CN1939919B - A broad-spectrum, low-toxicity phthalocyanine fungicide and its preparation method and application - Google Patents
A broad-spectrum, low-toxicity phthalocyanine fungicide and its preparation method and application Download PDFInfo
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- CN1939919B CN1939919B CN2005101077730A CN200510107773A CN1939919B CN 1939919 B CN1939919 B CN 1939919B CN 2005101077730 A CN2005101077730 A CN 2005101077730A CN 200510107773 A CN200510107773 A CN 200510107773A CN 1939919 B CN1939919 B CN 1939919B
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- phthalocyanine
- zinc phthalocyanine
- substituted zinc
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- mono carboxylic
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- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 231100000053 low toxicity Toxicity 0.000 title abstract description 4
- 230000000855 fungicidal effect Effects 0.000 title abstract 3
- 239000000417 fungicide Substances 0.000 title abstract 3
- 239000011701 zinc Substances 0.000 claims abstract description 43
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- SRPWOOOHEPICQU-UHFFFAOYSA-N trimellitic anhydride Chemical compound OC(=O)C1=CC=C2C(=O)OC(=O)C2=C1 SRPWOOOHEPICQU-UHFFFAOYSA-N 0.000 claims abstract description 4
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Abstract
一种广谱、低毒性的酞菁类杀菌剂，即2-单羧基取代酞菁锌-寡聚赖氨酸偶合物及其制备方法和用途。该杀菌剂是以醋酸锌，邻苯二甲酸酐和偏苯三甲酸酐为起始原料，经固相合成、水解、层析柱分离而得到较纯的2-单羧基取代酞菁锌，然后将2-单羧基取代酞菁锌与寡聚赖氨酸偶合得到最终产物。这种新型的杀菌剂具有多种用途，能杀死不同种类的细菌，具有一定的广谱性。另一方面，该杀菌剂含有能与细菌表面特异性结合的标记物质，可达到特异性杀死细菌而不伤及正常细胞的低毒性的目的。研究发现，该药物在很小的浓度和光剂量下对牙周病的主要致病菌牙龈卟啉菌的杀伤率高于97％，但同时对人牙周膜细胞的影响很小，因此可作为治疗牙周病的有效药物。
A broad-spectrum, low-toxicity phthalocyanine fungicide, that is, 2-monocarboxy substituted zinc phthalocyanine-oligolysine conjugate, its preparation method and application. The bactericide is based on zinc acetate, phthalic anhydride and trimellitic anhydride as starting materials, and obtains relatively pure 2-monocarboxyl substituted zinc phthalocyanine through solid-phase synthesis, hydrolysis, and chromatographic column separation, and then Coupling of 2-monocarboxy substituted zinc phthalocyanine with oligolysine to obtain the final product. This new type of fungicide has multiple uses, can kill different types of bacteria, and has a certain broad spectrum. On the other hand, the bactericide contains a marker substance that can specifically bind to the surface of the bacteria, so as to achieve the purpose of specifically killing bacteria without harming normal cells with low toxicity. The study found that the killing rate of the drug on Porphyrophyllum gingivalis, the main pathogen of periodontal disease, was higher than 97% at a small concentration and light dose, but at the same time, it had little effect on human periodontal ligament cells, so it can be used as a Effective drug for the treatment of periodontal disease.
Description
Technical field
The present invention relates to a class and have the optionally preparation method of new phthalocyanine class photosensitizers, and as a kind of sterilant of wide spectrum low toxicity in the application aspect the periodontal disease therapeutic.
Background technology
The use cytotoxic substance is one of the scheme of inhibition or kill bacteria (Photodynamicantimicrobial chemotherapy (PACT) .J Antimicrobial Chemotherapy.1998,42:13-28), compare with traditional antibiotic, have the wide advantage of bacterial species scope that can suppress or kill, but its also weakness of selective difference simultaneously.This invention design also develops and a kind of bacterium is had the new type bactericide of selective affinity, to overcome the weakness of this poor selectivity.
(Photodynamic antimicrobial chemotherapy is a kind of new treatment method PACT) to light power sterilization chemical therapy, is characterized in utilizing medicine to produce singlet oxygen with killing bacteria under the effect of special wavelength light.The objective of the invention is to prepare the metal phthalocyanine compound that porphyromonas gingivalis is had certain targeting, make it under the effect of light, can kill porphyromonas gingivalis, and big injury is arranged, thereby become the active drug of treatment periodontopathy to contiguous normal cell is unlikely.Common photodynamic therapy (Photodynamic Therapy, PDT) be mainly used in the treatment of some solid malignant, successfully be applied to bladder cancer, the esophageal carcinoma, bronchogenic carcinoma, oral carcinoma, skin carcinoma, pleura mesothelioma, nasopharyngeal carcinoma, laryngocarcinoma, liver cancer, mammary cancer and the cancer of the brain.Recently, photodynamic therapy also begins to be used for otherwise treatment.For example 2000, the photodynamic therapy that is used for through united States food and drug administration's approval is treated senile macula retinae sex change (age related macular degeneration, AMD) photosensitizers Visudyne is first medicine that can effectively treat senile macular degeneration SMD.1993, optical dynamic therapy new drug phytochrome (photofrin) goes through to go on the market in Canada, indicate that PDT formally becomes the 4th kind of sophisticated tumor therapeuticing method except that operation, radiation and chemotherapy, also started the climax of the world of medicine's searching s-generation and third generation PDT medicine simultaneously.Phthalocyanine and derivative thereof not only can be used as dyestuff, and have also obtained using widely at photoelectric material, nonlinear optical material, catalyzer, the contour sciemtifec and technical sphere of optical recording medium material.Phthalocyanine and derivative thereof are with its favorable photo-thermal stability, and phototoxicity is little, and a certain specific wavelength between 600nm-800nm has strong advantages such as absorption, becomes the outstanding person in the photosensitizers of new generation.This invention mainly is preparation one a class new phthalocyanine class photosensitizers, and makes itself and the marker coupling that bacterium surface is had avidity on this basis, to increase the selectivity of this photosensitizers, has also reduced it to Normocellular toxicity simultaneously.
Modal carious tooth and the periodontopathy etc. of mainly containing in the oral disease.For the second time national oral health epidemiological investigation shows that China adult's permanent teeth caries prevalence rate is 49.88%, and children's deciduous teeth caries prevalence rate is 76.55%.Periodontal disease is by the oral cavity pathogenic bacteria, and is caused as the hyper-proliferative of the porphyromonas gingivalis of Gram-negative.As untimely treatment, periodontitis will cause the formation in around teeth cavity, cause odontoseisis, even the early fallout of tooth.Suppressing or elimination oral cavity pathogen growth, can prevent and treat the acute attack of periodontitis or control disease effectively, is the key of treatment periodontitis.The oral cavity germ is also relevant with other healthy aspects, and increasing research report points out that the oral cavity germ may be relevant with the morbidity of arteriosclerosis, heart attack, apoplexy, premature labor even tumour.For example, cause the bacterium porphyromonas gingivalis of periodontopathy, once at human body alimentary canal and artery-clogging, cause cardiopathic tamper the inside to be detected.Treating at present the scaling and the root planing of periodontopathy clinically, mainly is to remove dental plaque or tooth dirt with the method for machinery, in recent years, and also more and more frequent affix antibiotic therapy.Yet the latter tends to cause the resistance of bacterium and to the destruction of oral cavity microenvironment.Thereby considerable patient duplicates infection, further treatment after treatment.This shows that eliminating the oral cavity germ with photodynamic therapy has unique advantage and great practical significance in carious tooth and periodontopathy control.
Summary of the invention
The purpose of this invention is to disclose a kind of new phthalocyanine class photosensitizers, i.e. 2-mono carboxylic substituted zinc phthalocyanine and each seed amino acid, polypeptide and have the synthetic method of the conjugates between the compound of amino group.This invention is with the conjugates (2-ZnPcC of a kind of compound 2-mono carboxylic substituted zinc phthalocyanine-oligomerization Methionin wherein
1-PL, wherein C
1Represent single carboxyl that replaces, PL represents oligomerization Methionin) synthetic method be example.And with this photosensitizers 2-ZnPcC
1-PL is applied to the treatment of periodontopathy aspect as a kind of antibacterial agent that bacterium is had target character.There is no at present the relevant report of this compound at home and abroad.
It is template that the present invention adopts with Glacial acetic acid zinc, ammonium molybdate is a catalyzer, the mol ratio that makes precursor Tetra hydro Phthalic anhydride and trimellitic anhydride was greater than 3: 1, and under 160 ℃-190 ℃ solid phase condition, reacted 3-4 hour, synthesize 2-monoamide substituted zinc phthalocyanine, then under 90 ℃-100 ℃ temperature condition with the hydrolysis of 2-monoamide substituted zinc phthalocyanine, obtain the crude product of 2-mono carboxylic substituted zinc phthalocyanine after 24 hours.Next we use silica gel as stationary phase, and with N, dinethylformamide (DMF) and acetone carry out separating repeatedly as mixtures of eluents to the crude product of 2-mono carboxylic substituted zinc phthalocyanine, finally obtain purer 2-mono carboxylic substituted zinc phthalocyanine.At last the carboxyl of 2-mono carboxylic substituted zinc phthalocyanine is activated and carries out coupling with oligomerization Methionin and obtain final product 2-ZnPcC
1-PL.
Method (the Synthesis of UnsymmetricallySubstituted Subphthalocyanines of the synthetic single substituted metal phthalocyanine derivative of tradition, Chem.Eur.J.2000,6, No.12) generally be the earlier synthetic inferior phthalocyanine of replacement that do not have, and then synthesize and obtain final single substituted metal phthalocyanine derivative with containing substituent precursor (such as 3-carboxyl phthalonitrile) and metal.And the method applied in the present invention not only can reduce the complicacy of synthetic step and operation, and the separating and purifying method of wherein optimizing is important.
Therefore the 2-mono carboxylic substituted zinc phthalocyanine that this invention synthesizes is compared with many carboxyl substituted Phthalocyanine Zinc owing to only have a hydroxy-acid group, the deliquescent decline of product that causes carrying out having avoided a large amount of commissures in the process of coupling with oligomerization Methionin.Therefore the mono carboxylic substituted zinc phthalocyanine has more potentiality aspect synthetic expanding.
The final product 2-ZnPcC of this invention
1-PL is by introducing the oligomerization Methionin group of one section biologically active, making its surface have a large amount of positive charges.Like this, on the one hand, because the electrostatic repulsion effect between the molecule has reduced 2-ZnPcC
1Gathering between the-PL molecule; On the other hand, owing to have the positive charge of capacity, thereby impel 2-ZnPcC
1-PL molecule his-and-hers watches are worn the targeting of the Gram-negative bacteria of negative charge.This invention shows bacterium and cells in vitro activity experiment by coated plate counting process and mtt assay: photosensitizers 2-ZnPcC
1-PL has good lethal effect to gram-negative porphyromonas gingivalis, but simultaneously to the influence of people's periodontal ligament cell very little (as Fig. 6, shown in Figure 7).Therefore this result of study will have broad application prospects aspect the treatment of periodontopathy.
Description of drawings
Fig. 1 is the synthetic synoptic diagram of 2-monoamide substituted zinc phthalocyanine.
Fig. 2 is the synthetic synoptic diagram of 2-mono carboxylic substituted zinc phthalocyanine.
Fig. 3 is the synoptic diagram that utilizes each component that the HPLC analyser collects in the trace analysis sepn process under 677nm: (1) is the analytic curve of no substituted zinc phthalocyanine; (2) be the HPLC analytic curve of the final product among the embodiment one, can clearly judge a component according to curve is that 2-monoamide substituted zinc phthalocyanine and another component are no substituted zinc phthalocyanine; (3) be the analytic curve of the component that eluted earlier in the embodiment three chromatographic separation processes, because curve contains 2-monoamide substituted zinc phthalocyanine and no substituted zinc phthalocyanine so suitable coincideing can be thought in the component that is eluted earlier with (2); (4) be the analytic curve of the component that elute after the repeated isolation second time among the embodiment three; (5) be the analytic curve of the final sample that obtains among the embodiment three; (6) be the gradient flow process, wherein A is a water, and B is N, dinethylformamide (DMF).
Fig. 4 is the mass spectrum of the final sample 2-mono carboxylic substituted zinc phthalocyanine that obtains among the embodiment three.Wherein main peak 621.8 (theoretical value is 621.92) is the molecular ion peak of this compound, and this peak is the molecular ion peak of no substituted zinc phthalocyanine through the peak of 576.4 (theoretical value is 576.9) after the ms/ms.
Fig. 5 is the synoptic diagram that 2-mono carboxylic substituted zinc phthalocyanine and oligomerization Methionin carry out coupling.
(1) is at wavelength 670nm, energy density 1.2J/cm among Fig. 6
2Lasing under, the photosensitizers 2-ZnPcC1-PL of different solubility is to the bacteriostasis rate curve of porphyromonas gingivalis; (2) be the bacteriostasis rate curve of photosensitizers under different-energy density of 10uM under the 670nm.Wherein said bacteriostasis rate=(control group number mean value-experimental group number mean value)/control group number mean value.
Fig. 7 is at wavelength 670nm, energy density 15J/cm
2Lasing under 10uM photosensitizers 2-ZnPcC1-PL to porphyromonas gingivalis and the inhibiting comparison diagram of people's periodontal ligament cell.
Embodiment
Synthesizing of embodiment one 2-monoamide substituted zinc phthalocyanine
Trimellitic anhydride 2.40g (the 0.0125mol that in having the 500ml three-necked bottle of reflux and stirrer, adds abundant porphyrize, Merck), Tetra hydro Phthalic anhydride 12.96g (0.08750mol), Glacial acetic acid zinc 22.00g (0.1002mol), urea 60g (1mol), ammonium molybdate 0.50g (0.4mmol), ammonium chloride 2.00g (0.0374mol).In oil bath, be heated to 170 ℃, reacted 4 hours.The HCl that reaction finishes to use 0.5M in the back washs for several times, is washed till neutrality with pure water again, obtains the 22.25g solid.Productive rate 67% judges wherein that by HPLC 22% is 2-monoamide substituted zinc phthalocyanine.
Synthesizing of embodiment two 2-mono carboxylic substituted zinc phthalocyanines
Get the prepared 2-monoamide substituted zinc phthalocyanine of 15.00g embodiment one in the three-necked bottle of 250ml, add the KOH 100ml of 1M, at 100 ℃ of following stirring and refluxing 24h.Question response finishes the back suction filtration, obtains green solid, adds 0.5M KOH washing and suction filtration, till filtrate is colourless.Then for several times, wash with water again to neutrality and dry with the HCl of 1M washing.
The separation and purification of embodiment three 2-mono carboxylic substituted zinc phthalocyanines
Select for use 40cm long, internal diameter is the chromatography column of 3cm, is sorbent material with 100 purpose silica gel, DMF: the mixed solvent of acetone=3: 1 is an eluent, use DMF: the mixed solvent wet method dress post of acetone=3: 1, adorning the post height is 30cm.Thick product 1.85g after the previous step reaction treatment is dissolved among the DMF of 37ml.Each application of sample amount is 1ml, and pillar can use repeatedly repeatedly.Can find that in elution process glaucous phthalocyanine sample is divided into two parts, collect second section (afterwards eluting).With collected sample lyophilize.The sample that drying is good carried out post once more according to above-mentioned method to be separated, and can remove no substituted zinc phthalocyanine and 2-monoamide substituted zinc phthalocyanine so repeatedly for three to four times.At last again sample can be obtained purer 2-mono carboxylic substituted zinc phthalocyanine with acetone solution and wash-out.The sample of collecting in the purge process uses HPLC high performance liquid chromatography trace analysis.
Embodiment four 2-mono carboxylic substituted zinc phthalocyanines-oligomerization Methionin conjugates (2-ZnPcC
1-PL) synthetic
Take by weighing 20.95mg (0.0337mM) 2-mono carboxylic substituted zinc phthalocyanine and put into the round-bottomed flask that 50ml has stirrer, add N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide hydrochloride (EDC) 9.68mg (0.0505mM), N-maloyl imines 5.81mg (0.0505mM) adds 6mlDMSO at last and makes the solid sample dissolving.Under the normal temperature lucifuge condition, make the carboxylic acid substituent activation.Add oligomerization Methionin 56.2mg (0.0225mM) and 0.6ml pyridine behind the 24h and continue reaction 24h.After question response is complete, add the 10ml pure water, drain with Maxi Dry Lyo vacuum concentration/Freeze Drying Equipment, the solid after draining with the dissolving of 50ml pure water, is got supernatant liquor after centrifugal, clear liquid extracts 4-5 time repeatedly with methylene dichloride, to remove impurity such as unreacted EDC completely, N-maloyl imines, the water intaking layer is drained with the same method, get water miscible blue solid, i.e. 2-ZnPcC
1-PL 81.7mg.
Embodiment five photosensitizers (2-ZnPcC
1-PL) to the inhibiting research of porphyromonas gingivalis
Make cell suspension (2.5 * 10 with PBS dilution porphyromonas gingivalis
6-3.0 * 10
6Individual bacterium/ml), be inoculated in 96 porocyte culture plates with every hole 92ul adds 8ul different concns photosensitizers 2-ZnPcC in 96 orifice plates
1-PL, the experimental concentration (each different concentration is done repeated experiments 3 times) to reach final design also is provided with the blank hole in the experiment.In the darkroom, use the corresponding time of laser illumination of wavelength 670nm under the room temperature.Every hole taking-up 10ul dilutes 10 with PBS after the illumination
4Get 100ul coated plate (microbial culture plate) doubly, afterwards the microbial culture plate is put into the anaerobism culture bag, cultivate down, wait to grow (about 24 hours) counting behind the bacterium colony at 37 ℃.Described in the explanation of result of study such as accompanying drawing 6, photosensitizers 2-ZnPcC under low energy densities effect very
1-PL just has good lethal effect to porphyromonas gingivalis, its inhibiting rate even can reach more than 99% under a certain specific drug level and energy density.
Embodiment six photosensitizers (2-ZnPcC
1-PL) to the research of periodontal ligament cell influence
With the periodontal ligament cell of switching behind the three generations, with behind the tryptic digestion with 5 * 10
4Individual cell/ml is inoculated in 96 porocyte culture plates, every hole 200ul.Treat cell attachment after 2 hours, add photosensitizers 2-ZnPcC
1-PL uses the corresponding time of laser illumination of wavelength 670nm to reach final experimental concentration (each different concentration is respectively done repeated experiments 3 times) in the darkroom under the room temperature.Sucking-off substratum after the illumination, and add fresh substratum and put into 37 ℃ CO
2Cultivated 24 hours in the incubator.Every hole adds 5ul MTT reagent and continues cultivation 4 hours after 24 hours.The sucking-off substratum adds the solid particulate after 200ul DMSO dissolves metabolism, and treating to dissolve fully the back is to detect its absorbancy under the 578nm with microplate reader at wavelength.Fig. 7 has shown photosensitizers 2-ZnPcC
1The influence of-PL pair cell, and compare with porphyromonas gingivalis.
Claims (4)
1. a wide spectrum, hypotoxic phthalocyanine bactericide, promptly 2-mono carboxylic substituted zinc phthalocyanine-oligomerization Methionin conjugates is characterized in that, its expression formula is 2-ZnPcC
1-PL (C wherein
1Represent single carboxyl, PL represents oligomerization Methionin), its structural formula is:
2. sterilant 2-ZnPcC as claimed in claim 1
1-PL is characterized in that, it is by 2-mono carboxylic substituted zinc phthalocyanine and the coupling of oligomerization Methionin and obtain, and wherein the structural formula of 2-mono carboxylic substituted zinc phthalocyanine is:
3. the wide spectrum of a claim 1, hypotoxic phthalocyanine bactericide 2-ZnPcC
1The preparation method of-PL is characterized in that, this method may further comprise the steps:
(1) be template with Glacial acetic acid zinc, ammonium molybdate is a catalyzer, and the mol ratio that makes precursor Tetra hydro Phthalic anhydride and trimellitic anhydride is greater than 3: 1, and synthesizes 2-monoamide substituted zinc phthalocyanine under 160 ℃-190 ℃ solid phase condition;
(2) with the product of step (1) 90 ℃ of-100 ℃ of following hydrolysis, generate the crude product of 2-mono carboxylic substituted zinc phthalocyanine;
(3) utilize the crude product separation and purification of the isolating way of liquid chromatography with step (2) gained, concrete grammar is that as stationary phase, the mixed solvent of DMF and acetone carries out chromatographic separation as eluent with silica gel, and the component that elutes after collecting; Again with the sample collected according to foregoing separating step repeated multiple times, can obtain purer 2-mono carboxylic substituted zinc phthalocyanine;
(4) with the product of step (3) gained at normal temperatures with its with the hydroxy-acid group activation, and carry out coupling with oligomerization Methionin and obtain 2-ZnPcC
1-PL.
4. the wide spectrum of a claim 1, hypotoxic phthalocyanine bactericide 2-ZnPcC
1The purposes of-PL is characterized in that, this sterilant is as the application of bacterial oral disease medicines such as preparation treatment periodontopathy.
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