CN103601727A - Use of novel amine compound modified protoporphyrin - Google Patents
Use of novel amine compound modified protoporphyrin Download PDFInfo
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- CN103601727A CN103601727A CN201310507593.6A CN201310507593A CN103601727A CN 103601727 A CN103601727 A CN 103601727A CN 201310507593 A CN201310507593 A CN 201310507593A CN 103601727 A CN103601727 A CN 103601727A
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- aminoethyl
- protoporphyrin
- ammonium iodide
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- ethylenediamine
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- 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
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- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
Abstract
The present invention discloses a use of N,N-dimethylethylenediamine or N,N-diethylethylenediamine or N-(2-aminoethyl)-trimethyl ammonium iodide or N-(2-aminoethyl)-triethyl ammonium iodide modified protoporphyrin. The N,N-dimethylethylenediamine or N,N-diethylethylenediamine or N-(2-aminoethyl)-trimethyl ammonium iodide or N-(2-aminoethyl)-triethyl ammonium iodide modified protoporphyrin has the following structure. Experiment results show that: the N,N-dimethylethylenediamine or N,N-diethylethylenediamine or N-(2-aminoethyl)-trimethyl ammonium iodide or N-(2-aminoethyl)-triethyl ammonium iodide modified protoporphyrin has a good in vitro photodynamic antibacterial performance, and provides good treatment effects for photodynamic treatments of mice infections caused by bacteria, fungi and the like.
Description
Technical field
The present invention relates to N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified the purposes of protoporphyrin.
Background technology
In recent years, antibiotic abuse caused resistant organism appearance and propagation, and " superbacteria " (superbug) to have produced some multi-drug resistant bacterias.Because " superbacteria " almost all has resistance to all microbiotic, therefore its potential Outbreak has caused the fear of countries in the world, scientists is just endeavouring to seek to defeat novel drugs and the new tool of superbacteria, and the new anti-infective strategy of researchdevelopment also becomes extremely urgent.
Light power Ceftriaxone therapy (Photodynamic antimicrobial chemotherapy, PACT) is one of new therapy of at present tool prospect
[1-3].PACT is based on the synergistic oxidative damage mechanism of light, photosensitizers and three kinds of factors of oxygen, single drug can cause the resistance of bacterium hardly, research shows microbial culture remaining after PACT treatment and goes down to posterity 10 times, do not find that its filial generation produces resistivity to PACT.In addition, PACT there will not be lethal that photosensitizers causes, also can be because of concentration and the not enough generation resistance problem that waits of time shutter of photosensitizers
[4].Meanwhile, superbacteria mostly occurs in wound infection Chu, lung, blood and urethra, and except blood infection, other position adopts PACT to be still easy to realize.Thereby from sterilization effect, resistance with facilitate use angle to consider, PACT all has very large advantage.At present, all kinds of photosensitizerss of overseas utilization have carried out a large amount of explorations and application to the light power deactivation of various bacteria
[5-8], especially the effect at aspects such as blood products sterilization, sterilizations has obtained extensive approval, and the security of PACT simultaneously is also proved.
The synthetic desirable photosensitizers of design, makes it have good selectivity, increases the permeability of cell walls, reaches the effect of deactivation microorganism, is the key of PACT.Consider that bacterial metabolism and breeding are very fast, thereby the photosensitive drug of design selective bacterium picked-up, it is preferentially gathered in bacterium but not in surrounding tissue or cell, can realizes selectivity sterilizing.In report in the past, the photosensitizers antimicrobial spectrum of using as antibacterials is narrower, what have is effective to Gram-negative bacteria, what have is effective to gram-positive microorganism, the photosensitive drug of our design has the characteristic of wide spectrum, can effectively kill different types of bacterium, prevent the appearance of resistant organism, for the popularization of PACT therapy, there is realistic meaning.
[1]Wainwright?M.Photodynamic?antimicrobial?chemotherapy(PACT)[J].JAntimicrob?Chem-other，1998，42(1)：13-28.
[2]Luksiene?Z，Peciulytie?D，Jurkoniene?S，et?al.Inactivation?of?possible?fungal?food?contaminants?by?photosensitization[J].Food?Technol?Biotechnol，2005，43(4)：335-341.
[3]Malik?Z，Ladan?H，Nitzan?Y.Photodynamic?inactivation?of?gram?negative?bacteria：problems?and?possible?solutions[J].JPhotochem?Photobiol?B，1992，14(3)：262-266.
[4]Tavares?A，Carvalho?C?M，Faustino?M?A，et?al.Antimicrobial?photodynamic?therapy：study?of?bacterial?recovery?Viability?and?potential?development?of?resistance?after?treatment[J].Mar?Drugs，2010，8(1)：91-105.
[5]Wainwright?M.‘Safe’photoantimicrobials?for?skin?and?soft-tissue?infections[J].Int?J?Antimicrob?Agents，2010，36(1)：14-18.
[6]Tegos?G?P，Demidova?T?N，Arcila-Lopez?D，et?al.Cationic?fullerenes?are?effectiVe?and?selective?antimicrobial?photosensitizers[J].Chem?Biol，2005，12(10)：1127-1135.
[7]Szpakowska?M，Reiss?J，Graczyk?A，et?al.Susceptibility?of?Pseudomonas?aeruginosa?to?a?photodynamic?effect?of?the?arginine?hematoporphyrin?derivatiVe[J].Int?J?Antimicrob?Agents，1997，8(1)：23-27.
[8]Ben-Hur?E，Barshtein?G，Chen?S，et?al.Photodynamic?treatment?ofred?blood?cell?concentrates?for?virus?inactivation?enhances?red?blood?cell?aggregation：protection?with?antioxidants[J].Photochem?Photobiol，1997，66(4)：509-512.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, N is provided, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified the purposes of protoporphyrin.
Technical scheme of the present invention is summarized as follows:
N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin in the application of preparing light power antibacterials, described N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin and is had following structure:
Wherein M is H, Fe, Mn, Cu, Zn, Co or Mg;
Described medicine is light power antibacterials.
Experimental results show that: N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin and is had stronger inhibition and killing action at light power antibiosis.
Accompanying drawing explanation
Fig. 1 N, N-dimethyl-ethylenediamine is modified the techtology inspection (3d) of protoporphyrin P-H treatment mouse wound infection skin wound.
Fig. 2 N, N-dimethyl-ethylenediamine is modified the techtology inspection (14d) of protoporphyrin P-H treatment mouse wound infection skin wound.
Embodiment
N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified preparation method's reference of protoporphyrin:
[1]Uchoa?A?F，Oliveira?C?S，Baptista?M?S，et?al.Relationship?between?structure?and?photoactivity?of?porphyrins?derived?from?protoporphyrin?IX[J].J?Porphyr?Phthalocya，2010，14(9)：832-845
[2]Woodburn?K?W，Bellinger?G?C?A，Phillips?D?R，et?al.Synthesis?of?porphyrins?derived?from?the?amidation?of?protoporphyrin?IX?for?use?as?potential?chemotherapeutic?agents[J].Aust?J?Chem，1992，45(10)：1745-1751.
Embodiment 1
N, N-dimethyl-ethylenediamine and N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified the optical dynamic therapy effect of protoporphyrin to the methicillin-resistant staphylococcus aureus of vitro culture (MRSA) and Pseudomonas aeruginosa.N, N-dimethyl-ethylenediamine and N, the structural formula that N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin is:
Wherein M=H, Fe, Mn, Cu, Zn, Co or Mg;
Experimental procedure:
(1) preparation of liquid: precision takes appropriate N, N-dimethyl-ethylenediamine and N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin, be dissolved in 1ml LB liquid nutrient medium, by proportional diluted method, with LB liquid nutrient medium, prepare the drug solution that a series of concentration is successively decreased, concentration is followed successively by 500,250,125,63,32,16,8,4,2,1 μ M.
(2) draw the drug solution 100 μ L of above-mentioned different concns, add in 96 orifice plates, 3 secondary holes of each concentration, growth control group and blank group add the LB liquid nutrient medium that does not contain medicine.
(3) administration group and growth control group add the bacterium liquid 100 μ L that diluted successively, and (bacteria containing amount reaches 10
5cFU/mL), blank group does not add bacterium liquid.
(4) 96 orifice plates lucifuge on shaking table is hatched to 30min, take out with laser apparatus irradiation 1h, be placed in incubator and hatch 24h.Blank group is irradiation not, directly hatches 24h.
(5) take out 96 orifice plates, with the comparison of growth control group, observe the muddy degree of bacterium liquid, first limpid drug level is minimal inhibitory concentration (MIC, in Table 1-2).
Table 1N, N-dimethyl-ethylenediamine and N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin to the minimal inhibitory concentration of MRSA (μ M)
Table 2N, N-dimethyl-ethylenediamine and N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin to the minimal inhibitory concentration of Pseudomonas aeruginosa (μ M)
Embodiment 2
N, N-dimethyl-ethylenediamine is modified the antibacterial mouse of protoporphyrin P-H light power and is comprised in body experimental procedure:
Research based on external bacteria levels shows, we design photosensitive drug under illumination, can effectively kill Gram-negative bacteria (MRSA) and gram-positive microorganism (Pseudomonas aeruginosa), so in experimentation on animals we by the suspension balanced mix (10 of MRSA and Pseudomonas aeruginosa
10cFU) be seeded to the mouse skin surface of a wound, set up infection model.This model infects even more serious compared with single culture, more have realistic meaning, and can effectively confirm the broad spectrum of our photosensitive drug.
Select 40 of adult BALB/c female mices, body weight 20-22g, Beijing Vital River Experimental Animals Technology Co., Ltd. provides, and credit number is SCXK (capital) 2009-0007.Be placed in room temperature 20-25 ℃, relative humidity 35-75%, in the experimental situation of ad lib and drinking-water, adaptability is raised one week, by body weight, is divided at random model group and the high, medium and low dosage treatment group of PACT, 10 every group.
Adopt method (300mg/kg) the anesthesia BALB/c mouse of abdominal injection 5% Chloral Hydrate, then under aseptic condition, perform the operation.First laboratory animal is fixed on autoclaving plate, local preserved skin, 75% ethanol disinfection, does in mouse back the circular incision that diameter is 1cm with punch tool, reaches subcutaneous layer, and destroys part muscle surface manadesma, after the surface of a wound completes, with sterile gauze, covers.Draw 50 μ L Pseudomonas aeruginosas and MRSA mixing suspension (10
10cFU) be seeded to the mouse skin surface of a wound, set up infection model.After 30min, drip 50 μ L drug solutions in the mouse skin surface of a wound, administration concentration is respectively 200 μ M, 100 μ M, 50 μ M.After 30min, the high, medium and low dosage treatment group of PACT is carried out irradiation, and laser radiation energy density is 60J/cm
2(light application time 10min), spot diameter is 1.5cm.
After PACT treatment, observe mouse skin wound healing state every day, and in 3d, 7d, 10d and 14d, the surface of a wound is traced on Semitransparent Paper, again as template, homogeneous hard paper is cut into pattern size, with hard paper quality, represent surface of a wound size (in Table 3), and calculate as follows Wound healing rate:
Wound healing rate (%)=(wound area-surface of a wound area does not heal in beginning)/beginning wound area * 100
Each experimental group of table 3 3d, 7d, mouse skin wound healing rate after 10d and 14d
After the mouse skin surface of a wound completes, 3d and 14d draw materials in wound part, after formalin solution is fixing, paraffin section is made in organizational routine dehydration, transparent, waxdip, embedding, with slicing machine, be cut into 3-5 μ m thickness, after HE dyeing at the Histological Study (seeing Fig. 1-2) of the optical microphotograph Microscopic observation mouse skin surface of a wound.
Result shows, tissue pathological slice shows that PACT treatment can obviously promote granulation tissue growth, and accelerating wound, shortens mouse skin wound healing time.Wherein, middle dosage treatment group effect is better than high dose group and low dose group.
Claims (2)
1.N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin in the application of preparing light power antibacterials, described N, N-dimethyl-ethylenediamine or N, N-diethyl ethylenediamine or N-(2-aminoethyl)-trimethylammonium ammonium iodide or N-(2-aminoethyl)-triethyl iodate ammonium is modified protoporphyrin and is had following structure:
Wherein M is H, Fe, Mn, Cu, Zn, Co or Mg;
2. purposes according to claim 1, is characterized in that described medicine is optical dynamic therapy medicine.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108373472A (en) * | 2018-04-25 | 2018-08-07 | 西南大学 | A kind of sterilization material and its preparation method and application containing protoporphyrin |
| CN111848656A (en) * | 2020-06-24 | 2020-10-30 | 天津大学 | Ion-modified protoporphyrin gallium compound and preparation method and application thereof |
| US11147984B2 (en) | 2020-03-19 | 2021-10-19 | Know Bio, Llc | Illumination devices for inducing biological effects |
| CN113677204A (en) * | 2019-02-15 | 2021-11-19 | 桑科能源股份有限公司 | Use of protoporphyrin IX derivatives for improving plant health |
| US11524173B2 (en) | 2015-07-28 | 2022-12-13 | Know Bio, Llc | Systems and methods for phototherapeutic modulation of nitric oxide |
| US11654294B2 (en) | 2021-03-15 | 2023-05-23 | Know Bio, Llc | Intranasal illumination devices |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11524173B2 (en) | 2015-07-28 | 2022-12-13 | Know Bio, Llc | Systems and methods for phototherapeutic modulation of nitric oxide |
| US11617895B2 (en) | 2015-07-28 | 2023-04-04 | Know Bio, Llc | Systems and methods for phototherapeutic modulation of nitric oxide |
| CN108373472A (en) * | 2018-04-25 | 2018-08-07 | 西南大学 | A kind of sterilization material and its preparation method and application containing protoporphyrin |
| CN113677204A (en) * | 2019-02-15 | 2021-11-19 | 桑科能源股份有限公司 | Use of protoporphyrin IX derivatives for improving plant health |
| EP3923729A4 (en) * | 2019-02-15 | 2022-11-23 | Suncor Energy Inc. | The use of protoporphyrin ix derivatives to improve the health of plants |
| CN113677204B (en) * | 2019-02-15 | 2024-03-05 | 桑科能源股份有限公司 | Use of protoporphyrin IX derivatives to improve plant health |
| US11147984B2 (en) | 2020-03-19 | 2021-10-19 | Know Bio, Llc | Illumination devices for inducing biological effects |
| US11684798B2 (en) | 2020-03-19 | 2023-06-27 | Know Bio, Llc | Illumination devices for inducing biological effects |
| US11752359B2 (en) | 2020-03-19 | 2023-09-12 | Know Bio, Llc | Illumination devices for inducing biological effects |
| CN111848656A (en) * | 2020-06-24 | 2020-10-30 | 天津大学 | Ion-modified protoporphyrin gallium compound and preparation method and application thereof |
| CN111848656B (en) * | 2020-06-24 | 2023-03-14 | 天津大学 | Ion-modified protoporphyrin gallium compound and preparation method and application thereof |
| US11654294B2 (en) | 2021-03-15 | 2023-05-23 | Know Bio, Llc | Intranasal illumination devices |
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Application publication date: 20140226 |