CN102827226B - Silicon phthalocyanine modified by uridine derivatives and preparation method and application of silicon phthalocyanine - Google Patents
Silicon phthalocyanine modified by uridine derivatives and preparation method and application of silicon phthalocyanine Download PDFInfo
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Abstract
The invention discloses silicon phthalocyanine modified by uridine derivatives and a preparation method and application of the silicon phthalocyanine, and belongs to the field of preparation of photodynamic drugs or photosensitizer. The silicon phthalocyanine modified by the uridine derivatives can be used as a photosensitizer for photodynamic therapy, photodynamic diagnosis or photodynamic disinfection, has the advantages of high selectivity, high photodynamic activity and the like, and is explicit in composition and easy to prepare and industrialize.
Description
Technical field
The invention belongs to photo-dynamical medicine or photosensitizers preparation field, be specifically related to silicon phthalocyanine of a kind of uridine derivatives modification and its preparation method and application.
Background technology
Phthalocyanine complex is the important functional materials of a class, can develop into the functional materials of different purposes by different structural modifications.On phthalocyanine ring, introduce suitable substituent and central ion, just be likely developed as oxide catalyst, desulfurization catalyst, nonlinear optical material, photosensitive drug, liquid crystal material, optical recording material or light-guide material, but how to regulate and control substituting group and central ion, obtaining objective function compound, is but to need creationary work.
Phthalocyanine complex as photosensitizers the application prospect in optical dynamic therapy (Photodynamic Therapy) noticeable.So-called optical dynamic therapy (or claiming photodynamic therapy) in fact, is that the Photosensitive reaction of photosensitizers (or claiming photosensitive drug) is in the application of medical field.Its mechanism is, first photosensitizers is injected to body, (this period of waiting time be allow medicine enrichment relatively in target body) after a period of time, rayed target body (can import light source by interventional techniques such as optical fiber to endoceliac target) 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 can cancerous tissue be carried out selective destruction and needn't be performed surgical operation, and side effect is little, thereby gets most of the attention.
Meanwhile, 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.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 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 using clinically and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan, use be 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 preferably red light district (650-800nm), 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 maximum absorption wavelength, be positioned at and easily see through the ruddiness region of tissue and the feature such as photosensitization ability is strong, phthalocyanine complex draws attention as the application of photosensitizers.In various phthalocyanine complexes, 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 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 that high light power is active, 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 the axial modification silicon phthalocyanine photosensitizers easy, cost is low.In addition, the photosensitizers (comprising 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 patent No. is that the Chinese invention patent of ZL200410013289.7 and ZL200610200598.4 has been introduced a series of axial replacement silicon phthalocyanine title complexs, 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 title complexs 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 the infiltration dynamics to the input of novel photosensitive agent and intellecture property one after another; in this case; only have and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate 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 a kind of uridine derivatives modification and its preparation method and application.Silicon phthalocyanine of the present invention has that photodynamic activity is high, selectivity is high, composition is clear and definite, it is easy to prepare and be easy to realize the advantages such as industrialization, and as photosensitizers, application has significant advantage.
For achieving the above object, the present invention adopts following technical scheme:
The silicon phthalocyanine that uridine derivatives is modified, its structural formula is as follows:
or
.
The silicon phthalocyanine that described uridine derivatives is modified is axial symmetrical dibasic silicon phthalocyanine, and axially substituting group is connected with silicon by Sauerstoffatom; Silicon phthalocyanine or title silicon phthalocyanine are that central ion is the phthalocyanine complex of silicon.Phthalocyanine, English name phthalocyanine, is the abbreviation of four benzo tetraazatetradecane porphyrins.According to axial substituting group feature, the silicon phthalocyanine called after that described uridine derivatives is modified: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine.Uridine in above-mentioned, is the molecule that builds nucleic acid, claims again uridine.
The preparation method of the silicon phthalocyanine that a kind of uridine derivatives as above is modified comprises the following steps:
(1) under ice-water bath ~ room temperature, uridine or 5-methyl-uridin and tosic acid are placed in to acetone stirring reaction 2 ~ 20 hours, both molar ratios are 1:8 ~ 12, by solvent method, extraction process and chromatography purification, obtain 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin;
(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin are reactant, and both molar ratios are 1:4 ~ 10; Take toluene, dimethylbenzene or dioxane as solvent, and solvent load is that 1mmol phthalocyanine silicon dichloride needs 40 ~ 400ml, under the existence of sodium hydride and the protection of nitrogen, reacts 18 ~ 48 hours at 100 ~ 130 ℃, obtains crude product; By solvent method, extraction process, and/or chromatography removes excessive raw material and impurity, obtains two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine.
The silicon phthalocyanine that a kind of uridine derivatives as above is modified be applied to prepare photo-dynamical medicine or photosensitizers.Described photosensitizers, can be described as photosensitive medicament at biomedicine field, or claims 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 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 medical or life use device.
The method of 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 that uridine derivatives is modified, be mixed with containing certain density photosensitive medicament, the concentration of the silicon phthalocyanine that uridine derivatives is modified is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament; Other described 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) silicon phthalocyanine provided by the invention is prepared easyly, and preparation speed is fast, is easy to separation and purification, and productive rate is high, and raw material is easy to get, so preparation cost is low, is easy to industrialization.
(2) the axial group of silicon phthalocyanine provided by the invention is uridine derivatives, uridine is biomolecules in body, thereby the biocompatibility of the silicon phthalocyanine providing, biological selectivity is higher simultaneously, for example experiment shows, they are significantly higher than the light power restraining effect to normal liver cell L-O2 to the light power restraining effect of liver cancer cell HepG2.
(3) the axial group of silicon phthalocyanine provided by the invention is uridine derivatives, because the molecular volume of uridine derivatives is larger, and there is suitable wetting ability, thereby silicon phthalocyanine provided by the present invention is difficult for forming aggregate in the aqueous solution, substantially with monomer, form and exist, guaranteed the performance of its photodynamic activity.Common photosensitizers easily forms aggregate in aqueous solution, and the formation of aggregate has weakened the photosensitization ability of photosensitizers greatly, finally causes photosensitizers inactivation.
(4) maximum absorption wavelength of silicon phthalocyanine provided by the invention in the aqueous solution is positioned at 680-681nm 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 carrying out other phthalocyanine complexes 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.
(5) silicon phthalocyanine structure provided by the invention clearly, location isomer not.The chemically modified of the present invention to 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 target compound structure.If the periphery at phthalocyanine ring is introduced substituting group, 16 the possible the position of substitution of periphery existence due to phthalocyanine ring, may produce a plurality of isomer, cause product to contain isomer or separation costs increase.
(6) the present invention selects silicon as the central ion of phthalocyanine complex, and it is good for other common ion (zinc, aluminium, magnesium and gallium) that the biological safety of silicon and biocompatibility are wanted, and the quantum yield of silicon phthalocyanine generation active oxygen is high.
(7) 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..
(8) silicon phthalocyanine provided by the invention is to obtain by a large amount of shaker tests, and it has high photodynamic activity.For example, under red light irradiation, two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine of 0.001mM can 100% suppresses the growth of hepatoma Hep G 2 cells.A large amount of simultaneous tests show, the photodynamic activity of silicon phthalocyanine provided by the invention is significantly higher than other similar compounds, for example, two [glucosyloxy] silicon phthalocyanine, two [5-(1,2, 3, 4-bis-2-O-sec.-propyls)-newborn glycosyloxy] silicon phthalocyanine, two (cytosine(Cyt) oxygen base) silicon phthalocyanine, two (2, 4-dimethyl-6-2-pyrimidinyl oxy) silicon phthalocyanine, two (Portugal's oxygen base) silicon phthalocyanine, 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 etc.
Embodiment
The preparation method of the silicon phthalocyanine that uridine derivatives of the present invention is modified is: under (1) ice-water bath ~ room temperature, uridine (or 5-methyl-uridin) and tosic acid are placed in to acetone stirring reaction 2 ~ 20 hours, both molar ratios are 1:8 ~ 12, by solvent method, extraction process and chromatography purification, obtain 2 ', 3 '-O-sec.-propyl-uridine (or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin).(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine (or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin) is reactant, and both molar ratios are 1:4 ~ 10; Take toluene, dimethylbenzene or dioxane as solvent, and solvent load is that 1mmol phthalocyanine silicon dichloride needs 40 ~ 400ml, under the existence of sodium hydride and the protection of nitrogen, reacts 18 ~ 48 hours at 100 ~ 130 ℃, obtains crude product; By solvent method, extraction process, and/or chromatography removes excessive raw material and impurity, obtains two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine.
The silicon phthalocyanine that uridine derivatives provided by the invention is modified 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 that uridine derivatives provided by the invention is modified can be used for preparing photosensitive (medicine) agent, for the sterilization of 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 medical or life use device.
The application of the silicon phthalocyanine that uridine derivatives provided by the invention is modified 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 680nm.
The basic skills that the silicon phthalocyanine that utilizes uridine derivatives provided by the invention to modify is prepared 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.Other described 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 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 to keep chemical stability and the biocompatibility of photosensitive medicament.
The preparation of using for topical, can be dissolved in silicon phthalocyanine of the present invention in 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, tosic acid acetone soln is slowly added drop-wise in uridine acetone soln to the preferred 6h of stirring at normal temperature 2 ~ 10 h().Reaction mixture is added to and is contained in 4% sodium bicarbonate frozen water solution, with methylene dichloride (or trichloromethane), repeatedly extract, collected organic layer, adds dried over mgso, concentrated after filtering, and is dried to obtain yellow powder shape product, 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-)。
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, obtains blue coarse product.Crude product passes through silicagel column purifying, and 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 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)-5-methyl-uridin oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-5-methyl-uridin
By 5-methyl-uridin 258mg(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, tosic acid acetone soln is slowly added drop-wise in 5-methyl-uridin acetone soln to the preferred 16h of stirring at normal temperature 12 ~ 20 h(), obtain faint yellow gluey thing.Reaction mixture is added to while stirring containing in 4% sodium bicarbonate frozen water solution, adjusts pH=8.With methylene dichloride, repeatedly extract, collected organic layer, adds dried over mgso, concentrated after filtering, the dry crude product that obtains.Crude product is by silicagel column purifying, and use ethyl acetate is eluent, collects elution fraction, and concentrate drying obtains product, productive rate 85%.
The characterization data of product is as follows: HRMS(ESI) m/z:299.0491 [M+H]
+.
IR（KBr，cm
-1）：?1383（CH
3），1123（-O-），1727（C=O），3067，1204，1650（NH），1693（C=C），3067，1204（-OH）。
1H?NMR?(CDCl
3，400MHz，ppm)：δ8.92（s，1H，?pyrimidine?-NH）,?7.14（s，1H,?pyrimidine-NCH），5.49（d，
J?=3.6Hz，1H，1′-H），?5.30（s，1H,?OH），5.07-5.10(m，1H，2′-H)，4.97-4.99（m，1H，3′-H），?4.25-4.28（m，1H，3′-H），3.90-3.93（m，1H，5′-H），?3.78-3.82（m，1H，5′-H），1.92(s，3H，pyrimidine-Me),?1.57(s，3H，Me),?1.36(s，3H，Me)。
Synthesizing of (2) two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine
Under nitrogen protection; by phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition methyluridine 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 add trichloromethane and dissolve, washing, collected organic layer, adds dried over mgso, filters, concentrated, obtains blue coarse product.Crude product is by silicagel column purifying, and use ethyl acetate is eluent, collects target product.After concentrating, by gel chromatography (S-X3 type), be further purified (use tetrahydrofuran (THF) is moving phase), concentrated, dry blue-greenish colour powdery product, the productive rate 41% of obtaining.The maximum absorption band of product in DMF is positioned at 676 nm places, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, 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/z:?1157.3338?[M+Na]
+。
IR(KBr, cm
-1): 739,760,911,1081,1123,1291,1334,1428,1519(Pc ring), 3447 (NH), 2926(CH
3).
1H?NMR?(CDCl
3，400MHz，ppm)：δ9.62-9.64(m，8H，Pc-H
α)，?8.40-8.42(m，8H，Pc-H
β),?7.43(s，2H，pyrimidine-NH)，4.73(s，2H，pyrimidine-NCH)，4.17(d，
J?=3.6Hz，2H，1′-H)，2.17-1.90(m，2H，2′-H)，1.82-1.84(m，2H，3′-H)，1.52(s，6H，Me)，?0.88(s，6H，Me)，0.61(s，6H，Me)，0.41?(d，
J?=5.6Hz，2H，4′-H)，?-1.29?to?-1.32(m，2H，5′-H)，?-2.28?to?-2.40(m，2H，5′-H)。
Embodiment 3
Reaction solvent toluene in embodiment 1-2 is replaced with to dimethylbenzene or dioxane, also can obtain corresponding target compound.
Embodiment 4
The method that the silicon phthalocyanine that utilizes uridine derivatives of the present invention to modify is prepared photo-dynamical medicine (i.e. photosensitive (medicine) agent) 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 blue solution (being photosensitive medicament) uniformly, in photosensitive medicament, the concentration of silicon phthalocyanine is 1 ~ 0.01 mM (preferably 0.08mM).Other described 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 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 to keep chemical stability and the biocompatibility of photosensitive medicament.
Silicon phthalocyanine 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 5
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 680nm.
Embodiment 6
By of the present invention two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine is dissolved in 1% castor oil derivative (Cremophor EL, wt%), in the aqueous solution, make the photosensitive medicament of 0.08mM.Test their dark toxicity and photodynamic activities to human liver cancer cell HepG2.
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 that contains different concns photosensitizers, abandon thereafter nutrient solution, with PBS, clean after cell, add new nutrient solution (not containing photosensitizers).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); Irradiation group, is not 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 is 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, uridine derivatives of the present invention is modified silicon phthalocyanine, under red light irradiation, can kill and wound cancer cells, and the concentration of the silicon phthalocyanine of modifying when the uridine derivatives of implementing described in 1-2 is 0.001mM (1 * 10
-6mol/L), time, can 100% kill and wound cancer cells.Under same concentration, if do not carry out illumination, uridine derivatives of the present invention is modified silicon phthalocyanine cancer cells is not is not killed and wounded and growth-inhibiting effect, shows that they do not have dark toxicity.By investigating the concentration of silicon phthalocyanine and the dose-effect relationship of cell survival rate, obtain the toxic limit medium dose (IC under illumination condition
50, kill the required drug level of 50% cancer cells), respectively: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine is 6nM (6 * 10
-9mol/L), two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine is 50nM (5 * 10
-8mol/L).Extremely low IC
50value, illustrates that uridine derivatives modification silicon phthalocyanine of 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 7
According to the experimental technique of above-described embodiment 6, uridine derivatives more of the present invention is modified the light power restraining effect of silicon phthalocyanine to human liver cancer cell HepG2 and normal liver cell L-O2, and result shows: the silicon phthalocyanine that the uridine derivatives described in embodiment 1-2 is modified is significantly higher than the light power restraining effect to normal liver cell L-O2 to human liver cancer cell HepG2 photodynamic killing effect.Two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine IC to human liver cancer cell HepG2
50value is 6nM (3.1 * 10
-8mol/L), the IC and to normal liver cell L-O2
50value is 68nM (6.8 * 10
-8mol/L), both differ 11 times.This illustrates that uridine derivatives modification silicon phthalocyanine of the present invention has higher selectivity, can carry out selective destruction to cancer cells.
Embodiment 8
Change the human liver cancer cell HepG2 in above-described embodiment 6 into people's cancer of the stomach BGC823 cell, other conditions are constant, result is as follows: uridine derivatives of the present invention is modified silicon phthalocyanine, under red light irradiation, all can kill and wound cancer cells, the concentration of the silicon phthalocyanine of modifying when uridine derivatives described in embodiment 1-2 is 0.001mM (1 * 10
-6mol/L), time, can 100% kill and wound cancer cells.Under same concentration, if do not carry out illumination, uridine derivatives of the present invention is modified silicon phthalocyanine cancer cells is not is not killed and wounded and growth-inhibiting effect, shows that they do not have dark toxicity.The IC of the silicon phthalocyanine Photodynamic therapy people cancer of the stomach BGC823 cell that the uridine derivatives described in embodiment 1-2 is modified
50value, respectively: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine is 31nM (3.1 * 10
-8mol/L), two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine is 120nM (1.2 * 10
-7mol/L).Low IC
50value, illustrates that uridine derivatives modification silicon phthalocyanine of the present invention has high photodynamic activity.
Embodiment 9
According to the method described in embodiment 6, silicon phthalocyanine and the photodynamic activity of following other phthalocyanine complexes to people's cancer of the stomach BGC823 cell that uridine derivatives more of the present invention is modified.
Described following other phthalocyanine complexes are a kind of of following title complex: two [glucosyloxy] silicon phthalocyanine, and two [5-(1,2, 3, 4-bis--O-sec.-propyl)-newborn glycosyloxy] silicon phthalocyanine, two (cytosine(Cyt) oxygen base) silicon phthalocyanine, two (2, 4-dimethyl-6-2-pyrimidinyl oxy) silicon phthalocyanine, two (Portugal's oxygen base) silicon phthalocyanine, 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 that uridine derivatives of the present invention is modified is all significantly higher than other similar compounds.In same concentration (1.0 * 10
-6mol/L), under, the silicon phthalocyanine that uridine derivatives of the present invention is modified is at least the more than 3 times of above-mentioned other phthalocyanine compounds to the light power restraining effect of cancer of the stomach BGC823 cell.
Embodiment 10
The silicon phthalocyanine that uridine derivatives of the present invention is modified is dissolved in 1% castor oil derivative (Cremophor EL, wt%) PBS damping fluid, makes the photosensitive medicament of 0.3mM, tests them the light power of fungi is suppressed to active.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 that uridine derivatives of the present invention is modified can 100% Killing Candida Albicans, and solvent control group, irradiation group, not administration of an irradiation group all do not affect the growth of Candida albicans in an administration.
Embodiment 11
Tested silicon phthalocyanine that uridine derivatives of the present invention modifies as photosensitizers the effect for the sterilization of light power.
First, described silicon phthalocyanine is dissolved in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution, makes the photosensitive medicament of 0.3mM.Then joined and contain 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 that uridine derivatives of the present invention is modified can be killed more than 95% intestinal bacteria.
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 that uridine derivatives is modified, is characterized in that: its structural formula is as follows:
or
;
Its chemical name is: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine.
2. a preparation method for the silicon phthalocyanine that uridine derivatives as claimed in claim 1 is modified, is characterized in that: described preparation method comprises the following steps:
(1) under ice-water bath ~ room temperature, uridine or 5-methyl-uridin and tosic acid are placed in to acetone stirring reaction 2 ~ 20 hours, both molar ratios are 1:8 ~ 12, purifying, obtain 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin;
(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyl-uridin are reactant, and both molar ratios are 1:4 ~ 10; Take toluene, dimethylbenzene or dioxane as solvent; solvent load is that 1mmol phthalocyanine silicon dichloride needs 40 ~ 400ml; under the existence of sodium hydride and the protection of nitrogen; at 100 ~ 130 ℃, react 18 ~ 48 hours; remove excessive raw material and impurity; obtain two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyl-uridin oxygen base] silicon phthalocyanine.
3. an application for the silicon phthalocyanine that uridine derivatives as claimed in claim 1 is modified, is characterized in that: for the preparation of photo-dynamical medicine or photosensitizers.
4. the application of the silicon phthalocyanine that uridine derivatives according to claim 3 is modified, it is characterized in that: the method for preparing photo-dynamical medicine or photosensitizers is: water, or the mixed solution of water and other material, as solvent, dissolve the silicon phthalocyanine that uridine derivatives is modified, be mixed with containing certain density photosensitive medicament, the concentration of the silicon phthalocyanine that uridine derivatives is modified is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive to keep chemical stability and the biocompatibility of photosensitive medicament;
Other described 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;
In solvent, the massfraction of other material is not higher than 10%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005025A1 (en) * | 1992-08-17 | 1994-03-03 | Sandoz Ltd. | Use of optical brighteners and phthalocyanines as photosensitizers |
| CN1459473A (en) * | 2002-05-17 | 2003-12-03 | 希毕克斯影像有限公司 | IV phthalocyanine and naphthalene phthalocyanine dye for electrophoresis, magnetophoresis or electromagneto phoresis display device |
| CN1583762A (en) * | 2004-06-11 | 2005-02-23 | 福州大学 | Axial substituted phthalocyanine compound, its preparation and application in optical kinetic treatment |
| CN1861603A (en) * | 2006-06-21 | 2006-11-15 | 福州大学 | Silicon phthalocyanine compound and composite, their preparation and application thereof |
| EP2186862A2 (en) * | 2008-10-31 | 2010-05-19 | Westfälische Wilhelms-Universität Münster | The manufacture and products thereof of photosensitizing nanomaterials and their use in photodynamic treatment |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0653744B2 (en) * | 1985-11-12 | 1994-07-20 | 日本電信電話株式会社 | Alkyl cyanophthalocyanine compound |
-
2012
- 2012-08-28 CN CN201210309152.0A patent/CN102827226B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005025A1 (en) * | 1992-08-17 | 1994-03-03 | Sandoz Ltd. | Use of optical brighteners and phthalocyanines as photosensitizers |
| CN1459473A (en) * | 2002-05-17 | 2003-12-03 | 希毕克斯影像有限公司 | IV phthalocyanine and naphthalene phthalocyanine dye for electrophoresis, magnetophoresis or electromagneto phoresis display device |
| CN1583762A (en) * | 2004-06-11 | 2005-02-23 | 福州大学 | Axial substituted phthalocyanine compound, its preparation and application in optical kinetic treatment |
| CN1861603A (en) * | 2006-06-21 | 2006-11-15 | 福州大学 | Silicon phthalocyanine compound and composite, their preparation and application thereof |
| EP2186862A2 (en) * | 2008-10-31 | 2010-05-19 | Westfälische Wilhelms-Universität Münster | The manufacture and products thereof of photosensitizing nanomaterials and their use in photodynamic treatment |
Non-Patent Citations (5)
| Title |
|---|
| JP昭62-111984A 1987.05.22 * |
| 李在国.2" 3"-异丙叉尿苷.《有机中间体制备》.2001 * |
| 李在国.2",3"-异丙叉尿苷.《有机中间体制备》.2001,第321页. * |
| 蒋雄杰.酞菁硅配合物的轴向修饰、表征及在光动力治疗中的应用.《福州大学硕士研究生学位论文》.2006,第9-11、17-31、38-44页. * |
| 酞菁硅配合物的轴向修饰、表征及在光动力治疗中的应用;蒋雄杰;《福州大学硕士研究生学位论文》;20060630;第9-11、17-31、38-44页 * |
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