CN102827226A - 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 the silicon phthalocyanine that a kind of uridine derivatives is modified.
Background technology
Phthalocyanine complex is one type of important functional material, modifies the functional materials that can develop into different purposes through various structure.On the phthalocyanine ring, introduce suitable substituent and central ion; Just might 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, but is to need creationary work.
Phthalocyanine complex is noticeable as the application prospect of photosensitizers in optical dynamic therapy (Photodynamic Therapy).So-called optical dynamic therapy (or claim PDT) in fact, is the application that the photosensitization of photosensitizers (or claiming photosensitive drug) is reflected at medical field.Its mechanism is; Earlier photosensitizers is injected body, (this section waiting time be let medicine enrichment relatively in target body) after a period of time is with the rayed target body of specific wavelength (can be by interventional techniques such as optical fiber importing light source to endoceliac target); Be enriched in photosensitizers in the 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 of treatment cancer.With traditional therapy, to compare like surgical operation, chemotherapy, radiotherapy, the photodynamic therapy biggest advantage is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and spinoff is little, thereby gets most of the attention.
Simultaneously, research in recent years shows that also PDT also can be treated non-Cancerous diseases such as infectation of bacteria, oral disease, degeneration of macula illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be used for the sterilization of light power, most importantly is used for the sterilization of water body, blood and blood derivatives.Simultaneously, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, also is 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 disease; Scientific circles generally believe; Optical dynamic therapy will become the important therapy of 21 century, so, will become an important and tempting new high-tech industry as the photosensitizers of optical dynamic therapy core.
So far, get permission the formal clinically photosensitizers that uses and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan; What use is Photofrin (U.S. FDA is used for clinical anticancer in nineteen ninety-five official approval Photofrin), and it is the mixture of the porporino oligopolymer that from cow blood, extracts and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect; But also exposed critical defect: maximum absorption wavelength (380-420nm) is not at the red light district preferable to the tissue transmitance (650-800nm); The skin phototoxicity is big; Be mixture, form instability etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international research focus.
Be positioned at characteristics such as the ruddiness zone that be prone to see through tissue and photosensitization ability are strong owing to have maximum absorption wavelength, phthalocyanine complex draws attention as the application of photosensitizers.In various phthalocyanine complexes; Owing to 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, do not have dark toxicity.The axial substituted phthalocyanine silicon (Pc4) of U.S. Case Western Reserve university development has shown higher photodynamic activity, has got into the I clinical trial phase.But, the complex synthetic route of Pc4, preparation cost is high, poor stability.Therefore, press for the axial modification silicon phthalocyanine photosensitizers that the new photosensitive activity of screening is high, preparation is easy, 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, also is 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 because the refinement of photosensitizers and optical dynamic therapy potential tremendous economic social value, great range of application and treatment focus, prepare more axial replacement silicon phthalocyanine title complexs with photosensitive activity is very necessary as drug candidate more.
What is worth mentioning is; States such as America and Europe, Japan strengthen the input of novel photosensitive agent and the infiltration dynamics of intellecture property one after another; In this case; Have only and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate the patent protection paces, could guarantee autonomy and the commanding elevation of China at this important medical field of optical dynamic therapy.
Summary of the invention
The silicon phthalocyanine that the object of the present invention is to provide a kind of uridine derivatives to modify.Silicon phthalocyanine of the present invention have photodynamic activity height, selectivity high, form clear and definite, preparation is easy and be easy to realize advantage such as industrialization, use as photosensitizers to have significant advantage.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
The silicon phthalocyanine that a kind of uridine derivatives is modified, its structural formula is following:
The silicon phthalocyanine that described uridine derivatives is modified is axial symmetrical dibasic silicon phthalocyanine, and axially substituting group links to each other with silicon through 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 characteristics, 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-methyluridine oxygen base] silicon phthalocyanine.Uridine in above-mentioned is the molecule that makes up nucleic acid, claims uridine again.
The preparation method of the silicon phthalocyanine that a kind of aforesaid uridine derivatives is modified may further comprise the steps:
(1) under ice-water bath ~ room temperature; Uridine or 5-methyluridine and tosic acid were placed the acetone stirring reaction 2 ~ 20 hours; Both molar ratios are 1:8 ~ 12, through solvent method, extraction process and chromatography purification, obtain 2 '; 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyluridine;
(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyluridine are reactant, and both molar ratios are 1:4 ~ 10; With toluene, YLENE or dioxane is solvent, and solvent load needs 40 ~ 400ml for the 1mmol phthalocyanine silicon dichloride, and under the existence and protection of nitrogen gas of sodium hydride, 100 ~ 130 ℃ were reacted 18 ~ 48 hours down, obtain crude product; Through solvent method, extraction process, and/or excessive raw material and the impurity of chromatography removal obtain two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyluridine oxygen base] silicon phthalocyanine.
The silicon phthalocyanine that a kind of aforesaid uridine derivatives is modified be applied to prepare photo-dynamical medicine or photosensitizers.Said photosensitizers can be described as photosensitive medicament at biomedicine field, or claims the photosensitive drug preparation, is called light power medicament again.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 an infectation of bacteria, or oral disease, or degeneration of macula 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 medical or life is sterilized with the light power of 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, and the silicon phthalocyanine that the urine-soluble glycoside derivates is modified; Be mixed with and contain 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 processing, add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament; Described other material is castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, the miscellany of one or more in dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, the YMS 2.
Beneficial effect of the present invention and outstanding advantage are:
(1) silicon phthalocyanine provided by the invention prepares 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 a uridine derivatives; Uridine is a biomolecules in the body; Thereby the biocompatibility of the silicon phthalocyanine that is provided; Biological selectivity is higher simultaneously, and for example experiment shows that 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 a uridine derivatives; Because the molecular volume of uridine derivatives is bigger; And suitable wetting ability is arranged; Thereby silicon phthalocyanine provided by the present invention difficult aggregate that forms in the aqueous solution, exist with monomer formation basically, guaranteed the performance of its photodynamic activity.Common photosensitizers is prone in aqs soln, form aggregate, and the formation of aggregate has weakened the photosensitization ability of photosensitizers greatly, causes the photosensitizers inactivation at last.
(4) maximum absorption wavelength of silicon phthalocyanine provided by the invention in the aqueous solution is positioned at the 680-681nm place, and molar absorption coefficient (reaches 10 greatly
5The order of magnitude), its spectral quality not only is superior to first-generation photosensitizers greatly, and is superior to 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 of treatment light is further enhanced, this is that ten minutes is favourable for optical dynamic therapy and light power diagnosis.
(5) silicon phthalocyanine structure provided by the invention clearly, location isomer not.The present invention is to the chemically modified of phthalocyanine precursor structure, be through the phthalocyanine ring axially rather than introduce substituted radical at the periphery of phthalocyanine ring and realize, thereby clearly, there is not isomer in the target compound structure.If the periphery at the phthalocyanine ring is introduced substituting group, because there are 16 possible the position of substitution in the periphery of phthalocyanine ring, then possibly produce a plurality of isomer, cause product to contain isomer or separation costs increase.
(6) the present invention selects the central ion of silicon as 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 silicon phthalocyanine produces the quantum yield height of active oxygen.
(7) silicon phthalocyanine provided by the invention has higher light stability, and its light stability is higher than other similar photosensitizerss, the for example Pc4 of the U.S..
(8) silicon phthalocyanine provided by the invention is to obtain through 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 liver cancer HepG2 cell.A large amount of simultaneous tests show that 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-two 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) silicon phthalocyanine, two [4-(4-ethanoyl piperazine) phenoxy] silicon phthalocyanine, two [4-(3-carboxyl propyl group) phenoxy] silicon phthalocyanine; Two (4-formic acid phenoxy) silicon phthalocyanine, two (3-formic acid phenoxy) silicon phthalocyanine, two (3; 5-dioctyl phthalate phenoxy) silicon phthalocyanine, two (1-diamantane-methoxyl group) silicon phthalocyanine, two (2-diamantane-oxyethyl group) silicon phthalocyanine; Four-a-[4-(4-ethanoyl piperazine) phenoxy] zinc phthalocyanine, four-a-(4-formic acid phenoxy) zinc phthalocyanine 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-methyluridine) and tosic acid were placed the acetone stirring reaction 2 ~ 20 hours; Both molar ratios are 1:8 ~ 12, through solvent method, extraction process and chromatography purification, obtain 2 '; 3 '-O-sec.-propyl-uridine (or 2 ', 3 '-O-sec.-propyl-5-methyluridine).(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine (or 2 ', 3 '-O-sec.-propyl-5-methyluridine) is a reactant, and both molar ratios are 1:4 ~ 10; With toluene, YLENE or dioxane is solvent, and solvent load needs 40 ~ 400ml for the 1mmol phthalocyanine silicon dichloride, and under the existence and protection of nitrogen gas of sodium hydride, 100 ~ 130 ℃ were reacted 18 ~ 48 hours down, obtain crude product; Through solvent method, extraction process, and/or excessive raw material and the impurity of chromatography removal obtain two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyluridine 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 the 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 an infectation of bacteria, or oral disease, or degeneration of macula 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; Be used 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 medical or life is sterilized with the light power of 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 provided by the laser of specific wavelength by ordinary light source; The wavelength region of light source is 600～800nm, preferred 680nm.
The basic skills that the silicon phthalocyanine that utilizes uridine derivatives provided by the invention to modify prepares 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 is as solvent; Dissolve silicon phthalocyanine according to the invention; Be mixed with and contain 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, Schardinger dextrins, glucose, tween, YMS 2.Also can be earlier with hydrochloric acid or sulfuric acid or etc. acidic substance silicon phthalocyanine of the present invention is converted into the form of salt, use above-mentioned dissolution with solvents then.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Preparation for topical is used can be dissolved in silicon phthalocyanine of the present invention in the perviousness solvent, maybe will be injected in ointment, washing lotion or the gel.The aqueous solution of the preferred 5-35% of said perviousness solvent (wt%) methyl-sulphoxide.
Below adopt non-limiting example that the present invention is described further.
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
Uridine 245mg (1mmol) is dissolved in 10 ~ 30ml (preferred 20 ml) acetone, tosic acid 8 ~ 12mmol (preferred 10 mmol) is dissolved in 10 ~ 30ml (preferred 20 ml) acetone.Under the ice-water bath tosic acid acetone soln slowly is added drop-wise in the uridine acetone soln stirring at normal temperature 2 ~ 10 h (preferred 6h).Reaction mixture is added to contains in 4% the sodium hydrogencarbonate frozen water solution, repeatedly extract with methylene dichloride (or trichloromethane), collected organic layer adds dried over mgso, filters the back and concentrates, dry yellow powder shape product, productive rate 85%.
The characterization data of product is following: 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; With phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition uridine protection product (0.260 ~ 0.650mmol; Preferred 0.52mmol) joins among toluene 10 ~ 40ml (preferably 20ml) reflux 12 ~ 48 hours (preferred 24 hours) with NaH (0.48 ~ 0.60mmol, preferred 0.42mmol).Rotary evaporation in vacuo is removed solvent, and washing gets the blue coarse product.Crude product uses ETHYLE ACETATE to be eluent through the silicagel column purifying, collects to be further purified (THF is an eluent) through gel chromatography (S-X3 type) after second component concentrates, and collects target components, gets blue product, productive rate 66% behind the concentrate drying.The maximum absorption band of product in DMF is positioned at 678 nm places, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 681nm place at 1% castor oil derivative.
The structure of product is shown below, and characterization data is following:
HRMS（ESI）m/z:?1129.2948?[M+Na]
+。
IR (KBr, cm
-1): 734,760,911,1081,1291,1336,1429,1522 (Pc rings); 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-methyluridine oxygen base] silicon phthalocyanine
Synthesizing of (1) 2 ', 3 '-O-sec.-propyl-5-methyluridine
5-methyluridine 258mg (1mmol) is dissolved in 10 ~ 30ml (preferred 20 ml) acetone, tosic acid 8 ~ 12mmol (preferred 10 mmol) is dissolved in 10 ~ 30ml (preferred 20 ml) acetone.Under the ice-water bath tosic acid acetone soln slowly is added drop-wise in the 5-methyluridine acetone soln, stirring at normal temperature 12 ~ 20 h (preferred 16h) obtain faint yellow gluey thing.Reaction mixture is added to while stirring contains in 4% the sodium hydrogencarbonate frozen water solution adjustment pH=8.Repeatedly extract with methylene dichloride, collected organic layer adds dried over mgso, filters the back and concentrates, and drying obtains crude product.Crude product uses ETHYLE ACETATE to be eluent through the silicagel column purifying, collects elution fraction, and concentrate drying gets product, productive rate 85%.
The characterization data of product is following: 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-methyluridine oxygen base] silicon phthalocyanine
Under nitrogen protection; With phthalocyanine silicon dichloride (40 mg; 0.065mmol), the isopropylidene of above-mentioned acquisition methyluridine protection product (0.260 ~ 0.650mmol; Preferred 0.52mmol) joins among toluene 10 ~ 40ml (preferably 20ml) reflux 12 ~ 48 hours (preferred 24 hours) with NaH (0.48 ~ 0.60mmol, preferred 0.42mmol).Rotary evaporation in vacuo removal solvent adds the trichloromethane dissolving, washing, and collected organic layer adds dried over mgso, filters, and concentrates, and gets the blue coarse product.Crude product uses ETHYLE ACETATE to be eluent through the silicagel column purifying, collects title product.Concentrate the back and be further purified (using THF to be moving phase), concentrated, dry blue-greenish colour powdery product, the productive rate 41% of getting through gel chromatography (S-X3 type).The maximum absorption band of product in DMF is positioned at 676 nm places, and (Cremophor EL, wt%) maximum absorption wavelength in the aqueous solution is positioned at the 680nm place at 1% castor oil derivative.
The structure of product is shown below, and characterization data is following:
。
HRMS（ESI）m/z:?1157.3338?[M+Na]
+。
IR (KBr, cm
-1): 739,760,911,1081,1123,1291,1334,1428,1519 (Pc rings), 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 among the embodiment 1-2 is replaced with YLENE 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 prepares photo-dynamical medicine (promptly 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 is as solvent; Dissolve silicon phthalocyanine according to the invention; Be mixed with blue solution (being photosensitive medicament) uniformly, the concentration of silicon phthalocyanine is 1 ~ 0.01 mM (preferred 0.08mM) in the photosensitive medicament.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N; Dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, YMS 2.Also can be earlier with hydrochloric acid or sulfuric acid or etc. acidic substance silicon phthalocyanine of the present invention is converted into the form of salt, use above-mentioned dissolution with solvents then.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Silicon phthalocyanine of the present invention is dissolved in the aqueous solution of 5 ~ 35% (wt%) 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 method for use of the photosensitive medicament of the non-phthalocyanine of the present invention of utilization or porphyrin compound preparation in the method for use in the light power sterilization and the prior art or photosensitizers is identical, but the supporting suitable light source of need, and described suitable light source can be connected that suitable spectral filter provides or provided by the laser of specific wavelength by ordinary light source; The wavelength region of light source is 300-800nm, preferred 680nm.
Embodiment 6
With of the present invention two [5 '-(2 '; 3 '-O-sec.-propyl)-and uridine oxygen base] silicon phthalocyanine or two [5 '-(2 '; 3 '-O-sec.-propyl)-and 5-methyluridine oxygen base] silicon phthalocyanine is dissolved in 1% castor oil derivative (Cremophor EL wt%) in the aqueous solution, processes 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 the cell culture fluid, processes the cell culture fluid that contains the different concns photosensitizers.Test cell was cultivated 2 hours in the nutrient solution that contains the different concns photosensitizers respectively, abandon nutrient solution thereafter, behind PBS cleaning cell, add new nutrient solution (not containing photosensitizers).Illumination experimental group, pair cell are carried out red light irradiation, and (used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm
-2); The irradiation group did not place the dark place 20 minutes with cell.After illumination or the 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.
Above-mentioned wavelength is that halogen lamp through 500W connects the spectral filter that heat insulation tank adds greater than 610nm and provides greater than the ruddiness of 610nm.
The result shows, uridine derivatives of the present invention is modified silicon phthalocyanine, under red light irradiation, can kill and wound cancer cells, when the concentration of implementing the silicon phthalocyanine that the described uridine derivatives of 1-2 modifies is 0.001mM (promptly 1 * 10
-6Mol/L) time, can 100% kill and wound cancer cells.Under the 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 the growth-inhibiting effect, shows that they do not have dark toxicity.Through the concentration of investigation silicon phthalocyanine and the dose-effect relationship of cell survival rate, obtain the toxic limit medium dose (IC under illumination condition
50, promptly kill the required drug level of 50% cancer cells), be respectively: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine is 6nM (promptly 6 * 10
-9Mol/L), two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyluridine oxygen base] silicon phthalocyanine is 50nM (promptly 5 * 10
-8Mol/L).Extremely low IC
50Value explains that uridine derivatives modification silicon phthalocyanine of the present invention has high photodynamic activity.
(Cremophor EL, wt%) aqueous solution changes 1% castor oil derivative into (Cremophor EL, wt%) phosphate buffer soln (PBS) also can obtain same experimental result with above-mentioned 1% castor oil derivative.
Embodiment 7
Experimental technique according to the foregoing description 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 the result shows: the silicon phthalocyanine that the described uridine derivatives of 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 is to the IC of human liver cancer cell HepG2
50Value is 6nM (promptly 3.1 * 10
-8Mol/L), and to the IC of normal liver cell L-O2
50Value is 68nM (promptly 6.8 * 10
-8Mol/L), both differ 11 times.This explains 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 the foregoing description 6 into people's cancer of the stomach BGC823 cell; Other conditions are constant; The result is following: 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 the described uridine derivatives of embodiment 1-2 is 0.001mM (promptly 1 * 10
-6Mol/L) time, can 100% kill and wound cancer cells.Under the 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 the growth-inhibiting effect, shows that they do not have dark toxicity.The silicon phthalocyanine light power that the described uridine derivatives of embodiment 1-2 is modified kills and wounds the IC of people's cancer of the stomach BGC823 cell
50Value is respectively: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine is 31nM (promptly 3.1 * 10
-8Mol/L), two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyluridine oxygen base] silicon phthalocyanine is 120nM (promptly 1.2 * 10
-7Mol/L).Low IC
50Value explains that uridine derivatives modification silicon phthalocyanine of the present invention has high photodynamic activity.
Embodiment 9
According to embodiment 6 described methods, the silicon phthalocyanine that uridine derivatives more of the present invention is modified and following other phthalocyanine complexes are to the photodynamic activity of people's cancer of the stomach BGC823 cell.
Said following other phthalocyanine complexes are a kind of of following title complex: two [glucosyloxy] silicon phthalocyanine, and two [5-(1,2; 3,4-two-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) silicon phthalocyanine, two [4-(4-ethanoyl piperazine) phenoxy] silicon phthalocyanine, two [4-(3-carboxyl propyl group) phenoxy] silicon phthalocyanine; Two (4-formic acid phenoxy) silicon phthalocyanine, two (3-formic acid phenoxy) silicon phthalocyanine, two (3; 5-dioctyl phthalate phenoxy) silicon phthalocyanine, two (1-diamantane-methoxyl group) silicon phthalocyanine, two (2-diamantane-oxyethyl group) silicon phthalocyanine; Four-a-[4-(4-ethanoyl piperazine) phenoxy] zinc phthalocyanine, four-a-(4-formic acid phenoxy) zinc phthalocyanine
The result shows that the photodynamic activity of the silicon phthalocyanine that uridine derivatives of the present invention is modified all is 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 more than 3 times of above-mentioned other phthalocyanine compounds to the light power restraining effect of cancer of the stomach BGC823 cell at least.
Embodiment 10
The silicon phthalocyanine that uridine derivatives of the present invention is modified is dissolved in 1% castor oil derivative, and (Cremophor EL wt%) in the PBS damping fluid, processes the photosensitive medicament of 0.3mM, tests their the light power of fungi is suppressed active.Used fungi is Candida albicans CMCC (F) C1a (Candida albicans, C. albicans), and bacteria suspension concentration is 2 * 10
6Cells/ml.(used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm under red light irradiation
-2), the silicon phthalocyanine that uridine derivatives of the present invention is modified can 100% be killed Candida albicans, and solvent control group, an administration irradiation group, not administration of an irradiation group all do not influence the growth of Candida albicans.
Embodiment 11
The silicon phthalocyanine of having tested uridine derivatives modification of the present invention is used for light power disinfectant effect as photosensitizers.
At first, (Cremophor EL wt%) in the aqueous solution, processes the photosensitive medicament of 0.3mM said silicon phthalocyanine to be dissolved in 1% castor oil derivative.Then it is joined and contain in the colibacillary water, the content that makes silicon phthalocyanine is 0.03mM, contains colibacillary water with red light irradiation after 2 hours.Colibacillary survival before and after the inspection irradiation, the result is illustrated under the red light irradiation, and the silicon phthalocyanine that uridine derivatives of the present invention is modified can be killed the intestinal bacteria more than 95%.
The above is merely preferred embodiment of the present invention, and all equalizations of doing according to claim of the present invention change and modify, and all should belong to covering scope of the present invention.
Claims (5)
1. the silicon phthalocyanine modified of a uridine derivatives, it is characterized in that: its structural formula is following:
or?
.
2. the silicon phthalocyanine that uridine derivatives according to claim 1 is modified is characterized in that: the silicon phthalocyanine that described uridine derivatives is modified is axial symmetrical dibasic silicon phthalocyanine, and axially substituting group links to each other with silicon through Sauerstoffatom; According to axial substituting group characteristics, called after: two [5 '-(2 ', 3 '-O-sec.-propyl)-uridine oxygen base] silicon phthalocyanine or two [5 '-(2 ', 3 '-O-sec.-propyl)-5-methyluridine oxygen base] silicon phthalocyanine.
3. the preparation method of the silicon phthalocyanine modified of a uridine derivatives as claimed in claim 1, it is characterized in that: described preparation method may further comprise the steps:
(1) under ice-water bath ~ room temperature, uridine or 5-methyluridine and tosic acid were placed the 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-methyluridine;
(2) with phthalocyanine silicon dichloride and 2 ', 3 '-O-sec.-propyl-uridine or 2 ', 3 '-O-sec.-propyl-5-methyluridine are reactant, and both molar ratios are 1:4 ~ 10; With toluene, YLENE or dioxane is solvent; Solvent load needs 40 ~ 400ml for the 1mmol phthalocyanine silicon dichloride, and under the existence and protection of nitrogen gas of sodium hydride, 100 ~ 130 ℃ were reacted 18 ~ 48 hours down; 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-methyluridine oxygen base] silicon phthalocyanine.
4. the application of the silicon phthalocyanine of a uridine derivatives modification as claimed in claim 1 is characterized in that: be used to prepare photo-dynamical medicine or photosensitizers.
5. the application of the silicon phthalocyanine that uridine derivatives according to claim 4 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, and wherein the massfraction of other material is not higher than 10%; As solvent; The silicon phthalocyanine that the urine-soluble glycoside derivates is modified is mixed with and contains certain density photosensitive medicament, and the concentration of the silicon phthalocyanine that uridine derivatives is modified is not higher than its saturation concentration; In the solution of processing, add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament;
Described other material is castor oil derivative, methyl-sulphoxide, ethanol, glycerine, N, the miscellany of one or more in dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, the YMS 2.
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