CN103435639A - Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof - Google Patents
Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses axial nucleoside asymmetrically-modified silicon phthalocyanine and a preparation method and application thereof, belonging to the preparation field of a photodynamic medicine or a photosensitizer. The axial nucleoside asymmetrically-modified silicon phthalocyanine disclosed by the invention can be applied to photodynamic treatment, photodynamic diagnosis or photodynamic disinfection as a photosensitizer, has the structural characteristic of axial asymmetric substitution, and shows good amphipathicity and excellent 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 develop into the functional materials of different purposes by different structural modifications.Introduce suitable substituent and central ion on the phthalocyanine ring, just likely be developed as oxide catalyst, desulfurization catalyst, nonlinear optical material, photosensitive drug, liquid crystal material, optical recording material or light-guide material, obtaining the objective function compound but how to regulate and control substituting group and central ion, is but to need creationary work.
Phthalocyanine compound as photosensitizers the application prospect in optical dynamic therapy (Photodynamic Therapy) noticeable.So-called optical dynamic therapy (or claiming photodynamic therapy) in fact, is the application of the Photosensitive reaction of photosensitizers (or claiming photosensitive drug) at medical field.Its mechanism is, first photosensitizers is injected to body, (this period waiting time be allow medicine enrichment relatively in target body) after a period of time, rayed target body (to endoceliac target, can import light source by interventional techniques such as optical fiber) with specific wavelength, be enriched in photosensitizers in target body under optical excitation, inspire a series of optical physics photochemical reactions, produced active oxygen, and then destroyed target body (for example cancer cells and cancerous tissue).
In some developed countries, optical dynamic therapy has become the 4th kind of ordinary method for the treatment of cancer.With traditional therapy, as surgical operation, chemotherapy, radiotherapy are compared, the advantage of photodynamic therapy maximum is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and side effect is little, thereby gets most of the attention.
Simultaneously, research in recent years also shows, photodynamic therapy also can be treated the non-Cancerous diseases such as bacterium infection, oral disease, macular degeneration illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be for light power sterilization, most importantly for the sterilization of water body, blood and blood derivatives.Simultaneously, 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 optical dynamic therapy in the potentiality aspect treatment tumour and Other diseases, scientific circles generally believe, optical dynamic therapy will become the important therapy of 21 century, so, as the photosensitizers of 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 be the Photofrin(U.S. FDA in nineteen ninety-five official approval Photofrin for clinical anticancer), it is the mixture of the haematoporphyrin oligopolymer that extracts from cow blood and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect, but also exposed critical defect: maximum absorption wavelength (380-420nm) is not to tissue transmitance red light district (650-800nm) preferably, the skin phototoxicity is large, mixture, form unstable etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international study hotspot.
Owing to having the characteristics such as maximum absorption wavelength is positioned at the ruddiness zone that easily sees through tissue and the photosensitization ability is strong, phthalocyanine compound draws attention as the application of photosensitizers.In various phthalocyanine compounds, because following reason silicon phthalocyanine is paid much attention to as the application of novel photosensitive agent: (1) silicon phthalocyanine can axially introduced two substituting groups, thereby can more effectively stop the phthalocyanine ring to be assembled, guarantee the performance of phthalocyanine photosensitization ability; (2) biocompatibility of silicon higher, without dark toxicity.The axial substituted phthalocyanine silicon (Pc4) of U.S. Case Western Reserve university development has shown high light power activity, has entered the 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 the axial modification silicon phthalocyanine photosensitizers easy, that cost is low.In addition, the photosensitizers (comprising the phthalocyanines photosensitizers) of clinical trial at present also lacks the selectivity to tumor tissues and cancer cells, is also the current problem that needs emphasis to overcome.
The Chinese invention patent that the patent No. is ZL200410013289.7 and ZL200610200598.4 has been introduced a series of axial replacement silicon phthalocyanine compounds, its preparation and the application in optical dynamic therapy (this invention and the application are same contriver) thereof.But, due to photosensitizers and the potential tremendous economic social value of optical dynamic therapy, the refinement of range of application and treatment focus greatly, prepare the axial replacement silicon phthalocyanine compounds with photosensitive activity is very necessary as drug candidate more.
What is particularly worth mentioning is that; the state such as American-European, Japanese strengthens one after another to the input of novel photosensitive agent and the infiltration dynamics of intellecture property; in this case; only have and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate the patent protection paces, guarantee China is in autonomy and the commanding elevation of this important medical field of optical dynamic therapy.
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, has shown good amphipathic and high photodynamic activity, and as photosensitizers, application has significant advantage.
For achieving the above object, the present invention adopts following technical scheme:
The silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides, its structural formula is as follows:
Axial substituent R wherein
1, R
2be selected from respectively following group:
R
1for
,
,
,
in a kind of;
R
2for
,
,
,
,
in a kind of.
The silicon phthalocyanine of the asymmetric modification of described axial nucleosides is axial asymmetric dibasic silicon phthalocyanine, and axially substituting group is connected with silicon by Sauerstoffatom; Silicon phthalocyanine or title silicon phthalocyanine are the phthalocyanine compounds that central ion is silicon.Phthalocyanine, English name phthalocyanine, be the abbreviation of four benzo tetraazatetradecane porphyrins.The constructional feature of the silicon phthalocyanine of the asymmetric modification of described axial nucleosides is: on one side axially substituting group is uridine, cytidine or adenosine derivative, Yi Bian 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 ', a kind of in 3 '-O-sec.-propyl-2-chlorine adenosine is reactant, both molar ratios are 1:1 ~ 10, take toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, 100 ~ 130 ℃ are reacted 1 ~ 20 hour, remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group;
(2) take a kind of in the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group and triethylene glycol, triethylene glycol monomethyl ether, TEG, TEG monomethyl ether is reactant; both molar ratios are 1:1 ~ 10; take toluene, dimethylbenzene or dioxane as solvent; under the protection of nitrogen; 100 ~ 130 ℃ are reacted 1 ~ 20 hour; remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and low polyoxyethylene glycol.
The silicon phthalocyanine of the asymmetric modification of axial nucleosides as above is applied to prepare photo-dynamical medicine or photosensitizers.Described photosensitizers, can be described as photosensitive medicament at biomedicine field, or claim the photosensitive drug preparation, is called again light power medicament.Prepared photo-dynamical medicine or photosensitizers can be used for optical dynamic therapy, light power diagnosis or the sterilization of light power.Described optical dynamic therapy can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Described non-Cancerous disease, can be that bacterium infects, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.Described smooth 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 medical or that live and use device.
The method for preparing photo-dynamical medicine or photosensitizers is: 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, axially the concentration of the silicon phthalocyanine of the asymmetric modification of nucleosides is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament; Described other material is one or more the miscellany in castor oil derivative (Cremophor EL), 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) the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention is axial Asymmetrical substitute silicon phthalocyanine, and axially group is respectively nucleosides and amino-ethyl phenoxy group (or low polyoxyethylene glycol), has good amphipathic and unique Asymmetrical substitute characteristics.
(2) the axial group of the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention contains nucleoside derivates, and nucleosides is biomolecules in body, thus the biocompatibility of the silicon phthalocyanine provided and biological selectivity higher.
(3) maximum absorption wavelength of the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention in the aqueous solution is positioned at the 686-688nm place, and molar absorption coefficient (reaches 10 greatly
5the order of magnitude), its spectral quality not only is better than first-generation photosensitizers greatly, and is better than carrying out other phthalocyanine compounds of clinical experiment.For example, the maximum absorption wavelength of silicon phthalocyanine provided by the invention with respect to the Pc4 red shift of the U.S. nearly 10nm, the tissue penetration ability 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, location isomer not.The chemically modified of the present invention to the phthalocyanine precursor structure be by realizing in the axial of phthalocyanine ring rather than at the periphery introducing substituted radical of phthalocyanine ring, thereby clearly, there is not isomer in the target compound structure.If the periphery at the phthalocyanine ring is introduced substituting group, 16 the possible the position of substitution of periphery existence due to the phthalocyanine ring, may produce a plurality of isomer, causes product to contain isomer or separation costs increase.
(5) the present invention selects the central ion of silicon as phthalocyanine compound, and the biological safety of silicon and biocompatibility are wanted the good ion common in other (zinc, aluminium, magnesium and gallium), and the quantum yield of silicon phthalocyanine generation active oxygen is high.
(6) silicon phthalocyanine provided by the invention has higher light stability, and its light stability for example, higher than other similar photosensitizerss, the Pc4 of the U.S..
(7) the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention is to obtain by a large amount of shaker tests, there is high photodynamic activity, for example, under red light irradiation, only [5 '-(2 ' of 15nM, 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine just can 100% suppresses the growth of Human gastric careinoma cells BGC823, IC
50value (killing the required drug level of 50% cancer cells) can be low to moderate 4nM.
(8) a large amount of simultaneous tests shows, the photodynamic activity of the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention silicon phthalocyanine provided by the invention is significantly higher than the symmetrical silicon phthalocyanine of modifying of corresponding axial nucleosides.The light power antitumour activity of the asymmetric modification silicon phthalocyanine of the axial nucleosides of major part provided by the invention is higher than symmetrical silicon phthalocyanine, i.e. two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine of modifying of axial amino-ethyl phenoxy group.The light power antitumour activity of the asymmetric modification silicon phthalocyanine of the axial nucleosides of major part provided by the invention is also higher than the symmetrical silicon phthalocyanine that replaces of axially low polyoxyethylene glycol, 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] and oxyethyl group } silicon phthalocyanine, two 2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } silicon phthalocyanine, two 2-{2-[2-(2-methoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine, two 2-{2-[2-(2-ethoxy ethoxy) oxyethyl group] and oxyethyl group } oxyethyl group } silicon phthalocyanine etc.Simultaneously, the anticancer work of light power of the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the invention also is significantly higher than other phthalocyanine compounds, as axial two (4-kharophen phenoxy group) silicon phthalocyanine, two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine, two [4-(3-carboxyl propyl group) 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-ethanoyl piperazine) phenoxy group] ZnPc, four-a-(4-formic acid phenoxy group) ZnPc etc.
(9) the Asymmetrical substitute silicon phthalocyanine is synthetic larger with separating difficulty, and the axial Asymmetrical substitute silicon phthalocyanine that is not all anticipations can effectively obtain.Show through lot of experiments, can effectively 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, under 100 ~ 130 ℃, react 1 ~ 20 hour, remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, the asymmetric modification silicon phthalocyanine of the axial nucleosides obtained and 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; take toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, react 1 ~ 20 hour under 100 ~ 130 ℃; wash with column chromatography for separation and remove excessive raw material and impurity by solvent, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and low polyoxyethylene 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 the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Non-Cancerous disease of the present invention, can be that bacterium infects, 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, for the sterilization of light power, described smooth 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 medical or that live and use device.
The application of the silicon phthalocyanine of the asymmetric modification of axial nucleosides provided by the invention in optical dynamic therapy, light power diagnosis and the sterilization of light power, need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, the wavelength region of light source is 600～800nm, preferably 686-688nm.
The basic skills of utilizing the silicon phthalocyanine of the asymmetric modification of axial nucleosides provided by the invention to prepare photo-dynamical medicine (or photosensitizers) is: make 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.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also can be first with hydrochloric acid or sulfuric acid or etc. acidic substance silicon phthalocyanine of the present invention is converted into to the form of salt, then use above-mentioned dissolution with solvents.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament.
The preparation of using for topical, can be dissolved in silicon phthalocyanine of the present invention in the perviousness solvent, maybe will be injected in ointment, washing lotion or gel.The preferred 5-35%(wt% of described perviousness solvent) aqueous solution of methyl-sulphoxide.
The invention will be further described below to adopt non-limiting example.
Embodiment 1
Synthesizing of two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-uridine
By uridine 245mg(1mmol) be dissolved in 10 ~ 30ml (preferably 20 ml) acetone, by preferred 10 mmol of tosic acid 8 ~ 12mmol() be dissolved in 10 ~ 30ml (preferably 20 ml) acetone.Under ice-water bath, the tosic acid acetone soln slowly is added drop-wise in the uridine acetone soln to the preferred 6h of stirring at normal temperature 2 ~ 10 h().Reaction mixture is added to and contains in 4% sodium bicarbonate frozen water solution, repeatedly extract with methylene dichloride (or trichloromethane), collected organic layer, add dried over mgso, concentrated after filtering, dry yellow powder shape product, the productive rate 85% of obtaining.
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-)。
1H NMR (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)。
Synthesizing of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition uridine protection product (0.260 ~ 0.650mmol; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferably 20ml) reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo is removed solvent, and washing, obtain the blue coarse product.Crude product passes through the silicagel column purifying, and the use ethyl acetate is eluent, collects after second component concentrates and is further purified (tetrahydrofuran (THF) is eluent) by gel chromatography (S-X3 type), collects target components, obtains blue product, productive rate 66% after concentrate drying.The maximum absorption band of product in DMF is positioned at 678 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at the 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).
1H NMR (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 =8.0 Hz，2H，pyrimidine-NCH)，4.43(d，
J =4.0 Hz，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
Synthesizing of two [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-cytidine
By cytidine 250mg(1mmol) be dissolved in 10 ~ 30ml (preferably 20 ml) acetone, by preferred 10 mmol of tosic acid 8 ~ 12mmol() be dissolved in 10 ~ 30ml (preferably 20 ml) acetone.Under ice-water bath, the tosic acid acetone soln slowly is added drop-wise in the cytidine acetone soln, the preferred 6h of stirring at normal temperature 4 ~ 10 h(), centrifugal, collect white precipitate, precipitation washing with acetone three to four times, with a small amount of DMF, dissolve, add ethyl acetate and separate out, membrane filtration, vacuum-drying, obtain white powdered 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).
1H NMR (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)。
Synthesizing of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition cytidine protection product (0.260 ~ 0.650mmol; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferably 20ml) reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo is removed solvent, and washing, obtain the blue coarse product.Crude product is by the silicagel column purifying, and using ethyl acetate/DMF (volume ratio 20:1) mixed solvent is eluent, removes light green impurity, then take DMF as eluent, 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 677 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at the 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).
1H NMR (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 =6.8 Hz，2H，pyrimidine-H), 4.51(d，
J =3.6 Hz，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
Synthesizing of two [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-adenosine
Adenosine (1mmol) is dissolved in 10 ~ 30ml (preferably 20 ml) acetone, by preferred 10 mmol of tosic acid 8 ~ 12mmol() be dissolved in 10 ~ 30ml (preferably 20 ml) acetone.Under ice-water bath, the tosic acid acetone soln slowly is added drop-wise in the amino adenosine acetone soln of 2-to the preferred 6h of stirring at normal temperature 24 ~ 72 h(), be poured in 4% sodium bicarbonate frozen water solution, separate out white precipitate, suction filtration, drying.Carry out Soxhlet with trichloromethane and extract purifying, obtain the white powder product after drying.Productive rate 85%.
Synthesizing of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40 mg; 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 (preferably 20ml) reflux 12 ~ 48 hours (preferably 36 hours).Rotary evaporation in vacuo is removed solvent, and washing, obtain the blue coarse product.Crude product is by the silicagel column purifying, and use acetone is eluent, and concentrated target components obtains blue product, productive rate 60% after drying.The maximum absorption band of product in DMF is positioned at 677 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at the 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).
1H NMR (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)，-1.38 to -1.33 (m，2H，4′-H)， -2.38 to -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
Synthesizing of two [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine
By 2-chlorine adenosine 309mg(1mmol) be dissolved in 10 ~ 30ml (preferably 20 ml) acetone, by preferred 10 mmol of tosic acid 8 ~ 12mmol() be dissolved in 10 ~ 30ml (preferably 20 ml) acetone.Under ice-water bath, the tosic acid acetone soln slowly is added drop-wise in the acetone soln of 2-chlorine adenosine to the preferred 22h of stirring at normal temperature 12 ~ 36 h().Reaction mixture is poured in 4% sodium bicarbonate frozen water solution, uses dichloromethane extraction, collected organic layer, add dried over mgso, concentrated after filtering, and obtains white powder product, productive rate 83% after drying.
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）。
1H NMR (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)。
Synthesizing of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition 2-chlorine adenosine protection product (0.260 ~ 0.650mmol; preferred 0.52mmol) and NaH(0.48 ~ 0.60mmol; preferred 0.42mmol) join in toluene 10 ~ 40ml (preferably 20ml) reflux 12 ~ 48 hours (preferably 24 hours).Rotary evaporation in vacuo is removed solvent, and methylene dichloride dissolves, washing, collected organic layer, MgSO
4drying, filter, and concentrated filtrate obtains crude product.Crude product is by the silicagel column purifying, and the use ethyl acetate is eluent, removes light blue component, then take tetrahydrofuran (THF) as eluent, collect target product, be further purified by gel column after concentrating, obtain obtaining blue product, productive rate 60% after concentrated, vacuum-drying.
The maximum absorption band of product in DMF is positioned at 677 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution is positioned at the 680nm place.
The structure of product is shown below, and characterization data is as follows:
HRMS（ESI）： m/z 1243.2866 [M+Na]
+ 。
1H NMR (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 =14.0 Hz，2H，5′-H)，-2.29(d，
J =15.5Hz，2H，5′-H)。
Embodiment 5
Synthetic and the physico-chemical property of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (structure is shown below):
Under nitrogen protection; by phthalocyanine silicon dichloride (244.7mg; 0.4mmol); the 4-(2-amino-ethyl) phenol 1.2 ~ 2 mmol (preferably 1.6mmol) and NaH join toluene or dimethylbenzene or dioxane 20 ~ 50ml (preferred toluene; 30ml), reflux 12 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo, except desolventizing, is used the 100ml methylene dichloride to dissolve, the centrifugal insolubles of removing, and dichloromethane solution water extraction (3 * 100ml), collected organic layer, then use dilute hydrochloric acid (0.1 ~ 0.5 mmol) extraction, collects water layer.With in 1M sodium hydroxide and water layer, separate out blue precipitation, centrifugal, washing, vacuum-drying, obtain blue product, productive rate 45%.The maximum absorption band of product in DMSO is positioned at 684 nm places, and the maximum absorption wavelength in the aqueous solution is positioned at the 689nm place.
The structural characterization data of product are as follows: MS(ESI) m/z:813.0 [M]
-;
1h NMR (DMSO-d6, ppm): δ 9.68 (m, 8H, Pc-H α), (8.54 m, 8H, Pc-H β), 5.40 (d, J=8.4 Hz, 4H, CHAr), 2.21 (d, J=8.3 Hz, 4H, CHAr), 1.97 (t, J=7.0 Hz, 4H, CH2), 1.70 (t, J=6.8 Hz, 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 synthesizing and physico-chemical property of axial uridine/asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group:
But this compound called after: [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine.
Add preferably 2.5 mmol of 1 ~ 10mmol(in toluene (or dimethylbenzene or dioxane) solution of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (the described compound of embodiment 5) of 1mmol) 2 ', 3 '-O-sec.-propyl-uridine, continue reaction 1 ~ 20 hour after adding the NaH of catalytic amount under 110 ~ 130 ℃, monitor reaction end 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, drying.By silicagel column purification of crude product, at first utilize tetrahydrofuran (THF) for eluting solvent, after the complete wash-out of the first band, take DMF as eluting solvent, collect the target elution fraction, revolve and steam to a small amount of solvent, micro-pore-film filtration, revolve steaming, drying obtains the blue-greenish colour product, productive rate approximately 20%.The maximum absorption band of product in DMF is positioned at the 679nm place, is positioned at the 688nm place in water.
The maximum absorption band of product in DMF is positioned at the 679nm place, is positioned at the 688nm place in water.The HR-MS of product (ESI): m/z 906.3038[M+H]
+.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) : δ 9.55~9.85 (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, can obtain the structure 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) that is shown below.The maximum absorption band of this compound in DMF is positioned at the 678nm place, is positioned at the 688nm place in water, mass spectrum (ESI): m/z 959.2[M+H]
+.
Embodiment 8
Synthetic and the physico-chemical property of the axial 2-chlorine adenosine that structure is shown below/asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group:
But this compound called after: [5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine
Add preferably 3 mmol of 1 ~ 10mmol(in toluene (or dimethylbenzene or dioxane) solution of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (the described compound of embodiment 5) of 1mmol) 2 ', 3 '-O-sec.-propyl-2-chlorine adenosine, continue reaction 1 ~ 10 hour after adding the NaH of catalytic amount under 110 ~ 130 ℃, monitor reaction end 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, drying.By silicagel column purification of crude product, utilize tetrahydrofuran (THF) for eluting solvent, after the complete wash-out of the first band, using DMF instead is eluting solvent, collects the target elution fraction, revolves and steams to a small amount of solvent, and micro-pore-film filtration, revolve steaming, and drying obtains blue product, productive rate approximately 21%.
The maximum absorption band of product in DMF is positioned at the 677nm place, is positioned at the 688nm place in water.Other characterization datas of product: HR-MS (ESI): m/z 1016.2842[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) : δ 9.55~9.85 (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, can obtain the axial adenosine that structure is shown below/asymmetric modification silicon phthalocyanine of amino-ethyl phenoxy group (i.e. [5 '-(2 ', 3 '-O-sec.-propyl) adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine).The maximum absorption band of this compound in DMF is positioned at the 677nm place, is positioned at the 688nm place in water, its mass spectrum MS (ESI): m/z 982.3[M]
-.
Embodiment 10
Synthetic and the physico-chemical property of the asymmetric modification silicon phthalocyanine of axial uridine/triethylene glycol that structure is shown below:
But this compound 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] add preferably 1.5 mmol of 1 ~ 10mmol(in toluene (or dimethylbenzene or dioxane) solution of [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (the described compound of embodiment 6)) triethylene glycol monomethyl ether, after adding the NaH of catalytic amount, under 110 ~ 130 ℃, react 1 ~ 20 hour, monitor reaction end 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, drying.By silicagel column purification of crude product, utilize ethyl acetate for eluting solvent, collect the target elution fraction, revolve and steam to a small amount of solvent, filter, revolve steaming, drying obtains blue product, productive rate approximately 15%.The maximum absorption band of product in DMF is positioned at the 677nm place, is positioned at the 688nm place in water, its HR-MS (ESI): m/z 1009.3066 [M+Na]
+.
Embodiment 11
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 respectively, productive rate is 10-20%.The maximum absorption band of these compounds in DMF is positioned at the 677-680nm place, is positioned at the 688-690nm place in water.
Embodiment 12
Synthetic and the physico-chemical property of the asymmetric modification silicon phthalocyanine of axial cytidine/triethylene glycol that structure is shown below:
But this compound 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 (the described compound of embodiment 7) alternate embodiment 10,3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, can obtain [5 '-(2 ', 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 the 678nm place, be positioned at the 689nm place in water, its MS (ESI): m/z 1002.4 [M]
+.
Embodiment 13
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 respectively, productive rate is 13-22%.The maximum absorption band of these compounds in DMF is positioned at the 678-680nm place, is positioned at the 688-690nm place in water.
Embodiment 14
Synthetic and the physico-chemical property of the asymmetric modification silicon phthalocyanine of axial 2-chlorine adenosine/triethylene glycol that structure is shown below:
But this compound 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 (the described compound of embodiment 8) alternate embodiment 10,3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, can obtain [5 '-(2 ', 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 the 679nm place, be positioned at the 689nm place in water, its MS (ESI): m/z 1058.3 [M]
+.
Embodiment 15
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 respectively, productive rate is 13-22%.The maximum absorption band of these compounds in DMF is positioned at the 679-681nm place, is positioned at the 688-690nm place in water.
Embodiment 16
Synthetic and the physico-chemical property of the asymmetric modification silicon phthalocyanine of axial adenosine/triethylene glycol that structure is shown below:
But this compound 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 (the described compound of embodiment 9) alternate embodiment 10,3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, can obtain [5 '-(2 ', 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 the 679nm place, be positioned at the 689nm place in water, its MS (ESI): m/z 1025.6 [M]
+.
Embodiment 17
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 respectively, productive rate is 15-25%.The maximum absorption band of these compounds in DMF is positioned at the 678-680nm place, is positioned at the 688-690nm place in water.
Embodiment 18
The method of utilizing the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention to prepare photo-dynamical medicine (i.e. photosensitive (medicine) agent) is: 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, axially the concentration of the silicon phthalocyanine of the asymmetric modification of nucleosides is not higher than its saturation concentration (preferably 1 ~ 0.01 mM).Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament.
The asymmetric modification silicon phthalocyanine of nucleosides of the present invention is dissolved in to 5 ~ 35%(wt%) aqueous solution of methyl-sulphoxide, can be used as the preparation that topical is used.
Embodiment 19
Photo-dynamical medicine, photosensitive (medicine) agent that the present invention is prepared, at optical dynamic therapy, or light power diagnosis, or the using method in the sterilization of light power is identical with the using method of the photosensitive medicament that uses non-phthalocyanine of the present invention or porphyrin compound to prepare in prior art or photosensitizers, but need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, the wavelength region of light source is 300-800nm, preferably 675-690nm.
Embodiment 20
The asymmetric modification silicon phthalocyanine of the present invention's axial nucleosides of the present invention is dissolved in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution, makes the photosensitive medicament of 0.08mM.Test their dark toxicity and photodynamic activities to people's cancer of the stomach BGC823 cell.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, makes the cell culture fluid containing the different concns photosensitizers.Test cell is cultivated 2 hours respectively in the nutrient solution that contains the different concns photosensitizers, abandon thereafter nutrient solution, after cleaning cell with PBS, add new nutrient solution (not containing photosensitizers).The illumination experiment group, cell is carried out to red light irradiation, and (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power that irradiates light is 15mw * cm
-2); The irradiation group, be not placed in dark place 20 minutes by cell.After illumination or not illumination, the survival rate of cell adopts mtt assay to investigate.Concrete experimental procedure referring to "
bioorganic & Medicinal Chemistry Letters ", 2006,16,2450-2453.
The ruddiness that above-mentioned wavelength is greater than 610nm is that the halogen lamp by 500W connects heat insulation tank and strengthens in the spectral filter of 610nm and 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 (3 * 10
-6mol/L), the time, can 100% kill and wound cancer cells.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 the 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, kill the required drug level of 50% cancer cells) be respectively:
4 nM ([5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, the i.e. described compound of embodiment 6);
150 nM ([5 '-(2 ', 3 '-O-sec.-propyl)-cytidine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, the i.e. described compound of embodiment 7);
7 nM ([5 '-(2 ', 3 '-O-sec.-propyl)-2-chlorine adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, i.e. described compound of embodiment 8);
5 nM ([5 '-(2 ', 3 '-O-sec.-propyl)-adenosine oxygen base] [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, the i.e. described compound of embodiment 9);
The axial uridine of 6-20 nM(/ the low asymmetric modification silicon phthalocyanine of polyoxyethylene glycol, i.e. described compound of embodiment 10-11);
The axial cytidine of 200-310 nM(/ the low asymmetric modification silicon phthalocyanine of polyoxyethylene glycol, i.e. described compound of embodiment 12-13);
The axial 2-chlorine of 7-15 nM(adenosine/the low asymmetric modification silicon phthalocyanine of polyoxyethylene glycol, i.e. described compound of embodiment 14-15);
The axial adenosine of 5-18 nM(/ the low asymmetric modification silicon phthalocyanine of polyoxyethylene glycol, i.e. described compound of embodiment 16-17).
Visible, the axial asymmetric modification silicon phthalocyanine of nucleosides IC
50be worth lowlyer, it (is 4-7 * 10 that part of compounds even is low to moderate 4-7nM
-8mol/L).Extremely low IC
50value, illustrate that the asymmetric modification silicon phthalocyanine of axial nucleosides provided by the present invention has high photodynamic activity.
Change above-mentioned 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution into 1% castor oil derivative (Cremophor EL, wt%) phosphate buffer soln (PBS), also can obtain same experimental result.
Embodiment 21
According to the described method of embodiment 20, measured symmetrical silicon phthalocyanine, axial symmetrical silicon phthalocyanine, the axial symmetrical photodynamic activity of silicon phthalocyanine to people's cancer of the stomach BGC823 cell of modifying of low polyoxyethylene glycol modified of amino-ethyl phenoxy group modified of axial nucleosides.
Result shows, axially the nucleosides symmetry is modified 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's cancer of the stomach BGC823 cell
50value is respectively 31nM, 410nM, 10nM and 9nM.
Axially the symmetrical silicon phthalocyanine of modifying of amino-ethyl phenoxy group, be the IC that two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine light power suppresses people's cancer of the stomach BGC823 cell
50value is 20nM.
Axially the symmetrical replacement of triethylene glycol silicon phthalocyanine, axial TEG symmetry replace the IC that silicon phthalocyanine light power suppresses people's cancer of the stomach BGC823 cell
50value is 50-30nM.
The result of comparing embodiment 20 and embodiment 21, the light power antitumour activity that can find the asymmetric modification silicon phthalocyanine of axial nucleosides of the present invention is significantly higher than the symmetrical silicon phthalocyanine of modifying of corresponding axial nucleosides, and most of axially light power antitumour activity of the asymmetric modification silicon phthalocyanine of nucleosides is significantly higher than symmetrical silicon phthalocyanine and the symmetrical silicon phthalocyanine that replaces of axially low polyoxyethylene glycol modified of axial amino-ethyl phenoxy group.
Embodiment 22
According to the described method of embodiment 18, the asymmetric modification of axial nucleosides more of the present invention and following other phthalocyanine compounds photodynamic activity to people's cancer of the stomach BGC823 cell.
Described following other phthalocyanine compounds are a kind of of following title complex: axial two (4-kharophen phenoxy group) silicon phthalocyanine; two [4-(4-ethanoyl piperazine) phenoxy group] silicon phthalocyanine; two [4-(3-carboxyl propyl group) 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-ethanoyl piperazine) 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 all is significantly higher than other similar compounds.In same concentration (1.0 * 10
-6mol/L), under, the silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention is at least more than 3 times of above-mentioned other phthalocyanine compounds to the light power restraining effect of cancer of the stomach BGC823 cell.
Embodiment 23
The silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention is dissolved in 1% castor oil derivative (Cremophor EL, wt%) PBS damping fluid, makes the photosensitive medicament of 0.3mM, test their light power inhibition activity to fungi.Fungi is Candida albicans CMCC (F) C1a(Candida albicans, 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 that irradiates light is 15mw * cm
-2), the silicon phthalocyanine of the asymmetric modification of axial nucleosides of the present invention can be killed 60% Candida albicans, and the solvent control group, irradiation group, not administration of an irradiation group all do not affect the growth of Candida albicans in an administration.
Embodiment 24
The silicon phthalocyanine of having tested the asymmetric modification of axial nucleosides of the present invention is the effect for the sterilization of light power as photosensitizers.
At first, the silicon phthalocyanine of the asymmetric modification of described axial nucleosides is dissolved in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution, makes the photosensitive medicament of 0.3mM.Then it is joined and contains in colibacillary water, the content that makes silicon phthalocyanine is 0.03mM, after 2 hours, with red light irradiation, contains colibacillary water.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 be killed the intestinal bacteria more than 70%.
The foregoing is only preferred embodiment of the present invention, all equalizations of doing 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. the silicon phthalocyanine of the asymmetric modification of an axial nucleosides, it is characterized in that: its structural formula is as follows:
Axial substituent R wherein
1, R
2be selected from respectively following group:
R
1for
,
,
,
in a kind of;
R
2for
,
,
,
,
in a kind of.
2. a method for preparing the silicon phthalocyanine of the asymmetric modification of axial nucleosides as claimed in claim 1 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-uridine, 2 ', 3 '-O-sec.-propyl-cytidine, 2 ', 3 '-O-sec.-propyl-adenosine, 2 ', a kind of in 3 '-O-sec.-propyl-2-chlorine adenosine is reactant, both molar ratios are 1:1 ~ 10, take toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, 100 ~ 130 ℃ are reacted 1 ~ 20 hour, remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group;
(2) take a kind of in the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group and triethylene glycol, triethylene glycol monomethyl ether, TEG, TEG monomethyl ether is reactant; both molar ratios are 1:1 ~ 10; take toluene, dimethylbenzene or dioxane as solvent; under the protection of nitrogen; 100 ~ 130 ℃ are reacted 1 ~ 20 hour; remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and low polyoxyethylene glycol.
3. the application of the silicon phthalocyanine of the asymmetric modification of an axial nucleosides as claimed in claim 1 is characterized in that: the silicon phthalocyanine of the asymmetric modification of described axial nucleosides is for the preparation of photo-dynamical medicine or photosensitizers.
4. the application of the silicon phthalocyanine of the asymmetric modification of axial nucleosides according to claim 3, it is characterized in that: the method for preparing photo-dynamical medicine or photosensitizers is: the mixed solution of 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, axially the concentration of the silicon phthalocyanine of the asymmetric modification of nucleosides is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament;
Described other material is one or more the miscellany in castor oil derivative, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
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