CN114621290B - Phosphorus-carbole compound with different spatial structures, and preparation method and application thereof - Google Patents

Phosphorus-carbole compound with different spatial structures, and preparation method and application thereof Download PDF

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CN114621290B
CN114621290B CN202210232860.2A CN202210232860A CN114621290B CN 114621290 B CN114621290 B CN 114621290B CN 202210232860 A CN202210232860 A CN 202210232860A CN 114621290 B CN114621290 B CN 114621290B
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刘海洋
杨武
李梦媛
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South China University of Technology SCUT
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Abstract

The invention discloses a phosphorus-carbole compound with different spatial structures, and a preparation method and application thereof. The invention takes 5- (pentafluorophenyl) dipyrromethene compound and aldehyde as raw materials, and the phosphorus-carbole compound with various space structures is obtained through cyclization reaction, oxidation reaction and central atom coordination reaction in sequence. The compound can be used as a photosensitizer applied to photodynamic therapy, has higher application value, and has the following structure: r is R 1 ＝R 2 ＝R 4 ＝H，R 3 ＝OH，R 5 ＝Br；R 1 ＝R 2 ＝R 5 ＝H，R 3 ＝OH，R 4 ＝Br；R 1 ＝R 5 ＝H，R 2 ＝R 3 ＝R 4 ＝OCH 3 ；R 2 ＝R 4 ＝H，R 1 ＝R 3 ＝R 5 ＝OCH 3 ；

Description

Phosphorus-carbole compound with different spatial structures, and preparation method and application thereof
Technical Field
The invention belongs to the field of biochemistry, and particularly relates to a phosphorus-containing compound with different spatial structures, and a preparation method and application thereof.
Background
Photodynamic therapy (PDT) is a novel method of treating a variety of diseases, including cancer and infectious microorganisms. Upon irradiation, photosensitizers can transfer energy into adjacent molecular oxygen, thereby generating toxic Reactive Oxygen Species (ROS), ultimately leading to cancer cell death. PDT treatment can induce irreversible damage to cell membranes, mitochondria and lysosome structures of tumor cells, and finally causes death of the tumor cells, and compared with conventional treatments such as surgery, chemotherapy or radiotherapy, photodynamic therapy has the advantages of small wound, low toxicity to surrounding tissues and high selectivity. In addition, it is not resistant, can continue repeated treatments, and protects organs. An ideal photodynamic therapy drug should be able to target tumor cells and eliminate rapidly. The corrines (corrines) are important molecules in porphyrin families, and although they are not found in nature, their structural framework is similar to the corrines (corrines) ring in vitamin B12, belonging to the porphyrin family of cavity-tightening compounds; on the other hand, the carbole has an 18 pi conjugated electron system and three ring internal proton hydrogens, so that the carbole has unique photophysical performance, remarkable coordination chemical capability and chemical activity. With the deep research of the synthesis, properties and application of the carbole compound by scientific researchers, the Corroli derivative has very wide application prospect in the fields of catalytic chemistry, biochemistry, photochemistry, electrochemistry, coordination chemistry and the like. Corrrole has stronger Q-band absorption and is easier to metabolize than porphyrin because of their poor structural stability, but so far, studies on the photodynamic therapy of the corroles have been further developed. Research results show that the monohydroxy carbole compound has better phototoxicity to NPC cells of nasopharynx cancer, and the carbole photosensitizer is mainly distributed on mitochondria of the cancer cells and damages the cancer cells mainly through an apoptosis pathway (see Zhenhua Liang, haiyang Liu, guangbin Jiang, et al, chinese Journal of Chemistry,2016,34 (10): 997-1005). In vitro photodynamic activity studies have shown that polyhydroxy carboloy exhibits significant phototoxicity to human tumor cells HeLa, A549, BEL-7402 and HepG2 and aggregates predominantly in the nuclei of tumor cells, which effect photodynamic therapy primarily through Reactive Oxygen Species (ROS) -mediated mitochondrial damage and intracellular DNA damage (see, e.g., zhen-Huan Liang, hai-Yang Liu, rong Zhou, et al, journal of Membrane Biology,2016,249 (4): 419-428). The hydroxy-substituted carbole and its gallium (III) complex have the best photodynamic activity on breast cancer and have less toxicity on normal cells. Cell uptake and intracellular localization experiments indicate that p-hydroxy-carbole and its gallium (III) complex can be rapidly taken up by breast cancer cells MDA-MB-231 and are mainly localized in mitochondria and lysosomes, and in vivo experiments indicate that it has good biosafety (see, for reference, yan-Mei Sun, xiao Jiang, ze-Yu Liu, et al European Journal of Medicinal Chemistry,2020, 208:112794). The invention synthesizes a plurality of novel phosphorus carborols with different space structures, improves the hydrophilicity, the fluorescence intensity and the cell uptake, and the compound has not been reported so far.
Disclosure of Invention
To solve the drawbacks and disadvantages of the prior art, a primary object of the present invention is to provide a phosphorus-containing compound with different spatial structures. The compounds have utility as photosensitizers for force therapy.
Another object of the present invention is to provide a method for preparing the above-mentioned phosphorus-containing compound with different spatial structures.
It is still another object of the present invention to provide the use of a phosphorus-containing compound of different spatial structure as described above.
The invention aims at realizing the following technical scheme:
a phosphorus-containing compound with different spatial structures has the following structural formula:
wherein, compound I: r is R 1 ＝R 2 ＝R 4 ＝H，R 3 ＝OH，R 5 ＝Br；
Compound II: r is R 1 ＝R 2 ＝R 5 ＝H，R 3 ＝OH，R 4 ＝Br；
Compound iii: r is R 1 ＝R 5 ＝H，R 2 ＝R 3 ＝R 4 ＝OCH 3 ；
Compound IV: r is R 2 ＝R 4 ＝H，R 1 ＝R 3 ＝R 5 ＝OCH 3 。
The preparation method of the phosphorus-carbole compound with different spatial structures comprises the following steps:
(1) Taking a solvent as a medium, performing cyclization reaction on a 5- (pentafluorophenyl) dipyrromethene compound and aldehyde under the catalysis of trifluoroacetic acid, and generating a carbolic compound under the oxidation of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ);
(2) And (3) in the nitrogen or inert gas atmosphere, taking a solvent as a medium, and carrying out reflux reaction on the carbolic compound in the step (1) and phosphorus trichloride to obtain the phosphorus carbolic complex.
Preferably, the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) to aldehyde in step (1) is 2 to 3:1, wherein the aldehyde is one of 2-bromo-4-hydroxybenzaldehyde, 3-bromo-4-hydroxybenzaldehyde, 2,4, 6-trimethoxybenzaldehyde and 3,4, 5-trimethoxybenzaldehyde.
Preferably, the temperature of the epoxidation reaction and the oxidation reaction in the step (1) is 20-40 ℃, and the time of the epoxidation reaction is 6-12 h; the time of the oxidation reaction is 1-4 h.
Preferably, triethylamine is required to be added before the oxidation reaction in the step (1), and the molar ratio of the triethylamine to the trifluoroacetic acid is 1-3: 1.
preferably, the molar ratio of trifluoroacetic acid to aldehyde in step (1) is 0.05-1:1.
Preferably, the solvent in the step (1) is dichloromethane, and the volume ratio of the mol of the 5- (pentafluorophenyl) dipyrromethene compound to the solvent is 1mmoL: 60-160 mL.
Preferably, the solvent of step (2) is pyridine.
Preferably, the molar ratio of the carbolic compound to phosphorus trichloride in the step (2) is 1:30 to 100.
Preferably, the molar to solvent volume ratio of the carbolic compound of step (2) is 1mmoL: 80-240 mL.
Preferably, the temperature of the reflux reaction in the step (2) is 120-130 ℃ and the time is 2-6 h.
The preparation flow of the phosphorus carbozole compound is as follows:
the phosphorus-containing carbopol compound with different spatial structures is applied to the field of photosensitizer medicine preparation.
Compared with the prior art, the invention has the following advantages:
according to the invention, the phosphorus-containing compound with different space structures is synthesized, phosphorus coordination atoms are introduced into the phosphorus-containing compound, the light absorption intensity and the fluorescence intensity of Q bands are increased, the hydrophilicity, the light stability and the fluorescence quantum yield are improved, meanwhile, the phosphorus-containing compound belongs to nonmetallic coordination-containing compound, the phosphorus-containing compound belongs to essential elements of human bodies, and the phosphorus which is a product of complete decomposition of the phosphorus-containing compound in vivo is almost free from toxic and side effects. Hydroxyl is introduced into the carbolic ring, so that the water solubility and the biocompatibility can be improved, and the hydroxyl is different in the benzene ring position, so that the difference of the singlet quantum yield and the photodynamic effect is obvious. The introduction of heavy atoms (bromine) on the carbolic ring has effects on photophysical properties, singlet quantum yield and photo-nuclease activity. When hydroxyl is introduced into the para position of the benzene ring of the phosphorus carbomer, and heavy atom bromine is introduced into the ortho position and the meta position, the single-state quantum yield is obviously improved, and the phototoxicity and dark toxicity of photodynamic are obviously improved, wherein when bromine is in the meta position, the phototoxicity is obviously better than that of bromine in the ortho position. Methoxy groups are introduced into the benzene rings 2,4,6 or 3,4,5 at the positions of the meso, the aggregation effect between the meso molecules can be weaker compared with that of hydroxyl groups, and when the benzene rings at the positions of the meso are monohydroxy or dihydroxy, the photodynamic dark toxicity is large, and the dihydroxy dark toxicity is larger than the monohydroxy dark toxicity. When methoxy groups are introduced into phosphorus carbomer benzene rings 2,4,6 or 3,4,5, dark toxicity is obviously reduced, phototoxicity is obviously improved, phototoxicity to lung cancer (A549), breast cancer (MAD-MB-231) and liver cancer (HepG 2) is very excellent, and other existing carbomers have not found that the phosphorus carbomers have excellent photodynamic effects to various cancer cells at the same time.
Drawings
FIG. 1 shows the maximum absorbance of the Soret bands of compounds I to VI.
FIG. 2 is a high resolution mass spectrum of Compound I.
FIG. 3 is a high resolution mass spectrum of Compound I.
FIG. 4 is a high resolution mass spectrum of Compound II.
FIG. 5 is a high resolution mass spectrum of Compound II.
FIG. 6 is a high resolution mass spectrum of Compound V.
FIG. 7 is a high resolution mass spectrum of Compound V.
FIG. 8 is a high resolution mass spectrum of Compound VI.
FIG. 9 is a high resolution mass spectrum of Compound VI.
FIG. 10 is a high resolution mass spectrum of Compound III.
FIG. 11 is a high resolution mass spectrum of Compound III.
FIG. 12 is a high resolution mass spectrum of Compound IV.
FIG. 13 is a high resolution mass spectrum of Compound IV.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
The specific conditions are not noted in the examples of the present invention, and are carried out according to conventional conditions or conditions suggested by the manufacturer. The raw materials, reagents, etc. used, which are not noted to the manufacturer, are conventional products commercially available.
Example 1
The synthesis of 2-bromo-4-hydroxyphosphole-carbozole complex (Compound I) is described in two steps:
(1) Synthesis of 2-bromo-4-hydroxycarbazole
8.01mmoL 5- (pentafluorophenyl) dipyrromethene Compound 2.5g,3.241mmoL 2-bromo-4-hydroxybenzaldehyde 648mg, dried in 500mL of dichloromethane (CH) 2 Cl 2 ) In the above, stirring was carried out for 5min, 0.16mL of trifluoroacetic acid (TFA) was added thereto, and after stirring at room temperature for 12h, 0.32mL of triethylamine (Et) 3 N), stirring at room temperature for 10min, adding 6.480 mmol of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) 1.472g, stirring at room temperature for 1h, evaporating dichloromethane under reduced pressure, purifying by column chromatography, and developing solvent dichloromethane: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:1, giving 389mg (15% yield) of 2-bromo-4-hydroxy-carbole.
(2) Synthesis of 2-bromo-4-hydroxy phosphorus carbozole complex
0.125mmoL 2-bromo-4-hydroxy-carbole 100mg,10mmoL phosphorus trichloride 0.873mL, in 30mL dry pyridine, nitrogen protection, at 128 ℃ for 2h, slowly adding 1mL water at room temperature for extraction, evaporating solvent under reduced pressure,the residual solid was dissolved in Ethyl Acetate (EA), and the organic phase was extracted 3 times with saturated brine, and anhydrous sodium sulfate (Na 2 SO 4 ) Drying, column chromatography purification, developing solvent ethyl acetate: n-hexane (EA: HEX) volume ratio = 1:1, giving 68mg (63% yield) of 2-bromo-4-hydroxyphosphole carbolate complex. 1 H NMR(500MHz,CDCl 3 +10vol％CD 3 OD)δ9.27(dd,J＝4.5,2.3Hz,2H),8.83-8.66(m,6H),7.88(t,J＝11.1Hz,1H),7.40(t,J＝2.3Hz,1H),7.08(dd,J＝8.2,2.5Hz,1H). 19 F NMR(471MHz,CDCl 3 +10vol％CD 3 OD)δ-133.06(dt,J＝23.3,10.0Hz,2F),-133.41(dt,J＝23.2,14.4Hz,2F),-148.76(q,J＝20.7,16.4Hz,2F),-157.99(qd,J＝22.6,8.4Hz,4F). 31 P NMR(202MHz,CDCl 3 +10vol％CD 3 OD)δ-173.53.
The high resolution mass spectrum is shown in figures 2-3.
Example 2
The synthesis of 3-bromo-4-hydroxyphosphole-carbozole complex (Compound II) is described in two steps:
(1) Synthesis of 3-bromo-4-hydroxycarbazole
8.01mmoL 5- (pentafluorophenyl) dipyrromethene Compound 2.5g,3.241mmoL 3-bromo-4-hydroxybenzaldehyde 648mg, dried in 500mL of dichloromethane (CH) 2 Cl 2 ) In the above, stirring was carried out for 5min, 0.16mL of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 12h, and 0.32mL of triethylamine (Et) 3 N), stirring at room temperature for 10min, adding 6.480 mmol of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) 1.472g, stirring at room temperature for 1h, evaporating dichloromethane under reduced pressure, purifying by column chromatography, and developing solvent dichloromethane: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:1, giving 337mg of 3-bromo-4-hydroxy-carbole (13% yield).
(2) Synthesis of 3-bromo-4-hydroxy phosphorus carbozole complex
0.125mmoL 3-bromo-4-hydroxycarbazole 100mg,10mmoL phosphorus trichloride 0.873mL, in 30mL dry pyridine, nitrogen protection, at 128 ℃ for 2h, slowly adding 1mL water at room temperature for extraction, evaporating the solvent under reduced pressure, dissolving the residual solid with Ethyl Acetate (EA), extracting the organic phase 3 times with saturated saline solution, and anhydrous sodium sulfate (Na 2 SO 4 ) The drying is carried out,purifying by column chromatography, wherein the developing agent is ethyl acetate: n-hexane (EA: HEX) volume ratio = 1:1, yielding 86mg (80% yield) of 3-bromo-4-hydroxyphosphole carbolate complex. 1 H NMR(500MHz,CDCl 3 +10vol％CD 3 OD)δ9.47(dd,J＝4.5,2.5Hz,2H),9.01(dq,J＝7.9,4.4,3.9Hz,6H),7.63(d,J＝2.1Hz,1H),7.50(dd,J＝7.9,2.2Hz,1H),7.19(d,J＝7.9Hz,1H). 19 F NMR(471MHz,CDCl 3 +10vol％CD 3 OD)δ-140.12–-140.34(m,4F),-156.06(t,J＝20.0Hz,2F),-164.88–-165.10(m,4F). 31 P NMR(202MHz,CDCl 3 +10vol％CD 3 OD)δ-177.93.
The high resolution mass spectrum is shown in figures 4-5.
Comparative example 1
The synthesis of 2, 4-dihydroxyphosphorus carbozole complex (compound V) is described in three steps:
(1) Synthesis of 2, 4-dimethoxy carbole
1.282mmol of 5- (pentafluorophenyl) dipyrromethene compound 400mg,0.641mmoL 2,4-dimethoxybenzaldehyde 106mg in 200mL of dried dichloromethane (CH 2 Cl 2 ) Stirring for 5min, adding 0.04mL of trifluoroacetic acid (TFA), stirring at room temperature for 12h, and adding 0.08mL of triethylamine (Et 3 N), stirring at room temperature for 10min, adding 1.282mmol of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) 292mg, stirring at room temperature for 1h, evaporating dichloromethane under reduced pressure, purifying by column chromatography, wherein the developing solvent is dichloromethane: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:2, 68mg of 2, 4-dimethoxy carbole was obtained (14% yield).
(2) Synthesis of 2, 4-dihydroxyl carbole
0.065mmol of 2, 4-dimethoxy carbole 50mg in 50mL of dry dichloromethane (CH 2 Cl 2 ) In the presence of nitrogen, stirring at-10deg.C for 0.5h, slowly dropwise adding 10.4mmoL boron tribromide (1 moL/L in dichloromethane) 10.4mL, stirring at that temperature for 0.5h, standing at room temperature for 18h, slowly adding 11mL of methanol for extraction and deactivation, evaporating solvent under reduced pressure, dissolving residual solid in Ethyl Acetate (EA), extracting organic phase with saturated saline for 3 times, and extracting organic phase with anhydrous sodium sulfate (Na 2 SO 4 ) Drying, purifying by column chromatography, and developing with developing agentEthyl acetate: n-hexane (EA: HEX) volume ratio = 1:4, yielding 15mg (31% yield) of 2, 4-dihydroxycarbole.
(3) Synthesis of 2, 4-dihydroxyphosphorus carbole complex
0.123mmoL 2, 4-dihydroxycarbole 90mg,9.756mmoL phosphorus trichloride 0.851mL, in 30mL dry pyridine, under nitrogen protection, at 128 ℃ for 2h, then slowly adding 1mL water at room temperature for extraction and deactivation, evaporating solvent under reduced pressure, dissolving residual solid in Ethyl Acetate (EA), extracting organic phase with saturated saline for 3 times, anhydrous Na 2 SO 4 Drying, purifying by column chromatography, wherein the developing agent is ethyl acetate: n-hexane (EA: HEX) volume ratio=1:1, giving 15mg (15% yield) of 2, 4-dihydroxyphosphorus carbolate complex.
The high resolution mass spectrum is shown in figures 6-7.
Comparative example 2
The synthesis of 3, 4-dihydroxyphosphorus carbozole complex (compound VI) is described in three steps:
(1) Synthesis of 3, 4-dimethoxy carbole
1.282mmol of 5- (pentafluorophenyl) dipyrromethene compound 400mg,0.641mmoL 3,4-dimethoxybenzaldehyde 106mg in 200mL of dried dichloromethane (CH 2 Cl 2 ) In the above, stirring for 5min, then adding 0.04mL of trifluoroacetic acid (TFA), stirring at room temperature for 12h, and adding 0.08mL of triethylamine (Et) 3 N), stirring at room temperature for 10min, adding 1.282mmol of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) 292mg, stirring at room temperature for 1h, and evaporating dichloromethane (CH) under reduced pressure 2 Cl 2 ) Purifying by column chromatography, wherein the developing agent is methylene dichloride: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:3, giving 57mg of 3, 4-dimethoxy carbole (12% yield).
(2) Synthesis of 3, 4-dihydroxyl carbole
0.13mmoL 3, 4-dimethoxy carbole 100mg in 100mL dry dichloromethane (CH 2 Cl 2 ) In the presence of nitrogen, stirring at-10deg.C for 0.5h, slowly dropwise adding 21mmoL boron tribromide (1 moL/L in dichloromethane) 21mL, stirring at that temperature for 0.5h, reacting at room temperature for 18h, slowly adding 10.5mL methanol for extraction and deactivation, evaporating solvent under reduced pressure, and removing acetic acid ethyl acetateThe residual solid was dissolved in Ester (EA), and the organic phase was extracted 3 times with saturated brine, and anhydrous sodium sulfate (Na 2 SO 4 ) Drying, purifying by column chromatography, wherein the developing agent is methylene dichloride: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:4, giving 65mg of 3, 4-dihydroxycarbole (68% yield).
(3) Synthesis of 3, 4-dihydroxyphosphorus carbole complex
0.088mmoL 3, 4-dihydroxycarbole 65mg,7.04mmoL phosphorus trichloride 0.614mL, in 30mL dry pyridine, nitrogen protection, at 128 ℃ for 2h, then slowly adding 1mL water at room temperature for extraction and deactivation, decompressing and evaporating the solvent, dissolving the residual solid with Ethyl Acetate (EA), extracting the organic phase 3 times with saturated saline, and anhydrous sodium sulfate (Na 2 SO 4 ) Drying, purifying by column chromatography, wherein the developing agent is ethyl acetate: n-hexane (EA: HEX) volume ratio=1:1, yielding 25mg (36% yield) of 3, 4-dihydroxyphosphorus carbolate complex. 1 H NMR(500MHz,Methanol-d 4 )δ9.50(d,J＝3.1Hz,2H),9.03(q,J＝4.2Hz,4H),8.96(dd,J＝4.9,2.9Hz,2H),7.69(d,J＝8.1Hz,1H),6.78(d,J＝2.2Hz,1H),6.74(dd,J＝8.1,2.5Hz,1H). 19 F NMR(471MHz,Methanol-d4)δ-140.30(ddd,J＝55.9,23.5,9.9Hz,4F),-156.05(td,J＝20.5,8.6Hz,2F),-164.97(td,J＝21.2,20.8,9.5Hz,4F). 31 P NMR(202MHz,Methanol-d 4 )δ-178.36.
The high resolution mass spectrum is shown in figures 8-9.
Example 3
The synthesis of 2,4, 6-trimethoxy phosphorus carbozole complex (compound III) is described in two steps:
(1) Synthesis of 2,4, 6-trimethoxy-carbole
3.845mmoL 5- (pentafluorophenyl) dipyrromethene compound 1.2g,1.621mmoL 2,4,6-trimethoxybenzaldehyde 318mg in 600mL dry dichloromethane (CH) 2 Cl 2 ) In the above, stirring for 5min, then adding 0.12mL of trifluoroacetic acid (TFA), stirring at room temperature for 12h, and adding 0.24mL of triethylamine (Et) 3 N), stirring at room temperature for 10min, adding 736mg of 3.242mmoL 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ), stirring at room temperature for 1h, and evaporating dichloromethane (CH) under reduced pressure 2 Cl 2 ) Column chromatography purificationThe developing agent is methylene dichloride: n-hexane (CH) 2 Cl 2 : HEX) volume ratio = 1:4, yielding 39mg of 2,4, 6-trimethoxy carbole (3% yield).
(2) Synthesis of 2,4, 6-trimethoxy phosphorus carbole complex
0.126mmoL 2,4, 6-trimethoxy carbole 100mg,9.915mmoL phosphorus trichloride 0.865mL, in 30mL dry pyridine, nitrogen protection, placed at 128 ℃ for 2h, then slowly adding 1mL water at room temperature for extraction and deactivation, evaporating solvent under reduced pressure, ethyl Acetate (EA) dissolving residual solid, extracting organic phase with saturated saline 3 times, anhydrous sodium sulfate (Na 2 SO 4 ) Drying, purifying by column chromatography, wherein the developing agent is ethyl acetate: n-hexane (EA: HEX) volume ratio=1:4, giving 58mg (54% yield) of 2,4, 6-trimethoxy phosphorus carbolate complex. 1 H NMR(500MHz,Chloroform-d)δ9.31(qq,J＝5.4,2.3Hz,2H),8.86–8.78(m,6H),6.65–6.55(m,2H),4.09(d,J＝3.7Hz,3H),3.65–3.40(m,6H). 19 F NMR(471MHz,Chloroform-d)δ-136.78–-137.07(m,4F),-152.86(t,J＝19.3Hz,2F),-161.94(d,J＝24.3Hz,4F). 31 P NMR(202MHz,Chloroform-d)δ-177.32,-184.28.
The high resolution mass spectrum is shown in figures 10-11.
Example 4
The synthesis of 3,4, 5-trimethoxy phosphorus carbozole complex (compound IV) is described in two steps:
(1) Synthesis of 3,4, 5-trimethoxy-carbole
3.845mmoL 5- (pentafluorophenyl) dipyrromethene compound 1.2g,1.621mmoL 3,4,5-trimethoxybenzaldehyde 318mg in 600mL dry dichloromethane (CH) 2 Cl 2 ) In the above, stirring for 5min, then adding 0.12mL of trifluoroacetic acid (TFA), stirring at room temperature for 12h, and adding 0.24mL of triethylamine (Et) 3 N), stirring at room temperature for 10min, adding 3.242mmoL 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) 736mg, stirring at room temperature for 1 hr, evaporating dichloromethane under reduced pressure, purifying by column chromatography, and developing with CH as developing solvent 2 Cl 2 : hex=1:4, yielding 142mg of 3,4, 5-trimethoxy carbole (11% yield).
(2) Synthesis of 3,4, 5-trimethoxy phosphorus carbole complex
0.126mmoL 3,4, 5-trimethoxy carbole 100mg,9.915mmoL phosphorus trichloride 0.865mL, in 30mL dry pyridine, nitrogen protection, placed at 128 ℃ for 2h, then slowly adding 1mL water at room temperature for extraction and deactivation, evaporating solvent under reduced pressure, ethyl Acetate (EA) dissolving residual solid, extracting organic phase with saturated saline 3 times, anhydrous sodium sulfate (Na 2 SO 4 ) Drying, purifying by column chromatography, wherein the developing agent is ethyl acetate: n-hexane (EA: HEX) vol=1:5, giving 82mg (76% yield) of 3,4, 5-trimethoxy phosphorus carbolate complex 1 H NMR(500MHz,Chloroform-d)δ9.36(dtt,J＝11.1,4.5,2.3Hz,2H),9.07–8.96(m,2H),8.88(dt,J＝12.5,4.5Hz,4H),7.52–7.40(m,2H),4.21–4.11(m,3H),3.96(ddd,J＝12.5,6.4,3.5Hz,6H). 19 F NMR(471MHz,Chloroform-d)δ-136.68–-137.41(m,4F),-152.31(dh,J＝74.8,19.8,19.2Hz,2F),-161.56(ddd,J＝78.3,37.1,19.1Hz,4F). 31 P NMR(202MHz,Chloroform-d)δ-176.87,-184.07,-191.60.
The high resolution mass spectrum is shown in figures 12-13.
And simultaneously, the photostability of the compound I, the compound II, the compound III, the compound V and the compound VI is tested, and the method comprises the following steps:
preparing 10mmol/L of phosphorus-carbozole complex DMSO solution for later use. The test was performed using a 3cm two-way cuvette with a diluted carbol concentration of 2.5. Mu. Mol/L. The working solution of the cuvette was placed in a red LED lamp (625.+ -.2 nm, 3W/m) 2 ) After irradiation for 0, 10, 20, 30, 40, 50 and 60min, respectively, the absorbance spectra at 300-750nm were scanned, and the maximum absorbance of the Soret band was recorded for analysis, the results of which are shown in fig. 1.
Meanwhile, the singlet oxygen yield of the compound I, the compound II, the compound III, the compound IV, the compound V and the compound VI is tested, and the method comprises the following steps:
1, 3-diphenyl isobenzofuran (DPBF) is used as a probe to detect singlet oxygen generated by the phosphorus-carbole complex. 3mL of a 1. Mu. Mol/L solution containing carboDMF was added to a 3cm two-way cuvette, and the absorbance at about 625nm of the LED lamp was recorded. Subsequently, 6. Mu.L of 20mmol/L of DPBF solution was added, at which time the final DPBF concentration was 40. Mu. Mol/L,stirring uniformly. Then in the LED lamp (625+ -2 nm, 3W/m) 2 ) The absorbance at 417nm was recorded by irradiation for 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 and 120s, respectively. All experiments required measurement and correction of absorbance at 417nm of photo-bleaching induced DPBF. DMF solution of Tetraphenylporphyrin (TPP) as reference for calculation of the carbolic acid 1 O 2 Quantum yield (. Phi.) Δ =0.62), the results of which are shown in table 1:
TABLE 1
The patent carries out in vitro cytotoxicity experiments of individual cancer cells on the compound I, the compound II, the compound III, the compound V and the compound VI, and the steps are as follows:
and (3) researching a cytotoxicity experiment of the phosphorus-carbole complex by adopting an MTT method. Taking cells in log phase, counting the cells, paving 96-well plates, and the number of cells in each well is about 5 multiplied by 10 3 Then, 100. Mu.L of the cell culture medium was added thereto, and the mixture was placed in a cell culture tank (37 ℃ C., 5% CO) 2 ). And when the cells grow to the density of about 80% in each hole, adding a phosphorus-carbole complex for incubation, wherein the phosphorus-carbole complex is modified by DMSO and a cell culture medium, and the volume ratio of DMSO in the final hole is 1%. The control group was added with the same volume of PBS buffer. A minimum of 3 duplicate wells per treatment group. After adding the phosphorus-carbole complex, the mixture is continued to be processed at 37 ℃ and 5 percent CO 2 Incubate for 4h in the ambient. Red LED lamp for illumination group (625 + -2 nm, 3W/m) 2 ) The light is irradiated for 1h at the position with the height of about 20 cm. After further incubation for 20h, the medium was discarded and 100. Mu.L of cell culture medium containing 10. Mu.L of MTT solution at a concentration of 5mg/mL was added to each well. After further incubation for 4h with MTT solution, the medium was discarded, and DMSO (100. Mu.L) was added to each well to dissolve the blue-violet crystalline formazan and shaking-in for 15min. The absorbance at 490nm was recorded using a multifunctional microplate reader. DMSO control group, i.eThe above procedure was repeated, changing the drug addition treatment to the addition of cell culture medium containing 1% dmso. The results of the dark condition treatment group, i.e., the no light treatment, are shown in table 2.
TABLE 2
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (9)

1. A phosphorus-containing compound with different spatial structures is characterized by having the following structural formula:
wherein, compound I: r is R 1 ＝R 2 ＝R 4 ＝H，R 3 ＝OH，R 5 ＝Br；
Compound II: r is R 1 ＝R 2 ＝R 5 ＝H，R 3 ＝OH，R 4 ＝Br；
Compound iii: r is R 1 ＝R 5 ＝H，R 2 ＝R 3 ＝R 4 ＝OCH 3 ；
Compound IV: r is R 2 ＝R 4 ＝H，R 1 ＝R 3 ＝R 5 ＝OCH 3 。
2. The method for preparing a phosphorus-carbole compound with different spatial structures as claimed in claim 1, which is characterized by comprising the following steps:
(1) Taking a solvent as a medium, performing cyclization reaction on a 5- (pentafluorophenyl) dipyrromethene compound and aldehyde under the catalysis of trifluoroacetic acid, and then generating a carbolic compound under the oxidation of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone;
(2) In nitrogen or inert gas atmosphere, taking a solvent as a medium, and carrying out reflux reaction on the carbolic compound in the step (1) and phosphorus trichloride to obtain a phosphorus carbolic complex;
the aldehyde in the step (1) is one of 2-bromo-4-hydroxybenzaldehyde, 3-bromo-4-hydroxybenzaldehyde, 2,4, 6-trimethoxybenzaldehyde and 3,4, 5-trimethoxybenzaldehyde.
3. The method for preparing a phosphorus-carbole compound with different spatial structures according to claim 2, wherein the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone and aldehyde in the step (1) is 2-3: 1.
4. the method for preparing a phosphorus-containing compound with different spatial structures according to claim 2, wherein the molar ratio of the phosphorus-containing compound to phosphorus trichloride in the step (2) is 1:30 to 100.
5. The method for preparing a phosphorus-carbole compound with different space structures according to claim 2, wherein the temperature of the cyclization reaction and the oxidation reaction in the step (1) is 20-40 ℃, and the time of the cyclization reaction is 6-12 h; the time of the oxidation reaction is 1-4 h.
6. The method for preparing a phosphorus-carbole compound with different spatial structures according to claim 2, wherein the reflux reaction in the step (2) is carried out at a temperature of 120-130 ℃ for 2-6 h.
7. The method for preparing a phosphorus-carbole compound with different space structures according to claim 2, wherein triethylamine is required to be added before the oxidation reaction in the step (1), and the molar ratio of the triethylamine to the trifluoroacetic acid is 1-3: 1, a step of; the molar ratio of the trifluoroacetic acid to the aldehyde in the step (1) is 0.05-1:1.
8. The method for preparing a phosphorus-carbole compound with different spatial structures according to claim 2, wherein the solvent in the step (1) is dichloromethane; the volume ratio of the mol of the 5- (pentafluorophenyl) dipyrromethene compound to the solvent is 1mmoL: 60-160 mL;
the solvent in the step (2) is pyridine; the volume ratio of the mol of the carbole compound to the solvent is 1mmoL: 80-240 mL.
9. The use of a phosphorus-carbole compound of different spatial structures in the field of photosensitizer drug preparation as described in claim 1.
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