CN104119320B - Application of pyridine-4-ethynyl carbazole organic salt derivative - Google Patents
Application of pyridine-4-ethynyl carbazole organic salt derivative Download PDFInfo
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical class 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 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical class N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three 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
- A61K41/008—Two-Photon or Multi-Photon PDT, e.g. with upconverting dyes or photosensitisers
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- 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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pyridine-4-ethynyl carbazole organic salt derivative, which is characterized in that: has a structure shown in a formula (I),wherein: r0Is a hydrogen atom orR1Is C1-C12 alkyl or aryl; r2Is methyl or ethyl; r3Is halogen ion, substituted benzene sulfonate, anthraquinone sulfonate, alkyl sulfonate or alkyl carboxylate ion; preferably, the halogen is selected from chlorine, bromine or iodine. The compound can be used as a photosensitizer for two-photon photodynamic therapy and photodynamic sterilization.
Description
Technical Field
The present invention relates to the field of photodynamic therapy. More particularly, relates to an application of a pyridine-4-ethynyl carbazole organic salt derivative.
Background
Photodynamic Therapy (PDT) is also called photochemotherapy, mainly refers to selective killing of tumor cells or pathogenic microorganisms by using photochemical effect generated by a photo-activated photosensitizer, is a new emerging technology of marginal science and clinical treatment formed by cross permeation of multiple subjects such as medicine, photo-physics, photochemistry, photobiology and the like, and is successfully applied to the treatment of malignant tumors at present. After a photosensitizer is applied to a human body and is excited by light with a proper wavelength, a series of photochemical reactions occur in biological substances (DNA, protein, unsaturated fatty acid and the like) in target tumor tissues to generate active intermediate substances, so that the tumor treatment effect is achieved (M.Korbelik, Photochem.Photobiol.Sci,2011,10: 664-. The advantages of photodynamic therapy over other traditional tumor treatment techniques are its high efficacy and safety. The photodynamic sterilization is based on photodynamic action, means that active substances generated by a photosensitizer under the excitation of specific wavelength are utilized to effectively kill bacteria and viruses, and the photodynamic sterilization has a good application prospect in the treatment of infectious diseases.
Generally, the working wavelength of the photodynamic therapy is concentrated in the range of 500-700nm, and the photodynamic killing depth to human tissues is only a few millimeters, so the photodynamic therapy is mainly suitable for the surface cavity tumor of skin or internal organs, and is difficult to play a good therapeutic effect on deep tumor tissues, thereby the application in the clinical range is limited. Two-photon photodynamic therapy is an emerging photodynamic therapy in recent years. The working wavelength range of the two-photon photodynamic therapy is expanded from a visible light waveband to a near infrared waveband matched with a biological optical window of 700-1000nm by combining the characteristic of two-photon absorption of the photosensitizer. Therefore, the two-photon photodynamic therapy has the advantages of good tissue penetrability, small light damage, high space selectivity and the like, and can greatly improve the action depth of the photodynamic therapy. Meanwhile, the process of two-photon absorption can only occur at the focus of the laser, so that the pathological cells can be damaged with high selectivity, and the damage to surrounding normal tissues is reduced.
Photosensitizer molecules play a critical role in the drug system of photodynamic therapy. Once inside the body, photosensitizers accumulate in cancer cells and kill them when excited with light of a specific wavelength. At present, the photosensitizers reported at home and abroad mainly comprise hematoporphyrin derivatives, phthalocyanine derivatives, porphin derivatives, metal complex photosensitizers, quinone photosensitizers, squaric acid photosensitizers and the like. These photosensitizers all adopt the working principle of single photon absorption, have short working wavelength, and have small two-photon absorption cross section, so that the application of the photosensitizers in two-photon photodynamic therapy is limited. Therefore, the preparation of photosensitizers with large two-photon absorption cross-sections is an urgent problem to be solved for the effective implementation of two-photon photodynamic therapy.
Disclosure of Invention
The invention aims to solve the first technical problem of providing a pyridine-4-ethynyl carbazole organic salt derivative which has the characteristics of simple molecular structure and easy synthesis.
The second technical problem to be solved by the invention is to provide the application of the pyridine-4-ethynyl carbazole organic salt derivative in photodynamic therapy.
The third technical problem to be solved by the invention is to provide the application of the pyridine-4-ethynyl carbazole organic salt derivative in two-photon photodynamic therapy.
The fourth technical problem to be solved by the invention is to provide the application of the pyridine-4-ethynyl carbazole organic salt derivative in the preparation of two-photon photodynamic therapy medicines.
In order to solve the first technical problem, the invention provides a pyridine-4-ethynyl carbazole organic salt derivative which has a structure shown in a formula (I),
wherein: r0Is a hydrogen atom orR1Is C1-C12 alkyl or aryl; r2Is methyl or ethyl; r3Is halogen ion, substituted benzene sulfonate, anthraquinone sulfonate, alkyl sulfonate or alkyl carboxylate ion; preferably, the halogen is selected from chlorine, bromine or iodine.
The compound shown in the formula (I) is prepared by the following method:
the reaction equation is as follows:
wherein,
mixing the compound with the formula (A) and a corresponding alkylating reagent in acetonitrile according to the proportion of 1:1.5-1:5, reacting for 10-24 hours under the condition of heating reflux, filtering to obtain a crude product, and recrystallizing or washing with methanol to obtain a corresponding pure target product.
Preferably, the alkylating agent is selected from chloroalkanes, bromoalkanes, iodoalkanes, alkyl-substituted benzenesulfonic acids, alkyl-substituted anthraquinone sulfonic acids, alkyl-substituted sulfonates or phosphates or any mixture thereof.
The synthesis of compounds of the formula (A) can be found in the article entitled "Design of high efficiency for two-photon polymerization initiator" by Jin-Feng Xing et al, which is published under the heading of "Design of radio stability and large two-photon cross-section accessed by N-benzyl3,6-bis- (phenyl) carboxylate derivatives" J.Mather.chem., 2007,17, 1433-.
In order to solve the second technical problem, the invention adopts the following technical scheme:
the pyridine-4-ethynylcarbazole organic salt derivative can generate photodynamic activity under the excitation of 300-1300nm light, can damage cancer cells or sterilize photodynamic, and can be used for photodynamic therapy.
In order to solve the third technical problem, the invention adopts the following technical scheme:
the pyridine-4-ethynylcarbazole organic salt derivative has a larger two-photon absorption cross section under the laser irradiation of 700-1300nm, can photodamage biological target molecules such as DNA and the like, and can be used for two-photon photodynamic therapy.
In order to solve the fourth technical problem, the invention adopts the following technical scheme:
the pyridine-4-ethynylcarbazole organic salt derivative can be used for preparing two-photon photodynamic therapeutic drugs.
The pyridine-4-ethynylcarbazole organic salt compound has larger two-photon absorption in the wavelength range of 700-1300nm, can be excited by the wavelength in the corresponding range to generate photodynamic activity, the two-photon absorption cross section adopts Spitifer PRO-F1KXP type tunable femtosecond laser amplification level (repetition frequency 1000Hz and pulse width 120fs) of Newport company in America, and a nonlinear transmission method is adopted for measurement in view of low fluorescence quantum efficiency of molecules.
The pyridine-4-ethynylcarbazole organic salt derivative is used as a photosensitizer for two-photon photodynamic therapy and photodynamic sterilization. The compound can generate active oxygen species such as superoxide anions, singlet oxygen and the like by light excitation under the oxygen-rich condition, can react with target molecules (such as DNA and the like) to generate active free radicals such as methyl free radicals and the like under the oxygen-free condition, can lead the DNA to generate photoinduced fracture, and further kills tumor cells, pathological cells and bacteria. Meanwhile, the compound has a higher two-photon absorption cross section in the wavelength range of 700-1300nm, can generate photodynamic activity by the excitation of near-infrared band light, and can be used for two-photon photodynamic therapy.
The invention has the following beneficial effects:
the pyridine-4-ethynylcarbazole organic salt compound of the invention generates active oxygen species such as superoxide anion, singlet oxygen and the like under an oxygen-rich condition, can react with target molecules (such as DNA and the like) to generate active free radicals such as methyl free radical and the like under an anaerobic condition, can lead the DNA to generate photoinduced fracture, and further kills tumor cells, pathological cells and bacteria. DNA fragmentation experiments prove that molecules are damaged by two-photon light under the excitation of 800nm light of a femtosecond laser. Cell experiments prove that the molecules can kill tumor cells by utilizing photodynamic active light, and have good application prospects in two-photon photodynamic therapy.
The pyridine-4-ethynylcarbazole organic salt compound can effectively inhibit the growth activity of escherichia coli under the illumination condition, has obvious contrast of light-dark toxicity, and has good application prospect in the preparation of photodynamic bactericidal drugs and the treatment of infectious diseases.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 shows the superoxide anion radical signal in dimethyl sulfoxide (DMSO) of the compound of example 1 detected by ESR;
FIG. 2 shows singlet oxygen radical signal in dimethyl sulfoxide (DMSO) of the compound of example 1 detected by ESR;
FIG. 3 shows the methyl radical signal detected by ESR after interaction of the compound of example 1 with DNA in oxygen-depleted PBS buffer;
FIG. 4 shows an electrophoretogram of the compound of example 1 cleaving pBR322DNA under a series of conditions using solar simulator light;
FIG. 5A shows the measurement results of two-photon absorption cross section of the compound of example 1 at a wavelength of 760nm in a solvent;
FIG. 5B shows the two-photon absorption cross-section measurement results of the compound of example 1 at a wavelength of 800nm in a solvent;
FIG. 6 shows an electrophoretogram of pBR322DNA photocleaved by the compound of example 1 under irradiation of 800nm femtosecond laser;
FIGS. 7A and 7B are graphs showing the effect of the compound of example 1 on photoinduced apoptosis of tumor cells;
fig. 8A and 8B are graphs showing the effect of the compound photodynamic sterilization in example 1.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
Synthesis of Compounds
The synthesis of 3,6-bis (pyridin-4-ylethynyl) -N-pentylcarbazole iodonium salt has the following reaction equation:
3,6-bis [2- (methylpyridinium-4-yl) -ethynyl ] -N-pentylcarbazole (1.5g,3.9mmol) was dissolved in 120mL of anhydrous acetonitrile, iodomethane (2.5mL) was added, and the mixture was refluxed for 20 hours. Cooling and filtering to obtain a crude product. The crude solid was recrystallized from methanol, filtered under suction and dried to give 1.6g of a yellow solid.
The final product had the following NMR spectrum values:
1H NMR(400MHz,DMSO-d6,ppm)：9.03(d,4H,J＝6.5Hz),8.77(s,2H),8.28(d,4H,J＝6.5Hz),7.95(s,4H),4.58(t,2H,J＝6.4Hz),1.87(m,2H),1.36(m,4H),0.87(t,3H,J＝5.8Hz)。
example 2
Compound two-photon photodamage DNA
The effect of pyridine-4-ethynylcarbazole organic salts of the present invention on photodamage of pBR322DNA under various conditions will be described in detail below, using the compound of example 1 as an example, with reference to FIGS. 1-5.
Use of 5, 5-dimethyl-1-oxopyrroline (DMPO) as superoxide radical (O)2 -.) The paramagnetic resonance spectrum of the compound in DMSO is measured under the excitation of a mercury lamp to obtain a graph1, fine split constant of the quartet with DMPO-O in the literature2 -.The splitting constants of the compounds are consistent, and the fact that the compounds generate superoxide radicals under the action of light excitation and oxygen is proved.
The paramagnetic resonance spectrum of the compound in DMSO is measured under the excitation of a mercury lamp by using 2,2,2, 2-tetramethyl-4-piperidone (TEMP) as a spin trapping agent of singlet oxygen, a triplet peak shown in figure 2 is obtained, the fine splitting constant of the triplet is consistent with that of TEMPO in the literature, and the singlet oxygen free radical is generated by the compound under the excitation of light and the action of oxygen.
The compound was dissolved in PBS buffer (50. mu.M), added to pBR322DNA (30. mu.M), and N-charged2After 20 minutes, the paramagnetic resonance spectrum of the system was measured under the excitation of a mercury lamp using 5, 5-dimethyl-1-pyrroline oxide (DMPO) as a radical scavenger, and a 6-fold peak shown in FIG. 3 was obtained, the fine split constant of which is consistent with that of DMPO-CH3 in the literature, thus proving that the compound can be photoexcited to react with DNA through electron transfer under anaerobic conditions and generate methyl radicals.
mu.L of supercoiled pBR322DNA (base pair concentration 31. mu.M) and 20. mu.M of the compound in PBS (pH7.4) were irradiated with light using a solar simulator (. lamda.gtoreq.400 nm) for 25min, 15. mu.L of the electrophoresis buffer was added thereto, mixed, and 15. mu.L of the mixture was taken out using a micro syringe and subjected to agarose electrophoresis separation for 1 hour (Tris-acetic acid-EDTA buffer, pH 8.0). The gel was stained in 1mg/L EB water for 45 minutes, rinsed with clear water for 30 minutes, and analyzed using a gel imaging system. The results obtained are shown in FIG. 4: line4 shows that the compound is effective in changing the supercoiled Structure (SC) of pBR322 plasmid DNA to circular plasmid form (NC) under light conditions, without significant change in the supercoiled structure of the DNA without light or light added with the compound. The above-mentioned phenomena demonstrate that the compound of example 1 can photodisrupt supercoiled pBR322DNA under both aerobic and anaerobic conditions, and has high activity.
The compound is dissolved in DMSO to be prepared into 2 × 10-3M solution, subjecting the compound to femtosecond laser with amplification level of 760nm and 800nm by nonlinear permeation methodThe two-photon absorption cross section of the compound at 760nm is 522GM, and the two-photon absorption cross section at 800nm is 400 GM.
50L of a mixed solution of supercoiled pBR322DNA (base pair concentration 31M) and 10 to 40M of a compound in PBS (pH7.4) was irradiated with agarose electrophoresis after 40 minutes using an imaging system with a laser of 800nm as a light source (Spitifer PRO-F1KXP type tunable femtosecond laser amplification stage, repetition rate 1000Hz, pulse width 120fs, manufactured by Newport corporation, USA) and with a spot not focused and an average power of about 100 mW. The results obtained are shown in FIG. 6: line2-4 shows that the compound can effectively realize photodamage to DNA under the irradiation of 800nm laser, and the supercoiled structure of the DNA is not obviously changed under the condition of not adding the compound. The above-mentioned phenomena prove that the compound of example 1 can cause DNA two-photon photodamage under the condition of two-photon excitation, and has high two-photon photodynamic activity.
Example 3
Photodynamic killing of cells by compounds
The photoinduced killing effect of the compound on cervical cancer cells (HeLa) is realized by adopting a laser confocal microscope. HeLa cells were cultured for 24 hours, then 3. mu.M of the compound of example 1 was added thereto, and the cells were further cultured for 2 hours and then observed under a confocal fluorescence microscope. The observation was carried out under a microscope using a laser wavelength of 405 nm. As shown in fig. 7A, it was clearly observed that the cell to which the compound was added rapidly underwent cell membrane rupture to generate bubbles and cause apoptosis with the lapse of time. In contrast, as shown in FIG. 7B, no significant change occurred in cells without compound addition over time. Indicating that the compound can generate photodynamic killing on cancer cells under the condition of laser excitation.
Example 4
Photodynamic sterilization experiment of compounds
After mixing the compound (3. mu.M) with a PBS suspension (pH7.4) of E.coli (. about.108 cells/mL), incubation was carried out at 37 ℃ for 30 minutes in the absence of light, followed by irradiation with a solar simulator (. lamda.gtoreq.400 nm) for 30 minutes, and incubation was carried out at 37 ℃ for 1 hour in the absence of light using the same concentration ratio for the control sample without light. The treated E.coli was diluted with PBS and spread on 3 MPetifilmTM E.coli Count Plate and incubated at 37 ℃ for 48 hours in the absence of light. Bacterial Colony Counts (CFU) were counted using an automated Colony Counter (Shineso G6Colony Counter). The results are shown in fig. 8A and 8B, where the number of colonies of e.coli under light was reduced by 2-3 orders of magnitude after light irradiation compared to that without light irradiation, and the results indicate that the compound-induced photodynamic reaction can effectively inhibit the activity of e.coli.
Referring to the results of examples 1 to 4, it can be demonstrated that the pyridine-4-ethynylcarbazole organic salt compound of the present invention has two-photon photodynamic activity, can cause photodynamic damage to target molecules (such as DNA, etc.) in a living body under the two-photon excitation condition, can also generate photodynamic killing to tumor cells under the two-photon excitation condition, and can be used as a photodynamic combination drug for photodynamic therapy of cancer and skin-related diseases. Meanwhile, the compounds also have photodynamic bactericidal activity, can inhibit the growth activity of thalli under the excitation of light, and can be used as a combined medicament for treating bacterial infectious diseases.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications belonging to the technical solutions of the present invention are within the scope of the present invention.
Claims (2)
1. An application of pyridine-4-ethynylcarbazole organic salt derivatives in photodynamic bactericidal drugs is characterized in that: has the structure shown in the following description,
the bacterium is Escherichia coli.
2. The use of a pyridine-4-ethynylcarbazole organic salt derivative according to claim 1 in photodynamic bactericidal drugs, characterized in that: the pyridine-4-ethynyl carbazole organic salt derivative can be sensitized by light excitation with the wavelength of 300-1300 nm; has the characteristic of two-photon absorption in the wavelength range of 700-1300 nm.
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