CN103435639B - Silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application - Google Patents
Silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application Download PDFInfo
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Abstract
The invention discloses silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application, belong to photo-dynamical medicine or photosensitizers preparation field.The asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention can be used for the sterilization of optical dynamic therapy, light power diagnosis or light power as photosensitizers, and it has the constructional feature of axial Asymmetrical substitute, shows good amphipathic and high photodynamic activity.
Description
Technical field
The invention belongs to photo-dynamical medicine or photosensitizers preparation field, be specifically related to silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application.
Background technology
Phthalocyanine compound is the important functional materials of a class, can be developed into the functional materials of different purposes by different structural modifications.Phthalocyanine ring is introduced suitable substituent and central ion, just oxide catalyst, desulfurization catalyst, nonlinear optical material, photosensitive drug, liquid crystal material, optical recording material or light-guide material is likely developed as, but how regulating and controlling substituting group and central ion to obtain objective function compound, is but need creationary work.
Phthalocyanine compound is noticeable as the application prospect of photosensitizers in optical dynamic therapy (PhotodynamicTherapy).So-called optical dynamic therapy (or claiming photodynamic therapy) in fact, is the application of Photosensitive reaction at medical field of photosensitizers (or claiming photosensitive drug).Its mechanism is, first photosensitizers is injected body, after a period of time (this section waiting time be allow medicine relative enrichment in target body), with the rayed target body (light source can be imported by interventional techniques such as optical fiber to endoceliac target) of specific wavelength, be enriched in photosensitizers in target body under optical excitation, inspire a series of optical physics photochemical reaction, produced active oxygen, and then destroy target body (such as cancer cells and cancerous tissue).
In some developed countries, optical dynamic therapy has become the 4th kind of ordinary method of Therapeutic cancer.With traditional therapy, as surgical operation, chemotherapy, radiotherapy are compared, the maximum advantage of photodynamic therapy to be carried out selective destruction to cancerous tissue and need not perform surgical operation, and side effect is little, thus gets most of the attention.
Meanwhile, research in recent years also shows, photodynamic therapy also can treat the non-Cancerous diseases such as bacteriological infection, oral disease, macular degeneration illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be used for the sterilization of light power, most importantly for the sterilization of water body, blood and blood derivatives.Meanwhile, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, is also an important use of photosensitive drug.
The key of optical dynamic therapy is photosensitizers, and light power curative effect depends on the quality of photosensitizers.Based on the potentiality of optical dynamic therapy in treatment tumour and Other diseases, scientific circles generally believe, optical dynamic therapy will become the important therapy of 21 century, and so, the photosensitizers as optical dynamic therapy core will become an important and tempting new high-tech industry.
So far, get permission the formal photosensitizers used clinically and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan, use Photofrin(U.S. FDA in nineteen ninety-five official approval Photofrin for clinical anticancer), it be extract from cow blood and carry out the mixture of the haematoporphyrin oligopolymer of chemical modification.Hematoporphyrin derivative shows certain curative effect, but also expose critical defect: maximum absorption wavelength (380-420nm) is not to tissue transmitance preferably red light district (650-800nm), skin phototoxicity is large, mixture, composition instability etc., thus clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international study hotspot.
Be positioned at easily through the red light region of tissue and the feature such as photosensitization ability is strong owing to having maximum absorption wavelength, phthalocyanine compound draws attention as the application of photosensitizers.In various phthalocyanine compound, because following reason silicon phthalocyanine is paid much attention to as the application of novel photosensitive agent: (1) silicon phthalocyanine axially can introduce two substituting groups, thus can more effectively stop phthalocyanine ring to be assembled, ensure the performance of phthalocyanine photosensitization ability; (2) biocompatibility of silicon higher, without dark toxicity.The axial substituted phthalocyanine silicon (Pc4) of CaseWesternReserve university of U.S. development shows high light photodynamic activity, has entered I clinical trial phase.But the complex synthetic route of Pc4, preparation cost is high, poor stability.Therefore, in the urgent need to screen new photosensitive activity high, prepare easy, that cost is low axis and modify silicon phthalocyanine photosensitizers.In addition, the photosensitizers (comprising phthalocyanines photosensitizers) of current clinical trial also lacks the selectivity to tumor tissues and cancer cells, is also the current problem needing emphasis to overcome.
The patent No. is that the Chinese invention patent of ZL200410013289.7 and ZL200610200598.4 describes a series of axial substituted silicon phthalocyanine compound, its preparation and the application (this invention and the application are same contriver) in optical dynamic therapy thereof.But, due to the refinement of photosensitizers and the potential tremendous economic social value of optical dynamic therapy, greatly range of application and treatment focus, prepare the axial substituted silicon phthalocyanine compound with photosensitive activity more alternatively medicine be very necessary.
What is particularly worth mentioning is that; the state such as American-European, Japanese strengthens the infiltration dynamics of input to novel photosensitive agent and intellecture property one after another; in this case; only have the exploitation paying much attention to have independent intellectual property right medicine and accelerate patent protection paces, guarantee China is in the autonomy of this important medical field of optical dynamic therapy and commanding elevation.
Summary of the invention
The object of the present invention is to provide silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application.Silicon phthalocyanine of the present invention has the constructional feature of axial Asymmetrical substitute, shows good amphipathic and high photodynamic activity, has significant advantage as photosensitizers application.
For achieving the above object, the present invention adopts following technical scheme:
A silicon phthalocyanine for the asymmetric modification of axial nucleosides, its structural formula is as follows:
，
Wherein axial substituted base R
1, R
2be selected from following group respectively:
R
1for
,
,
,
in one;
R
2for
,
,
,
,
in one.
The silicon phthalocyanine of the described asymmetric modification of axial nucleosides is axial asymmetric dibasic silicon phthalocyanine, and axial substituted base is connected with silicon by Sauerstoffatom; Silicon phthalocyanine or claim silicon phthalocyanine, the phthalocyanine compound of to be central ion be silicon.Phthalocyanine, English name phthalocyanine is the abbreviation of four benzo tetraazatetradecane porphyrins.The constructional feature of the silicon phthalocyanine of the described asymmetric modification of axial nucleosides is: axial substituted base is uridine, cytidine or adenosine derivative, while be amino-ethyl phenoxy group or triethylene glycol or TEG derivative.
The preparation method of the asymmetric modification silicon phthalocyanine of described axial nucleosides, comprises the following steps:
(1) with two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine and 2 ', 3 '-O-sec.-propyl-uridine, 2 ', 3 '-O-sec.-propyl-cytidine, 2 ', 3 '-O-sec.-propyl-adenosine, 2 ', one in 3 '-O-sec.-propyl-2-chlorine adenosine is reactant, both molar ratios are 1:1 ~ 10, with toluene, dimethylbenzene or dioxane for solvent, under the protection of nitrogen, 100 ~ 130 DEG C are reacted 1 ~ 20 hour, remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain axial nucleosides and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group;
(2) with the one in axial nucleosides and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group and triethylene glycol, triethylene glycol monomethyl ether, TEG, TEG monomethyl ether for reactant; both molar ratios are 1:1 ~ 10; with toluene, dimethylbenzene or dioxane for solvent; under the protection of nitrogen; 100 ~ 130 DEG C are reacted 1 ~ 20 hour; remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain axial nucleosides and the asymmetric modification silicon phthalocyanine of oligoethylene glycol.
The silicon phthalocyanine of the asymmetric modification of axial nucleosides as above is applied to prepares photo-dynamical medicine or photosensitizers.Described photosensitizers, can be described as photosensitive medicament at biomedicine field, or claims photosensitive drug preparation, is also called light power medicament.Prepared photo-dynamical medicine or photosensitizers can be used for the sterilization of optical dynamic therapy, light power diagnosis or light power.Described optical dynamic therapy can be the optical dynamic therapy of malignant tumour, 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 bacteriological infection, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.Described light power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization that is medical or life device.
The method preparing photo-dynamical medicine or photosensitizers is: with water, or the mixed solution of water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve the silicon phthalocyanine of the asymmetric modification of axial nucleosides, be mixed with containing certain density photosensitive medicament, the concentration of the silicon phthalocyanine of the asymmetric modification of axial nucleosides is not higher than its saturation concentration; Antioxidant, buffer reagent and isotonic agent is added as additive to keep chemical stability and the biocompatibility of photosensitive medicament in the solution made; Other described material is the miscellany of one or more in castor oil derivative (CremophorEL), methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Beneficial effect of the present invention and outstanding advantage are:
(1) axial nucleosides provided by the invention asymmetric modification silicon phthalocyanine is axial Asymmetrical substitute silicon phthalocyanine, axial group is nucleosides and amino-ethyl phenoxy group (or oligoethylene glycol) respectively, has excellent amphipathic and unique Asymmetrical substitute feature.
(2) the axial group of axial nucleosides provided by the invention asymmetric modification silicon phthalocyanine contains nucleoside derivates, and nucleosides is biomolecules in body, and biocompatibility and the biological selectivity of thus provided silicon phthalocyanine are higher.
(3) the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention maximum absorption wavelength is in aqueous positioned at 686-688nm place, and molar absorption coefficient (reaches 10 greatly
5the order of magnitude), its spectral quality is not only better than first-generation photosensitizers greatly, and is better than other phthalocyanine compounds carrying out clinical experiment.Such as, the maximum absorption wavelength of silicon phthalocyanine provided by the invention is relative to the nearly 10nm of Pc4 red shift of the U.S., and the tissue penetration for the treatment of light is further enhanced, this is very favourable for optical dynamic therapy and light power diagnosis.
(4) silicon phthalocyanine structure provided by the invention clearly, not location isomer.The present invention is to the chemically modified of phthalocyanine precursor structure, and be introduce substituted radical by the axis at phthalocyanine ring instead of the periphery at phthalocyanine ring to realize, thus target compound structure clearly, not exists isomer.If introduce substituting group at the periphery of phthalocyanine ring, there are 16 possible the position of substitution in the periphery due to phthalocyanine ring, then may produce multiple isomer, causes product to contain isomer or separation costs increase.
(5) the present invention selects silicon as the central ion of phthalocyanine compound, and the biological safety of silicon and biocompatibility want good for other common ion (zinc, aluminium, magnesium and gallium), and the quantum yield that silicon phthalocyanine produces active oxygen is high.
(6) silicon phthalocyanine provided by the invention has higher light stability, its light stability higher than other similar photosensitizerss, the Pc4 of the such as U.S..
(7) axial nucleosides provided by the invention asymmetric modification silicon phthalocyanine is obtained by a large amount of shaker tests, there is high photodynamic activity, such as, under red light irradiation, only 15nM [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine just 100% can suppress the growth of Human gastric careinoma cells BGC823, IC
50value (killing the drug level needed for 50% cancer cells) can be low to moderate 4nM.
(8) a large amount of simultaneous tests shows, the photodynamic activity of axial nucleosides provided by the invention asymmetric modification silicon phthalocyanine silicon phthalocyanine provided by the invention is significantly higher than corresponding axial nucleosides symmetry and modifies silicon phthalocyanine.The light power antitumour activity of the axial nucleosides of major part provided by the invention asymmetric modification silicon phthalocyanine modifies silicon phthalocyanine, i.e. two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine higher than axial amino-ethyl phenoxy group symmetry.The light power antitumour activity of the axial nucleosides of major part provided by the invention asymmetric modification silicon phthalocyanine also replaces silicon phthalocyanine higher than axial oligoethylene glycol symmetry, as two [(2-oxyethyl group) oxyethyl group] silicon phthalocyanine, two [2-(2-methoxy ethoxy) oxyethyl group] silicon phthalocyanine, two { 2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine, two { 2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } silicon phthalocyanine, two { 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } silicon phthalocyanine, two { 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] oxyethyl group } oxyethyl group } silicon phthalocyanine etc.Simultaneously, the anticancer work of light power of axial nucleosides provided by the invention asymmetric modification silicon phthalocyanine is also significantly higher than other phthalocyanine compounds, as axial two (4-kharophen phenoxy group) silicon phthalocyanine, two [4-(4-Acetylpiperazine) phenoxy group] silicon phthalocyanine, two [4-(3-carboxypropyl) phenoxy group] silicon phthalocyanine, two (4-formic acid phenoxy group) silicon phthalocyanine, two (3-formic acid phenoxy group) silicon phthalocyanine, two (3, 5-dioctyl phthalate phenoxy group) silicon phthalocyanine, two (1-diamantane-methoxyl group) silicon phthalocyanine, two (2-diamantane-oxyethyl group) silicon phthalocyanine etc., replace ZnPc, as four-a-[4-(4-Acetylpiperazine) phenoxy group] ZnPc, four-a-(4-formic acid phenoxy group) ZnPc etc.
(9) synthesis of Asymmetrical substitute silicon phthalocyanine and separating difficulty are comparatively large, and the axial Asymmetrical substitute silicon phthalocyanine of not all anticipation can effectively obtain.Show through lot of experiments, effectively can obtain axial Asymmetrical substitute silicon phthalocyanine of the present invention, and their synthetic route is easier, has industrialization prospect.
Embodiment
The preparation method of the silicon phthalocyanine of the asymmetric modification of the axial nucleosides of the present invention is: (1) is with two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine and 2 ', 3 '-O-sec.-propyl-uridine (or 2 ', 3 '-O-sec.-propyl-cytidine, or 2 ', 3 '-O-sec.-propyl-adenosine, or 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine) be reactant, both molar ratios are 1:1 ~ 10, with toluene, dimethylbenzene or dioxane are solvent, under the protection of nitrogen, react 1 ~ 20 hour at 100 ~ 130 DEG C, excessive raw material and impurity is removed by solvent cleaning and column chromatography for separation, the axial nucleosides obtained and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group.(2) with axial nucleosides and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group and triethylene glycol (or triethylene glycol monomethyl ether; or TEG; or TEG monomethyl ether) be reactant; both molar ratios are 1:1 ~ 10; with toluene, dimethylbenzene or dioxane for solvent, under the protection of nitrogen, react 1 ~ 20 hour at 100 ~ 130 DEG C; washed by solvent and remove excessive raw material and impurity with column chromatography for separation, obtain axial nucleosides and the asymmetric modification silicon phthalocyanine of oligoethylene glycol.
The silicon phthalocyanine of the asymmetric modification of axial nucleosides provided by the invention can be used for preparing photo-dynamical medicine or photosensitive (medicine) agent, be applied in optical dynamic therapy or light power diagnosis, optical dynamic therapy of the present invention can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or leukemic ex vivo bone marrow light power purification treatment, or the optical dynamic therapy of non-Cancerous disease.Non-Cancerous disease of the present invention can be bacteriological infection, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.
The silicon phthalocyanine of the asymmetric modification of axial nucleosides provided by the invention can be used for preparing photosensitive (medicine) agent, sterilize for light power, described light power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization that is medical or life device.
The application of silicon phthalocyanine in the sterilization of optical dynamic therapy, light power diagnosis and light power of the asymmetric modification of axial nucleosides provided by the invention, need supporting suitable light source, described suitable light source can be connected suitable spectral filter to provide by ordinary light source or be provided by the laser of specific wavelength, the wavelength region of light source is 600 ~ 800nm, preferred 686-688nm.
The basic skills utilizing the silicon phthalocyanine of the asymmetric modification of axial nucleosides provided by the invention to prepare photo-dynamical medicine (or photosensitizers) is: use water, or the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve silicon phthalocyanine of the present invention, be mixed with containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturation concentration.Other described material can be one or more mixed following: castor oil derivative (CremophorEL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also can first with hydrochloric acid or sulfuric acid or etc. acidic substance silicon phthalocyanine of the present invention is converted into the form of salt, then use above-mentioned dissolution with solvents.Antioxidant, buffer reagent and isotonic agent can be added as additive to keep chemical stability and the biocompatibility of photosensitive medicament in the solution made.
For the preparation of topical, can silicon phthalocyanine of the present invention be dissolved in penetrating solvents, maybe will be injected in ointment, washing lotion or gel.The preferred 5-35%(wt% of described penetrating solvents) aqueous solution of methyl-sulphoxide.
The invention will be further described below to adopt non-limiting example.
Embodiment 1
The synthesis of two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine
The synthesis of (1) 2 ', 3 '-O-sec.-propyl-uridine
By uridine 245mg(1mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone, by preferred for tosic acid 8 ~ 12mmol(10mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone.Under ice-water bath, tosic acid acetone soln is slowly added drop-wise in uridine acetone soln, the preferred 6h of stirring at normal temperature 2 ~ 10h().Be added to by reaction mixture in the sodium bicarbonate ice water solution containing 4%, repeatedly extract with methylene dichloride (or trichloromethane), collected organic layer, adds dried over mgso, concentrated after filtering, dry product as yellow powder, productive rate 85%.
The characterization data of product is as follows: MS(EI-60) m/z:283.4 [M-H]
-.
IR（KBr，cm
-1）：1467，2935（CH
3）；1703（C=O）；1671（C=C）；1467，2935（CH
2）；3245（NH,OH）；1121(-O-)。
1HNMR(DMSO-d6，400MHz，ppm)：δ11.39（s，1H，pyrimidine-NH）,7.80（d，
J=8.0Hz，1H，pyrimidine-NCH）,5.84（s，1H，1′-H）,5.64（d，
J=8.0Hz，1H，pyrimidine-COCH）,5.09（s，1H,OH）,4.90(t，
J=5.6Hz，1H，2′-H),4.75（s，1H，3′-H）,4.07（s，1H，4′-H）,3.56-3.59（m，2H，5′-H）,1.49(s，3H，Me),1.29(s，3H，Me)。
The synthesis of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40mg; 0.065mmol), the isopropylidene protection product (0.260 ~ 0.650mmol of above-mentioned acquisition uridine; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferred 20ml), reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo removes solvent, and washing, obtains blue coarse product.Crude product is by silica column purification, and use ethyl acetate is eluent, is further purified (tetrahydrofuran (THF) is eluent), collects target components, obtain blue product, productive rate 66% after concentrate drying after collection second component is concentrated by gel chromatography (S-X3 type).The maximum absorption band of product in DMF is positioned at 678nm place, and the maximum absorption wavelength in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution is positioned at 681nm place.
The structure of product is shown below, and characterization data is as follows:
。
HRMS（ESI）m/z:1129.2948[M+Na]
+。
IR(KBr, cm
-1): 734,760,911,1081,1291,1336,1429,1522(Pc ring); 1695,1718(C=O); 1374(CH3); 3444(NH); 1081(Si-O).
1HNMR(CDCl
3，400MHz，ppm)：δ9.66-9.68(m，8H，Pc-H
α),8.44-8.46(m，8H，Pc-H
β),7.44(s，2H，pyrimidine-NH)，4.86(d，
J=8.0Hz，2H，pyrimidine-NCH)，4.43(d，
J=4.0Hz，2H，pyrimidine-COCH)，4.06(d，
J=8.0Hz，2H，1′-H)，1.89-1.91(m，2H，2′-H)，1.36-1.39(m，2H，3′-H)，0.88(s，6H，Me)，0.65(s，6H，Me)，0.41(d，
J=5.6Hz，2H，4′-H),-1.24(d，
J=11.6Hz，2H，5′-H)，-2.41(d，
J=9.6Hz，2H，5′-H)。
Embodiment 2
The synthesis of two [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] silicon phthalocyanine
The synthesis of (1) 2 ', 3 '-O-sec.-propyl-cytidine
By cytidine 250mg(1mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone, by preferred for tosic acid 8 ~ 12mmol(10mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone.Under ice-water bath, tosic acid acetone soln is slowly added drop-wise in cytidine acetone soln, the preferred 6h of stirring at normal temperature 4 ~ 10h(), centrifugal, collect white precipitate, precipitation washing with acetone three to four times, dissolve with a small amount of DMF, add ethyl acetate to separate out, membrane filtration, vacuum-drying, obtain white powder product, productive rate 95%.
The characterization data of product is as follows: IR(KBr, cm
-1): 1383(CH
3); 1123(-O-); 1727(C=O); 3067,1204,1650(NH
2); 1693(C=C); 3067,1204(-OH).
1HNMR(DMSO-d6，400MHz，ppm)：δ9.49(s，1H，pyrimidine-H)，8.41(s，1H,NH
2)，8.09(d，
J=7.6Hz,1H,NH
2)，6.05(d，
J=7.6Hz,1H,pyrimidine-H)，5.76(d，
J=1.2Hz,1H,1′-H)，4.86(t，
J=3.0Hz,1H,2′-H)，4.70-4.72(m，1H，3′-H)，4.21(d，
J=2.8Hz,1H,4′-H)，3.51-3.61(m，2H，5′-H)，1.45(s，3H,Me)，1.25(s，3H,Me)。
The synthesis of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40mg; 0.065mmol), the isopropylidene protection product (0.260 ~ 0.650mmol of above-mentioned acquisition cytidine; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferred 20ml), reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo removes solvent, and washing, obtains blue coarse product.Crude product, by silica column purification, uses ethyl acetate/DMF (volume ratio 20:1) mixed solvent to be eluent, and removing light green impurity, is then eluent with DMF, collects target product.Be further purified by gel chromatography (S-X3 type) after concentrated, obtain blue product after vacuum-drying, productive rate 52%.The maximum absorption band of product in DMF is positioned at 677nm place, and the maximum absorption wavelength in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution is positioned at 681nm place.
The structure of product is shown below, and characterization data is as follows:
HRMS（ESI）m/z:1127.3377[M+Na]
+。IR(KBr, cm
-1): 742,760,910,1081,1123,1291,1335,1428,1519(Pc ring); 3370 (NH
2); 1081(Si-O).
1HNMR(DMSO-d6，400MHz，ppm)：δ9.70-9.76(m，8H，Pc-H
α)，8.53-8.58(m，8H，Pc-H
β)，7.25(s(br)，2H，NH
2)，7.06(s(br)，2H，NH
2)，5.38(d，
J=6.8Hz，2H，pyrimidine-H),4.51(d，
J=3.6Hz，2H，pyrimidine-H)，4.33(d，
J=7.6Hz，2H，1′-H)，1.85-1.88(m，2H，2′-H),1.24-1.31(m，2H，3′-H)，0.76(s，6H，Me)，0.68(d，
J=6.0Hz，2H，4′-H)，0.57(s，6H，Me)，-1.45(d，
J=9.2Hz，2H，5′-H)，-2.31(d，
J=10.4Hz，2H，5′-H)。
Embodiment 3
The synthesis of two [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] silicon phthalocyanine
The synthesis of (1) 2 ', 3 '-O-sec.-propyl-adenosine
Adenosine (1mmol) is dissolved in 10 ~ 30ml (preferred 20ml) acetone, by preferred for tosic acid 8 ~ 12mmol(10mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone.Tosic acid acetone soln is slowly added drop-wise in 2-amino adenosine acetone soln under ice-water bath, the preferred 6h of stirring at normal temperature 24 ~ 72h(), be poured in 4% sodium bicarbonate ice water solution, separate out white precipitate, suction filtration, dry.Carry out surname extraction with trichloromethane to purify, after drying, obtain white powder product.Productive rate 85%.
The synthesis of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40mg; 0.065mmol), 2 '; 3 '-O-sec.-propyl-adenosine (0.260 ~ 0.650mmol; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferred 20ml), reflux 12 ~ 48 hours (preferably 36 hours).Rotary evaporation in vacuo removes solvent, and washing, obtains blue coarse product.Crude product is by silica column purification, and use acetone is eluent, and concentrated target components, obtains blue product after drying, productive rate 60%.The maximum absorption band of product in DMF is positioned at 677nm place, and the maximum absorption wavelength in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution is positioned at 681nm place.
The structure of product is shown below, and characterization data is as follows:
。
MS（EI）m/z:1152.7[M]
+。
IR(KBr, cm
-1): 1618,1426,1256,802,692(Pc ring); 1715,1250(C=O, O-C-O); 2922,2862,1435, (CH
3)
;2996,1445 (CH
2)
;1324 (C-N); 1010(Si-O).
1HNMR(CDCl
3，400MHz，ppm)：δ9.53-9.58(m，8H，Pc-H
α)，8.34-8.40(m，8H，Pc-H
β)，8.02(s，2H，pyrimidine-H)，5.65(s，4H，NH
2)，5.36(s，2H，imidazole-H)，4.51(d，
J=5.4Hz,2H,1′-H)，2.11-2.14(m，2H，2′-H)，1.10(s，6H，Me)，0.91(s，6H，Me)，0.70(d，
J=6.0Hz，2H，3′-H)，-1.38to-1.33(m，2H，4′-H)，-2.38to-2.33(m，2H，5′-H)。
Ultimate analysis: calculated value C (60.41%), N (21.86%), H (4.20%) is (with C
58h
48n
18o
8si calculates); Measured value C (60.16%), N (21.25%), H (4.90%).
Embodiment 4
The synthesis of two [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] silicon phthalocyanine
The synthesis of (1) 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine
By 2-chlorine adenosine 309mg(1mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone, by preferred for tosic acid 8 ~ 12mmol(10mmol) be dissolved in 10 ~ 30ml (preferred 20ml) acetone.Under ice-water bath, tosic acid acetone soln is slowly added drop-wise in the acetone soln of 2-chlorine adenosine, the preferred 22h of stirring at normal temperature 12 ~ 36h().Reaction mixture is poured in 4% sodium bicarbonate ice water solution, with dichloromethane extraction, collected organic layer, adds dried over mgso, concentrated after filtering, obtain white powder product after drying, productive rate 83%.
The characterization data of product is as follows: the characterization data of product is as follows: HRMS (ESI): 342.0968 [M+H]
+.
IR（KBr，cm
-1）：3475,3409,3154（-OH,-NH
2）；1656（N-C）；1598（-NH
2）；1472（-CH
2-），1313(-CCH
3-)；1098（C-O-C）。
1HNMR(DMSO-d6，400MHz，ppm)：δ8.37(s，1H，imidazole-H),7.89（s（br），2H,NH
2）,6.06（d，
J=2.4Hz,1H,1′-H），5.28-5.30(m，1H，2′-H)，5.10-5.12（m，1H，OH）,4.93-4.95（m，1H，3′-H），4.21-4.23（m，1H，4′-H），3.54-3.57（m，2H，5′-H），1.55(s，3H，Me),1.33(s，3H，Me)。
The synthesis of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40mg; 0.065mmol), the isopropylidene protection product (0.260 ~ 0.650mmol of above-mentioned acquisition 2-chlorine adenosine; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferred 20ml), reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo removes solvent, and methylene dichloride dissolves, washing, collected organic layer, MgSO
4drying, filter, concentrated filtrate obtains crude product.Crude product is by silica column purification, and use ethyl acetate is eluent, removes light blue component, be then eluent with tetrahydrofuran (THF), collect target product, be further purified by gel column after concentrated, blue product is obtained obtaining, productive rate 60% after concentrated, vacuum-drying.
The maximum absorption band of product in DMF is positioned at 677nm place, and the maximum absorption wavelength in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution is positioned at 680nm place.
The structure of product is shown below, and characterization data is as follows:
。
HRMS（ESI）：m/z1243.2866[M+Na]
+。
1HNMR(CDCl
3，400MHz，ppm)：δ9.62-9.63(m，8H，Pc-H
α),8.39-8.41(m，8H，Pc-H
β),6.43(s，4H，NH
2)，5.39(s，2H，imidazole-H)，4.58(d，
J=3.0Hz，2H，1′-H),2.19(d，
J=9.0Hz，2H，2′-H)，1.79-1.81(m，2H，3′-H),0.92(s，6H，Me)，0.89-0.91(m，2H，4′-H)，0.76(s，6H，Me)，-1.28(d，
J=14.0Hz，2H，5′-H)，-2.29(d，
J=15.5Hz，2H，5′-H)。
Embodiment 5
The synthesis of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (structure is shown below) and physico-chemical property:
Under nitrogen protection; by phthalocyanine silicon dichloride (244.7mg; 0.4mmol); 4-(2-amino-ethyl) phenol 1.2 ~ 2mmol (preferred 1.6mmol) and NaH joins toluene or dimethylbenzene or dioxane 20 ~ 50ml (preferred toluene; 30ml), reflux 12 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo is except desolventizing, and use 100ml methylene dichloride to dissolve, centrifugal removing insolubles, dichloromethane solution use water extraction (3 × 100ml), collected organic layer, then uses dilute hydrochloric acid (0.1 ~ 0.5mmol) to extract, and collects water layer.With in 1M sodium hydroxide and water layer, separate out blue precipitate, centrifugal, washing, vacuum-drying, obtains blue product, productive rate 45%.The maximum absorption band of product in DMSO is positioned at 684nm place, and maximum absorption wavelength is in aqueous positioned at 689nm place.
The structural characterization data of product are as follows: MS(ESI) m/z:813.0 [M]
-;
1hNMR (DMSO-d6, ppm): δ 9.68 (m, 8H, Pc-H α), 8.54 (m, 8H, Pc-H β), 5.40 (d, J=8.4Hz, 4H, CHAr), 2.21 (d, J=8.3Hz, 4H, CHAr), 1.97 (t, J=7.0Hz, 4H, CH2), 1.70 (t, J=6.8Hz, 4H, CH; IR(KBr, cm
-1): 1607.9,1524,1429.3,1335.8,1290.8,1166.1,1122.9,1080.9,912.2,760.5,735.6,3054,3020,1504,2922.8,2851.5,1472,3434,3358.6,1252.3.
Embodiment 6
Structure is shown below the synthesis of the asymmetric modification silicon phthalocyanine of axial uridine/amino-ethyl phenoxy group and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine.
The preferred 2.5mmol of 1 ~ 10mmol(is added in toluene (or dimethylbenzene or the dioxane) solution of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 5 compound) of 1mmol) 2 ', 3 '-O-sec.-propyl-uridine, at 110 ~ 130 DEG C, reaction 1 ~ 20 hour is continued after adding the NaH of catalytic amount, reaction end is monitored by TLC, reaction mixture is revolved and steams to a small amount of, add a small amount of DMF to dissolve, and then separate out precipitation after adding a large amount of water, membrane filtration is except desolventizing and reaction raw materials and by product, dry.By silica column purification crude product, first utilizing tetrahydrofuran (THF) for eluting solvent, after the complete wash-out of the first band, take DMF as eluting solvent, collect target elution fraction, revolve and steam to a small amount of solvent, micro-pore-film filtration, revolve steaming, drying obtains blue-greenish colour product, productive rate about 20%.The maximum absorption band of product in DMF is positioned at 679nm place, is positioned at 688nm place in water.
The maximum absorption band of product in DMF is positioned at 679nm place, is positioned at 688nm place in water.HR-MS (ESI): m/z906.3038 [M+H] of product
+.IR（KBr，cm-1）：3427.3,3223.4,3054.2,2932.8,1686.5,1610.8,1524.3,1502.7,1336.3,1124.3,1083.2,737.3。1H-NMR(DMSO-d6，ppm):δ9.55~9.85(m,8H,Pc~Hα)，8.40~8.70(m,8H,Pc~Hβ)，7.92~8.01(s,1H)，5.42~5.49(d,2H)，4.56~4.62(d,1H)，4.31~4.38(t,2H)，2.89~2.90(s,1H)，2.73~2.74(s,2H)，2.17~2.24(d,2H)，2.03~2.12(t,2H)，1.82~1.92(t,2H)，1.69~1.74(t,1H)，1.52~1.59(t,1H)，0.70~0.82(s,3H)，0.55~0.66(s,3H)，-1.35~-1.25(m,1H)，-2.35~-2.25(m,1H)。
Embodiment 7
With 2 ', in 3 '-O-sec.-propyl-cytidine alternate embodiment 62 ', 3 '-O-sec.-propyl-uridine, structure can be obtained to be shown below the asymmetric modification silicon phthalocyanine of axial cytidine/amino-ethyl phenoxy group (i.e. [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine).The maximum absorption band of this compound in DMF is positioned at 678nm place, is positioned at 688nm place in water, mass spectrum (ESI): m/z959.2 [M+H]
+.
Embodiment 8
The synthesis of the asymmetric modification silicon phthalocyanine of axial 2-chlorine adenosine/amino-ethyl phenoxy group that structure is shown below and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine
The preferred 3mmol of 1 ~ 10mmol(is added in toluene (or dimethylbenzene or the dioxane) solution of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 5 compound) of 1mmol) 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine, at 110 ~ 130 DEG C, reaction 1 ~ 10 hour is continued after adding the NaH of catalytic amount, reaction end is monitored by TLC, reaction mixture is revolved and steams to a small amount of, add a small amount of DMF to dissolve, and then separate out precipitation after adding a large amount of water, membrane filtration is except desolventizing and reaction raw materials and by product, dry.By silica column purification crude product, utilize tetrahydrofuran (THF) for eluting solvent, after the complete wash-out of the first band, using DMF instead is eluting solvent, collects target elution fraction, and revolve and steam to a small amount of solvent, micro-pore-film filtration, revolves steaming, and drying obtains blue product, productive rate about 21%.
The maximum absorption band of product in DMF is positioned at 677nm place, is positioned at 688nm place in water.Other characterization datas of product: HR-MS (ESI): m/z1016.2842 [M]
-.IR（KBr，cm
-1）：3408.5,3208.5,2927.7,1635.3,1522.9,1506.0,1334.2,1124.3,1079.8,914.4,738.4。
1H-NMR(DMSO-d
6，ppm):δ9.55~9.85(m,8H,Pc~H
α)，8.40~8.70(m,8H,Pc~H
β)，7.90~7.96(s,1H)，6.00~6.29(s,2H)，5.28~5.42(d,2H)，2.87~2.88(s,1H)，2.70~2.73(s,1H)，2.08~2.20(d,2H)，1.96~2.06(t,2H)，1.78~1.91(t,2H)，1.28~1.35(t,1H)，1.18~1.25(t,1H)，1.02~1.06(t,1H)，0.63~0.85(s,3H)，0.44~0.62(s,3H)，-1.45~-1.30(m,1H)，-2.25~-2.05(m,1H)。
Embodiment 9
With 2 ', in 3 '-O-sec.-propyl-adenosine alternate embodiment 82 ', 3 '-O-sec.-propyl-2-chlorine adenosine, the asymmetric modification silicon phthalocyanine of axial adenosine/amino-ethyl phenoxy group (i.e. [5 '-(2 ', 3 '-O-sec.-propyl) adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine) that structure is shown below can be obtained.The maximum absorption band of this compound in DMF is positioned at 677nm place, is positioned at 688nm place in water, its mass spectrum MS (ESI): m/z982.3 [M]
-.
Embodiment 10
The synthesis of the asymmetric modification silicon phthalocyanine of axial uridine/triethylene glycol that structure is shown below and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine.
At [5 '-(2 ' of 1mmol, 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 6 compound) toluene (or dimethylbenzene or dioxane) solution in add the preferred 1.5mmol of 1 ~ 10mmol() triethylene glycol monomethyl ether, react 1 ~ 20 hour at 110 ~ 130 DEG C after adding the NaH of catalytic amount, reaction end is monitored by TLC, reaction mixture is revolved and steams to a small amount of, add a small amount of DMF to dissolve, and then separate out precipitation after adding a large amount of water, membrane filtration is except desolventizing and reaction raw materials and by product, dry.By silica column purification crude product, utilize ethyl acetate for eluting solvent, collect target elution fraction, revolve and steam to a small amount of solvent, filter, revolve steaming, drying obtains blue product, productive rate about 15%.The maximum absorption band of product in DMF is positioned at 677nm place, is positioned at 688nm place in water, its HR-MS (ESI): m/z1009.3066 [M+Na]
+.
Embodiment 11
Respectively with the triethylene glycol monomethyl ether in triethylene glycol, TEG, TEG monomethyl ether alternate embodiment 10, can obtain the asymmetric modification silicon phthalocyanine of axial uridine/glycol derivative that structure is shown below, productive rate is 10-20%.The maximum absorption band of these compounds in DMF is positioned at 677-680nm place, is positioned at 688-690nm place in water.
Embodiment 12
The synthesis of the asymmetric modification silicon phthalocyanine of axial cytidine/triethylene glycol that structure is shown below and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine.
With [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] [5 '-(2 ' in [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 7 compound) alternate embodiment 10, 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, [5 '-(2 ' can be obtained, 3 '-O-sec.-propyl)-cytidine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine, the maximum absorption band of this compound in DMF is positioned at 678nm place, 689nm place is positioned in water, its MS (ESI): m/z1002.4 [M]
+.
Embodiment 13
Respectively with the triethylene glycol monomethyl ether in triethylene glycol, TEG, TEG monomethyl ether alternate embodiment 12, can obtain the asymmetric modification silicon phthalocyanine of axial cytidine/glycol derivative that structure is shown below, productive rate is 13-22%.The maximum absorption band of these compounds in DMF is positioned at 678-680nm place, is positioned at 688-690nm place in water.
Embodiment 14
The synthesis of the asymmetric modification silicon phthalocyanine of axial 2-chlorine adenosine/triethylene glycol that structure is shown below and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine.
With [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [5 '-(2 ' in [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 8 compound) alternate embodiment 10, 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, [5 '-(2 ' can be obtained, 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine, the maximum absorption band of this compound in DMF is positioned at 679nm place, 689nm place is positioned in water, its MS (ESI): m/z1058.3 [M]
+.
Embodiment 15
Respectively with the triethylene glycol monomethyl ether in triethylene glycol, TEG, TEG monomethyl ether alternate embodiment 14, can obtain the asymmetric modification silicon phthalocyanine of axial 2-chlorine adenosine/glycol derivative that structure is shown below, productive rate is 13-22%.The maximum absorption band of these compounds in DMF is positioned at 679-681nm place, is positioned at 688-690nm place in water.
Embodiment 16
The synthesis of the asymmetric modification silicon phthalocyanine of axial adenosine/triethylene glycol that structure is shown below and physico-chemical property:
This compound can called after: [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine.
With [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] [5 '-(2 ' in [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (described in embodiment 9 compound) alternate embodiment 10, 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, [5 '-(2 ' can be obtained, 3 '-O-sec.-propyl)-adenosine oxygen base] [(2-(2-(2-methoxy ethoxy) oxyethyl group) oxyethyl group)] silicon phthalocyanine, the maximum absorption band of this compound in DMF is positioned at 679nm place, 689nm place is positioned in water, its MS (ESI): m/z1025.6 [M]
+.
Embodiment 17
Respectively with the triethylene glycol monomethyl ether in triethylene glycol, TEG, TEG monomethyl ether alternate embodiment 16, can obtain the asymmetric modification silicon phthalocyanine of axial adenosine/glycol derivative that structure is shown below, productive rate is 15-25%.The maximum absorption band of these compounds in DMF is positioned at 678-680nm place, is positioned at 688-690nm place in water.
Embodiment 18
The method utilizing axial nucleosides of the present invention asymmetric modification silicon phthalocyanine to prepare photo-dynamical medicine (i.e. photosensitive (medicine) agent) is: with water, or the mixed solution (wherein the massfraction of other material is not higher than 10%) of water and other material is as solvent, dissolve the silicon phthalocyanine of the asymmetric modification of axial nucleosides, be mixed with containing certain density photosensitive medicament, the concentration of the silicon phthalocyanine of the asymmetric modification of axial nucleosides is not higher than its saturation concentration (preferably 1 ~ 0.01mM).Other described material can be one or more mixed following: castor oil derivative (CremophorEL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Antioxidant, buffer reagent and isotonic agent can be added as additive to keep chemical stability and the biocompatibility of photosensitive medicament in the solution made.
Asymmetric for nucleosides of the present invention modification silicon phthalocyanine is dissolved in 5 ~ 35%(wt%) aqueous solution of methyl-sulphoxide, can be used as the preparation of topical.
Embodiment 19
Photo-dynamical medicine prepared by the present invention, photosensitive (medicine) agent, at optical dynamic therapy, or light power diagnosis, or light power sterilization in using method identical with the using method of photosensitive medicament prepared by the phthalocyanine used in prior art described in non-invention or porphyrin compound or photosensitizers, but need supporting suitable light source, described suitable light source can be connected suitable spectral filter to provide by ordinary light source or be provided by the laser of specific wavelength, the wavelength region of light source is 300-800nm, preferred 675-690nm.
Embodiment 20
Asymmetric for axial nucleosides of the present invention for the present invention modification silicon phthalocyanine is dissolved in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution, makes the photosensitive medicament of 0.08mM.Test them to the dark toxicity of people cancer of the stomach BGC823 cell and photodynamic activity.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, makes the cell culture fluid containing different concns photosensitizers.Test cell is cultivated 2 hours respectively in the nutrient solution containing different concns photosensitizers, abandons nutrient solution thereafter, after cleaning cell with PBS, add new nutrient solution (not containing photosensitizers).Illumination experiment group, (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power irradiating light is 15mw × cm to carry out red light irradiation to cell
-2); Not irradiation group, is placed in dark place 20 minutes by cell.After illumination or not illumination, the survival rate of cell adopts mtt assay to investigate.Specific experiment step see "
bioorganic & MedicinalChemistryLetters ", 2006,16,2450-2453.
The ruddiness that above-mentioned wavelength is greater than 610nm connects by the halogen lamp of 500W the spectral filter that heat insulation tank strengthens in 610nm to provide.
Result shows, the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention, under red light irradiation, can kill and wound cancer cells, when the concentration of the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention is 0.003mM (namely 3 × 10
-6mol/L), time, 100% cancer cells can be killed and wounded.Under same concentration, if do not carry out illumination, the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention is not is not killed and wounded and growth-inhibiting effect cancer cells, shows that they do not have dark toxicity.By the dose-effect relationship of concentration and cell survival rate, find the toxic limit medium dose (IC of the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention under red light irradiation
50, namely kill the drug level needed for 50% cancer cells) be respectively:
4nM ([5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, i.e. compound described in embodiment 6);
150nM ([5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, i.e. compound described in embodiment 7);
7nM ([5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, i.e. compound described in embodiment 8);
5nM ([5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, i.e. compound described in embodiment 9);
The asymmetric modification silicon phthalocyanine of the axial uridine/oligoethylene glycol of 6-20nM(, i.e. compound described in embodiment 10-11);
The asymmetric modification silicon phthalocyanine of the axial cytidine/oligoethylene glycol of 200-310nM(, i.e. compound described in embodiment 12-13);
The asymmetric modification silicon phthalocyanine of the axial 2-chlorine adenosine/oligoethylene glycol of 7-15nM(, i.e. compound described in embodiment 14-15);
The asymmetric modification silicon phthalocyanine of the axial adenosine/oligoethylene glycol of 5-18nM(, i.e. compound described in embodiment 16-17).
Visible, the asymmetric modification silicon phthalocyanine IC of axial nucleosides
50be worth lower, part of compounds is even low to moderate 4-7nM (i.e. 4-7 × 10
-8mol/L).Extremely low IC
50value, illustrates that axial nucleosides asymmetric modification silicon phthalocyanine provided by the present invention has high photodynamic activity.
Change above-mentioned 1% castor oil derivative (CremophorEL, the wt%) aqueous solution into 1% castor oil derivative (CremophorEL, wt%) phosphate buffer soln (PBS), also can obtain same experimental result.
Embodiment 21
According to the method described in embodiment 20, determine axial nucleosides symmetry and modify silicon phthalocyanine, axial amino-ethyl phenoxy group symmetry modification silicon phthalocyanine, the symmetrical silicon phthalocyanine of modifying of axial oligoethylene glycol to the photodynamic activity of people cancer of the stomach BGC823 cell.
Result shows, axial nucleosides symmetry modifies silicon phthalocyanine, two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine, two [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] silicon phthalocyanine, two [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] silicon phthalocyanine and two [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] silicon phthalocyanine light power suppresses the IC of people cancer of the stomach BGC823 cell
50value is respectively 31nM, 410nM, 10nM and 9nM.
Axial amino-ethyl phenoxy group symmetry modifies silicon phthalocyanine, and namely two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine light power suppresses the IC of people cancer of the stomach BGC823 cell
50value is 20nM.
Axial triethylene glycol symmetry replaces silicon phthalocyanine, axial TEG symmetry replaces the IC that silicon phthalocyanine light power suppresses people cancer of the stomach BGC823 cell
50value is 50-30nM.
The result of comparing embodiment 20 and embodiment 21, can find that the light power antitumour activity of axial nucleosides of the present invention asymmetric modification silicon phthalocyanine is significantly higher than corresponding axial nucleosides symmetry and modifies silicon phthalocyanine, and the light power antitumour activity of most of axial nucleosides asymmetric modification silicon phthalocyanine is significantly higher than axial amino-ethyl phenoxy group symmetry modification silicon phthalocyanine and axial oligoethylene glycol symmetry replaces silicon phthalocyanine.
Embodiment 22
According to the method described in embodiment 18, the asymmetric modification of axial nucleosides more of the present invention and other phthalocyanine compounds following are to the photodynamic activity of people cancer of the stomach BGC823 cell.
Described other phthalocyanine compounds following are one of following title complex: axially two (4-kharophen phenoxy group) silicon phthalocyanine, two [4-(4-Acetylpiperazine) phenoxy group] silicon phthalocyanine, two [4-(3-carboxypropyl) phenoxy group] silicon phthalocyanine, two (4-formic acid phenoxy group) silicon phthalocyanine, two (3-formic acid phenoxy group) silicon phthalocyanine, two (3, 5-dioctyl phthalate phenoxy group) silicon phthalocyanine, two (1-diamantane-methoxyl group) silicon phthalocyanine, two (2-diamantane-oxyethyl group) silicon phthalocyanine, four-a-[4-(4-Acetylpiperazine) phenoxy group] ZnPc, four-a-(4-formic acid phenoxy group) ZnPc.
Result shows, the photodynamic activity of the silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention is all significantly higher than other similar compounds.In same concentration (1.0 × 10
-6mol/L), under, the light power restraining effect of silicon phthalocyanine to cancer of the stomach BGC823 cell of the asymmetric modification of axial nucleosides of the present invention is at least more than 3 times of other phthalocyanine compounds above-mentioned.
Embodiment 23
The silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention is dissolved in 1% castor oil derivative (CremophorEL, wt%) PBS damping fluid, makes the photosensitive medicament of 0.3mM, test their light power inhibit activities to fungi.Fungi is Candida albicans CMCC (F) C1a(Candidaalbicans, C.albicans), bacteria suspension concentration is 2 × 10
6cells/ml.Under red light irradiation, (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power irradiating light is 15mw × cm
-2), the silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention can kill 60% Candida albicans, and solvent control group, irradiation group, an irradiation not administration group all do not affect the growth of Candida albicans in an administration.
Embodiment 24
The effect that the silicon phthalocyanine testing the asymmetric modification of axial nucleosides of the present invention is sterilized for light power as photosensitizers.
First, the silicon phthalocyanine of the asymmetric modification of described axial nucleosides is dissolved in 1% castor oil derivative (CremophorEL, the wt%) aqueous solution, makes the photosensitive medicament of 0.3mM.Then joined containing in colibacillary water, make the content of silicon phthalocyanine be 0.03mM, after 2 hours, contain colibacillary water with red light irradiation.Check colibacillary survival condition before and after irradiation, result shows under red light irradiation, and the silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention can kill the intestinal bacteria of more than 70%.
The foregoing is only preferred embodiment of the present invention, all equalizations done according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Claims (4)
1. a silicon phthalocyanine for the asymmetric modification of axial nucleosides, is characterized in that: its structural formula is as follows:
，
Wherein axial substituted base R
1, R
2be selected from following group respectively:
R
1for
;
R
2for
,
,
,
,
in one.
2. prepare a method for the silicon phthalocyanine of the asymmetric modification of axial nucleosides as claimed in claim 1, it is characterized in that: comprise the following steps:
(1) with two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine and 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine is reactant, both molar ratios are 1:1 ~ 10, with toluene, dimethylbenzene or dioxane for solvent, under the protection of nitrogen, 100 ~ 130 DEG C are reacted 1 ~ 20 hour, remove excessive raw material and impurity, obtain axial nucleosides and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group by solvent cleaning and column chromatography for separation;
(2) with the one in axial nucleosides and the asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group and triethylene glycol, triethylene glycol monomethyl ether, TEG, TEG monomethyl ether for reactant; both molar ratios are 1:1 ~ 10; with toluene, dimethylbenzene or dioxane for solvent; under the protection of nitrogen; 100 ~ 130 DEG C are reacted 1 ~ 20 hour; remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain axial nucleosides and the asymmetric modification silicon phthalocyanine of oligoethylene glycol.
3. an application for the silicon phthalocyanine of the asymmetric modification of axial nucleosides as claimed in claim 1, is characterized in that: the silicon phthalocyanine of the described asymmetric modification of axial nucleosides is for the preparation of photo-dynamical medicine or photosensitizers.
4. application according to claim 3, it is characterized in that: the method preparing photo-dynamical medicine or photosensitizers is: the mixing solutions using water or water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve the silicon phthalocyanine of the asymmetric modification of axial nucleosides, be mixed with containing certain density photosensitive medicament, the concentration of the silicon phthalocyanine of the asymmetric modification of axial nucleosides is not higher than its saturation concentration; Antioxidant, buffer reagent and isotonic agent is added as additive to keep chemical stability and the biocompatibility of photosensitive medicament in the solution made;
Other described material is the mixture of one or more in castor oil derivative, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
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| 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 |
| CN108456298B (en) * | 2018-05-15 | 2020-06-05 | 长春理工大学 | Soluble asymmetric phthalocyanine modified amphiphilic polymer and synthesis method thereof |
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| CN114249785B (en) * | 2020-09-23 | 2024-04-05 | 常州方圆制药有限公司 | Preparation method of 2-adenosine N-pyrazole derivative regadenoson |
| CN116284095A (en) * | 2023-01-18 | 2023-06-23 | 福州大学 | Silicon phthalocyanine ring nucleophilic addition compound with strong absorption in near infrared region, preparation and application thereof |
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