CN117659113A - Cholic alcohol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine and preparation method and application thereof - Google Patents
Cholic alcohol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine and preparation method and application thereof Download PDFInfo
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 title claims abstract description 78
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 55
- RWMKKWXZFRMVPB-UHFFFAOYSA-N silicon(4+) Chemical class [Si+4] RWMKKWXZFRMVPB-UHFFFAOYSA-N 0.000 title claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title abstract description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 116
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 54
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000008685 targeting Effects 0.000 claims abstract description 18
- 238000002428 photodynamic therapy Methods 0.000 claims abstract description 14
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 14
- JACPFCQFVIAGDN-UHFFFAOYSA-M sipc iv Chemical class [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].C=1C=CC=C(C(N=C2[N-]C(C3=CC=CC=C32)=N2)=N3)C=1C3=CC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 JACPFCQFVIAGDN-UHFFFAOYSA-M 0.000 claims abstract description 11
- BUMGIEFFCMBQDG-UHFFFAOYSA-N dichlorosilicon Chemical compound Cl[Si]Cl BUMGIEFFCMBQDG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002243 precursor Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- NVRVNSHHLPQGCU-UHFFFAOYSA-N 6-bromohexanoic acid Chemical compound OC(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000002438 mitochondrial effect Effects 0.000 claims abstract description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims abstract description 4
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000012632 fluorescent imaging Methods 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- 238000003760 magnetic stirring Methods 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000000799 fluorescence microscopy Methods 0.000 abstract description 8
- 210000003470 mitochondria Anatomy 0.000 abstract description 8
- 238000010992 reflux Methods 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000003463 organelle Anatomy 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- -1 Triphenylphosphine cation Chemical class 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000025608 mitochondrion localization Effects 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BIPMOHJEGXNOJY-UHFFFAOYSA-N C1(=CC=CC=C1)P(C1=CC=CC=C1)OC(O)=O Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)OC(O)=O BIPMOHJEGXNOJY-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910018557 Si O Inorganic materials 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SANFHSDFVUTGEA-UHFFFAOYSA-N dichlorosilicon(2+) Chemical compound Cl[Si+2]Cl SANFHSDFVUTGEA-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine and a preparation method and application thereof, wherein the preparation method comprises the following steps: (1) Preparing a precursor 6-triphenylphosphine-based hexanoic acid by magnetically stirring triphenylphosphine and 6-bromohexanoic acid in toluene solution; (2) Precursor 6-triphenylphosphine caproic acid and dichlorosilicon phthalocyanine, cholesterol and anhydrous K 2 CO 3 Reflux preparation of cholesterol and triphenylphosphine based modified asymmetric axial substituted silicon phthalocyanine in toluene, and application of the same as a novel photosensitizer for mitochondrial marking and fluorescence imaging guided photodynamic therapy in photodynamic therapyBecomes a mitochondrion targeting photosensitizer with application potential.
Description
Technical Field
The invention belongs to the field of complexes, in particular to cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (IV) phthalocyanine, and a preparation method and application thereof.
Background
Photodynamic therapy (PDT) has been used in the clinical treatment of various solid tumors such as skin, ophthalmic, breast and ovarian cancers. The photosensitizer is a core substance for PDT treatment, and phthalocyanine and derivatives thereof are used as a second-generation PDT treatment photosensitizer, and have the characteristics of large conjugated system, high extinction coefficient, high singlet oxygen quantum yield and the like, and are widely paid attention to. However, due to the strong interactions and hydrophobicity between the planar structures of phthalocyanines, they are prone to aggregation in aqueous and organic solvents, resulting in fluorescence quenching and reduced singlet oxygen quantum yields. In addition, the diffusion distance of singlet oxygen generated during PDT is limited, and it is difficult to achieve the maximization of the imaging guided photodynamic therapy effect. Organelles are an important component of cell survival, supporting normal function of the cell, and destruction of the organelles of tumor cells can accelerate cell death. Thus, the synthesis of water-soluble phthalocyanine photosensitizers with specific targeting organelles is one of the effective methods of improving the efficacy of PDT treatments.
In cells, cholesterol is abundant in a major part of various tissues and fat sheets and is also an important component of cell membrane systems, and cholesterol is transported in the blood mainly by human serum low density lipoproteins and preferentially interacts with tumor cell expression through receptor-mediated endocytosis. By limiting the usefulness of cholesterol and impeding the synthetic pathway of cholesterol, the growth of cancer cells can be prevented. It was found that molecules modified with cholesterol can interact with the membrane system enriched in cholesterol in cells. The introduction of cholesterol moieties into the photosensitizer facilitates accumulation of the photosensitizer in tumor tissue, targeting and uptake of the photosensitizer in cells. Triphenylphosphine (TPP) has been widely reported as a mitochondrial targeting group. Triphenylphosphine cation (TPP) + ) Covalently linked to lipophilic alkyl groups, alkylated triphenylphosphine selectively accumulated in the mitochondria due to the negative charge of the mitochondria.
Aiming at the problems of low solubility, easy aggregation, weak cell targeting capability and the like of phthalocyanine molecules, the introduction of cholesterol and Triphenylphosphine (TPP) groups with large steric hindrance and cell targeting capability at the axial position of the phthalocyanine is considered, on one hand, the phthalocyanine is endowed with larger steric hindrance to prevent the formation of aggregates and improve the solubility thereof, on the other hand, the Triphenylphosphine (TPP) groups with cell targeting capability are introduced into the phthalocyanine to facilitate the uptake of the phthalocyanine by cancer cells and improve the cell targeting capability thereof,
meanwhile, cholesterol is combined with a lipid layer as an anchor through hydrophobic interaction, so that the mediated TPP substituted phthalocyanine can be quickly and effectively ingested by cancer cells. Finally, no report on the related asymmetric axial substitution of silicon (IV) phthalocyanine modified by cholesterol and triphenylphosphine groups is available at home and abroad.
Disclosure of Invention
The invention aims to provide an asymmetric axial substituted silicon (IV) phthalocyanine modified by cholesterol and triphenylphosphine and a preparation method thereof.
The invention also provides application of the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine as a mitochondrion targeting marker and a fluorescence imaging guided photodynamic therapy photosensitizer.
The invention aims at realizing the following, namely the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex is a compound with the following structure:
the invention relates to a cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex: the cholesterol and triphenylphosphine group with large steric hindrance and cell targeting capability are respectively introduced into the axial positions of silicon phthalocyanine to synthesize a novel asymmetric silicon phthalocyanine complex. On the one hand, the steric hindrance of the cholesterol and triphenylphosphine groups inhibits the self-aggregation behavior of the phthalocyanine to a certain extent and improves the solubility of the phthalocyanine; on the other hand, the cholesterol and triphenylphosphine group can be quickly absorbed by cancer cells, and the targeting ability of mitochondria is provided, so that the targeting ability and bioavailability of tumor cells of phthalocyanine can be improved, and the cholesterol and triphenylphosphine group modified asymmetric silicon phthalocyanine complex becomes a fluorescent imaging agent and photodynamic therapy photosensitizer with potential.
The preparation method of the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine comprises the following steps: (1) Preparing a precursor 6-triphenylphosphine-based hexanoic acid by magnetically stirring triphenylphosphine and 6-bromohexanoic acid in toluene solution; (2) Precursor 6-triphenylphosphine caproic acid and dichlorosilicon phthalocyanine, cholesterol and anhydrous K 2 CO 3 Reflux-preparing cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon phthalocyanine in toluene.
Further, 6-bromophenyl caproic acid and triphenylphosphine are adopted as raw materials, the raw materials are magnetically stirred in toluene solution for preparation, chloroform and acetone are used for recrystallization after the reaction is finished, the mixture is placed in ice water bath for standing, and white crystals are obtained after the crystals are separated out, filtered by suction and dried in vacuum.
Further, the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon phthalocyanine in the step (2) is prepared by adopting dichlorosilicon phthalocyanine and 6-triphenylphosphine group caproic acid as raw materials and reacting with cholesterol in toluene solution under magnetic stirring, after the reaction is finished, dissolving and washing with dichloromethane, recovering an organic phase, removing a solvent by reduced pressure rotary evaporation, and separating and purifying a crude product by silica gel column chromatography by using dichloromethane/ethanol with the volume ratio of 50:1 as an eluent.
The invention relates to application of cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine as a mitochondrion targeting marker and a fluorescence imaging guided photodynamic therapy phthalocyanine photosensitizer.
Specifically, the preparation method of the cholesterol and triphenylphosphine group modified asymmetric axially substituted silicon (IV) phthalocyanine complex comprises the following steps:
(1) The precursor 6-triphenylphosphine-caproic acid (6-triphenylphosphine-caproic acid is called TPP-COOH for short) is prepared by stirring and refluxing triphenylphosphine and 6-bromocaproic acid in toluene at 120 ℃ for 18 hours in a reaction vessel (2) the precursor 6-triphenylphosphine-caproic acid (TPP-COOH) and di-phenyl-phosphinocarbonic acid are preparedChlorsilicon phthalocyanine, cholesterol, anhydrous K 2 CO 3 And (3) preparing cholesterol and triphenylphosphine group modified asymmetric axially substituted silicon) phthalocyanine (cholesterol and triphenylphosphine group modified asymmetric axially substituted silicon (IV) phthalocyanine is called Chol-SiPc-TPP for short) in toluene by reflux.
The 6-triphenylphosphine-based caproic acid (the 6-triphenylphosphine-based caproic acid is abbreviated as TPP-COOH) is preferably triphenylphosphine and 6-bromocaproic acid, toluene is stirred and refluxed at 120 ℃ for 18 hours in a reaction vessel, the mixture is cooled to room temperature after the reaction is finished, then the mixture is decompressed and concentrated, chloroform and acetone are used for recrystallization operation, the mixture is placed in a water bath at 0 ℃ for 2 hours, after crystals are separated out, suction filtration is carried out, white crystals are obtained, and the white crystals are obtained after the white crystals are dried in a vacuum drying oven at 60 ℃.
The cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex (cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine is called Chol-SiPc-TPP for short in the invention) is preferably dichlorosilicon (IV) phthalocyanine, cholesterol and anhydrous K 2 CO 3 Stirring and refluxing the mixture in toluene solution at 140 ℃ for 24 hours, and then continuously adding 6-triphenylphosphine-caproic acid (TPP-COOH) and anhydrous K 2 CO 3 And toluene was refluxed at 140 ℃ with stirring for 24 hours. After the reaction is finished and cooled to room temperature, filtering, dissolving and washing with dichloromethane, removing the solvent by rotary evaporation, purifying by a silica gel column by using dichloromethane/ethanol=50/1 (volume ratio) as an eluent, and drying to obtain blue powder.
The invention relates to application of the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex as a mitochondrion targeting marker and a fluorescence imaging guided photodynamic therapy phthalocyanine photosensitizer.
The invention has the beneficial effects that: the invention synthesizes a novel cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex with mitochondrial targeting markers and fluorescence imaging guided photodynamic therapy. The novel cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex not only can inhibit the aggregation behavior of the phthalocyanine to a certain extent by utilizing the steric hindrance of cholesterol and triphenylphosphine group structures, but also can improve the solubility of the silicon phthalocyanine and improve the tumor cell targeting capability of the silicon phthalocyanine by respectively introducing the cholesterol and the triphenylphosphine group into the axial position of the silicon phthalocyanine, thereby synchronously realizing fluorescence imaging and photodynamic therapy, and enabling the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon (IV) phthalocyanine complex to become a mitochondrion targeting photosensitizer with application potential.
Drawings
FIG. 1 is a graph of fluorescence imaging and mitochondrial localization of cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (IV) phthalocyanine (Chol-SiPc-TPP) in breast cancer cells.
FIG. 2 is a graph of the in vitro photodynamic activity of cholesterol and triphenylphosphine modified asymmetric axially substituted silicon (IV) phthalocyanine (Chol-SiPc-TPP) on breast cancer cells.
Detailed Description
The invention is illustrated in detail below with reference to examples:
example 1
1) Synthesis of 6-triphenylphosphine-caproic acid (abbreviated as TPP-COOH in the present invention)
Triphenylphosphine (1.97 g,7.5 mmol), 6-bromohexanoic acid (1.17 g,6 mmol), toluene (30 mL) were stirred and refluxed at 120 ℃ for 18 hours in a reaction vessel, cooled to room temperature after the reaction was completed, concentrated under reduced pressure, recrystallized by chloroform and acetone, kept stand in a water bath at 0 ℃ for 2 hours, filtered off with suction after crystals are separated out, white crystals were obtained, and dried in a vacuum drying oven at 60 ℃ to obtain white crystals (6-triphenylphosphine-hexanoic acid) (the invention is abbreviated as TPP-COOH) 1.9 g, with a yield of 84%. Synthesis characterization: 1 H NMR (400 MHz, CDCl3，δ/ppm) 7.81 (m, J = 56.2 Hz, 15H; H 1 ), 3.65 (t, J = 27.5 Hz, 2H; H 2 ), 2.41 (t, J = 13.3 Hz, 2H; H 3 ), 3.65 (m, J = 25.3 Hz, 6H; H 4 )。FR-IR nmax/cm -1 : 1117 (O-C=O), 1437 (H-C-H) 1707 (C=O), 3442 (-OH) 。
2) Synthesis of Chol-and triphenylphosphine-modified asymmetric axially substituted silicon (IV) phthalocyanine (abbreviated as Chol-SiPc-TPP in the invention)
To the dichlorosilane phthaleinCyanine SiPcCl 2 (0.24 g,0.40 mmol), cholesterol (0.15 g,0.40 mmol), anhydrous K 2 CO 3 (0.14 g,1.0 mmol) and toluene (30 mL) were placed in a 100 mL round bottom flask and after stirring and refluxing at 140℃for 24 hours, TPP-COOH (0.30 g,0.80 mmol) obtained in step 1, anhydrous K, were added 2 CO 3 (0.07 g,0.5 mmol) and toluene (30 mL) were stirred at 140℃under reflux for a further 24 hours. After the reaction is finished, cooling to room temperature, filtering, dissolving and washing with dichloromethane, rotationally steaming to remove the solvent, purifying by a silica gel column by using dichloromethane/ethanol) =50/1 (volume ratio) as an eluent, and drying to obtain blue powder (Chol-SiPc-TPP), wherein the yield is 12%. Synthesis characterization: 13 CNMR (δ/ppm): 166.89, 149.91(s), 135.43(s), 135.08(s), 134.89(s), 131.53(s), 130.49, 123.98(s), 118.46(s), 117.89(s), 117.75(s), 76.81(s), 35.89(s), 34.51(s), 34.01(s), 33.91, 31.84(s), 29.76(s), 29.29(s), 28.05(s), 27.73(s), 26.60(s), 25.57(s), 24.49(s), 24.36(s), 22.76(s), 21.70(s), 21.69(s), 19.72(s), 11.79(s). ESI-MS analysis shows that C 62 H 47 N 11 O 2 Si has a calculated M/z value of 1305.64, found to be 1305.17 [ M ]]。 FR-IR nmax/cm -1 : 3410, 2950 (aromatic C-H), 1670, 1520, 1470 (C-C), 1380, 1290 (C-O), 1060 (Si-O), 985, 841, 734。
Example two
The specific steps are the same as those in the first embodiment: in procedure 2), the TPP-COOH mass was changed to (0.60 g,1.60 mmol), the cholesterol mass was changed to (0.30 g,0.80 mmol), and the dichlorosilicon phthalocyanine SiPcCl 2 (0.48 g,0.80 mmol). Other reaction conditions were the same, and a blue powder was obtained in a yield of 21.48%.
Example III
The specific steps are the same as those in the first embodiment: in procedure 2), the TPP-COOH mass was changed to (1.20 g,3.20 mmol), the cholesterol mass was changed to (0.60 g,1.60 mmol), and the dichlorosilane phthalocyanine SiPcCl 2 (0.56 g,1.60 mmol). Other reaction conditions were the same, and a blue powder was obtained in 40.5% yield.
Example IV
Lysosome-lipid droplet targeted cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (IV) phthalocyanine (Chol-SiPc-TPP) fluorescence imaging and mitochondrial localization in breast cancer cells
MCF-7 cells were placed in 20 mm copolymerized Jiao Fuyo dishes at 37℃with 5% CO 2 For 12 hours. Old medium was removed, and the Chol-SiPc-TPP obtained in any of examples one to three was diluted to 2 mM with fresh medium and incubated with cells for 10 hours, respectively, and the cells were rinsed 3 times with phosphate buffer. Then, the cells were stained with a medium solution of Mito-Tracker (20 nM) at 37℃for 30 minutes in the absence of light, and observed under a confocal microscope. Chol-SiPc-TPP: two-photon excitation, excitation wavelength 860 nm, and collection wavelength 650-750 nm. Mito-Tracker: single photon excitation, excitation wavelength 488 nm, collection wavelength: 500-540 nm.
Evaluation of in vitro photodynamic Activity of mitochondrial Targeted Cholesterol and triphenylphosphine-modified asymmetric axial substituted silicon (IV) phthalocyanine (Chol-SiPc-TPP) on breast cancer cells
In order to examine the in vitro photodynamic effect of the prepared cholesterol and triphenylphosphine group modified asymmetric axially substituted silicon (IV) phthalocyanine (Chol-SiPc-TPP), a Cell Counting Kit-8 (CCK-8) cell activity detection kit was selected for carrying out cytotoxicity experiments. Density is 8×10 3 After the MCF-7 cells of each cell/well are inoculated into a 96-well plate for incubation for 24 hours, DMEM medium solutions of Chol-SiPc-TPP with different concentrations (0 mu M, 0.1 mu M, 0.2 mu M, 0.3 mu M, 0.4 mu M and 0.5 mu M) are added for incubation for 24 hours. Then using laser (671 nm,100 mW/cm) 2 ) Cells were irradiated for 10 min and incubated for 3 hours. Finally, CCK-8 reagent (10 mL) was added to each well and the cells were incubated for an additional 2 hours. The OD value at 450 nm was measured with a multifunctional microplate reader. Cell Activity= [ OD (drug-added) -OD (blank)]/[ OD (0 dosing) -OD (blank)]×100%。
Claims (5)
1. An asymmetric axial substituted silicon (iv) phthalocyanine modified by cholesterol and triphenylphosphine, which is characterized in that: is a compound of the following chemical structure:
。
2. the process for preparing a cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (iv) phthalocyanine according to claim 1, comprising the steps of: (1) Preparing a precursor 6-triphenylphosphine-based hexanoic acid by magnetically stirring triphenylphosphine and 6-bromohexanoic acid in toluene solution; (2) Precursor 6-triphenylphosphine caproic acid and dichlorosilicon phthalocyanine, cholesterol and anhydrous K 2 CO 3 Reflux-preparing cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon phthalocyanine in toluene.
3. The process for preparing a cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (iv) phthalocyanine according to claim 2, wherein: the 6-triphenylphosphine-based hexanoic acid is prepared by magnetically stirring 6-bromohexanoic acid and triphenylphosphine serving as raw materials in toluene solution, recrystallizing with chloroform and acetone after the reaction is finished, standing in ice water bath, filtering after the crystals are separated out, and vacuum drying to obtain white crystals.
4. The process for preparing a cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (iv) phthalocyanine according to claim 2, wherein: the cholesterol and triphenylphosphine group modified asymmetric axial substituted silicon phthalocyanine in the step (2) is prepared by adopting dichlorosilicon phthalocyanine and 6-triphenylphosphine group caproic acid as raw materials and reacting with cholesterol in toluene solution under magnetic stirring, after the reaction is finished, dissolving and washing with dichloromethane, recovering an organic phase, removing a solvent by reduced pressure rotary evaporation, and separating and purifying a crude product by silica gel column chromatography by using dichloromethane/ethanol with the volume ratio of 50:1 as an eluent.
5. Use of the cholesterol and triphenylphosphine-modified asymmetric axially substituted silicon (iv) phthalocyanine of claim 1 as a mitochondrial targeting marker and a fluorescent imaging guided photodynamic therapy phthalocyanine photosensitizer.
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