CN103570732A - Porphin compound, as well as preparation method and application thereof - Google Patents
Porphin compound, as well as preparation method and application thereof Download PDFInfo
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- CN103570732A CN103570732A CN201310525057.9A CN201310525057A CN103570732A CN 103570732 A CN103570732 A CN 103570732A CN 201310525057 A CN201310525057 A CN 201310525057A CN 103570732 A CN103570732 A CN 103570732A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
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Abstract
The invention relates to porphin compound, as well as a preparation method and application thereof. The chemical structural formula of the compound is shown in the specification. The preparation method comprises the following steps: adding 5-(4'-phenol)-10,15,20-triphenylporphyrin into an organic solvent, stirring and dissolving; adding brominated 1-(6'-bromohexyl)-3-ammonium methylpyridine and alkali, and maintaining for 6-8 hours at a temperature of 80-85 DEG C under the protection of nitrogen; extracting, washing, drying, standing, separating and purifying after the reaction is finished. The porphin compound can be applied to preparation of photodynamic anti-tumor medicaments. The compound is definite in structure and simple in preparation, and experiment results indicate that the compound has an excellent application prospect in the field of medicines.
Description
Technical field
The invention belongs to preparation and the Application Areas thereof of antitumor drug, particularly a kind of porphyrins and preparation thereof and application.
Background technology
Optical dynamic therapy (Photodynamic Therapy, PDT) is a kind of novel method for the treatment of malignant tumour.From coming out so far in decades, PDT has obtained the achievement attracting people's attention in the clinical treatment of cancer, with its effectively, safety, side effect is little, can synergetic property, the advantage such as repeatability and relatively low cost shows one's talent, and in the treatment of tumour, demonstrate very strong vitality, for middle and advanced stage, particularly cannot (or refusal) adopt the cancer patients of traditional method treatment that a chance is provided, increased a kind for the treatment of means (Ackroyd R et al., Photochem Photobiol, 74 (5): 656,2001).
The principle of photodynamic therapy is after photosensitizers is absorbed by target cell, under certain wavelength laser irradiates, from ground state (S
0) transit to excited state (S
1), by between being string jump (Intersystem Crossing) further transit to triplet excited states (T
1), the photosensitizers in triplet state and around molecule react, and produce the free radical (as singlet oxygen) of high oxidation activity, kill and wound target cell; And destroy irradiation area blood vessel, block target cell nutrition and oxygen supply; Excitating organism immunomodulatory, causes neoplasm necrosis (H.B.Van den Bergh et al., Lasers Opthalmol.183 – 195,2003) simultaneously.
In optical dynamic therapy, photosensitizers as the carrier of energy, the bridge of reaction and play conclusive effect.Photosensitizers is with first photosensitizers Photofrin II (the M.A.Biel et al. in Holland's listing in 1993, Photochem.Photobiol.83:1063 – 1068,2007) be representative, its indication is tumour, although curative effect certainly clinically, but still have weak point: complicated component, it is indefinite to form, and excretion is slowly, need long-time lucifuge to prevent skin light sensitization (Huo Yan et al., Chin J LaserMed Surg, 1 (15): 48-55,2006).
Therefore,, in order to overcome some shortcomings of existing photosensitizers, in recent years, people are devoted to find more preferably photosensitizers always.
Porphyrins diffuses in cell through passive, and its diffuser efficiency reduces and improves (Ana P.Castanoa et al., Photodiagnosis and Photodynamic Therapy1:279-293,2004) with the outer pH value of born of the same parents.Conventionally, healthy tissues has different pH value (being respectively 7.0～8.0,5.85～7.68) from tumor tissues; And tumor tissues accelerates the outer pH value of its born of the same parents with metabolism to be reduced.Therefore, porphines can enter tumour cell more, completes the preferential gathering in tumor tissues.The chemical structure of this compounds is clear and definite, has higher purity, good photo and thermal stability, and the absorption of red light district is stronger, and in body, retention time is short; By can regulate hydrophobic partition ratio (the Choi C.F.et al. of photosensitizers to the chemically modified of porphine structure, Org Biomol Chem, 6 (12): 2173-2181,2008), being conducive to photosensitizers in absorption and the accumulation of pathological tissues, is comparatively desirable photosensitizers.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of porphyrins and its preparation method and application, and compound structure of the present invention is clear and definite, preparation is simple, and experimental result shows that it has in the good application prospect of field of medicaments.
A kind of porphyrins of the present invention, the chemical structural formula of described porphyrins is:
The preparation method of a kind of porphyrins of the present invention, comprising:
By 5-(4'-phenol)-10,15,20-Triphenylporphyrin adds in organic solvent, stirring and dissolving, then add bromination 1-(6'-bromine hexyl)-3-picoline ammonium and alkali, under nitrogen protection, 80 ℃-85 ℃ keep 6-8h, and TLC monitoring raw material point disappears, and reaction finishes, be dissolved in water, extraction, washing, dry, standing, separating-purifying, obtain bromination 1-[6'-[4 " (10 " ', 15 " ', 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl]-3-picoline ammonium; 5-(4'-phenol)-10,15 wherein, 20-Triphenylporphyrin, organic solvent, bromination 1-(6'-bromine hexyl) mol ratio of-3-picoline ammonium, alkali is 3:30:7:7.
Described organic solvent is DMF DMF or Isosorbide-5-Nitrae-dioxane.
Described alkali is potassium hydroxide, sodium hydroxide or lithium hydroxide.
Described extraction, washing, be dried and be: with DCM extraction 3 times, saturated NaHCO3 washes, and saturated NaCl washes, and anhydrous MgSO4 is dry.
Described separating-purifying is that column chromatography is purified, and the weighting agent in column chromatography is silica gel, and eluent is that volume ratio is the methylene dichloride of 10:1～1:1, the mixing solutions of methyl alcohol.
A kind of porphyrins of the present invention is in the application of preparing light power antitumor drug.
beneficial effect
(1) chemical structure of the compound that prepared by the present invention is simple, clearly, there is higher purity, good photo and thermal stability, the absorption of red light district is stronger, and porphines energy selectivity concentrates in target tissue, again porphines and quaternary ammonium salt are combined, utilize positive charge and the surface of cell membrane anion binding of quaternary ammonium salt, disturb the enzymic activity in film surface and tenuigenin, cause cellular metabolism to be obstructed and apoptosis;
(2) wetting ability of the compound that prepared by the present invention increases, can better concentrate in target tissue, in target tissue and healthy tissues, form good distribution ratio, while carrying out illumination, growth that can more effective inhibition tumour, and reduced the toxic side effect of its normal tissue;
(3) the present invention is by finding to the light power trial of colon cancer cell with to the light power trial of mouse S 180 sarcoma this kind of photosensitizers, when having illumination, photosensitizers can suppress the propagation of colon cancer cell and the growth of mouse S 180 sarcoma significantly, has the prospect that becomes light power antitumor drug.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read the content of the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
Embodiment 1
1. this compound: bromination 1-[6'-[4 " (10 " ', 15 " ', 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl] preparation method of-3-picoline ammonium is as follows:
Specifically comprise the following steps:
1) synthesizing of bromination 1-(6'-bromine hexyl)-3-picoline ammonium
Bromination 1-(6'-bromine hexyl)-3-picoline ammonium (reference literature Kharitonov, G.V.and Le Chin.Zhurnal Organicheskoi Khimii, 16 (11), 2388-90; 1980 preparations)
2) 5-(4'-phenol)-10,15,20-Triphenylporphyrin synthetic
5-(4'-phenol)-10,15,20-Triphenylporphyrin (reference literature Borocci, Stefano et al.Langmuir, 17 (23), 7198-7203; 2001 preparations)
3) bromination 1-[6'-[4 " (10 " ', 15 " ', 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl]-3-picoline ammonium synthetic
In the single port flask of 250ml, add 5-(4'-phenol)-10,15,20-Triphenylporphyrin 2g (3mmol), makes it to dissolve with organic solvent (30mmol).Add again bromination 1-(6'-bromine hexyl)-3-picoline ammonium 2.1g(7mmol) and alkali (7mmol).Nitrogen protection, heating keeps 80 ℃, and 8 hours, TLC monitoring raw material point disappeared, and reaction finishes.Be dissolved in water, with DCM extraction 3 times, saturated NaHCO3 washes, and saturated NaCl washes, and anhydrous MgSO4 is dry, standing.Column chromatography, obtains purple solid, is product, is a new compound.HNMR(δ,CDCl3,ppm):-2.75(s,2H,-NH),
1.23-1.39(m,2H,-CH2-CH2-CH2-),1.54-21.79(m,2H,-CH2-CH2-CH2-),1.95-2.09(m,2H,-CH2-CH2
-CH2-),2.10-2.27(m,2H,-CH2-CH2-CH2-),2.68(s,3H,pyridine-CH3),3.49-3.57(t,2H,-O-CH2-),4.20-4.29(t,2H,-N+-CH2-),5.01-5.87(m,8H,pyrrole-H),
7.71-7.87(m,2H,benzene-H),7.89-8.69(m,11H,benzene-H),8.82-8.96(m,6H,benzene-H),9.32-9.59(m,4H,-pyridine-H).ESI-MS(m/z):806.4(m+1)。
In step 3), organic solvent is DMF DMF.
In step 3), alkali is potassium hydroxide.
Step 3) in, in column chromatography for separation, weighting agent is silica gel, and eluent is that volume ratio is the methylene dichloride of 10:1, the mixing solutions of methyl alcohol.
2. the light power antiproliferative experiment of photosensitizers to colorectal carcinoma SW480 cell
Subject cell: colon cancer cell SW480
Tested medicine: bromination 1-[6'-[4 " (10 " ', 15 " ', 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl]-3-picoline ammonium (hereinafter to be referred as photosensitizers 1), hematoporphyrin derivative HpD(Beijing Pharmaceutical Ind. Inst. produces).
Light source: MTZ-1 type pulse laser cancer therapy machine; SD2490 type laser power measurement instrument.
Light power anti-tumour cell proliferative effect experiment: with after trysinization, the resuspended one-tenth cell suspension of perfect medium is inoculated in 96 orifice plates thereupon by the cell in logarithmic phase, and every hole 100 μ l, are placed in 37 ℃ of 5%CO
2incubator is cultivated, and adds five kinds of different photosensitizerss of same concentrations after 24h; 48h changes fresh culture into, then carries out illumination (XD-635AB type light power PDT laser therapeutic apparantus, power 15mW/cm
2, wavelength 530mm, irradiated cell 20min, light dosage 18J/cm
2); During 72h, carry out MTT detection.Cultivate and stop the MTT that front 4h adds 10 μ l5mg/ml, after nutrient solution is abandoned in suction, add 100 μ l DMSO termination reactions, microplate reader 570nm detects OD value.Experiment in triplicate.Experimental result, in Table 1, found that 1 pair of colon cancer cell of photosensitizers has antiproliferative effect.
1 pair of SW480 Colon Cancer Cells restraining effect of table 1 photosensitizers
3. the optical dynamic therapy experiment of photosensitizers to mouse S 180 sarcoma
Animal subject: outbreeding Kunming strain mouse mean body weight 18～24g, S
180sarcoma kind mouse (Chinese Academy of Sciences institute of materia medica provides)
Tested medicine: bromination 1-[6'-[4 " (10 " ', 15 " '; 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl]-3-picoline ammonium (hereinafter to be referred as photosensitizers 1); said medicine is dissolved in to the normal saline dilution of minimum tween-80 under aseptic condition to 0.5mg/mL solution for standby, hematoporphyrin derivative HpD(Beijing Pharmaceutical Ind. Inst. produces).
Light source: MTZ-1 type pulse laser cancer therapy machine; SD2490 type laser power measurement instrument.
Mouse S
180sarcoma light dynamic damage experiment: under aseptic condition in mouse anterior part of chest subcutaneous vaccination S
180sarcoma, when tumour is grown to diameter 4～6mm, choose well-grown, without the mouse of the hemispherical single tumour of ulcer tool, by brood same sex random packet, every group 8, mouse peritoneal drug administration by injection, and using drug solvent as blank, HpD is made into same concentrations solution as positive control, and after administration, 2h power density is 220mW/cm
2copper steam-dye laser (wavelength 530mm) radiation tumour 20min(light dosage 150J/cm
2); After illumination 5 days, put to death mouse, peel off tumour, weigh, and with control group inhibiting rate relatively.
Tumor control rate
in formula, T: the average knurl weight of administration group; C: the average knurl weight of control group
Experimental result is in Table 2, and 1 pair of tumour of photosensitizers has significant restraining effect.
The inhibition of 1 pair of tumour of table 2 photosensitizers
* P<0.05 and blank.
Claims (6)
1. a porphyrins, is characterized in that: the chemical structural formula of described porphyrins is:
2. a preparation method for porphyrins as claimed in claim 1, comprising:
By 5-(4'-phenol)-10,15,20-Triphenylporphyrin adds in organic solvent, stirring and dissolving, then add bromination 1-(6'-bromine hexyl)-3-picoline ammonium and alkali, under nitrogen protection, 80 ℃-85 ℃ keep 6-8h, and TLC monitoring raw material point disappears, and reaction finishes, be dissolved in water, extraction, washing, dry, standing, separating-purifying, obtain bromination 1-[6'-[4 " (10 " ', 15 " ', 20 " '-triphenyl porphines-5 " '-) phenoxy group] hexyl]-3-picoline ammonium; 5-(4'-phenol)-10,15 wherein, 20-Triphenylporphyrin, organic solvent, bromination 1-(6'-bromine hexyl) mol ratio of-3-picoline ammonium, alkali is 3:30:7:7.
3. the preparation method of a kind of porphyrins according to claim 2, is characterized in that: described organic solvent is DMF DMF or Isosorbide-5-Nitrae-dioxane.
4. the preparation method of a kind of porphyrins according to claim 2, is characterized in that: described alkali is potassium hydroxide, sodium hydroxide or lithium hydroxide.
5. the preparation method of a kind of porphyrins according to claim 2, it is characterized in that: described separating-purifying is that column chromatography is purified, weighting agent in column chromatography is silica gel, and eluent is that volume ratio is the methylene dichloride of 10:1～1:1, the mixing solutions of methyl alcohol.
6. a porphyrins as claimed in claim 1 is in the application of preparing light power antitumor drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162519A (en) * | 1988-03-11 | 1992-11-10 | Efamol Holdings Plc | Porphyrins and cancer treatment |
| CN1295574A (en) * | 1998-03-31 | 2001-05-16 | 阿斯特里德·沙斯塔克 | Porphyrins and their use as photosensitizer |
| WO2010033678A2 (en) * | 2008-09-18 | 2010-03-25 | Ceramoptec Industries, Inc. | Novel method and application of unsymmetrically meso-substituted porphyrins and chlorins for pdt |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162519A (en) * | 1988-03-11 | 1992-11-10 | Efamol Holdings Plc | Porphyrins and cancer treatment |
| CN1295574A (en) * | 1998-03-31 | 2001-05-16 | 阿斯特里德·沙斯塔克 | Porphyrins and their use as photosensitizer |
| WO2010033678A2 (en) * | 2008-09-18 | 2010-03-25 | Ceramoptec Industries, Inc. | Novel method and application of unsymmetrically meso-substituted porphyrins and chlorins for pdt |
Non-Patent Citations (2)
| Title |
|---|
| SURESH K. KOTTAKOTA ET AL: "Versatile Routes to Marine Sponge Metabolites through Benzylidene Rhodanines", 《ORGANIC LETTERS》, vol. 14, no. 24, 12 December 2012 (2012-12-12), pages 6313 - 5 * |
| 刘彦钦，等: "尾式卟啉-吡啶（三乙胺）季铵盐的合成", 《合成化学》, vol. 8, no. 2, 30 April 2000 (2000-04-30), pages 155 - 1 * |
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