and para hydroxybenzene propanoic acid as reactant, both molar ratios are 1:1 ~ 20, with first
Benzene, dimethylbenzene or dioxane are solvent, under the protection of nitrogen, react 1 ~ 20 hour, divided by column chromatography at 100 ~ 130 DEG C
Leave away the raw material except excess and impurity, obtain axial 3-(4-hydroxy phenyl) ethyl oxy carbonyl and 4-(2-carboxy ethyl) phenoxy group
Asymmetric modification silicon phthalocyanine.
After axial end hydroxyl replacement silicon phthalocyanine is dissolved into pure water, the nano-particle that self assembly is formed, granularity is at 100-
500nm。
Described axial end hydroxyl replaces silicon phthalocyanine and self-assembly can be applicable to prepare photo-dynamical medicine or photosensitizer.
Described photosensitizer, can be described as photosensitive medicament at biomedicine field, or claims photosensitive drug preparation, be also called light power medicament.Institute
Photo-dynamical medicine or the photosensitizer of preparation can be used for optical dynamic therapy, light power diagnosis or photodynamic disinfection.Described light power
Treatment can be the optical dynamic therapy of malignant tumor, or carcinoid optical dynamic therapy, or leukemic ex vivo bone marrow
Light power purification treatment, or the optical dynamic therapy of non-Cancerous disease.Described non-Cancerous disease, can be that antibacterial infects, or
It is oral disease, or degeneration of macula oculopathy, or arteriosclerosis, or traumatic infection, or dermatosis, or virus sense
Dye.Described photodynamic disinfection can be the light power sterilization purification of blood or blood derivatives, or the light power sterilizing of water
Sterilization, or the medical or photodynamic disinfection of life device.
Beneficial effects of the present invention and outstanding advantage are:
(1) axial end hydroxyl provided by the present invention replacement silicon phthalocyanine has high light power active anticancer, its activity
It is significantly higher than the substituted silicon phthalocyanine of end alkyl of correspondence, there is unexpected, significantly higher practical application effect.
(2) forming intramolecular hydrogen bond ability relatively by force due to terminal hydroxy group, the axial end hydroxyl that the present invention provides replaces silicon phthalocyanine
In water, easily form nanoassemble body, and the nanoassemble body formed has high light power active anticancer.
(3) the axial end hydroxyl replacement silicon phthalocyanine that the present invention provides as intermediate, can utilize the activity of terminal hydroxy group, passes through
Become ester reaction, connect containing the biological targeting molecule of carboxyl, such as folic acid, low density lipoprotein, LDL, antibody etc., and then constitute there is height
The silicon phthalocyanine base photosensitizer of targeting.
(4), during the axial end hydroxyl that the present invention provides replaces silicon phthalocyanine, some compounds have end carboxyl the most simultaneously.Due to
Terminal hydroxy group and end carboxyl are active reaction functional group, and based on therefore, it can this compound, synthesis has two kinds of targeting bases
The silicon phthalocyanine base photosensitizer of group.
(5) clearly, there is not position isomer in the silicon phthalocyanine structure that the present invention provides.The present invention is to phthalocyanine precursor structure
Chemical modification, is by axially rather than introducing substituted radical at the periphery of phthalocyanine ring and realize at phthalocyanine ring, thus target
Clearly, there is not isomer in compound structure.If the periphery at phthalocyanine ring introduces substituent group, owing to the periphery of phthalocyanine ring exists
16 possible the position of substitution, then may produce multiple isomers, causes product to contain isomer or separation costs increases.
(6) present invention selects silicon to want as the central ion of phthalocyanine compound, the biological safety of silicon and biocompatibility
Good in other common ion (zinc, aluminum, magnesium and gallium), and silicon phthalocyanine produces the quantum yield height of active oxygen.
(7) silicon phthalocyanine that the present invention provides has higher light stability, and its light stability is higher than other similar photosensitizer,
The Pc4 of the such as U.S..
Detailed description of the invention
Axial end hydroxyl of the present invention replaces the preparation method of silicon phthalocyanine: (1) is with phthalocyanine silicon dichloride and triethylene glycol, tetrem
Glycol, PEG400 or PEG600 are reactant, and both molar ratios are 1:1 ~ 20, with toluene, dimethylbenzene or dioxane
For solvent, under the protection of nitrogen, react 1 ~ 20 hour at 100 ~ 130 DEG C, remove excess by solvent method and column chromatography for separation
Raw material and impurity, the axial polyethyleneglycol modified silicon phthalocyanine obtained.(2) with phthalocyanine silicon dichloride and para hydroxybenzene propanoic acid for reaction
Thing, both molar ratios are 1:1 ~ 20, with toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, 100
React 1 ~ 20 hour at ~ 130 DEG C, removed raw material and the impurity of excess by solvent method and column chromatography for separation, obtain axial 3-(4-
Hydroxy phenyl) ethyl oxy carbonyl and 4-(2-carboxy ethyl) phenoxy group asymmetric modification silicon phthalocyanine.
The preparation method of the self-assembly that axial end hydroxyl of the present invention replaces silicon phthalocyanine is: axial end hydroxyl is replaced silicon phthalein
Cyanines are dissolved in pure water, are configured to 1-20 × 10-6 The concentration of mol/L, stands 5-10min, can obtain granularity be 100-500nm from
Assembly.
The substituted silicon phthalocyanine of axial end hydroxyl that the present invention provides can be used for preparing photo-dynamical medicine or photosensitive (medicine) agent, should
In optical dynamic therapy or light power diagnosis, optical dynamic therapy of the present invention can be that the light power of malignant tumor is controlled
Treat, or carcinoid optical dynamic therapy, or leukemic ex vivo bone marrow light power purification treatment, or non-Cancerous disease
Optical dynamic therapy.Non-Cancerous disease of the present invention, can be that antibacterial infects, or oral disease, or degeneration of macula
Oculopathy, or arteriosclerosis, or traumatic infection, or dermatosis, or virus infects.
The axial end hydroxyl that the present invention provides replaces silicon phthalocyanine and can be used for preparing photosensitive (medicine) agent, for photodynamic disinfection,
Described photodynamic disinfection can be the light power sterilization purification of blood or blood derivatives, or the light power sterilizing of water disappears
Poison, or the medical or photodynamic disinfection of life device.
The axial end hydroxyl that the present invention provides replaces silicon phthalocyanine in optical dynamic therapy, light power diagnosis and photodynamic disinfection
Application, need supporting suitable light source, described suitable light source can be connected suitable optical filter by ordinary light source to be provided
Or provided by the laser of specific wavelength, the wave-length coverage of light source is 600～800nm, preferably 670-690nm.
The axial end hydroxyl utilizing the present invention to provide replaces silicon phthalocyanine and prepares the most square of photo-dynamical medicine (or photosensitizer)
Method is: use the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve this
Inventing described silicon phthalocyanine, be configured to containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturated concentration.Described
Other material can be one or more mixing following: castor oil derivative (Cremophor EL), dimethyl sulfoxide, ethanol,
Glycerol, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, Polyethylene Glycol monostearate
Ester.Antioxidant, buffer agent and isotonic agent can be added as additive to keep the chemistry of photosensitive medicament in the solution made
Stability and biocompatibility.
It is (or photosensitive that the self-assembly utilizing the axial end hydroxyl that the present invention provides to replace silicon phthalocyanine prepares photo-dynamical medicine
Agent) basic skills be: directly dissolve axial end hydroxyl with pure water and replace silicon phthalocyanine, be configured to 1-20 × 10-6 Mol/L's is dense
Degree, stands 5-10min, and can obtain granularity is 100-500nm self-assembly.
The invention will be further described below to use non-limiting example.
Embodiment 1
Two (2-(2-(2-hydroxyl-oxethyl) ethyoxyl) ethyoxyl) synthesis of silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), triethylene glycol (1.640 ~ 3.280
Mmol, preferably 2.460 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~ 15 ml
In (preferably 10 ml), reflux 12 ~ 24 hours (preferably 14 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue coarse and produces
Thing.Crude product passes through silica column purification, uses ethyl acetate: chloroform (5:1) is eluant, collects second component, concentrates
Dried blue product, productivity 32.91%.Product maximum absorption band in DMF is positioned at 673 nm, at 1% Oleum Ricini
Maximum absorption wavelength in derivant (Cremophor EL, wt%) aqueous solution is positioned at 676 nm.
The structure of product is shown below, and characterizes data as follows:
MS(ESI): M/Z 838.4 (100%, M+).
1H NMR(CDCl3, 400MHz, ppm): δ 9.68-9.65 (m, 8H, Pc-Hα), δ 8.36-8.34
(m, 8H, Pc-Hβ), δ 3.33-3.31 (t, 4H, J=4Hz, CH2-6), δ 2.96-2.94 (t, 4H, J=4Hz,
CH2-5), δ 2.43-2.41 (t, 4H, J=4Hz, CH2-4), δ 1.53-1.51 (t, 4H, J=4Hz, CH2-3),
δ 0.50-0.47 (t, 4H, J=4Hz, CH2-2), δ -1.88--1.91 (t, 4H, J=4Hz, CH2-1).
Embodiment 2
Two (2-(2-(2-methoxy ethoxy) ethyoxyl) ethyoxyl) synthesis of silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), triethylene glycol monomethyl ether (1.640 ~
3.280 mmol, preferably 2.460 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~
In 15 ml (preferably 10 ml), reflux 12 ~ 24 hours (preferably 12 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue
Crude product.Crude product passes through silica column purification, and use ethyl acetate solvent is eluant, obtains after collecting second component concentrate drying
Blue product, productivity 32.91%.Product maximum absorption band in DMF is positioned at 674 nm, at 1% castor oil derivative
Maximum absorption wavelength in (Cremophor EL, wt%) aqueous solution is positioned at 677 nm.
The structure of product is shown below, and characterizes data as follows:
1H NMR (CDCl3, 400MHz, ppm): δ 9.65-9.58 (m, 8H, Pc-Hα), δ 8.41-8.35 (m, 8H, Pc-
Hβ), δ 3.13 (s, 6H, CH2-7), δ 3.12-3.08 (t, 4H, J=8Hz, CH2-6), δ 2.96-2.92 (t,
4H, J=8Hz, CH2-5), δ 2.47-2.43 (t, 4H, J=8Hz, CH2-4), δ 1.70-1.66 (t, 4H, J=
8Hz, CH2-3), δ 0.42-0.38 (t, 4H, J=8Hz, CH2-2), δ -1.89--1.93 (t, 4H, J=8Hz,
CH2-1).
Embodiment 3
Two (2-(2-(2-(2-hydroxyl-oxethyl) ethyoxyl) ethyoxyl) ethyoxyl) synthesis of silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), TEG (1.640 ~ 3.280
Mmol, preferably 2.460 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~ 15 ml
In (preferably 10 ml), reflux 12 ~ 24 hours (preferably 16 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue coarse and produces
Thing.Crude product passes through silica column purification, uses ethyl acetate: triethylamine (10:1) is that eluant washes away light blue component, then uses
Oxolane does eluant and collects second component, obtains blue product, productivity 38.85% after concentrate drying.Product in DMF
Big absworption peak is positioned at 673 nm, the maximum absorption wave in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution
Length is positioned at 676 nm.
The structure of product is shown below, and characterizes data as follows:
MS(ESI): M/Z 926.4 (100%, M+).
1H NMR(CDCl3, 400MHz, ppm): δ 9.68-9.64 (m, 8H, Pc-Hα), δ 8.39-8.34 (m,
8H, Pc-Hβ), δ 3.45-3.42 (m, 4H, CH2-8), δ 3.31-3.29 (t, 4H, J=4Hz, CH2-7), δ
3.23-3.20 (m, 4H, CH2-6), δ 2.96-2.93 (m, 4H, CH2-5), δ 2.48-2.46 (m, 4H, CH2-
4), δ 2.28-2.25 (t, 2H, J=4Hz, OH-9), δ 1.69-1.67 (m, 4H, CH2-3), δ 0.45-0.43
(t, 4H,J=4Hz, CH2-2), δ -1.87--1. 90 (t, 4H, J=4Hz, CH2-1).
Embodiment 4
Two (2-(2-(2-(2-methoxy ethoxy) ethyoxyl) ethyoxyl) ethyoxyl) synthesis of silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), TEG monomethyl ether (1.640 ~
3.280 mmol, preferably 2.460 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~
In 15 ml (preferably 10 ml), reflux 12 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue
Crude product.Crude product passes through silica column purification, and using ethyl acetate is that eluant collects second component, obtains blue after concentrate drying
Product, productivity 29.90%.Product maximum absorption band in DMF is positioned at 674 nm, at 1% castor oil derivative
Maximum absorption wavelength in (Cremophor EL, wt%) aqueous solution is positioned at 677 nm.
MS(ESI): M/Z 977.5 (100%, M+Na+).
1H NMR (CDCl3, 300MHz, ppm): δ 9.67-9.65 (m, 8H, Pc-Hα), δ 8.49-8.46
(m, 8H, Pc-Hβ), δ 6.43 (s, 6H, CH3-9), δ 3.09-2.98 (m, 8H, CH2-7,8), δ 2.83-
2.80 (q, 4H, CH2-6), δ 2.32-2.28 (t, 4H, J=6Hz, CH2-5), δ 1.59-1.56 (t, 4H, J=
6Hz, CH2-4), δ 1.23-1.19 (t, 4H, J=6Hz, CH2-3), δ 0.33-0.29 (t, 4H, J=6Hz,
CH2-2), δ -2.02--2.05 (t, 4H, J=6Hz, CH2-1).
Embodiment 5
Two (polyethoxy (PEG400)) silicon phthalocyanine:
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), PEG400(1.640 ~ 3.280
Mmol, preferably 1.640 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~ 15 ml
In (preferably 10 ml), reflux 12 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue coarse and produces
Thing.Crude product passes through silica column purification, uses chloroform: ethanol (10:1) is that eluant collects second component, concentrate drying
After blue product, productivity 14.00%.Product maximum absorption band in DMF is positioned at 672 nm, derives at 1% Oleum Ricini
Maximum absorption wavelength in thing (Cremophor EL, wt%) aqueous solution is positioned at 677 nm.
The structural characterization data of product are as follows:
MS(ESI): M/Z 1389.7 (100%, M+Na+).
1HNMR(CDCl3, 300Hz, ppm): δ 9.63-9.39 (m, 8H, Pc-Hα), δ 8.35-8.33 (m,
8H, Pc-Hβ), δ 3.66--1.92 (m, 74H, H-PEG400).
Embodiment 6
Two (polyethoxy (PEG600)) silicon phthalocyanine:
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), PEG600(1.640 ~ 3.280
Mmol, preferably 1.640 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~ 15 ml
In (preferably 10 ml), reflux 12 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue coarse and produces
Thing.Crude product passes through silica column purification, uses chloroform: ethanol (10:1) is that eluant collects second component, concentrate drying
After blue product, productivity 14.00%.Product maximum absorption band in DMF is positioned at 672 nm, derives at 1% Oleum Ricini
Maximum absorption wavelength in thing (Cremophor EL, wt%) aqueous solution is positioned at 677 nm.
The structural characterization data of product are as follows:
Elementary analysis (C84H122N8O30Si): value of calculation: C, 57.52%;H, 7.13%; N, 6.39%;Measured value: C
(56.31%), H (6.95%), N (7.85%).
1HNMR(CDCl3, 300Hz, ppm): δ 9.64-9.48 (m, 8H, Pc-Hα), δ 8.33 (m, 8H,
Pc-Hβ), δ 3.65--2.06 (m, 106H, H-PEG600).
Embodiment 7
The synthesis of [3-(4-hydroxy phenyl) ethyl oxy carbonyl] [4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), para hydroxybenzene propanoic acid (1.640 ~
3.280 mmol, preferably 4.920 mmol) and NaH(0.01 ~ 0.02 mmol, preferably 0.016 mmol) join toluene 7 ~
In 15 ml (preferably 10 ml), reflux 12 ~ 24 hours (preferably 12 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue
Crude product.Crude product oxolane dissolves, and is filtered to remove the most tolerant, then by silica column purification, use ethyl acetate: tetrahydrochysene
Furan (1:1) is that eluant collects second component, obtains blue product, productivity 35.00% after concentrate drying.Product is in DMF
Maximum absorption band is positioned at 683 nm, the absorption maximum in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution
Wavelength is positioned at 690 nm.
The structural characterization data of product are as follows:
HR-MS (-ESI) calcd for C50H34N8O6Si [M-1]- 869.2298, found 869.2280.
1H NMR(DMSO-d6, 400Hz, ppm): δ 9.72-9.68 (m, 8H, Pc-Hα), δ 8.57-8.53
(m, 8H, Pc-Hβ), δ 5.98-5.96 (d, 2H, J=8Hz, Ph-H-4), δ 5.46-5.44 (d, 2H, J=
8Hz, Ph-H-6), δ 5.14-5.12 (d, 2H, J=8Hz, Ph-H-3), δ 2.26-2.24 (d, 2H, J=8Hz,
Ph-H-5), δ 1.88-1.84 (t, 2H, J=8Hz, CH2-8), δ 1.66-1.62 (t, 2H, J=8Hz, CH2-7),
δ 0.18-0.15 (t, 2H, J=8Hz, CH2-2), δ -0.49--0.52 (t, 2H, J=8Hz, CH2-1).
Embodiment 8
The synthesis of two [4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine
Under nitrogen protection, by phthalocyanine silicon dichloride (100 mg, 0.164 mmol), para hydroxybenzene propanoic acid (1.640 ~
3.280 mmol, preferably 4.920 mmol) and NaH(0.01 ~ 0.03 mmol, preferably 0.03 mmol) join toluene 7 ~ 15
In ml (preferably 10 ml), reflux 12 ~ 24 hours (preferably 12 hours).Rotary evaporation in vacuo removes solvent, washing, obtains blue coarse
Product.Crude product DMF dissolves, and by silica column purification, is that eluant washes away the one the second components with oxolane (1:1),
Collect target product with DMF for eluant again, after concentrate drying, obtain blue product, productivity 40.00%.Product in DMF
Big absworption peak is positioned at 683 nm, the maximum absorption wave in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution
Length is positioned at 690 nm.
The structural characterization data of product are as follows:
MS(ESI): M/Z 870.3 (M-).
1H NMR(DMSO-d6, 300 Hz, ppm): δ 11.90 (s, 2H, COOH-5), δ 9.66-9.64 (m,
8H, Pc-Hα), δ 8.52-8.49 (m, 8H, Pc-Hβ), δ 5.42-5.39 (d, 2H, J=9Hz, Ph-H-2), δ
2.20-2.17 (d, 2H, J=9Hz, Ph-H-1), δ 1.84-1.79 (t, 2H, J=9Hz, CH2-4)δ 1.62-
1.57 (t, 2H, J=9Hz, CH2-3).
Embodiment 9
The axial end hydroxyl utilizing the present invention to provide replaces silicon phthalocyanine and prepares the most square of photo-dynamical medicine (or photosensitizer)
Method is: use the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve this
Inventing described silicon phthalocyanine, be configured to containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturated concentration.Described
Other material can be one or more mixing following: castor oil derivative (Cremophor EL), dimethyl sulfoxide, ethanol,
Glycerol, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, Polyethylene Glycol monostearate
Ester.Antioxidant, buffer agent and isotonic agent can be added as additive to keep the chemistry of photosensitive medicament in the solution made
Stability and biocompatibility.
Embodiment 10
It is (or photosensitive that the self-assembly utilizing the axial end hydroxyl that the present invention provides to replace silicon phthalocyanine prepares photo-dynamical medicine
Agent) basic skills be: directly dissolve axial end hydroxyl with pure water and replace silicon phthalocyanine, be configured to 1-20 × 10-6 Mol/L's is dense
Degree, stands 5-10min, and can obtain granularity is 100-500nm self-assembly (being measured by particles distribution instrument).
Embodiment 11
Photo-dynamical medicine prepared by the present invention, photosensitive (medicine) agent, at optical dynamic therapy, or light power diagnosis, or light is dynamic
Using method and prior art in power sterilization is used photosensitive medicine prepared by the phthalocyanine described in non-invention or porphyrin compound
The using method of agent or photosensitizer is identical, but needs supporting suitable light source, and described suitable light source can by ordinary light source even
Connecing suitable optical filter to provide or provided by the laser of specific wavelength, the wave-length coverage of light source is 300-800nm, preferably
670-690nm。
Embodiment 12
By axial end hydroxyl of the present invention replacement silicon phthalocyanine be dissolved in 1% castor oil derivative (Cremophor EL,
Wt%), in aqueous solution, the photosensitive medicament of 0.08mM is made.Test they light power inhibitory activity to human liver cancer cell HepG2.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, makes the cell containing variable concentrations photosensitizer and cultivate
Liquid.Test cell is cultivated 2 hours respectively in the culture fluid containing variable concentrations photosensitizer, abandons culture fluid thereafter, clear with PBS
After washing cell, add new culture fluid (without photosensitizer).Illumination experiment group, carries out red light irradiation (exciting light used to cell
Light source is the HONGGUANG that wavelength is more than 610nm, irradiates 30 minutes, and the power irradiating light is 15mw × cm-2)；Not irradiation group, by cell
It is placed in dark place 20 minutes.After illumination or not illumination, the survival rate of cell uses mtt assay to investigate.Specific experiment step sees
" Bioorganic & Medicinal Chemistry Letters ", 2006,16,2450-2453.
The above-mentioned wavelength HONGGUANG more than 610nm is to connect heat insulation tank by the Halogen light of 500W to strengthen the filter in 610nm
Mating plate provides.
Result shows, if not carrying out illumination, the axial end hydroxyl substituted phthalocyanine silicon of the present invention cancerous cell is not killed and
Growth inhibited effect, shows that they do not have dark toxicity.But, under red light irradiation, cancerous cell can be killed, by measure concentration and
The dose-effect relationship of cell survival rate, finds the axial end hydroxyl substituted phthalocyanine silicon of the present invention semilethal under red light irradiation
Concentration (IC50, drug level needed for i.e. killing 50% cancerous cell) it is respectively as follows:
3.4 nM (axial triethylene glycol replaces compound described in silicon phthalocyanine, i.e. embodiment 1)；
5.5nM (axial TEG replaces compound described in silicon phthalocyanine, i.e. embodiment 3);
120 nM (axial PEG400 replaces compound described in silicon phthalocyanine, i.e. embodiment 5)；
139 nM (axial PEG600 replaces compound described in silicon phthalocyanine, i.e. embodiment 6);
30nM ([3-(4-hydroxy phenyl) ethyl oxy carbonyl] [4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine, i.e. implement
Compound described in example 7);
Visible, axial end hydroxyl substituted phthalocyanine silicon is respectively provided with significant photodynamic activity, and part of compounds is even as low as 3-
6nM (i.e. 3-6 × 10-8 mol/L).Extremely low IC50Value, illustrates that silicon phthalocyanine provided by the present invention has high light power and lives
Property.
Change above-mentioned 1% castor oil derivative (Cremophor EL, wt%) aqueous solution into 1% castor oil derivative
(Cremophor EL, wt%) phosphate buffered solution (PBS), it is possible to obtain same experimental result.
Embodiment 13
According to the method described in embodiment 12, determine the part comparison silicon phthalocyanine light power to human liver cancer cell HepG2
Inhibitory activity.Result shows, the half lethal concentration (IC under red light irradiation50) be respectively as follows:
8.0 nM (axial triethylene glycol monomethyl ether replaces compound described in silicon phthalocyanine, i.e. embodiment 2)；
64 nM (axial TEG monomethyl ether replaces compound described in silicon phthalocyanine, i.e. embodiment 4);
Compound described in 320 nM(bis-[4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine, i.e. embodiment 6).
Visible, it is that axial triethylene glycol monomethyl ether replaces silicon that axial triethylene glycol replaces the light power active anticancer of silicon phthalocyanine
2.3 times of phthalocyanine, it is that axial TEG monomethyl ether replaces silicon that axial TEG replaces the light power active anticancer of silicon phthalocyanine
11.6 times of phthalocyanine, illustrate that axial end hydroxyl provided by the present invention replaces silicon phthalocyanine and has high light power active anticancer,
Its activity is significantly higher than the substituted silicon phthalocyanine of end alkyl of correspondence, has unexpected, significantly higher practical application effect.
The light power of [4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine resists it addition, [3-(4-hydroxy phenyl) ethyl oxy carbonyl]
10 times of cancer activity [4-(2-carboxy ethyl) phenoxy group] silicon phthalocyanine that is two, the axial end hydroxyl that also explanation invention is provided replaces
Silicon phthalocyanine has high light power active anticancer.
Embodiment 14
According to the method described in embodiment 10, prepare axial end hydroxyl replacement silicon phthalocyanine nanometer and certainly organize body, and according to enforcement
Method described in example 12, measures nanometer from organizing the body light power inhibitory activity to human breast cancer cell line Bcap-37 (RGD is negative).Knot
Fruit shows, the half lethal concentration (IC under red light irradiation50) be respectively as follows:
3.6 nM (axial triethylene glycol replace silicon phthalocyanine nanoassemble body, i.e. compound described in embodiment 1 from
Assembly)；
8.5 nM (axial TEG replace silicon phthalocyanine nanoassemble body, i.e. compound described in embodiment 3 from
Assembly);
89 nM (axial PEG400 replaces compound described in silicon phthalocyanine nanoassemble body, i.e. embodiment 5)；
The 103 axial PEG600 of nM(replace compound described in silicon phthalocyanine nanoassemble body, i.e. embodiment 6).
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with
Modify, all should belong to the covering scope of the present invention.
Claims (2)
1. the application of an axial end hydroxyl replacement silicon phthalocyanine, it is characterised in that: axial end hydroxyl replaces silicon phthalocyanine and is used for preparing
Anticancer photo-dynamical medicine；
Its structural formula is as follows:
Preparation method comprises the following steps:
(1) with the one in phthalocyanine silicon dichloride and triethylene glycol, TEG, PEG400, PEG600 as reactant, both throwings
Material mol ratio is 1:1 ~ 20, with toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, reacts at 100 ~ 130 DEG C
1 ~ 20 hour, obtain axial ethylene glycol by column chromatography for separation and modify silicon phthalocyanine；
(2) with phthalocyanine silicon dichloride and para hydroxybenzene propanoic acid as reactant, both molar ratios are 1:1 ~ 20, with toluene, two
Toluene or dioxane are solvent, under the protection of nitrogen, react 1 ~ 20 hour, obtained by column chromatography for separation at 100 ~ 130 DEG C
To axial 3-(4-hydroxy phenyl) ethyl oxy carbonyl and 4-(2-carboxy ethyl) phenoxy group asymmetric modification silicon phthalocyanine.
2. the application of the self-assembly of an axial end hydroxyl as claimed in claim 1 replacement silicon phthalocyanine, it is characterised in that: axle
Replace silicon phthalocyanine to terminal hydroxy group to be dissolved in pure water, be self-assembly of the nano-particle of 100-500nm, for preparing anticancer light
Dynamical medicine.
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| CN104844645B (en) * | 2015-04-21 | 2017-10-20 | 福州大学 | A kind of silicon phthalocyanine of axial ALA modifications and its preparation method and application |
| CN106243114B (en) * | 2016-07-28 | 2018-08-17 | 福州大学 | Molecular targeted azepine aromatic rings axial substituted phthalocyanine complex and preparation method |
| CN106565763B (en) * | 2016-11-11 | 2017-12-15 | 深圳市声光动力生物医药科技有限公司 | Axial substituted silicon phthalocyanine complex sensitive pH and preparation method thereof and application in medicine |
| CN106924732A (en) * | 2017-03-09 | 2017-07-07 | 南京理工大学 | A kind of ultrasonic therapy cancer target type haematoporphyrin injection and preparation method thereof |
| CN109793895A (en) * | 2019-02-25 | 2019-05-24 | 山东大学 | A kind of amido silicon phthalocyanine nanosphere, preparation method and application |
| CN115819446B (en) * | 2022-11-02 | 2024-04-05 | 山东大学 | Phthalocyanine-fluorescein organic photothermal agent, preparation method thereof and application thereof in organic near infrared photothermal treatment of antitumor drugs |
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