CN114315901B - Thiophene bridge-containing phosphorus oxide derivative and preparation method and application thereof - Google Patents
Thiophene bridge-containing phosphorus oxide derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic micromolecular photoelectric materials, and discloses a phosphorus oxide derivative containing a thiophene bridge, a preparation method and application thereof. The invention takes a phosphorus oxide primitive as a core, one site on a phosphorus-containing five-membered ring is connected with thiophene as pi bridge, triphenylamine and derivatives thereof are used as donor units, the other site is connected with strong electron withdrawing groups such as benzene cyano groups or pyridine, pyridine salt and the like, and the strong electron withdrawing groups and the phosphorus oxide primitive are used as acceptor units together. According to the invention, thiophene primitives are introduced into the structure, so that the electron pushing-pulling capability of molecules is enhanced, the conjugation of the molecules is prolonged, and the absorption and emission spectra of the molecules are red shifted. Meanwhile, the strong D-A structure is beneficial to reducing the energy level difference of a single-triplet state, improving the active oxygen generating capacity and further improving the photodynamic treatment effect; the fluorescent dye has excellent aggregation-induced emission, biocompatibility, accurate cancer cell and microorganism marking and high-efficiency killing capability in biological application, and has wide application prospect in the field of biomedicine.
Description
Technical Field
The invention relates to the technical field of organic micromolecular photoelectric materials, in particular to a phosphorus oxide derivative containing a thiophene bridge, a preparation method and application thereof.
Background
Cancer is one of the greatest threats facing human health at present, and the damage of immune system caused by cancer will lead to the organism being more vulnerable to invasion of microorganisms such as bacteria, viruses and the like. Thus, neither anti-tumor nor bacterial infections are sustained. Photodynamic therapy (Photodynamic therapy, PDT) has received increasing attention as an emerging clinical treatment modality compared to traditional cancer treatments (surgery, chemotherapy, radiation therapy, etc.), due to its unique advantages (non-invasive, space-time controllability, and negligible resistance) (Lasers surg. Med.2011,43 (7): 755-767).
In general, PDT relies primarily on three basic components, photosensitizers (PSs), light and oxygen. Reactive oxygen species (Reactive oxide species, ROS) generated during PDT have strong cytotoxicity, can rapidly react with biological substances to cause cell death, vascular injury, immune response and other anti-tumor effects, can also enable microorganisms to generate oxidative stress, and can inhibit microorganism growth. As one of the main components of PDT, the performance of PSs directly influences the effect of PDT (View, 2021, 20200121). To date, several PSs have been reported, such as inorganic nanocomposites, organometallic complexes, and metal-organic frameworks (chem.sci., 2019, 10, 3096). However, the materials have the defects of strong biotoxicity, complex preparation process, high manufacturing cost and the like, and limit the clinical application to a certain extent.
Therefore, how to provide a photosensitizer with flexible structure, simple preparation, good repeatability and low biotoxicity has great significance for the clinical development of photodynamic therapy.
Disclosure of Invention
The invention aims to provide a phosphorus oxide derivative containing a thiophene bridge, and a preparation method and application thereof, and solves the problems of high biological toxicity and complex preparation method of a photosensitizer provided by the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a thiophene-bridge-containing phosphorus oxide derivative, which comprises one of the following structures:
wherein R is 1 Is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 Haloalkyl having halogen at end, amino acid having special biological function, and special organismOne of a functional peptide chain or a nucleic acid having a specific biological function;
R 2 、R 4 、R 5 、R 6 、R 7 independently is one of hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, mercapto, halogen, diethylamine, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolinyl, indolyl, carboxyl, derivatives of carboxyl, acridinyl, spiroacridinyl, phenothiazinyl, phenoxazinyl, carbazolyl, tetrastyryl or anilino;
R 3 is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And a halogen alkyl group terminated with halogen;
R 8 is hydrogen, C 1～12 Alkyl, aryl derivatives, C 1～12 And one of a haloalkyl group having a halogen at the end, an amino acid having a specific biological function, a peptide chain having a specific biological function or a nucleic acid having a specific biological function;
R 9 for BF 4 - 、PF 6 - 、I - 、Br - 、Cl - Or HSO 3 - One of them.
Preferably, in the above-mentioned one thiophene-bridge-containing phosphorus oxide derivative, the R 1 、R 3 And R is 8 Wherein the halogen is independently one of fluorine, chlorine, bromine or iodine;
R 1 and R is 8 The special biological function of the cell membrane has the specific targeting function of cancer cells, the cell membrane penetrating function, the specific organelle targeting function or the cancer cell killing function independently.
The invention also provides a preparation method of the phosphorus oxide derivative containing the thiophene bridge, which comprises the following steps:
preparation of a phosphorus oxide derivative of one of the structures I to IV:
mixing a monobromo with a target substituent, terminal alkyne with the target substituent, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing a coupling reaction, and separating and purifying after the reaction is finished to obtain an internal alkyne intermediate; mixing an internal alkyne intermediate, substituted ethyl phenylphosphonate, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing cyclization reaction, and separating and purifying after the reaction is finished to obtain a phosphorus oxide indole derivative;
preparation of a phosphorus oxide derivative of structure V or VI:
mixing a phosphorus oxide derivative with a structure III or IV, an alkylating reagent and an organic solvent, heating and refluxing, and recrystallizing after the reaction is finished to obtain a pyridinium phosphorus oxide derivative containing halogen anions; mixing a pyridinium phosphorus oxide derivative containing halogen anions, a saturated aqueous solution of metal salt and an organic solvent, reacting for 0.5-24 h at room temperature, and washing after the reaction is finished to obtain the phosphorus oxide derivative.
Preferably, in the above preparation method of a thiophene-bridge-containing phosphorus oxide derivative, in the preparation of a phosphorus oxide derivative having one of the structures I to IV, the structure of the monobromide having the target substituent is as follows:
the structure of the terminal alkyne with the target substituent is as follows:
the structure of the substituted ethyl phenylphosphonate is shown below:
wherein R is 1 Is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 Haloalkyl having halogen at the end, amino acid having special biological function, and method for producing the sameOne of a peptide chain of a specific biological function or a nucleic acid having a specific biological function;
R 2 、R 4 、R 5 、R 6 、R 7 independently is one of hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, mercapto, halogen, diethylamine, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolinyl, indolyl, carboxyl, derivatives of carboxyl, acridinyl, spiroacridinyl, phenothiazinyl, phenoxazinyl, carbazolyl, tetrastyryl or anilino;
R 3 is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And a halogen alkyl group terminated with halogen;
R 1 the specific biological function of the cell membrane is cancer cell specific targeting function, cell membrane penetrating function, specific organelle targeting function or cancer cell killing function.
Preferably, in the preparation method of the phosphorus oxide derivative containing thiophene bridge, in the preparation of the phosphorus oxide derivative with one of the structures I to IV, the coupling reaction is a Sonogashira coupling reaction; the temperature of the coupling reaction is 70-85 ℃; the coupling reaction time is 6-24 hours; the catalyst for the coupling reaction is a mixture of tetra (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride and cuprous iodide; the volume ratio of the organic solvent for the coupling reaction is 2-4: 0.8 to 1.5 percent of triethylamine and tetrahydrofuran;
the temperature of the cyclization reaction is 80-150 ℃; the time of the cyclization reaction is 6-24 hours; the catalyst for the cyclization reaction is silver oxide, silver nitrate or silver acetate; the organic solvent for the cyclization reaction is one or more of N, N-dimethylformamide, 1, 4-dioxane and toluene.
Preferably, in the above preparation method of the phosphorus oxide derivative containing a thiophene bridge, in the preparation of the phosphorus oxide derivative having the structure V or VI, the alkylating agent is a 1-halogen substituent having an alkyl chain length of 1 to 12, wherein one end is halogen, and the other end is one of hydrogen, halogen, an aryl derivative, an amino acid having a specific biological function, a peptide chain having a specific biological function or a nucleic acid having a specific biological function; the halogen is one of fluorine, chlorine, bromine or iodine; the special biological function is cancer cell specific targeting function, cell membrane penetrating function, specific organelle targeting function or cancer cell killing function.
Preferably, in the preparation method of the phosphorus oxide derivative containing a thiophene bridge, in the preparation of the phosphorus oxide derivative with the structure of V or VI, the organic solvent in the first reaction is one or more of acetonitrile, toluene and dioxane, and the organic solvent in the second reaction is acetonitrile or dioxane.
Preferably, in the preparation method of the phosphorus oxide derivative containing thiophene bridge, in the preparation of the phosphorus oxide derivative with the structure of V or VI, the temperature of heating reflux is 80-150 ℃; the heating reflux time is 0.5-24 h.
Preferably, in the above preparation method of the phosphorus oxide derivative containing a thiophene bridge, the phosphorus oxide derivative having a structure of V or VI is prepared, and the metal salt in the saturated aqueous solution of the metal salt is one of sodium hexafluorophosphate, potassium hexafluorophosphate, sodium hexafluoroborate, potassium hexafluoroborate, sodium benzenesulfonate or potassium benzenesulfonate.
The invention also provides an application of the thiophene-bridge-containing phosphorus oxide derivative in cell imaging or preparation of a photodynamic tumor treatment drug.
In the invention, a phosphoindole oxide unit is taken as a core, one site on a phosphorus-containing five-membered ring is connected with thiophene as pi bridge, triphenylamine and derivatives thereof are taken as donor units, the other site is connected with a strong electron withdrawing group such as benzene cyano group, pyridine salt and the like, and the strong electron withdrawing group and the phosphoindole oxide are taken as acceptor units together. Compared with the existing phosphorus oxide derivative, the molecule provided by the invention introduces thiophene elements into the structure, enhances the electron pushing-pulling (D-A) capability of the molecule, prolongs the conjugation of the molecule, and makes the absorption and emission spectrum of the molecule red-shift. Meanwhile, the strong D-A structure is beneficial to reducing the energy level difference of single-triplet states, promoting intersystem crossing, improving the active oxygen generating capacity and further improving the photodynamic treatment effect.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention introduces thiophene element, enhances the electron pushing-pulling (D-A) capability of the molecule, prolongs the conjugation of the molecule, and makes the absorption emission spectrum of the molecule red-shifted.
(2) The phosphorus oxide derivative containing thiophene bridge has stronger ROS generating capability, and can also detect the generation of free radical ROS in a solution under the condition of not adding an additional substrate.
(3) The thiophene-bridge-containing phosphorus oxide derivative provided by the invention has excellent aggregation-induced emission property, good biocompatibility, accurate cancer cell and microorganism marking and high-efficiency killing capability in biological application, and has a wide application prospect in the biomedical field.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a graph of the active oxygen generating capacity of the compound α -Th-TPA- β -Py-PIO and the compound β -Th-TPA- α -Py-PIO of example 2 in phosphate buffered saline;
FIG. 2 is a graph of cell viability of the compound α -Th-TPA- β -Py-PIO and compound β -Th-TPA- α -Py-PIO of example 2 after treatment of sea-pulled cells with no light at various concentrations;
wherein A is the survival rate of the cells under the co-culture of the compound alpha-Th-TPA-beta-Py-PIO at different concentrations; b is the survival rate of the compound beta-Th-TPA-alpha-Py-PIO under the co-culture of different concentrations; c is the survival rate of the cells after light treatment under the co-culture of the compound alpha-Th-TPA-beta-Py-PIO at different concentrations; d is the survival rate of the cells after the compound beta-Th-TPA-alpha-Py-PIO is subjected to light treatment under the co-culture of different concentrations;
FIG. 3 is a fluorescence imaging of the compound α -Th-TPA- β -Py-PIO of example 2, the compound β -Th-TPA- α -Py-PIO, and the compound β -PM-PIO of example 3 in living cells;
wherein A is a fluorescence imaging diagram of a compound alpha-Th-TPA-beta-Py-PIO in living cells; b is a fluorescence imaging diagram of the compound beta-Th-TPA-alpha-Py-PIO in living cells; c is a fluorescence imaging diagram of the compound beta-PM-PIO in living cells;
FIG. 4 is a graph showing cell viability of the compound β -PM-PIO of example 3 after treatment of sea-tangled cells with no light at various concentrations;
wherein A is a cell viability graph after no irradiation treatment; b is a cell survival rate graph after illumination treatment;
FIG. 5 is a graph showing bacterial growth after light treatment of Staphylococcus aureus with the compound beta-PM-PIO of example 3 at various concentrations;
FIG. 6 is a graph of bacterial viability of the compound β -PM-PIO of example 3 after treatment with staphylococcus aureus at various concentrations with no light;
FIG. 7 is a fluorescence imaging of the compound β -PM-PIO of example 3 and the compound α -Th-TPA- β -Py-PIO of example 2 in Staphylococcus aureus;
wherein A is a fluorescent imaging diagram of a compound beta-PM-PIO in staphylococcus aureus; b is a fluorescence imaging diagram of a compound alpha-Th-TPA-beta-Py-PIO in staphylococcus aureus;
FIG. 8 is a fluorescent imaging of the compound β -PM-PIO of example 3 on Staphylococcus aureus biofilms at various times;
wherein A is a fluorescent imaging diagram of a compound beta-PM-PIO on a staphylococcus aureus biomembrane at 24h; b is a fluorescent imaging diagram of the compound beta-PM-PIO on staphylococcus aureus biomembrane at 48 h.
Detailed Description
The invention provides a thiophene-bridge-containing phosphorus oxide derivative, which comprises one of the following structures:
wherein R is 1 Is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And one of a haloalkyl group having a halogen at the end, an amino acid having a specific biological function, a peptide chain having a specific biological function or a nucleic acid having a specific biological function;
R 2 、R 4 、R 5 、R 6 、R 7 independently is one of hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, mercapto, halogen, diethylamine, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolinyl, indolyl, carboxyl, derivatives of carboxyl, acridinyl, spiroacridinyl, phenothiazinyl, phenoxazinyl, carbazolyl, tetrastyryl or anilino;
R 3 is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And a halogen alkyl group terminated with halogen;
R 8 is hydrogen, C 1～12 Alkyl, aryl derivatives, C 1～12 And one of a haloalkyl group having a halogen at the end, an amino acid having a specific biological function, a peptide chain having a specific biological function or a nucleic acid having a specific biological function;
R 9 for BF 4 - 、PF 6 - 、I - 、Br - 、Cl - Or HSO 3 - One of them.
In the present invention, R 1 、R 3 And R is 8 The halogen in (a) is independently preferably one of fluorine, chlorine, bromine or iodine, more preferably one of fluorine, chlorine or bromine, and still more preferably fluorine.
In the present invention, R 1 And R is 8 Independent of specific biological functions, preferably cancer cell specific targeting functionsThe cell membrane-penetrating function, the specific organelle-targeting function, or the cancer cell killing function is provided, and the cell membrane-penetrating function or the cancer cell killing function is more preferable, and the cancer cell killing function is more preferable.
The invention also provides a preparation method of the thiophene-bridge-containing phosphorus oxide derivative, which comprises the following steps:
the chemical equation of the preparation of the oxidized phosphorus indole derivative with one of the structures I-IV is shown as follows:
mixing a monobromo with a target substituent, terminal alkyne with the target substituent, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing a coupling reaction, and separating and purifying after the reaction is finished to obtain an internal alkyne intermediate; mixing an internal alkyne intermediate, substituted ethyl phenylphosphonate, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing cyclization reaction, and separating and purifying after the reaction is finished to obtain a phosphorus oxide indole derivative;
the chemical equation of the preparation of the oxidized phosphorus indole derivative with the structure of V or VI is shown as follows:
mixing a phosphorus oxide derivative with a structure III or IV, an alkylating reagent and an organic solvent, heating and refluxing, and recrystallizing after the reaction is finished to obtain a pyridinium phosphorus oxide derivative containing halogen anions; mixing a pyridinium phosphorus oxide derivative containing halogen anions, a saturated aqueous solution of metal salt and an organic solvent, reacting for 0.5-24 h at room temperature, and washing after the reaction is finished to obtain the phosphorus oxide derivative.
In the present invention, in the preparation of the oxidized phosphorus indole derivative having one of the structures I to IV, the structure of the monobromide having the objective substituent is as follows:
the structure of the terminal alkyne with the target substituent is as follows:
the structure of the substituted ethyl phenylphosphonate is shown below:
wherein R is 1 Is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And one of a haloalkyl group having a halogen at the end, an amino acid having a specific biological function, a peptide chain having a specific biological function or a nucleic acid having a specific biological function;
R 2 、R 4 、R 5 、R 6 、R 7 independently is one of hydrogen, alkyl, hydroxy, alkoxy, nitro, cyano, amino, mercapto, halogen, diethylamine, phenyl, tolyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyranyl, quinolinyl, indolyl, carboxyl, derivatives of carboxyl, acridinyl, spiroacridinyl, phenothiazinyl, phenoxazinyl, carbazolyl, tetrastyryl or anilino;
R 3 is hydrogen, C 1～12 Alkyl, C of (2) 1～12 Alkoxy, aryl derivatives, C 1～12 And a halogen alkyl group terminated with halogen;
R 1 the special biological function of the cell membrane has the specific targeting function of cancer cells, the cell membrane penetrating function, the specific organelle targeting function or the cancer cell killing function independently.
In the preparation of the oxidized phosphorus derivatives with one of the structures I to IV, the coupling reaction is preferably a Sonogashira coupling reaction; the temperature of the coupling reaction is preferably 70 to 85 ℃, more preferably 72 to 83 ℃, and even more preferably 78 ℃; the coupling reaction time is preferably 6 to 24 hours, more preferably 8 to 22 hours, and still more preferably 17 hours; the catalyst for the coupling reaction is preferably tetrakis (triphenylphosphine) palladium or a mixture of bis (triphenylphosphine) palladium dichloride and cuprous iodide, and more preferably tetrakis (triphenylphosphine) palladium; the organic solvent for the coupling reaction is preferably in a volume ratio of 2 to 4: the mixture of triethylamine and tetrahydrofuran is preferably 0.8 to 1.5, more preferably 2.3 to 3.7:0.9 to 1.3, more preferably 2.5:1.1.
in the present invention, in the preparation of the oxidized phosphorus indole derivative having one of the structures I to IV, the temperature of the cyclization reaction is preferably 80 to 150 ℃, more preferably 86 to 142 ℃, still more preferably 129 ℃; the time for the cyclization reaction is preferably 6 to 24 hours, more preferably 9 to 23 hours, and still more preferably 12 hours; the catalyst for the cyclization reaction is preferably silver oxide, silver nitrate or silver acetate, more preferably silver oxide or silver acetate, and still more preferably silver oxide; the organic solvent for the cyclization reaction is preferably one or more of N, N-dimethylformamide, 1, 4-dioxane and toluene, more preferably one or two of N, N-dimethylformamide and toluene, and still more preferably N, N-dimethylformamide.
In the preparation of the phosphorus oxide derivative of the structure V or VI, the alkylating reagent is preferably a 1-halogen substituent containing alkyl chain length of 1 to 12, wherein one end is preferably halogen, and the other end is preferably one of hydrogen, halogen, aryl derivative, amino acid with special biological function, peptide chain with special biological function or nucleic acid with special biological function, and is more preferably one of hydrogen, halogen or aryl derivative, and is more preferably hydrogen; halogen is preferably one of fluorine, chlorine, bromine or iodine, more preferably one of chlorine, bromine or iodine, and even more preferably bromine; the specific biological function is preferably a specific targeting function of cancer cells, a cell membrane penetrating function, a specific organelle targeting function or a killing function of cancer cells, more preferably a specific targeting function of cancer cells, a cell membrane penetrating function or a killing function of cancer cells, and even more preferably a killing function of cancer cells.
In the preparation of the oxidized phosphorus indole derivative having the structure V or VI, the organic solvent in the first reaction is preferably one or more of acetonitrile, toluene and dioxane, more preferably one or two of acetonitrile and dioxane, still more preferably acetonitrile; the organic solvent in the second reaction is acetonitrile or dioxane, and acetonitrile is further preferred.
In the present invention, in the preparation of the oxidized phosphorus indole derivative having the structure V or VI, the temperature of the heating reflux is preferably 80 to 150 ℃, more preferably 89 to 141 ℃, still more preferably 97 ℃; the heating reflux time is preferably 0.5 to 24 hours, more preferably 3 to 22 hours, and still more preferably 14 hours.
In the preparation of the phosphorus oxide derivative with the structure V or VI, the reaction temperature of the pyridine salt phosphorus oxide derivative containing halogen anions, the saturated aqueous solution of the metal salt and the organic solvent is preferably room temperature; the reaction time is preferably 0.5 to 24 hours, more preferably 6 to 20 hours, and still more preferably 16 hours.
In the preparation of the phosphorus oxide derivative having the structure V or VI, the metal salt in the saturated aqueous solution of the metal salt is preferably one of sodium hexafluorophosphate, potassium hexafluorophosphate, sodium hexafluoroborate, potassium hexafluoroborate, sodium benzenesulfonate or potassium benzenesulfonate, more preferably one of potassium hexafluorophosphate, sodium hexafluoroborate, potassium hexafluoroborate or potassium benzenesulfonate, and still more preferably potassium hexafluorophosphate.
The invention also provides an application of the thiophene-bridge-containing phosphorus oxide derivative in cell imaging or preparation of a photodynamic tumor treatment drug.
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A preparation method of a thiophene-bridge-containing phosphorus oxide derivative (a compound of alpha-Th-TPA-beta-CN-PIO and a compound of beta-Th-TPA-alpha-CN-PIO) comprises the following steps:
(1) 2.03g of Compound 1 (reported in the prior literature to be synthesized: dyes Pigm.2018,149, 843-850), 0.76g of Compound 2, 175mg of bis (triphenylphosphine) palladium dichloride, 95mg of cuprous iodide and 131mg of triphenylphosphine are weighed into a double-neck round bottom flask, 80mL of triethylamine and 20mL of ultra-dry tetrahydrofuran are added, the gas is repeatedly extracted for three times, and reflux reaction is carried out for 8 hours at 70 ℃ under the protection of nitrogen; after cooling to room temperature, extracting with saturated saline for three times; then, the mixture was subjected to column chromatography on silica gel using petroleum ether/methylene chloride (1/1 v/v) as an eluent to obtain 1.81g of yellow solid (intermediate 3) in 80% yield;
(2) 1.81g of compound 3, 1.36g of compound 4 and 1.84g of silver oxide are weighed in a double-neck round bottom flask, 60mLN, N-dimethylformamide is added, the gas is repeatedly extracted for three times, and reflux reaction is carried out for 10 hours at 100 ℃ under the protection of nitrogen; after cooling to room temperature, insoluble solids in the reaction were removed by filtration through celite; extracting the filtrate with saturated saline for three times; then petroleum ether/tetrahydrofuran (2/1 v/v) is used as an eluent to carry out chromatographic silica gel column separation to obtain yellow solid with the yield of 0.92g and 37 percent, which is a compound alpha-Th-TPA-beta-CN-PIO (namely, the structure I);
(3) The petroleum ether/tetrahydrofuran (1/1 v/v) is continuously used as an eluent for chromatographic silica gel column separation to obtain 0.37g of orange yellow solid with 15 percent of yield, which is the compound beta-Th-TPA-alpha-CN-PIO (namely, the structure II).
The compound beta-Th-TPA-alpha-CN-PIO: 1 H NMR(500MHz,CDCl 3 )δ(TMS,ppm):7.77(dd,J＝10.0,5.0Hz,1H),7.64–7.61(m,3H),7.59–7.54(m,3H),7.50–7.46(m,1H),7.42(d,J＝10.0Hz,2H),7.28(d,J＝10.0Hz,4H),7.21(d,J＝3.8Hz,1H),7.12(d,J＝7.2Hz,4H),7.06(dd,J＝5.0,5.0Hz,4H),7.01(d,J＝5.0Hz,1H),4.17–4.03(m,2H),1.27–1.24(m,3H). 13 C NMR(125MHz,CDCl 3 ),δ(TMS,ppm):147.81(d,J＝76.3Hz),147.22,143.73(d,J＝30.0Hz),140.63(d,J＝32.5Hz),137.82(d,J＝8.8Hz),133.35(d,J＝1.3Hz),132.28,130.92,130.77,130.72,129.861(d,J＝11.3Hz),129.69(d,J＝5.0Hz),129.59(d,J＝126.3Hz),129.40,127.94(d,J＝8.8Hz),127.31(d,J＝133.8Hz),126.85,126.68,124.78,124.41(d,J＝13.8Hz),123.48,123.16,122.53,118.71,111.63,62.41(d,J＝6.3Hz),16.54(d,J＝5.0Hz).
example 2
A method for synthesizing a thiophene-bridge-containing phosphorus oxide derivative (a compound of alpha-Th-TPA-beta-Py-PIO and a compound of beta-Th-TPA-alpha-Py-PIO) comprises the following steps:
(1) 2.03g of Compound 1 (reported in the prior literature to be synthesized: dyes Pigm.2018,149, 843-850), 0.52g of Compound 2, 175mg of bis (triphenylphosphine) palladium dichloride, 95mg of cuprous iodide and 131mg of triphenylphosphine are weighed into a double-neck round bottom flask, 80mL of triethylamine and 20mL of ultra-dry tetrahydrofuran are added, the gas is repeatedly extracted for three times, and reflux reaction is carried out for 8 hours at 70 ℃ under the protection of nitrogen; after cooling to room temperature, extracting with saturated saline for three times; then, the mixture was subjected to column chromatography on silica gel using petroleum ether/methylene chloride (1/1 v/v) as an eluent to obtain 1.61g of a yellow solid (intermediate 3) in a yield of 70%;
(2) 1.61g of compound 3, 1.50g of compound 4 and 1.71g of silver oxide are weighed in a double-neck round bottom flask, 60mLN, N-dimethylformamide is added, the gas is repeatedly extracted for three times, and reflux reaction is carried out for 10 hours at 100 ℃ under the protection of nitrogen; after cooling to room temperature, insoluble solids in the reaction were removed by filtration through celite; extracting the filtrate with saturated saline for three times; then petroleum ether/tetrahydrofuran (2/1 v/v) is used as an eluent to carry out chromatographic silica gel column separation to obtain yellow solid with the yield of 0.67g and 30 percent, which is a compound alpha-Th-TPA-beta-Py-PIO (namely, a structure III);
(3) The petroleum ether/tetrahydrofuran (1/1 v/v) is continuously used as an eluent for chromatographic silica gel column separation to obtain 0.22g of orange yellow solid with the yield of 10 percent, which is the compound beta-Th-TPA-alpha-Py-PIO (namely the structure IV).
The compound alpha-Th-TPA-beta-Py-PIO: 1 H NMR(400MHz,CD 2 Cl 2 )δ(TMS,ppm):8.81(d,J＝6.12Hz,2H),7.77-7.71(m,1H),7.55(dd,J＝3.9,1.2Hz,1H),7.50-7.36(m,4H),7.34-7.21(m,6H),7.16(d,J＝3.9Hz,1H),7.13-7.00(m,6H),6.99-6.94(m,2H),6.86-6.82(m,1H),4.12(m,2H),1.32(m,3H). 13 C NMR(125MHz,CD 2 Cl 2 )δ(TMS,ppm):151.15,148.44,147.65,147.56,142.03(d,J＝28.8Hz),141.00(d,J＝26.3Hz),133.91,132.96(d,J＝13.8Hz),131.93(d,J＝3.8Hz),129.76,129.30(d,J＝11.3Hz),128.11,127.81(d,J＝96.3Hz),127.03,126.03,126.01(d,J＝122.5Hz),125.19,124.59,123.86,123.74,123.63,123.31,122.70,62.99(d,J＝6.3Hz),16.69(d,J＝6.3Hz).HRMS(C 37 H 29 N 2 O 2 PS):m/z 596.1687(M + ,calcd 597.1784).
the compound beta-Th-TPA-alpha-Py-PIO: 1 H NMR(400MHz,CD 2 Cl 2 ),δ(TMS,ppm):8.53(d,J＝4.0Hz,2H),7.78–7.74(m,1H),7.68–7.65(m,1H),7.61–7.57(m,1H),7.54–7.49(m,1H),7.46–7.44(m,2H),7.42(d,J＝8.0Hz,2H),7.30–7.26(m,5H),7.11–7.03(m,9H),4.12–3.97(m,2H),1.25–1.22(m,3H). 13 C NMR(100MHz,CD 2 Cl 2 ),δ(TMS,ppm):150.00,148.15(d,J＝68.0Hz),147.69,144.81(d,J＝29.0Hz),142.06(d,J＝9.0Hz),140.98(d,J＝32.0Hz),133.71(d,J＝3.0Hz),131.31,131.28,131.08,130.38(d,J＝11.0Hz),129.22(d,J＝123.0Hz),129.78,128.15(d,J＝8.0Hz),127.94(d,J＝131Hz),127.39,127.04,125.18,124.90(d,J＝13.0Hz),123.86,123.79(d,J＝5.0Hz),123.49,123.06,62.85(d,J＝6.0Hz),16.71(d,J＝6.0Hz).HRMS(C 37 H 29 N 2 O 2 PS):m/z 596.1687(M + ,calcd 597.1789).
example 3
A synthetic method of a thiophene-bridge-containing phosphorus oxide derivative (compound beta-PM-PIO) comprises the following steps:
weighing 41.7mg of compound alpha-Th-TPA-beta-Py-PIO (namely structure III) in a eggplant-shaped bottle, dissolving in 5mL of acetonitrile, adding 0.1mL of methyl iodide, heating to 70 ℃, carrying out reflux reaction for 24h, cooling to room temperature, carrying out reduced pressure distillation on the solvent, drying the solvent in a spin-drying manner, precipitating the solvent by using a mixed solvent of normal hexane and dichloromethane, carrying out suction filtration, redissolving the precipitate by using 5mL of acetonitrile, adding 25mL of saturated potassium hexafluorophosphate solution, stirring for 2h at room temperature, and removing water by suction filtration after the reaction is finished because the product is completely insoluble in water; repeated washing with water and n-hexane finally gave 38mg of a dark red solid in 71.4% yield as β -PM-PIO (i.e. structure V).
Compound β -PM-PIO: 1 H NMR(500MHz,DMSO)δ(TMS,ppm):9.22(d,J＝10.0Hz,2H),8.39(d,J＝10.0Hz,2H),7.93-7.89(m,1H),7.61-7.53(m,2H),7.48-7.43(m,4H),7.36-7.33(m,4H),7.13-7.10(m,2H),7.06(d,J＝5.0Hz,4H),6.91(d,J＝10.0Hz,2H),6.88(d,J＝5.0Hz,1H),4.46(s,3H)4.15-4.11(m,2H),1.26-1.24(m,3H). 13 C NMR(125MHz,DMSO)δ(TMS,ppm):150.68(d,J＝17.6Hz),147.23(d,J＝95.0Hz),146.78,146.41,139.78(d,J＝32.8Hz),137.56(d,J＝27.7Hz),133.80,132.11(d,J＝3.8Hz),130.98(d,J＝12.6Hz),129.62,129.55,129.46,128.51,128.20(d,J＝8.8Hz),126.77,126.21(d,J＝97.5Hz),125.84,125.19(d,J＝110.0Hz),124.56,123.77,123.23,123.15(d,J＝13.75Hz),122.01,62.50(d,J＝6.3Hz),47.98,16.19(d,J＝6.3Hz).HRMS(C 38 H 32 N 2 O 2 PS + ):m/z 611.1943(M + ,calcd 611.1917).
experimental example 1
The compound α -Th-TPA- β -Py-PIO of example 2 and the compound β -Th-TPA- α -Py-PIO were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor at a concentration of 1 mM. The active oxygen generating capacity of both compounds in phosphate buffered saline was tested using 2',7' -dichloro fluorogenic diacetate as an active oxygen indicator. The final concentration of the compound was 1. Mu.M and the final concentration of the indicator was 10. Mu.M. Fluorescence wavelength intensity at 522nm with illumination time (10 mW/cm 2 White light) to indicate the rate of active oxygen production, the results are shown in figure 1. As can be seen from FIG. 1, the compound alpha-Th-TPA-beta-Py-PIO and the compound beta-Th-TPA-alpha-Py-PIO both have strong active oxygen generating capacity in phosphate buffer salt solution.
Experimental example 2
The compound α -Th-TPA- β -Py-PIO of example 2 and the compound β -Th-TPA- α -Py-PIO were dissolved in dimethyl sulfoxide (DMSO) to prepare a mother liquor at a concentration of 1 mM. Using sea-drawn cells as a cell model, incubating for 24h in a 96-well plate, after the sea-drawn cells are attached, incubating with a culture medium containing compounds at different concentrations under dark conditions for 24h, removing the culture medium, adding 0.5mg/mL of 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide (MTT), after 2-4h, removing MTT, adding DMSO, detecting absorption at 575nm by using an enzyme-labeled instrument, and calculating the survival rate of cells at different concentrations to reflect the biocompatibility, wherein the result is shown in fig. 2. As can be seen from FIG. 2, the compounds α -Th-TPA- β -Py-PIO and β -Th-TPA- α -Py-PIO have good biocompatibility, and in particular, the compound α -Th-TPA- β -Py-PIO has negligible toxicity to cells even at a high concentration of 30. Mu.M.
The compound α -Th-TPA- β -Py-PIO of example 2 and the compound β -Th-TPA- α -Py-PIO were dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Sea-tangled cells were used as cell model, incubated in 96-well plates for 24h, after which media containing different concentrations of the compounds were added after adherence, after 2h, a white light source (10 mW/cm 2 ) Illumination is carried out for 5min, incubation is continued for 24h under dark conditions, the culture medium is removed, MTT with the concentration of 0.5mg/mL is added, DMSO is added after MTT is removed and DMSO is added, absorption at 575nm is detected by using a microplate reader, and after calculation treatment, the survival rate of cells at different concentrations is obtained to reflect the photodynamic therapy effect, and the result is shown in figure 2. As can be seen from FIG. 2, the compound α -Th-TPA- β -Py-PIO and the compound β -Th-TPA- α -Py-PIO have good photodynamic killing effect, and half the killing of cells can be achieved at a concentration of 1. Mu.M.
Experimental example 3
The compound α -Th-TPA- β -Py-PIO of example 2, the compound β -Th-TPA- α -Py-PIO, and the compound β -PM-PIO of example 3 were dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Using sea-tangled cells as a cell model, incubation was performed in confocal dishes for 24h, after which 1. Mu.M of the compound-containing medium was added, after which 2h the fluorescence signal at 488nm excitation wavelength was observed using a confocal microscope, and the results are shown in FIG. 3. From FIG. 3, it can be seen that the non-alkylated molecules (compound α -Th-TPA- β -Py-PIO, compound β -Th-TPA- α -Py-PIO) are able to penetrate the cell membrane, target the endoplasmic reticulum, lysosomes, etc., while the alkylated compound β -PM-PIO targets the cell membrane.
Experimental example 4
The compound of example 3, β -PM-PIO, was dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Using sea-drawn cells as a cell model, incubating for 24 hours in a 96-well plate, after the sea-drawn cells are attached, incubating for 24 hours with a culture medium containing compounds with different concentrations under dark conditions, removing the culture medium, adding 0.5mg/mL of MTT, adding DMSO after 2-4 hours, removing MTT, detecting absorption at 575nm by using an enzyme-labeled instrument, and calculating to obtain the cell viability at different concentrations to reflect the biocompatibility of the cells, wherein the result is shown in FIG. 4. As can be seen from FIG. 4, the compound β -PM-PIO has good biocompatibility, and in particular, the compound α -Th-TPA- β -Py-PIO has negligible toxicity to cells even at a high concentration of 30. Mu.M.
The compound of example 3, β -PM-PIO, was dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Sea-tangled cells were used as cell model, incubated in 96-well plates for 24h, after which media containing different concentrations of the compounds were added after adherence, after 2h, a white light source (40 mW/cm 2 ) Illumination is carried out for 10min, incubation is continued for 24h under dark conditions, the culture medium is removed, 0.5mg/mL of MTT is added, after 2-4h, DMSO is added into MTT is removed, absorption at 575nm is detected by using a microplate reader, and after calculation treatment, the survival rate of cells at different concentrations is obtained to reflect the photodynamic therapy effect, and the result is shown in figure 4. As can be seen from FIG. 4, the compound β -PM-PIO has good photodynamic killing effect, but the required concentration and illumination intensity is higher than that of the non-alkylated compound (α -Th-TPA- β -Py-PI)O and β -Th-TPA- α -Py-PIO) are higher.
Experimental example 5
The compound of example 3, β -PM-PIO, was dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Bacteria were diluted 1×10 with phosphate buffered saline using staphylococcus aureus as a model of microorganisms 5 Is a bacterial liquid of (a) a strain. Bacterial solutions containing different concentrations of compounds were added to 96-well plates at 100 μl per well. Culturing the 96-well plate on a shaker for 30min, and using white light source (10 mW/cm 2 ) Irradiation was carried out for 10min, the temperature was set at 37℃and the rotational speed was 170rpm. Cultivation was continued after illumination and the absorbance of bacteria at 600nm was measured at different time points (0 h,2h,4h,6h,8h,12h,16h,24 h) using an enzyme-labeled instrument, and the results are shown in FIG. 5. As can be seen from FIG. 5, the growth of bacteria was completely inhibited at a concentration of 5. Mu.M.
Experimental example 6
The compound of example 3, β -PM-PIO, was dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Bacteria were diluted 1×10 with phosphate buffered saline using staphylococcus aureus as a model of microorganisms 5 Is a bacterial liquid of (a) a strain. Bacterial solutions containing different concentrations of compounds were added to 96-well plates at 100 μl per well. Culturing 96-well plate on shaking table for 30min, and adding white light source (40 mW/cm 2 ) Irradiation was carried out for 10min, the temperature was set at 37℃and the rotational speed was 170rpm. Cultivation was continued for 16 hours after the irradiation, and the absorption of bacteria at 600nm was measured using a microplate reader, and the results are shown in FIG. 6. As can be seen from fig. 6, the compound at a concentration of 5 μm can completely inhibit the growth of bacteria under the synergistic effect of dark toxicity and phototoxicity, and the antibacterial effect after the light treatment is more obvious.
Experimental example 7
The compound β -PM-PIO of example 3 and the compound α -Th-TPA- β -Py-PIO of example 2 were dissolved in DMSO to prepare mother solutions at a concentration of 1mM, respectively. Bacteria were diluted 1×10 with phosphate buffered saline using staphylococcus aureus as a model of microorganisms 8 Is a bacterial liquid of (a) a strain. After 10min of reaction with 1. Mu.M of the compound, 5. Mu.L of the mixture was placed on a slide glass, and the fluorescence signal at an excitation wavelength of 488nm was observed by using a confocal microscope, and the result is shown in FIG. 7. Compare A, B in FIG. 7It is known that alkylated compounds (β -PM-PIO) have a greater bacterial labelling capacity than the non-alkylated compounds (α -Th-TPA- β -Py-PIO).
Experimental example 8
The compound of example 3, β -PM-PIO, was dissolved in DMSO to prepare a mother liquor at a concentration of 1 mM. Bacteria were diluted 1×10 with phosphate buffered saline using staphylococcus aureus as a model of microorganisms 5 Is a bacterial liquid of (a) a strain. 1mL of the solution was placed in a confocal cuvette and allowed to stand at 37℃in an incubator for 24 hours and 48 hours, respectively, and after biofilm formation, a phosphate buffer solution containing 5. Mu.M of the compound was added again, and after 10 minutes of action, fluorescence signals at 488nm excitation wavelength were observed by using a confocal microscope, and the results are shown in FIG. 8. The biofilm in B in fig. 8 is significantly denser than the biofilm in a, indicating that β -PM-PIO is not only able to rapidly label bacterial biofilms, but also to monitor biofilm growth.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (7)
1. A thiophene-bridge-containing phosphorus oxide derivative, characterized in that the thiophene-bridge-containing phosphorus oxide derivative is selected from one of the following structures:
wherein R is 1 Is C 1～12 Alkoxy groups of (a);
R 2 、R 3 、R 4 、R 5 、R 7 independently hydrogen;
R 8 is C 1～12 Alkyl of (a);
R 9 is PF (physical pattern) 6 - 。
2. The process for preparing a thiophene-bridge-containing phosphorus oxide derivative according to claim 1, comprising the steps of:
preparation of thiophene-bridge-containing phosphorus oxide derivatives of structure III or IV:
mixing a monobromo with a target substituent, terminal alkyne with the target substituent, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing a coupling reaction, and separating and purifying after the reaction is finished to obtain an internal alkyne intermediate; mixing an internal alkyne intermediate, a formula I, a catalyst and an organic solvent, heating and refluxing under the condition of nitrogen, performing cyclization reaction, and separating and purifying after the reaction is finished to obtain a phosphorus oxide derivative containing a thiophene bridge;
preparation of thiophene-bridge-containing phosphorus oxide derivatives of structure V or VI:
mixing a phosphorus oxide derivative containing a thiophene bridge with a structure III or IV, an alkylating reagent and an organic solvent, heating and refluxing, and recrystallizing after the reaction is finished to obtain a pyridinium phosphorus oxide derivative containing halogen anions; mixing a pyridinium phosphorus oxide derivative containing halogen anions, a potassium hexafluorophosphate solution and an organic solvent, reacting for 0.5-24 hours at room temperature, and washing after the reaction is finished to obtain a phosphorus oxide derivative containing thiophene bridges;
wherein, in the preparation of the thiophene-bridge-containing phosphorus oxide derivative with the structure III or IV, the structure of the monobromide with the target substituent is as follows:
the structure of the terminal alkyne with the target substituent is as follows:
the structure of the internal alkyne intermediate is shown below:
wherein R is 3 、R 4 、R 5 、R 7 Independently hydrogen;
the structure of formula I is shown below:
wherein R is 1 Is C 1～12 Alkoxy groups of (a);
R 2 is hydrogen;
the catalyst for the coupling reaction is a mixture of bis (triphenylphosphine) palladium dichloride and cuprous iodide;
in the preparation of the thiophene-bridge-containing phosphorus oxide derivative with the structure of V or VI, the structure of the pyridinium phosphorus oxide derivative containing halogen anions is shown as follows:
wherein R is 1 Is C 1～12 Alkoxy groups of (a);
R 2 、R 3 、R 4 、R 5 、R 7 independently hydrogen;
R 8 is C 1～12 Alkyl of (a);
x is halogen.
3. The method for preparing a thiophene-bridge-containing phosphorus oxide derivative according to claim 2, wherein in the preparation of the thiophene-bridge-containing phosphorus oxide derivative having the structure III or IV, the coupling reaction is a Sonogashira coupling reaction; the temperature of the coupling reaction is 70-85 ℃; the coupling reaction time is 6-24 hours; the volume ratio of the organic solvent for the coupling reaction is 2-4: 0.8 to 1.5 percent of triethylamine and tetrahydrofuran;
the temperature of the cyclization reaction is 80-150 ℃; the time of the cyclization reaction is 6-24 hours; the catalyst for the cyclization reaction is silver oxide, silver nitrate or silver acetate; the organic solvent for the cyclization reaction is one or more of N, N-dimethylformamide, 1, 4-dioxane and toluene.
4. The method for producing a thiophene-bridge-containing phosphorus oxide derivative according to claim 2, wherein in the production of the thiophene-bridge-containing phosphorus oxide derivative having the structure V or VI, the alkylating agent is methyl iodide.
5. The method for preparing a thiophene-bridge-containing phosphorus oxide derivative according to claim 2 or 4, wherein in the preparation of the thiophene-bridge-containing phosphorus oxide derivative having the structure V or VI, the organic solvent in the first reaction is one or more of acetonitrile, toluene and dioxane, and the organic solvent in the second reaction is acetonitrile or dioxane.
6. The method for preparing a thiophene-bridge-containing phosphorus oxide derivative according to claim 5, wherein in the preparation of the thiophene-bridge-containing phosphorus oxide derivative having the structure V or VI, the temperature of the heating reflux is 80 to 150 ℃; the heating reflux time is 0.5-24 h.
7. The use of a thiophene-bridge-containing phosphorus oxide derivative according to claim 1 in the preparation of a medicament for photodynamic therapy of cervical cancer.
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