CN115636835B - Photosensitizer based on porphin structure, preparation and application - Google Patents
Photosensitizer based on porphin structure, preparation and application Download PDFInfo
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- CN115636835B CN115636835B CN202211278279.0A CN202211278279A CN115636835B CN 115636835 B CN115636835 B CN 115636835B CN 202211278279 A CN202211278279 A CN 202211278279A CN 115636835 B CN115636835 B CN 115636835B
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical group N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 20
- 238000005286 illumination Methods 0.000 claims description 17
- 229940126062 Compound A Drugs 0.000 claims description 14
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
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- JZRYQZJSTWVBBD-UHFFFAOYSA-N pentaporphyrin i Chemical group N1C(C=C2NC(=CC3=NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JZRYQZJSTWVBBD-UHFFFAOYSA-N 0.000 claims description 9
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- 229910001507 metal halide Inorganic materials 0.000 claims description 8
- 150000005309 metal halides Chemical class 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 235000019260 propionic acid Nutrition 0.000 claims description 7
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 7
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- 238000006862 quantum yield reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/542—Dye sensitized solar cells
Abstract
The invention discloses a photosensitizer based on a porphin structure, and preparation and application thereof. The photosensitizer is a compound with a general formula T structure, is modified based on a porphin ring structure, and has intramolecular charge transfer characteristic after oxygen, sulfur and nitrogen atoms conjugated with a parent nucleus structure p-pi are introduced, and the introduction of glycol chains on hetero atoms not only increases the water solubility of the photosensitizer, but also endows the photosensitizer with the property of W-RPA, compensates the problem that the porphin photosensitizer for PDT has poor effect on treating hypoxic tumors, and is beneficial to improving the clinical application effect.
Description
Technical Field
The invention relates to the field of photosensitization treatment of tumors. And more particularly to a photosensitizer based on a porphine structure, preparation and application.
Background
The incidence and mortality of cancers rise year by year, and the global cancer incidence increases by 60% in the next 20 years as shown in the global cancer report 2020 issued by the World Health Organization (WHO). In order to cope with increasingly severe cancer conditions, it is very necessary to develop a variety of tumor treatment modalities suitable for different patients.
For solid tumors in early and mid stages, the most immediate and effective treatment is surgical excision, however surgery is highly risky for elderly, focal vascular or nerve complex, liver and kidney dysfunction, long-term hypertension or diabetes, and therefore they are more suitable for minimally invasive/non-invasive treatment. The most commonly used noninvasive therapies at present are radiotherapy and chemical drug treatment, which generally have better tumor inhibition effect, however, the radiotherapy and chemotherapy lack of tumor specificity, can cause serious damage to normal cells or tissues of an organism, and are not suitable for patients with weak self-resistance. Immunotherapy is a tumor-specific noninvasive therapy, which avoids large-area wounds caused by surgery and damages of radiotherapy and chemotherapy to the body, but the existing immunotherapy has few indications, limited curative effect and certain drug resistance.
Photodynamic therapy (PDT) is a minimally invasive/non-invasive therapy that was used for clinical tumor treatment beginning in the sixty of the last century, and has the following mechanism of action: under the irradiation of an external light source, the photosensitizer absorbs the light energy and reacts with oxygen (O) 2 ) The action generates biologically toxic Reactive Oxygen Species (ROS), thereby killing tumor cells. Currently PDT has been widely used for clinical treatment of a variety of cancers such as pancreatic cancer, colon cancer, esophageal cancer, nasopharyngeal cancer, and the like. However, O of one of the three elements of PDT 2 The low levels in most solid tumors limit the effectiveness of tumor treatment to a large extent. Scientific researchers have proposed various solutions to this bottleneck problem, but the therapeutic effect has not been significantly improved. Therefore, solving the problem of inefficiency caused by intratumoral hypoxic environments remains a hot spot for research by researchers in the current PDT field.
Water-dependent reversible photoacid therapy (W-RPAT) is a recently proposed approach to tumor treatment, which is by the mechanism: the photosensitizer is excited by light to generate intramolecular charge transfer so that electron-donating group (such as alkylamino and alkoxy) generates electron-deficient property, and further the electron-donating group is bonded with hetero atom (such as oxygen, sulfur and nitrogen) to form ethylene glycol structure and water (H) 2 O) formation of intermolecular hydrogen bonds and activation of H 2 O makes it generate H + ，H 2 O remaining OH - Then locked to the photosensitizer without being free in solvent; after stopping the illumination, the transferred charges in the photosensitizer return and OH locked by the photosensitizer - Is released to take the active in the environmentProtons (including H + Or active protons in vital life substances), regenerating H 2 O. This cyclic process results in cell death. One great advantage of W-RPAT is that its therapeutic effect is not limited by the hypoxic environment of the tumor site. Thus W-RPAT has a distinct advantage over PDT in the photosensitization treatment of hypoxic tumors.
The porphin derivatives are biological source photosensitizers with high biocompatibility and singlet oxygen quantum yield, are core components of most of clinical photodynamic anti-tumor therapeutic drugs at present, but still face the problem of inefficiency caused by the hypoxic environment when treating large tumors. The structural modification of the porphin ring enables the photosensitizer to have the property of water-dependent reversible photoacid (W-RPA), so that the defect of poor treatment effect of the porphin photosensitizer on the hypoxic tumor can be overcome, and the clinical application effect can be improved. Therefore, the design and synthesis of the photosensitizer with the W-RPA property have potential application prospect.
Disclosure of Invention
To solve the above problems, a first object of the present invention is to provide a photosensitizer based on a porphine structure. The photosensitizer is modified based on a porphin ring structure, and after oxygen, sulfur and nitrogen atoms conjugated with a parent nucleus structure p-pi are introduced, the photosensitizer molecule has intramolecular charge transfer characteristic, and an ethylene glycol chain bonded on a hetero atom can not only improve the water solubility of the photosensitizer and reduce intermolecular stacking, but also endow the photosensitizer with the property of W-RPA, make up the problem that the porphin photosensitizer has poor treatment effect on hypoxic tumors, and is favorable for improving clinical application effects.
A second object of the present invention is to provide a method for preparing a photosensitizer as described above.
A third object of the present invention is to provide the use of a photosensitizer as described above for the preparation of a W-RPAT therapeutic drug for inactivating tumor cells.
In order to achieve the first object, the present invention adopts the following technical scheme:
the invention discloses a photosensitizer based on a porphine structure, which is characterized in that the photosensitizer is a compound with a structure of the following general formula T:
the R is 1 -R 12 Each independently represents H, hydroxy, alkyl, alkenyl, aryl, hydroxy, carbonyl, bromoalkyl, chloroalkyl, fluoroalkyl, bromoalkenyl, chloroalkenyl, fluoroalkenyl, bromoaryl, chloroaryl, fluoroaryl, cl, br, hydrophilic carboxylate, hydrophilic quaternary ammonium salt, hydrophilic phosphate,
two or more of (a) and (b); and R is 1 -R 12 At least one group is selected from the structures represented by one of formulas i-1 to i-24; the R is 1 -R 12 May be the same or different;
wherein in the structure of formula i-4, n 1 Take a value of 3<n 1 <9 or 17<n 1 <An integer of 30, A 1 Selected from alkyl, alkenyl, hydroxy, carboxy, hydrophilic carboxylate, hydrophilic quaternary ammonium salt or hydrophilic phosphate;
in the structures of the formulas i-1 to i-3 or the formulas i-5 to i-24, n 1 Is an integer of 1 to 50, n 2 Is an integer of 0 to 50, A 1 、A 2 Each independently represents H, alkyl, alkenyl, hydroxy, carboxy, hydrophilic carboxylate, hydrophilic quaternary ammonium salt or hydrophilic phosphate; a is that 1 、A 2 May be the same or different;
m represents two H, sn, mn, zn, mg, ni, fe, co, pd or one of the metal halides thereof respectively connected with the opposite N;
represents the bond between the substituent and the main structure.
The compounds of the general formula T structure provided by the invention are based on porphine structural units. Double bond nitrogen in porphine ringHas electron withdrawing property, R in T structure 1 -R 12 After oxygen, sulfur, nitrogen and other hetero atoms conjugated with the p-pi of the parent nucleus structure are introduced at any position, a photosensitizer with intramolecular charge transfer characteristic can be constructed, and the intramolecular charge transfer characteristic is also a precondition of W-RPA property. Unlike the prior art, the polyethylene glycol chain modified by the photosensitizer for PDT mainly plays a role in increasing water solubility, and the first ethylene glycol structure on hetero atoms provides a reaction site for combining water of the excited photosensitizer while increasing water solubility and reducing stacking among branches in the photosensitizer disclosed by the patent, so that the photosensitizer is an essential key structure for W-RPA effect. The linking unit between the porphin parent nucleus and the heteroatom has no decisive effect on the W-RPA property, but the linking unit with large conjugation degree can lead the absorption spectrum of the photosensitizer to be red-shifted, which is beneficial to tumor treatment. Therefore, the photosensitizer disclosed by the patent is different from other porphin photosensitizers for PDT, and the oxygen independent property of the W-RPA enables the photosensitizer disclosed by the patent to exert high-efficiency tumor killing effects on oxygen-enriched and hypoxic positions of tumors. In addition, the porphine photosensitizer protected by the patent extends the characteristics of safety and high efficiency of the porphine photosensitizer for PDT. Therefore, the photosensitizer has good application prospect in the field of tumor treatment.
Further, A 1 、A 2 Each independently represents C 1 ～C 5 Alkyl of C 1 ～C 5 Alkenyl groups of (a), hydrophilic carboxylate salts, hydrophilic quaternary ammonium salts or hydrophilic phosphate salts.
Further, R 1 -R 12 Each independently represents H, and the number of carbon atoms is C 1 ～C 5 Alkyl of C 1 ～C 5 Alkenyl groups of (C), hydrophilic carboxylate, hydrophilic quaternary ammonium salt, hydrophilic phosphate,
wherein in formula i-4, n 1 Take a value of 3<n 1 <An integer of 9;
in the formula i-5, the formula i-20 and the formula i-21, n 1 The value is 1 to n 1 An integer of 15 or less, n 2 The value is 0 to n 1 An integer of 15 or less, R 1 -R 12 At least one group selected from the group consisting of formula i-4, formula i-5, formula i-20, and formula i-21.
Further, the photosensitizer is selected from one of the following specific structures:
it should be noted that, the chlorin and tetrahydroporphin structures obtained by reducing the general formula T are also within the protection scope of the present patent because the functional groups are the same. In addition, the general formula T structure with various photoactivation properties including the W-RPA property (such as the W-RPA property and the ROS generation property) or the chlorin and tetrahydrochlorin structure obtained by reduction of the general formula T structure are also within the protection scope of the patent.
Of course, in a specific application, the person skilled in the art can also determine the affinity of the moleculeHydrophobic and other aspects, optionally designed R 1 -R 12 And A 1 、A 2 It is also within the scope of the present invention to improve the water solubility of photosensitizers by weak interactions with amphiphilic molecules such as DSPE-mPEG2000, cyclodextrins, meglumine, liposomes, etc.
In order to achieve the second object, the present invention adopts the following technical scheme:
the invention discloses a method for preparing the photosensitizer, which comprises the following steps:
when M represents two H's respectively linked to the opposite N's, the synthesis method comprises the following steps:
heating a mixture of a compound A, a compound B and anhydrous propionic acid for reaction, removing redundant solvent by rotary evaporation after the reaction is completed, adding dichloromethane to fully dissolve a crude product, adding a sodium carbonate aqueous solution, washing until the aqueous phase is neutral, drying an organic phase by anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a target compound;
when M represents Sn, mn, zn, mg, ni, fe, co, pd or a metal halide thereof, the synthetic method comprises the steps of:
heating a mixture of a compound A, a compound B and anhydrous propionic acid for reaction, removing redundant solvent after the reaction is completed, adding dichloromethane to fully dissolve a crude product, adding sodium carbonate aqueous solution, washing until the aqueous phase is neutral, drying an organic phase by using anhydrous sodium sulfate, concentrating, performing column chromatography to obtain a compound T1, performing metal complexation reaction on the compound T1 and metal halide in a polar solvent, and performing column chromatography to obtain a compound T2;
wherein the compound A is selected from R 1 -CHO、R 4 -CHO、R 7 -CHO、R 10 -one or more of CHO;
the compound B is selected fromOne or more of the following.
Further, the molar ratio of the compound A to the compound B is 1:0.1-100; by way of example only, and in an illustrative, the molar ratio of the compound A to the compound B may also be 1:0.1-0.5, 1:0.1-1, 1:0.1-2, 1:0.1-3, 1:0.1-4, 1:0.1-5, 1:0.1-6, 1:0.1-7, 1:0.1-8, 1:0.1-9, 1:0.1-10, 1:0.1-20, 1:0.1-50, 1:0.5-1, 1:0.5-2, 1:0.5-3, 1:0.5-4, 1:0.5-5' 1:0.5-6, 1:0.5-7, 1:0.5-8, 1:0.5-9, 1:0.5-10, 1:0.5-20, 1:0.5-50, 1:0.5-100, 1:1-2, 1:1-3, 1:1-4, 1:1-5, 1:1-6, 1:1-7, 1:1-8, 1:1-9, 1:1-10,1:5-6, 1:5-7, 1:5-8, 1:5-9, 1:5-10, 1:10-20, 1:10-50, 1:10-100, and the like.
Further, the molar ratio of T1 to metal halide is 1:1-10.
Further, the reaction temperature of the compound A and the compound B in anhydrous propionic acid is 80-150 ℃ and the reaction time is 4-72h.
Further, the temperature of the metal complex reaction is 60-200 ℃, and the reaction time is 10-720min.
Further, the organic phase was washed with Na 2 CO 3 The concentration of the aqueous solution is 0.1-1.6M.
In order to achieve the third object, the present invention adopts the following technical scheme:
the invention discloses an application of a photosensitizer in preparation of a W-RPAT therapeutic drug for inactivating tumor cells.
Further, the light source used in the treatment is a laser or LED light source; preferably, the wavelength of the light source is 450-880nm, the illumination time is 0.1-60min, and the illumination intensity is 5-200mW/cm 2 。
Further, the concentration of photosensitizer in the treatment is 0.001-100 μg/mL.
The beneficial effects of the invention are as follows:
the photosensitizer disclosed in the invention is a porphin photosensitizer, and the parent nucleus part of the photosensitizer has electron pulling property through R of the photosensitizer 1 -R 12 The photosensitizer with intramolecular charge transfer can be constructed after the position is introduced with oxygen, sulfur and nitrogen heteroatoms conjugated with the parent nucleus p-pi, and the introduction of polyethylene glycol chains on the heteroatoms can not only improve the water solubility of the photosensitizer and reduce moleculesThe photosensitizers are piled up, and meanwhile, the property of the photosensitizers W-RPA is also endowed, and the photosensitizers disclosed by the patent can generate high-efficiency tumor killing effect on the oxygen rich and deficient parts of solid tumors due to the property that the photosensitizers for W-RPA are independent of oxygen. The conjugated bridge (such as double bond, triple bond, benzene, naphthalene, benzothiophene, etc.) between the porphin parent nucleus and the hetero atom can effectively widen the absorption spectrum and increase the tissue penetration depth of the light source used in treatment. In addition, the photosensitizer disclosed by the patent can also generate ROS or thermal effects, and superposition of multiple effects is also beneficial to increasing tumor killing effect. The photosensitizers disclosed herein were developed on porphine structures of biological origin, and have higher biosafety than other photosensitizers of non-biological origin. Therefore, the photosensitizer has good clinical application prospect in the aspect of treating tumors by using W-RPAT.
Drawings
The following describes the embodiments of the present invention in further detail with reference to the drawings.
FIG. 1 is a HOMO and LUMO diagram of compound T-a synthesized in example 1;
FIG. 2 is an ultraviolet-visible spectrum and a fluorescence spectrum of T-a NPs prepared in example 5 in phosphate-exchanged solution (PBS, pH=7.4);
FIG. 3 shows singlet oxygen in example 7 1 O 2 ) The absorbance change at 380nm of the mixture of the capturing agent ABDA and PSs (T-b NPs or MB) under illumination (660 nm,20 mW/cm) 2 )；
FIG. 4 shows the change in the fluorescence peak area at 540-620nm under different illumination conditions for a PBS mixed solution of RB Base and T-a NPs of example 8 (C RB Base ＝6μM，C T-aNPs ＝12μM；635nm，20mW/cm 2 )；
FIG. 5 shows phototoxicity of T-b NPs to HeLa cells (660 nm,20 mW/cm) 2 ，10min)；
FIG. 6 shows phototoxicity (660 nm,20 mW/cm) of T-b NPs to A549 cells in example 11 2 ，10min)；
FIG. 7 shows the phototoxicity of T-c on HeLa cells in example 12 (635 nm,20mW +.cm 2 ，10min)。
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments and the accompanying drawings. It should be understood that the described embodiments are merely some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The reaction starting materials used in the examples may be synthesized by commercially available or reported methods, and are not limited thereto.
Example 1
Preparation of Compound T-a
The structural formula of the compound T-a is as follows:
(1) In ice bath, p-toluenesulfonyl chloride (10.0 g,48.0 mmol) was slowly added dropwise to a solution of tetraethyleneglycol monomethyl ether (10.0 g,48.0 mmol) and triethylamine (9.8 g,96.0 mmol) in methylene chloride (50 mL), and the reaction was stopped after 2 hours at room temperature. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and the organic solvent was distilled off to obtain crude product 1 as a yellow oil, which was used in the next reaction without purification.
(2) N-ethyl-N-hydroxyethyl aniline (0.8 g,4.9 mmol), compound 1 (1.8 g,5.0 mmol), potassium hydroxide (1.0 g,17.9 mmol) were added to 20mL of ultra-dry tetrahydrofuran, the reaction was stopped after refluxing for 24h at 70℃and the residue was dissolved in dichloromethane (30 mL) after evaporation of the solvent, the organic phase was washed with water and dried over anhydrous sodium sulfate, and the organic solvent was distilled off to give crude product 2 as a yellow oil which was used directly in the next reaction without purification.
(3) DMF (20 mL) and phosphorus pentachloride (440 mg,2.1 mmol) were stirred at room temperature for 30min, a solution of Compound 2 (450 mg,1.3 mmol) in DMF was slowly added dropwise thereto, the reaction was stopped after 12h at 50℃and the residue was dissolved with dichloromethane (30 mL) after removal of the solvent by evaporation, and the organic phase was taken up in saturated Na 2 CO 3 The aqueous solution was washed with water, dried over anhydrous sodium sulfate, and the remaining solvent was distilled off to give crude product 3 as a yellow oil, which was used in the next reaction without purification.
(4) To 40mL of anhydrous propionic acid were added compound 3 (1.0 g,2.6 mmol) and redistilled pyrrole (250 mg,3.7 mmol), the reaction was stopped after 20 hours at 140℃and the residue was dissolved in dichloromethane (30 mL) after evaporation of the solvent, and the organic phase was taken up in saturated Na 2 CO 3 Washing with water, drying, evaporating residual solvent to obtain dark green oily crude product, and purifying by column chromatography to obtain compound T-a.
1 H NMR(CDCl 3 ,400MHz):δ(ppm)9.03(s,8H),8.06-8.04(d,J＝7.6,8H),7.08-7.06(d,J＝7.2,8H),3.88-3.03(m,120H),1.42-1.39(t,J＝6.4,12H),-2.38(s,2H)；
13 C NMR(CDCl 3 ,150MHz)；δ167.80,132.42,132.14,130.92,130.02,129.92,129.90,129.75,128.81,71.93,70.80,70.74,70.61,70.57,68.15,59.14,40.98,14.16；
HR-MS(MALDI):m/z[M+MeOH+H] + calculated for C 97 H 143 N 8 O 21 ,1757.22221；found,1757.88696。
Example 2
Preparation of T-b:
t-b has the formula:
the synthesis procedure of compound T-b was substantially the same as that of T-a, with reference to example 1, except that N-ethyl-N-hydroxyethylaniline was changed to phenol, and the yield of compound T-b was 30%. The characterization of compound T-b is as follows:
1 H NMR(CDCl 3 ,600MHz):δ(ppm)8.90(s,8H),8.13-8.11(d,J＝8.4,8H),7.27-7.26(d,J＝8.4,8H),4.34-4.33(t,J＝4.2,8H),4.00-3.98(t,J＝5.4,8H),3.83-3.57(m,56H),3.40(s,12H),-2.69(s,2H)。
13 C NMR(CDCl 3 ,100MHz):δ167.61,160.67,158.59,152.64,146.28,135.53,134.76,133.51,133.15,122.23,121.88,119.71,114.59,112.80,71.96,70.94,70.73,70.68,70.55,69.90,67.67,59.09。
HR-MS(ESI):m/z[M+Na] + calculated for C 88 H 118 N 4 NaO 24 ,1638.90522；found,1639.21980。
example 3
Preparation of T-c
T-c formula:
t-b (120.0 mg, 73.7. Mu. Mol) was dissolved in 30mL of N, N-dimethylformamide, refluxed at 145℃for 30min, then a pyridine solution (5 mL) of tin chloride dihydrate (83.0 mg, 367.8. Mu. Mol) was slowly added dropwise, the reaction was stopped after continuing to reflux at 145℃for 20h, the residue was dissolved with methylene chloride (30 mL) after removing the solvent by evaporation, and the organic phase was taken up in saturated Na 2 CO 3 Washing with water, drying, evaporating residual solvent to obtain dark green oily crude product, and purifying by column chromatography to obtain compound T-c with 90% yield.
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1 H NMR(D 2 O,600MHz):δ(ppm)9.11-9.06(m,9H),8.16-8.14(d,J＝12,6H),7.29-7.27(d,J＝13.2 9H),4.38-3.49(m,120H)；
13 C NMR(CDCl 3 ,150MHz)：δ158.97,158.34,146.99,146.67,146.61,136.07,133.71,120.92,120.72,112.89,71.79,70.81,70.59,70.53,70.34,70.09,69.72,67.61,59.96；
HR-MS(ESI):m/z[M+MeOH+H] + calculated for C 89 H 121 Cl 2 N 4 O 25 Sn,1835.67134；found,1835.84611。
Example 4
Density functional theory calculation of photosensitizer T-a:
for the convenience of calculation, the last four glycol units in T-a with small influence on electron distribution are omitted, and theoretical simulation is carried out on the rest porphin compounds, wherein the specific steps are as follows: (1) The ground state molecular structure geometry was optimized with B3LYP-PCM/6-311+G (d, p); (2) Based on the optimized ground state geometric configuration, calculating excitation energy by using a TD-B3LYP-PCM method, thereby obtaining an excitation spectrum; (3) The geometry of the excited state is optimized in the same way on the excited state, so that a fluorescence spectrum is obtained. With these calculations, front molecular orbital information for the T-a photosensitizer can be obtained. As can be seen from fig. 1, in the ground state (HOMO), electrons are mainly distributed on the electron donating alkylamine and benzene ring bridge, after light excitation (LUMO), electrons are transferred to the porphin parent nucleus, and the electron density on the electron donating alkylamine and benzene ring bridge is significantly reduced, indicating that T-a has intramolecular electron transfer characteristics.
Example 5
Preparation of water-insoluble photosensitizer nanoparticles:
1mg of compound T-a in example 1 and 1mg of DSPE-PEG2000 are dissolved in 1mL of tetrahydrofuran, the mixture is evenly mixed by ultrasonic treatment for 10min, then the mixture is dropwise added into 5mL of PBS stirred (1500 r/min), the mixture is continuously stirred for 24h at normal temperature, the tetrahydrofuran in the solvent is removed by rotary evaporation, and oversized particles are removed by filtration through an aqueous filter membrane with the pore diameter of 0.22 mu m, so that the preparation of nano-particle T-a NPs is completed. The UV-visible spectrum and fluorescence spectrum of nanoparticle T-a NPs in PBS solution are shown in FIG. 2. From the graph, the T-a NPs have a plurality of obvious Q band absorption peaks at 550-660nm, and can be used for photosensitization treatment of tumors.
Example 6
Preparation of water-insoluble photosensitizer nanoparticles:
the preparation process and process parameters of T-b NPs are similar to those of T-a NPs except that the type of photosensitizer added is different, with reference to example 5, except that T-a is replaced with T-b.
Example 7
Detection of singlet oxygen in PBS by T-b NPs 1 O 2 )：
PBS solutions (OD) of T-b NPs in example 6 at 1.5ml, respectively 660nm =0.194) and 1.5ml of methylene blue (MB, OD 660nm =0.196) to 1.5ml of singlet oxygen scavenger 9, 10-anthryl-bis (methylene) dimalonate (ABDA, OD) max =1.952), and the two solutions are respectively placed in ultraviolet cuvettes (length, width, height are respectively 1×1×3.5 cm) at an optical power density of 20mW/cm 2 The change condition of the spectrum of the solution is recorded every 6s under the irradiation of 660nm laser, and the air in the solution is fully saturated by continuously stirring in the illumination process. The T-b NPs in example 6 were quantitatively calculated by comparing the absorbance change at 380nm of the various photosensitizers with the ABDA mixture 1 O 2 Quantum yield. MB in PBS solution 1 O 2 The quantum yield was 0.52, and as shown in FIG. 3, the comparison of the slope of the absorbance change at 380nm of the solution gave a quantum yield of 0.07 in PBS for the T-b NPs of example 6. The same procedure was used to test for the singlet oxygen quantum yields of 0.02 and 0.28 in PBS for T-a NPs in example 5 and T-c in example 3, respectively.
Example 8
Detection of W-RPA Properties of T-a NPs:
will H + The indicator RB Base (6. Mu.M) was mixed with the T-a NPs (12. Mu.M) of example 5 to prepare 3mL of a mixture (the solvent wasUltrapure water) and placed in a fluorescent cuvette (length, width, height, 1X 3.5cm, respectively). According to the excitation light of the indicator (532 nm, 10 mW/cm) 2 ) An optical path is set up at 90 degrees with the detector, and photosensitizer excitation light (635 nm,20mW/cm 2 ) The spot of (2) needs to cover the whole cuvette. And recording a fluorescence spectrogram before illumination, and recording the fluorescence spectrogram at intervals of 1min in the illumination process and under the condition of light shielding and vibration. And calculating the difference value between the fluorescence peak area of the 540-620nm wave band recorded each time and the fluorescence peak area before illumination to obtain the real-time fluorescence increase data of the illumination acid production. The specific data are shown in FIG. 4, and the result shows that under the illumination condition (0-6 min), T-a NPs can rapidly generate H + (fluorescence enhancement); and under illumination H + Can be accumulated to a certain concentration and kept constant (6-11 min); under the condition of light shielding and vibration, H in solution + The concentration was reduced, resulting in a decrease in fluorescence (11-12 min) and the final solvent pH returned to the initial state (12-13 min). The test method can be used for proving that the T-structure photosensitizer has W-RPA property.
Example 9
Detection of phototoxicity of T-b NPs to human cervical cancer (HeLa) cells under normoxic conditions:
HeLa cells (5000 cells/well) were seeded in 96-well plates at 37℃with 5% carbon dioxide (CO 2 ) After 24h incubation in a 95% air incubator, the medium was aspirated and the cell culture medium (200. Mu.l/well) containing the T-b NPs of example 6 at different concentrations (0, 1. Mu.M, 2. Mu.M, 4. Mu.M, 6. Mu.M) was re-added, and after further incubation for 4h, the medium was incubated with a laser (660 nm,20 mW/cm) 2 ) After 10min of irradiation, the MTT staining was continued after 24h of incubation and the cell viability was recorded with a microplate reader. The photosensitizing effect of T-b NPs is shown in FIG. 5, demonstrating the tumor killing effect of T-b NPs on HeLa cells under this illumination.
Example 10
Phototoxicity of T-b NPs on HeLa cells under nitrogen atmosphere (hypoxia):
HeLa cells (5000 cells/well) were seeded in 96-well plates at 37℃with 5% carbon dioxide (CO 2 ) After 24h incubation in a 95% air incubator, the broth was aspirated and added again with different concentrations (0, 1. Mu.M, 2. Mu.M, 4. Mu.M, 6. Mu.M)In example 6 of T-b NPs (200. Mu.l/well), the cells were further incubated for 3 hours, and then the 96-well plate was placed in a transparent square box (length. Times. Width. Times. Height=22.5 cm. Times. 16.5 cm. Times. 3.3 cm), and a vent was opened to N 2 After 1h, the vent and the air outlet are closed, so that the 96-well plate is in a sealed N state 2 The cassette was then placed in an incubator under an atmosphere for continuous cultivation for 1 hour, consuming the oxygen remaining in the culture broth. By laser (660 nm,20 mW/cm) 2 ) After 10min of irradiation, the MTT staining was continued after 24h of incubation and the cell viability was recorded with a microplate reader. The photosensitizing effect of T-b NPs is shown in FIG. 5, which demonstrates that T-b NPs still exhibit excellent cytotoxicity under extremely oxygen deficient conditions.
Example 11
Detection of cytotoxicity of T-b NPs against human non-small cell lung cancer (a 549) under normoxic conditions:
a549 cells (5000 cells/well) were seeded in 96-well plates at 37 ℃ with 5% carbon dioxide (CO 2 ) After 24h incubation in a 95% air incubator, the medium was aspirated and the cell culture medium (200. Mu.l/well) containing the T-b NPs of example 6 at different concentrations (0, 1. Mu.M, 2. Mu.M, 4. Mu.M, 6. Mu.M) was re-added, and after further incubation for 4h, the medium was incubated with a laser (660 nm,20 mW/cm) 2 ) After 10min of irradiation, the MTT staining was continued after 24h of incubation and the cell viability was recorded with a microplate reader. The photosensitizing effect of T-b NPs is shown in FIG. 6, which illustrates that T-b NPs have tumor killing effect on A549 cells under the illumination condition.
Example 12
Phototoxicity of T-c prepared in example 3 to HeLa cells under normoxic conditions was tested:
HeLa cells (5000 cells/well) were seeded in 96-well plates at 37℃with 5% carbon dioxide (CO 2 ) After 24h incubation in a 95% air incubator, the medium was aspirated and the cell culture medium (200. Mu.l/well) containing different concentrations (0, 5. Mu.M, 10. Mu.M, 15. Mu.M, 20. Mu.M) of T-c of example 3 was re-added, after further incubation for 4h, with a laser (325 nm,20 mW/cm) 2 ) After 10min of irradiation, the MTT staining was continued after 24h of incubation and the cell viability was recorded with a microplate reader. The photosensitization effect of T-c is shown in FIG. 7, which illustrates that T-c has tumor killing effect on HeLa cells under the illumination condition. Although the following are providedHowever, the highest singlet oxygen quantum yield, however, the therapeutic effect is general, which means that the singlet oxygen quantum yield and the therapeutic effect in the W-RPAT treatment are not in one-to-one correspondence.
It should be understood that the foregoing examples of the present invention are provided merely for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention, and that various other changes and modifications may be made therein by one skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims.
Claims (10)
1. A photosensitizer based on a porphine structure, characterized in that the photosensitizer is a compound having the structure:
2. a method for synthesizing a photosensitizer according to claim 1,
when preparing T-a, T-b, T-e or T-f, the synthetic method comprises the steps of:
heating a mixture of a compound A, a compound B and anhydrous propionic acid for reaction, removing redundant solvent by rotary evaporation after the reaction is completed, adding dichloromethane to fully dissolve a crude product, adding a sodium carbonate aqueous solution, washing until the aqueous phase is neutral, drying an organic phase by anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a target compound;
the compound A isWhen the compound B is pyrrole, obtaining a target compound T-a;
the compound A isWhen the compound B is pyrrole, obtaining a target compound T-B;
the compound A isWhen the compound B is pyrrole, obtaining a target compound T-e;
the compound A isWhen the compound B is pyrrole, obtaining a target compound T-f;
when preparing T-c or T-d, the synthetic method comprises the steps of:
heating a mixture of the compound A, the compound B and anhydrous propionic acid for reaction, removing redundant solvent by rotary evaporation after the reaction is completed, adding dichloromethane to fully dissolve a crude product, adding a sodium carbonate aqueous solution, washing until the aqueous phase is neutral, drying an organic phase by anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a compound T1; carrying out metal complexation reaction on T1 and metal halide in a polar solvent, and then carrying out column chromatography to obtain a compound T2;
the compound A isThe compound B is pyrrole, and when the metal halide is selected from tin chloride, a target compound T-c is obtained;
the compound A isAnd the compound B is pyrrole, and when the metal halide is selected from palladium chloride, the target compound T-d is obtained.
3. The synthetic method of claim 2 wherein the molar ratio of compound a to compound B is 1:0.1-100.
4. The synthetic method of claim 2 wherein the molar ratio of T1 to metal halide is 1:1-10.
5. The synthetic method according to claim 2, wherein the reaction temperature of the compound a and the compound B in anhydrous propionic acid is 80-150 ℃ and the reaction time is 4-72h.
6. The method according to claim 2, wherein the metal complex reaction is carried out at a temperature of 60-200 ℃ for a reaction time of 10-720min.
7. Use of a photosensitizer according to claim 1 for the preparation of a W-RPAT therapeutic drug for inactivating tumor cells.
8. The use according to claim 7, wherein the light source used in the treatment is a laser or LED light source.
9. The use according to claim 8, wherein the light source has a wavelength of 450-880nm, the illumination time is 0.1-60min, and the illumination intensity is 5-200mW/cm 2 。
10. The use according to claim 7, wherein the concentration of the photosensitizer in the treatment is 0.001-100 μg/mL.
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