CN103570732B - A kind of porphyrins and its preparation method and application - Google Patents
A kind of porphyrins and its preparation method and application Download PDFInfo
- Publication number
- CN103570732B CN103570732B CN201310525057.9A CN201310525057A CN103570732B CN 103570732 B CN103570732 B CN 103570732B CN 201310525057 A CN201310525057 A CN 201310525057A CN 103570732 B CN103570732 B CN 103570732B
- Authority
- CN
- China
- Prior art keywords
- porphyrins
- application
- preparation
- photosensitizer
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- RGHHSNMVTDWUBI-UHFFFAOYSA-N Oc1ccc(C=O)cc1 Chemical compound Oc1ccc(C=O)cc1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of porphyrins and its preparation method and application, chemical structural formula is:
Description
Technical field
The invention belongs to the preparation of antitumor drug and application thereof, particularly to a kind of porphyrins and preparation thereof and application.
Background technology
Optical dynamic therapy (PhotodynamicTherapy, PDT) is a kind of new method treating malignant tumor. From coming out so far in decades, PDT in the clinical treatment of cancer achieved with the achievement attracted people's attention, with it effectively, safety, side effect are little, can the advantage such as concertedness, repeatability and relatively low cost show one's talent, and in the treatment of tumor, demonstrate very strong vitality, for middle and advanced stage, particularly (or refusal) cancer patient of traditional treatment methods cannot be adopted to provide a chance, add a kind for the treatment of means (AckroydRetal., PhotochemPhotobiol, 74 (5): 656,2001).
The principle of photodynamic therapy is after photosensitizer is absorbed by target cell, under certain wavelength laser irradiates, from ground state (S0) transit to excited state (S1), by between being string jump (IntersystemCrossing) transit to triplet excited states (T further1), the photosensitizer being in triplet state reacts with surrounding molecular, produces the free radical (such as singlet oxygen) of high oxidation activity, kills target cell; And destroy irradiation area blood vessel, block target cell nutrition and oxygen supply; Excitating organism immunomodulating simultaneously, causes neoplasm necrosis (H.B.VandenBerghetal., LasersOpthalmol.183 195,2003).
In optical dynamic therapy, photosensitizer plays conclusive effect as the carrier of energy, the bridge of reaction. Photosensitizer is with first photosensitizer PhotofrinII (M.A.Bieletal. in Holland's listing in 1993, Photochem.Photobiol.83:1063 1068,2007) for representative, its indication is tumor, although curative effect is certainly clinically, but still having weak point: complicated component, it is indefinite to form, excretion is slowly, long-time lucifuge is needed to prevent skin photosensitization sense effect (HuoYanetal., ChinJLaserMedSurg, 1 (15): 48-55,2006).
Therefore, in order to overcome some shortcomings of existing photosensitizer, in recent years, people are devoted to find more preferably photosensitizer always.
Porphyrins is through passively diffusing in cell, and its diffuser efficiency reduces with the outer pH value of born of the same parents and improves (AnaP.Castanoaetal., PhotodiagnosisandPhotodynamicTherapy1:279 293,2004). Generally, normal structure has different pH value (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 and reduces. Therefore, porphin can enter tumor cell more, completes the preferential build in tumor tissues. The chemical constitution of this compounds is clear and definite, has higher purity, good photo and thermal stability, and the absorption of red light district is relatively strong, and internal retention time is short; By the chemical modification of porphine structure being regulated the hydrophobic partition coefficient (ChoiC.F.etal. of photosensitizer, OrgBiomolChem, 6 (12): 2173-2181,2008), be conducive to photosensitizer in the absorption of pathological tissues and accumulation, be ideal photosensitizer.
Summary of the invention
The technical problem to be solved is to provide a kind of porphyrins and its preparation method and application, the compound structure of the present invention clearly, preparation simple, test result indicate 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:
A kind of preparation method of the porphyrins of the present invention, including:
5-(4'-phenol)-10,15,20-Triphenylporphyrin is added in organic solvent, stirring and dissolving, adds bromination 1-(6'-bromine hexyl)-3-picoline ammonium and alkali, under nitrogen protection, 80 DEG C-85 DEG C keep 6-8h, TLC to monitor the disappearance of raw material point, and reaction terminates, it is dissolved in water, extracts, washing, dry, stand, separating-purifying, obtain bromination 1-[6'-[and 4 "-(10 " ', 15 " ', 20 " '-triphenyl porphin-5 " '-) phenoxy group] hexyl]-3-picoline ammonium; Wherein 5-(4'-phenol)-10,15,20-Triphenylporphyrin, organic solvent, bromination 1-(6'-bromine hexyl)-3-picoline ammonium, alkali mol ratio be 3:30:7:7.
Described organic solvent is N,N-dimethylformamide DMF or 1,4-dioxane.
Described alkali is potassium hydroxide, sodium hydroxide or Lithium hydrate.
Described extraction, washing, dry and be: extracting 3 times with DCM, saturated NaHCO3 washes, and saturated NaCl washes, and anhydrous MgSO4 dries.
Described separating-purifying is that column chromatography purifies, and the filler in column chromatography is silica gel, and eluent is volume ratio is the mixed solution of the dichloromethane of 10:1��1:1, methanol.
A kind of porphyrins of the present invention is in the application preparing light power antitumor drug.
Beneficial effect
(1) chemical constitution of compound prepared by the present invention is simple, clearly, there is higher purity, good photo and thermal stability, the absorption of red light district is relatively strong, and the porphin property of can select that concentration is in target tissue, again porphin and quaternary ammonium salt are combined, utilize positive charge and the surface of cell membrane anion binding of quaternary ammonium salt, the enzymatic activity in interference film surface and Cytoplasm, cause that cellular metabolism is obstructed and apoptosis;
(2) hydrophilic of compound prepared by the present invention increases, better concentration in target tissue, target tissue and normal structure can form good distribution ratio, when carrying out illumination, the growth of the more effective suppression tumor of energy, and reduce the toxic and side effects of its normal tissue;
(3) present invention is by finding this kind of photosensitizer light dynamic test to colon cancer cell and the light dynamic test to mouse S 180 sarcoma, when there being illumination, photosensitizer can suppress the propagation of colon cancer cell and the growth of mouse S 180 sarcoma significantly, has the prospect becoming light power antitumor drug.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. In addition, it is to be understood that after having read the content that the present invention lectures, the present invention can be made various changes or modifications by those skilled in the art, and these equivalent form of values fall within the application appended claims limited range equally.
Embodiment 1
1. this compound: bromination 1-[6'-[and 4 "-(10 " ', 15 " ', 20 " '-triphenyl porphin-5 " '-) phenoxy group] hexyl] preparation method of-3-picoline ammonium is as follows:
Specifically include following steps:
1) bromination 1-(6'-bromine hexyl) synthesis of-3-picoline ammonium
Bromination 1-(6'-bromine hexyl)-3-picoline ammonium (reference literature Kharitonov, G.V.andLeChin.ZhurnalOrganicheskoiKhimii, 16 (11), 2388-90; 1980 preparations)
2) synthesis of 5-(4'-phenol)-10,15,20-Triphenylporphyrin
5-(4'-phenol)-10,15,20-Triphenylporphyrin (reference literature Borocci, Stefanoetal.Langmuir, 17 (23), 7198-7203; 2001 preparations)
3) bromination 1-[6'-[and 4 "-(10 " ', 15 " ', 20 " '-triphenyl porphin-5 " '-) phenoxy group] hexyl] synthesis of-3-picoline ammonium
The single port flask of 250ml adds 5-(4'-phenol)-10,15,20-Triphenylporphyrin 2g (3mmol), with organic solvent (30mmol) so as to dissolve. Add bromination 1-(6'-bromine hexyl)-3-picoline ammonium 2.1g(7mmol) and alkali (7mmol). Nitrogen protection, heating keeps 80 DEG C, 8 hours, and TLC monitors raw material point and disappears, and reaction terminates. Being dissolved in water, extract 3 times with DCM, saturated NaHCO3 washes, and saturated NaCl washes, and anhydrous MgSO4 dries, and stands. Column chromatography, obtains violet solid, is product, is a noval chemical compound. HNMR (��, 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, filler is silica gel, and eluent is volume ratio is the mixed solution of the dichloromethane of 10:1, methanol.
2. the light power antiproliferative of colon cancer SW480 cell is tested by photosensitizer
Subject cell: Colon Carcinoma
Test medicine: bromination 1-[6'-[4 "-(10 " ', 15 " '; 20 " '-triphenyl porphin-5 " '-) phenoxy group] hexyl]-3-picoline ammonium (hereinafter referred to as photosensitizer 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 is tested: after being in the cell trypsinization of exponential phase, and the resuspended one-tenth cell suspension of complete medium is inoculated in 96 orifice plates, every hole 100 �� l therewith, is placed in 37 DEG C of 5%CO2Incubator is cultivated, and adds the photosensitizer that same concentrations is five kinds different after 24h; 48h changes fresh culture into, then carries out illumination (XD-635AB type light power PDT laser therapeutic apparatus, power 15mW/cm2, wavelength 530mm, irradiated cell 20min, light dosage 18J/cm2);MTT detection is carried out during 72h. Cultivating 4h before terminating and add the MTT of 10 �� l5mg/ml, inhale and add 100 �� lDMSO termination reactions after abandoning culture fluid, microplate reader 570nm detects OD value. Experiment is in triplicate. Experimental result is in Table 1, found that colon cancer cell is had antiproliferative effect by photosensitizer 1.
Table 1 photosensitizer 1 is to SW480 Colon Cancer Cells inhibitory action
3. the optical dynamic therapy of mouse S 180 sarcoma is tested by photosensitizer
Animal subject: outbreeding Kunming mice average weight 18��24g, S180Sarcoma kind Mus (offer of institute of materia medica of the Chinese Academy of Sciences)
Test medicine: bromination 1-[6'-[4 "-(10 " ', 15 " '; 20 " '-triphenyl porphin-5 " '-) phenoxy group] hexyl]-3-picoline ammonium (hereinafter referred to as photosensitizer 1); said medicine being aseptically dissolved in the normal saline dilution of minimum tween 80 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.
Mice S180Sarcoma Photodynamic polymer is tested: in mice anterior part of chest subcutaneous vaccination S under aseptic condition180Sarcoma, when tumor length to diameter 4��6mm, choose well-grown, have the mice of hemispherical single tumor without ulcer, by brood same sex random packet, often group 8, mouse peritoneal drug administration by injection, and using drug solvent as blank, HpD being made into same concentrations solution as positive control, after administration, 2h power density is 220mW/cm2Copper steam-dye laser (wavelength 530mm) radiates tumor 20min(light dosage 150J/cm2); After illumination 5 days, put to death mice, peel off tumor, weigh, and compare suppression ratio with matched group.
Tumor control rateIn formula, T: the average tumor weight of administration group; C: the average tumor weight of matched group
Experimental result is in Table 2, and tumor is had significant inhibitory action by photosensitizer 1.
Table 2 photosensitizer 1 inhibition to tumor
* P < 0.05 and blank.
Claims (1)
1. a porphyrins is in the application preparing light power antitumor drug, it is characterised in that: porphyrins suppresses propagation and the mice S of colon cancer cell in preparation180Application in the medicine of the growth of sarcoma;
Wherein the chemical structural formula of porphyrins is:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310525057.9A CN103570732B (en) | 2013-10-30 | 2013-10-30 | A kind of porphyrins and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310525057.9A CN103570732B (en) | 2013-10-30 | 2013-10-30 | A kind of porphyrins and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103570732A CN103570732A (en) | 2014-02-12 |
| CN103570732B true CN103570732B (en) | 2016-06-08 |
Family
ID=50043511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310525057.9A Active CN103570732B (en) | 2013-10-30 | 2013-10-30 | A kind of porphyrins and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103570732B (en) |
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 |
-
2013
- 2013-10-30 CN CN201310525057.9A patent/CN103570732B/en active Active
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 (1)
| Title |
|---|
| 尾式卟啉-吡啶（三乙胺）季铵盐的合成;刘彦钦，等;《合成化学》;20000430;第8卷(第2期);第155页化合物1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103570732A (en) | 2014-02-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617610B (en) | Preparation method of porphyrin photosensitizer and anticarcinogen diad | |
| CN113461697B (en) | Chlorin compound and preparation method and application thereof | |
| CN103341166B (en) | Erlotinib-phthalocyanine conjugate as molecule-targeting anticancer photosensitizer | |
| CN103923125A (en) | Water-soluble porphyrin photosensitizer and preparation method thereof | |
| CN106046008A (en) | Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative | |
| CN103881700B (en) | One class thienyl phosphorescent iridium complex and its preparation method and application | |
| CN103143013B (en) | Photosensitive medicinal preparation containing amino poly-carboxylic acid modification tetraphenylporphyrin compound and purpose thereof | |
| CN107344943A (en) | A kind of amido modified tetraphenylporphyrin compound and preparation method and application | |
| Reshetnickov et al. | Novel drug form of chlorin e6 | |
| CN103570732B (en) | A kind of porphyrins and its preparation method and application | |
| CN102558187B (en) | Tetrahydroporphin compound and preparation method and application thereof | |
| CN113616809B (en) | Application of supermolecule organic frame material in removing residual medicine in photodynamic therapy | |
| CN102134244A (en) | Medical photosensitizer and preparation method thereof | |
| CN106083872B (en) | Purpurin 18 ether derivative and its preparation method and application | |
| CN103304569B (en) | A kind of Erlotinib-phthalocyaconjugate conjugate and preparation method thereof | |
| CN106581675B (en) | Photosensitizer with dual photodynamic treatment effect and preparation method thereof | |
| CN102125549B (en) | Dihydroporphin photosensitizer as well as preparation method and application thereof | |
| CN106939003A (en) | Double carboxymethyl meso-tetrahenylchlorin compounds of one class and preparation method and application | |
| CN108864116A (en) | A kind of novel chlorin e 6 derivative and the preparation method and application thereof | |
| CN102068428A (en) | Dihydroporphin photosensitizer and preparation and application thereof | |
| CN107226817A (en) | A kind of pyropheophorbide-a methyl ether compound and preparation method and application | |
| CN101606933A (en) | Dihydro porphin photosensitizer and preparation thereof and application | |
| CN101591340A (en) | 5,10,15,20-four-(5-drewamine amyl)-chlorin and preparation thereof and doctor pesticide field application | |
| CN106810556A (en) | One class tetraphenyl methylene chlorin compound and preparation method and application | |
| CN101235004B (en) | Omega-amidosulphonic acid substituted hypocrellin derivatives, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |