CN114621290A - Phosphocorrole compounds with different spatial structures and preparation method and application thereof - Google Patents
Phosphocorrole compounds with different spatial structures and preparation method and application thereof Download PDFInfo
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- CN114621290A CN114621290A CN202210232860.2A CN202210232860A CN114621290A CN 114621290 A CN114621290 A CN 114621290A CN 202210232860 A CN202210232860 A CN 202210232860A CN 114621290 A CN114621290 A CN 114621290A
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- corrole
- phosphorus
- different spatial
- solvent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 phosphorus corrole compound Chemical class 0.000 claims abstract description 34
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 33
- 239000011574 phosphorus Substances 0.000 claims abstract description 33
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 74
- LYNARWYQOUZXDY-UHFFFAOYSA-N corrole Chemical compound N1C(C=C2NC(=CC=3NC4=CC=3)C=C2)=CC=C1C=C1C=CC4=N1 LYNARWYQOUZXDY-UHFFFAOYSA-N 0.000 claims description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 10
- UOTMHAOCAJROQF-UHFFFAOYSA-N 4-hydroxy-3-bromo-benzaldehyde Natural products OC1=CC=C(C=O)C=C1Br UOTMHAOCAJROQF-UHFFFAOYSA-N 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- CRBZVDLXAIFERF-UHFFFAOYSA-N 2,4,6-trimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C(OC)=C1 CRBZVDLXAIFERF-UHFFFAOYSA-N 0.000 claims description 6
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
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- 238000002474 experimental method Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000006862 quantum yield reaction Methods 0.000 description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 4
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1074—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms
- C09K2211/1085—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms with other heteroatoms
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Abstract
The invention discloses a phosphorus corrole compound with different space structures and a preparation method and application thereof. The invention takes 5- (pentafluorophenyl) dipyrromethene compound and aldehyde as raw materials, and obtains a plurality of phosphorus corrole compounds with different space structures 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 high application value, and has the following structure: r1＝R2＝R4＝H，R3＝OH，R5＝Br；R1＝R2＝R5＝H，R3＝OH，R4＝Br；R1＝R5＝H，R2＝R3＝R4＝OCH3；R2＝R4＝H，R1＝R3＝R5＝OCH3；
Description
Technical Field
The invention belongs to the field of biochemistry, and particularly relates to a phosphorus corrole compound with different space structures, and a preparation method and application thereof.
Background
Photodynamic therapy (PDT) is a new method of treatment for a variety of diseases, including cancer and infectious microorganisms. Photosensitizers, when excited by radiation, transfer energy to adjacent molecular oxygen, thereby generating toxic Reactive Oxygen Species (ROS) that ultimately lead to cancer cell death. PDT treatment can induce irreversible damage to the cell membrane, mitochondria and lysosomal structures of tumor cells, ultimately leading to their death, and compared to conventional treatments such as surgery, chemotherapy or radiotherapy, photodynamic therapy has the advantages of less trauma, low toxicity to surrounding tissues, and high selectivity. In addition, it is non-resistant, can be continuously treated repeatedly, and protects the organs. An ideal photodynamic therapy drug should be able to target tumor cells and eliminate rapidly. Corrole (corrole) compounds, as an important class of molecules in the porphyrin family, although they do not exist in nature, have a structural framework similar to the corrin (corrin) ring in vitamin B12, and belong to the porphyrin family compounds with a constricted cavity; on the other hand, the corrole has an 18 pi conjugated electron system and three intra-ring proton hydrogens, so that the corrole can show unique photophysical properties, remarkable coordination chemical capacity and chemical activity. With the intensive research on the synthesis, properties and application of Corrole compounds by researchers, the Corrole derivatives have a very wide application prospect in the fields of catalytic chemistry, biochemistry, photochemistry, electrochemistry, coordination chemistry and the like. Corroles have stronger Q-band absorption and are easier to metabolize than porphyrins because of their poor structural stability, but studies on the photodynamic therapy of corrole have yet to be further developed. The research result shows that the monohydroxycorrole compound has better phototoxicity on NPC cells of nasopharyngeal carcinoma, the corrole photosensitizer is mainly distributed on the mitochondria of the cancer cells and mainly destroys the cancer cells through an apoptosis pathway (the reference is shown in ZHENhua Liang, Haiyang Liu, Guangbin Jiang, et al. Chinese Journal of Chemistry,2016,34(10): 997-1005). Results of in vitro photodynamic activity studies indicate that polyhydroxy corrodes exhibit significant phototoxicity to human tumor cells HeLa, A549, BEL-7402 and HepG2 and accumulate predominantly in the nuclei of tumor cells, which effect photodynamic therapy mainly through Reactive Oxygen Species (ROS) -mediated mitochondrial damage and damage to intracellular DNA (see, Zhen-Hua Liang, Hai-Yang Liu, Rong Zhou, et al. journal of Membrane Biology,2016,249(4): 419-428). The hydroxyl-substituted corrole and the gallium (III) complex thereof have the best photodynamic activity on breast cancer and have low toxicity on normal cells. Cellular uptake and intracellular localization experiments have shown that p-hydroxycarbazole and its gallium (III) complex are rapidly taken up by MDA-MB-231 cells of breast cancer cells and are mainly localized in mitochondria and lysosomes, and in vivo experiments have shown that it has good biosafety (see Yan-Mei Sun, Xiao Jiang, Ze-Yu Liu, et al. The invention synthesizes a plurality of new phosphorus corrodes with different space structures, improves the hydrophilicity, the fluorescence intensity and the cellular uptake, and the compound has not been reported so far.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention aims to provide the phosphorus corrole compound with different space structures. The compounds have utility as photosensitizers for force therapy.
The invention also aims to provide a preparation method of the phosphorus corrole compound with different space structures.
The invention further aims to provide application of the phosphorus corrole compound with different spatial structures.
The purpose of the invention is realized by the following technical scheme:
phosphorus corrole compound of different space structures, its structural formula is as follows:
wherein, the compound I: r1＝R2＝R4＝H，R3＝OH，R5＝Br；
Compound ii: r is1＝R2＝R5＝H，R3＝OH，R4＝Br；
Compound III: r1＝R5＝H，R2＝R3＝R4＝OCH3；
A compound IV: r2＝R4＝H，R1＝R3＝R5＝OCH3。
The preparation method of the phosphorus corrole compound with different spatial structures comprises the following steps:
(1) taking a solvent as a medium, carrying out cyclization reaction on a 5- (pentafluorophenyl) dipyrromethene compound and aldehyde under the catalysis of trifluoroacetic acid, and oxidizing 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) to generate a corrole compound;
(2) and (2) under the atmosphere of nitrogen or inert gas, taking a solvent as a medium, and carrying out reflux reaction on the corrole compound obtained in the step (1) and phosphorus trichloride to obtain the phosphorus corrole complex.
Preferably, the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound to the 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (DDQ) to the aldehyde in the step (1) is 2-3: 1, 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 cyclization and the oxidation reaction in the step (1) are both 20-40 ℃, and the time of the cyclization reaction is 6-12 h; the time of the oxidation reaction is 1-4 h.
Preferably, triethylamine is 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 the trifluoroacetic acid to the aldehyde in the step (1) is 0.05-1: 1.
Preferably, the solvent in step (1) is dichloromethane, and the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound to the solvent is 1 mmoL: 60-160 mL.
Preferably, the solvent of step (2) is pyridine.
Preferably, the molar ratio of the corrole compound to the phosphorus trichloride in the step (2) is 1: 30 to 100.
Preferably, the molar to solvent ratio of the corrole compound in step (2) is 1 mmoL: 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 process of the phosphorus corrole compound is as follows:
the application of the phosphorus corrole compound with different space structures in the field of photosensitizer medicine preparation.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention synthesizes the phosphorus corrole compounds with different space structures, phosphorus coordination atoms are introduced into corrole, the light absorption intensity and the fluorescence intensity of a Q band are increased, the hydrophilicity, the light stability and the fluorescence quantum yield are improved, meanwhile, the phosphorus corrole belongs to non-metal coordination corrole, phosphorus belongs to essential elements of a human body, and the product phosphorus of the complete decomposition of the phosphorus corrole in the human body almost has no toxic or side effect. Hydroxyl is introduced into the corrole benzene ring, so that water solubility and biocompatibility can be improved, and the difference between the singlet quantum yield and the photodynamic effect caused by the difference of the hydroxyl at the benzene ring positions is obvious. The introduction of heavy atoms (bromine) on the corrole benzene ring has influence on photophysical properties, singlet quantum yield and the activity of the optical nuclease. Hydroxyl is introduced into para-position of benzene ring at the pyrrole meso position of phosphorus, and when heavy atom bromine is introduced into ortho-position and meta-position, the singlet quantum yield is obviously improved, and the photodynamic phototoxicity and dark toxicity are obviously improved, wherein when bromine is in meta-position, the phototoxicity is obviously superior to that of bromine at ortho-position. Methoxy groups are introduced into 2,4,6 or 3,4,5 benzene rings at meso positions of the corrole, the aggregation effect between corrole molecules is possibly weaker than that of hydroxyl groups, and when monohydroxy or dihydroxyl is on the benzene rings at meso positions, the photodynamic dark toxicity is high, and the dihydroxyl dark toxicity is higher than that of the monohydroxy. When methoxy groups are introduced into 2,4,6 or 3,4,5 benzene rings at the meso position of the phosphorocalized, the dark toxicity is obviously reduced, the phototoxicity is obviously improved, the phototoxicity on lung cancer (A549), breast cancer (MAD-MB-231) and liver cancer (HepG2) is very excellent, and the photodynamic action on various cancer cells is not found in other existing corroles.
Drawings
FIG. 1 shows the maximum absorbance of Soret bands for 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 the embodiments of the present invention are not limited thereto.
Those who do not specify specific conditions in the examples of the present invention follow conventional conditions or conditions recommended by the manufacturer. The raw materials, reagents and the like which are not indicated for manufacturers are all conventional products which can be obtained by commercial purchase.
Example 1
The synthesis process of the 2-bromo-4-hydroxyphosphatemopyrrole complex (compound I) is described in two steps:
(1) synthesis of 2-bromo-4-hydroxycholol
8.011mmoL 5- (pentafluorophenyl) dipyrromethene Compound 2.5g, 3.241mmoL 2-bromo-4-hydroxy648mg of benzaldehyde in 500mL of dry methylene Chloride (CH)2Cl2) After stirring for 5min, 0.16mL of trifluoroacetic acid (TFA) was added, and after stirring at room temperature for 12h, 0.32mL of triethylamine (Et)3N), stirring for 10min at room temperature, adding 6.482mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ)1.472g, stirring for 1h at room temperature, evaporating dichloromethane under reduced pressure, purifying by column chromatography, developing solvent dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio 1:1, yielding 389mg of 2-bromo-4-hydroxycarbazole (yield 15%).
(2) Synthesis of 2-bromo-4-hydroxyphosphere corrole complexes
0.125mmoL 2-bromo-4-hydroxycarbole 100mg, 10mmoL phosphorus trichloride 0.873mL in 30mL dry pyridine, placing under nitrogen protection, reacting at 128 deg.C for 2h, slowly adding 1mL water at room temperature, extracting, removing solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated salt water for 3 times, and anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, developing solvent ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:1 gave 68mg of 2-bromo-4-hydroxyphosphaeric corrole complex (yield 63%).1H NMR(500MHz,CDCl3+10vol％CD3OD)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).19F NMR(471MHz,CDCl3+10vol％CD3OD)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).31P NMR(202MHz,CDCl3+10vol％CD3OD)δ-173.53.
The high-resolution mass spectrum is shown in FIGS. 2-3.
Example 2
The synthesis process of the 3-bromo-4-hydroxyphosphere-corrole complex (compound II) is described in two steps:
(1) synthesis of 3-bromo-4-hydroxycholol
8.011mmoL 5- (pentafluorophenyl) dipyrromethene 2.5g, 3.241mmoL 3-bromo-4-hydroxybenzaldehyde 648mg in 500mL dry dichloromethane (CH)2Cl2) While stirring for 5min, 0.16mL trifluoroacetic acid (T) is addedFA), stirred at room temperature for 12h, 0.32mL triethylamine (Et) was added3N), stirring for 10min at room temperature, adding 6.482mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ)1.472g, stirring for 1h at room temperature, evaporating dichloromethane under reduced pressure, purifying by column chromatography, developing solvent dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio 1:1, 337mg of 3-bromo-4-hydroxycarbole was obtained (yield 13%).
(2) Synthesis of 3-bromo-4-hydroxyphosphere corrole complexes
0.125mmoL 3-bromo-4-hydroxycarbole 100mg, 10mmoL phosphorus trichloride 0.873mL in 30mL dry pyridine, placing under nitrogen protection, reacting at 128 deg.C for 2h, slowly adding 1mL water at room temperature, extracting, removing solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated salt water for 3 times, and anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:1 gave 86mg of 3-bromo-4-hydroxyphosphaeric corrole complex (yield 80%).1H NMR(500MHz,CDCl3+10vol％CD3OD)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).19F NMR(471MHz,CDCl3+10vol％CD3OD)δ-140.12–-140.34(m,4F),-156.06(t,J＝20.0Hz,2F),-164.88–-165.10(m,4F).31P NMR(202MHz,CDCl3+10vol％CD3OD)δ-177.93.
The high-resolution mass spectrum is shown in FIGS. 4-5.
Comparative example 1
The synthesis process of the 2, 4-dihydroxyphosphorus corrole complex (compound V) is described by three steps:
(1) synthesis of 2, 4-dimethoxycorrole
1.282mmoL 5- (pentafluorophenyl) dipyrromethene 400mg, 0.641mmoL 2, 4-dimethoxybenzaldehyde 106mg, in 200mL dry dichloromethane (CH)2Cl2) Stirring for 5min, adding 0.04mL trifluoroacetic acid (TFA), stirring at room temperature for 12h, and adding 0.08mL triethylamine (Et)3N), stirring for 10min at room temperature, adding 1.282mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ)292mg,stirring at room temperature for 1h, evaporating dichloromethane under reduced pressure, and purifying by column chromatography, wherein a developing agent is dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio of 1:2, 68mg of 2, 4-dimethoxycorrole was obtained (yield 14%).
(2) Synthesis of 2, 4-dihydroxycorroles
0.065mmoL 2, 4-Dimethylcholle 50mg in 50mL dry dichloromethane (CH)2Cl2) Stirring at-10 deg.C for 0.5 hr under protection of nitrogen, slowly adding 10.4mmoL of boron tribromide (1 moL/L in dichloromethane) 10.4mL, stirring at the same temperature for 0.5 hr, reacting at room temperature for 18 hr, slowly adding 11mL of methanol, extracting to kill reaction, evaporating solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated salt solution for 3 times, and collecting anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:4 gave 15mg of 2, 4-dihydroxycorrole (yield 31%).
(3) Synthesis of 2, 4-dihydroxyphosphocorrole complex
0.123mmoL 2, 4-dihydroxy corrole 90mg, 9.756mmoL phosphorus trichloride 0.851mL, in 30mL dry pyridine, nitrogen protection, reaction at 128 deg.C for 2h, then slowly adding 1mL water at room temperature to extract and kill reaction, distilling off solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated salt water for 3 times, anhydrous Na2SO4Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:1 gave 15mg of 2, 4-dihydroxyphosphorcarbazol complex (yield 15%).
The high-resolution mass spectrum is shown in FIGS. 6-7.
Comparative example 2
The synthesis process of the 3, 4-dihydroxyphosphocorrole complex (compound VI) is described by three steps:
(1) synthesis of 3, 4-dimethoxycorrole
1.282mmoL 5- (pentafluorophenyl) dipyrromethene 400mg, 0.641mmoL 3, 4-dimethoxybenzaldehyde 106mg, in 200mL dry dichloromethane (CH)2Cl2) After stirring for 5min, 0.04mL of trifluoroacetic acid (TFA) was added and the mixture was stirred at room temperature for 12hThen, 0.08mL of triethylamine (Et) was added3N), stirring at room temperature for 10min, adding 1.282mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ)292mg, stirring at room temperature for 1h, and evaporating dichloromethane (CH) under reduced pressure2Cl2) Column chromatography purification, wherein the developing solvent is dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio of 1:3, 57mg of 3, 4-dimethoxycorrole was obtained (yield 12%).
(2) Synthesis of 3, 4-dihydroxycorroles
0.13mmoL 3, 4-Dimethylcarbole 100mg in 100mL dry dichloromethane (CH)2Cl2) Under the protection of nitrogen, stirring at-10 deg.C for 0.5h, slowly adding 21mmoL boron tribromide (1 moL/L in dichloromethane) 21mL dropwise, stirring at the temperature for 0.5h, then reacting at room temperature for 18h, slowly adding 10.5mL methanol, extracting and quenching, evaporating under reduced pressure to remove solvent, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated salt water for 3 times, and removing anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing solvent is dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio of 1:4, 65mg of 3, 4-dihydroxycorrole was obtained (yield 68%).
(3) Synthesis of 3, 4-dihydroxyphosphocorrole complex
0.088mmoL 3, 4-dihydroxy corrole 65mg, 7.04mmoL phosphorus trichloride 0.614mL, in 30mL dry pyridine, nitrogen protection, reaction at 128 ℃ for 2h, then slowly adding 1mL water at room temperature to perform extraction and inactivation reaction, decompressing and distilling off the solvent, dissolving the residual solid with Ethyl Acetate (EA), extracting the organic phase with saturated salt water for 3 times, anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:1 gave 25mg of 3, 4-dihydroxyphosphorcarbazol complex (yield 36%).1H NMR(500MHz,Methanol-d4)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).19F 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).31P NMR(202MHz,Methanol-d4)δ-178.36.
The high-resolution mass spectrum is shown in FIGS. 8-9.
Example 3
The synthesis process of the 2,4, 6-trimethoxy phosphorus corrole complex (compound III) is described in two steps:
(1) synthesis of 2,4, 6-trimethoxy corrole
3.845mmoL 5- (pentafluorophenyl) dipyrromethene Compound 1.2g, 1.621 mmoL 2,4, 6-trimethoxybenzaldehyde 318mg, in 600mL dry dichloromethane (CH)2Cl2) After stirring for 5min, 0.12mL of trifluoroacetic acid (TFA) was added, the mixture was stirred at room temperature for 12h, and 0.24mL of triethylamine (Et) was added3N), stirring at room temperature for 10min, adding 736mg of 3.242mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ), stirring at room temperature for 1h, and evaporating dichloromethane (CH) under reduced pressure2Cl2) Column chromatography purification, wherein the developing solvent is dichloromethane: n-hexane (CH)2Cl2: HEX) volume ratio of 1:4, 39mg of 2,4, 6-trimethoxycorrole was obtained (yield 3%).
(2) Synthesis of 2,4, 6-trimethoxy phosphorus corrole complex
0.126mmoL 2,4, 6-trimethoxy carbazole 100mg, 9.915mmoL phosphorus trichloride 0.865mL, in 30mL dry pyridine, under nitrogen protection, reacting at 128 deg.C for 2h, slowly adding 1mL water at room temperature to perform extraction and quenching reaction, evaporating solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated saline solution for 3 times, and removing anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:4 gave 58mg of 2,4, 6-trimethoxyphosphonyl corrole complex (yield 54%).1H 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).19F 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).31P NMR(202MHz,Chloroform-d)δ-177.32,-184.28.
The high-resolution mass spectrum is shown in FIGS. 10-11.
Example 4
The synthesis process of the 3,4, 5-trimethoxy phosphorus corrole complex (compound IV) is described in two steps:
(1) synthesis of 3,4, 5-trimethoxy corrole
3.845mmoL 5- (pentafluorophenyl) dipyrromethene Compound 1.2g, 1.621 mmoL 3,4, 5-trimethoxybenzaldehyde 318mg, in 600mL dry dichloromethane (CH)2Cl2) After stirring for 5min, 0.12mL of trifluoroacetic acid (TFA) was added, the mixture was stirred at room temperature for 12h, and 0.24mL of triethylamine (Et) was added3N), stirring for 10min at room temperature, adding 736mg of 3.242mmoL 2, 3-dichloro-5, 6-dicyan p-benzoquinone (DDQ), stirring for 1h at room temperature, evaporating dichloromethane under reduced pressure, purifying by column chromatography with a developing agent CH2Cl2: HEX 1:4, 142mg of 3,4, 5-trimethoxycorrole was obtained (yield 11%).
(2) Synthesis of 3,4, 5-trimethoxy phosphorus corrole complex
0.126mmoL 3,4, 5-trimethoxy carbazole 100mg, 9.915mmoL phosphorus trichloride 0.865mL, in 30mL dry pyridine, under nitrogen protection, reacting at 128 deg.C for 2h, slowly adding 1mL water at room temperature to perform extraction and quenching reaction, evaporating solvent under reduced pressure, dissolving residual solid with Ethyl Acetate (EA), extracting organic phase with saturated saline solution for 3 times, and removing anhydrous sodium sulfate (Na)2SO4) Drying, purifying by column chromatography, and developing by ethyl acetate: n-hexane (EA: HEX) in a volume ratio of 1:5 to obtain 82mg (76% yield) of 3,4, 5-trimethoxyphosphorus corrole complex1H 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).19F 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).31P NMR(202MHz,Chloroform-d)δ-176.87,-184.07,-191.60.
The high-resolution mass spectrum is shown in FIGS. 12-13.
And simultaneously testing the light stability of the compound I, the compound II, the compound III, the compound V and the compound VI, wherein the method comprises the following steps:
preparing 10mmol/L DMSO solution of the phosphorus corrole complex for later use. Diluting the carbo-powder with a 3cm double-pass cuvetteThe pyrrole concentration was tested at 2.5. mu. mol/L. Placing the working solution in a red LED lamp (625 + -2 nm, 3W/m)2) Then, after irradiating for 0, 10, 20, 30, 40, 50 and 60min, respectively, the absorption 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.
Simultaneously, 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 corrole complex. A3 cm double-pass cuvette is adopted, 3mL of a solution containing 1 mu mol/L of corrole DMF is added firstly, and the absorbance of the corrole DMF at the wavelength of the LED lamp near 625nm is recorded. Subsequently, 6. mu.L of a 20mmol/L DPBF solution was added, at which point the final concentration of DPBF was 40. mu. mol/L, and stirred well. Then in an LED lamp (625 +/-2 nm, 3W/m)2) The change in absorbance at 417nm was recorded by irradiating for 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 and 120s, respectively. All experiments require measurement and correction of the absorbance at 417nm of DPBF caused by photobleaching. Solutions of Tetraphenylporphyrin (TPP) in DMF as reference for calculation of corrole1O2Quantum yield (phi)Δ0.62), the results are shown in table 1:
TABLE 1
The patent simultaneously carries out individual cancer cell in vitro cytotoxicity experiments on a compound I, a compound II, a compound III, a compound V and a compound VI, and the method comprises the following steps:
and (3) adopting an MTT method to research the cytotoxicity experiment of the phosphorus corrole complex. Taking log-phase cells, counting the cells, spreading in 96-well plates, the number of cells per well is about 5X 103Adding 100 μ L of the cells, and culturingMedium, placed in a cell incubator (37 ℃, 5% CO)2). And adding the phosphorus corrole complex for incubation when the cell grows to the density of about 80% in each hole, modifying the phosphorus corrole complex by DMSO and a cell culture medium, and finally enabling the volume ratio of the DMSO in each hole to be 1%. The control group was added with the same volume of PBS buffer. A minimum of 3 multiple wells per treatment group. After the phosphorus corrole complex is added, the temperature is kept at 37 ℃ and 5 percent of CO2Incubate for 4h at ambient. Red LED lamp for illumination group (625 +/-2 nm, 3W/m)2) The light is irradiated for 1h at the height of 20cm or so. After further incubation for 20h, the medium was discarded and 100. mu.L of cell culture medium containing 10. mu.L of 5mg/mL MTT solution was added to each well. MTT solution was added, incubation was continued for 4 hours, the medium was discarded, and DMSO (100. mu.L) was added to each well to dissolve formazan blue-violet crystal, followed by shaking for 15 min. The absorbance at 490nm was recorded using a multifunctional microplate reader. The DMSO control group was replaced by adding 1% DMSO in cell culture medium instead of drug. The results for the dark condition treatment group, i.e., no light treatment, are shown in table 2.
TABLE 2
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The phosphorus corrole compound with different spatial structures is characterized in that the structural formula is as follows:
wherein, the compound I: r1＝R2＝R4＝H，R3＝OH，R5＝Br；
Compound ii: r1＝R2＝R5＝H，R3＝OH，R4＝Br；
Compound iii: r is1＝R5＝H，R2＝R3＝R4＝OCH3；
A compound IV: r2＝R4＝H，R1＝R3＝R5＝OCH3。
2. The method for preparing the phosphorochloridite compound with different spatial structures in the claim 1 is characterized by comprising the following steps:
(1) taking a solvent as a medium, carrying out cyclization reaction on a 5- (pentafluorophenyl) dipyrromethene compound and aldehyde under the catalysis of trifluoroacetic acid, and oxidizing 2, 3-dichloro-5, 6-dicyan p-benzoquinone to generate a corrole compound;
(2) and (2) under the atmosphere of nitrogen or inert gas, taking a solvent as a medium, and carrying out reflux reaction on the corrole compound obtained in the step (1) and phosphorus trichloride to obtain the phosphorus corrole complex.
3. The method for preparing phosphocorrole compounds with different spatial structures according to claim 2, wherein the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone to the aldehyde in step (1) is 2-3: 1.
4. the method for preparing phosphorus corrole compounds with different steric structures according to claim 2, wherein the aldehyde in step (1) is one of 2-bromo-4-hydroxybenzaldehyde, 3-bromo-4-hydroxybenzaldehyde, 2,4, 6-trimethoxybenzaldehyde, and 3,4, 5-trimethoxybenzaldehyde.
5. The method for preparing phosphorochloridite compounds with different spatial structures according to claim 2, wherein the molar ratio of the corrole compound in the step (2) to the phosphorus trichloride is 1: 30 to 100.
6. The preparation method of the phosphorochloridite compound with different spatial structures according to claim 2, wherein the temperature of the cyclization and the oxidation reaction in the step (1) are both 20-40 ℃, and the time of the cyclization reaction is 6-12 h; the time of the oxidation reaction is 1-4 h.
7. The preparation method of the phosphorus corrole compound with different spatial structures according to claim 2, wherein the temperature of the reflux reaction in the step (2) is 120-130 ℃ and the time is 2-6 hours.
8. The preparation method of the phosphorocalole compound with different spatial structures according to claim 2, wherein triethylamine is added before the oxidation reaction in the step (1), and the molar ratio of the triethylamine to trifluoroacetic acid is 1-3: 1; the molar ratio of the trifluoroacetic acid to the aldehyde in the step (1) is 0.05-1: 1.
9. The method for preparing phosphorochloridite compounds with different spatial structures according to claim 2, wherein the solvent in the step (1) is dichloromethane; the molar ratio of the 5- (pentafluorophenyl) dipyrromethene compound to the solvent is 1 mmoL: 60-160 mL;
the solvent in the step (2) is pyridine; the molar ratio of the corrole compound to the solvent is 1 mmoL: 80-240 mL.
10. The use of a phosphacaroline compound of different steric structure according to claim 1 in the field of photosensitizer drug preparation.
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| CN115010946B (en) * | 2022-06-23 | 2024-03-15 | 华南理工大学 | Metal-organic coordination polymer M 2 CA X Preparation method and application thereof |
| CN115154601A (en) * | 2022-06-28 | 2022-10-11 | 华南生物医药研究院 | Preparation and application of corrole for potential photodynamic therapy of liver cancer |
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