CN114751953A - Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof - Google Patents
Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof Download PDFInfo
- Publication number
- CN114751953A CN114751953A CN202210372800.0A CN202210372800A CN114751953A CN 114751953 A CN114751953 A CN 114751953A CN 202210372800 A CN202210372800 A CN 202210372800A CN 114751953 A CN114751953 A CN 114751953A
- Authority
- CN
- China
- Prior art keywords
- reaction
- breast cancer
- phthalocyanine derivative
- photodynamic therapy
- anhydrous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 40
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 40
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical class N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002428 photodynamic therapy Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000003886 aromatase inhibitor Substances 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- 229940122815 Aromatase inhibitor Drugs 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 claims description 9
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- 229940057499 anhydrous zinc acetate Drugs 0.000 claims description 4
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 3
- 238000001914 filtration Methods 0.000 claims 1
- 239000013638 trimer Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 15
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 abstract description 14
- 229960000255 exemestane Drugs 0.000 abstract description 11
- 230000002147 killing effect Effects 0.000 abstract description 6
- 230000008685 targeting Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 28
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 20
- 239000003504 photosensitizing agent Substances 0.000 description 17
- 102000014654 Aromatase Human genes 0.000 description 11
- 108010078554 Aromatase Proteins 0.000 description 11
- 238000005286 illumination Methods 0.000 description 8
- 206010034972 Photosensitivity reaction Diseases 0.000 description 7
- 229940046844 aromatase inhibitors Drugs 0.000 description 7
- 208000007578 phototoxic dermatitis Diseases 0.000 description 7
- 231100000018 phototoxicity Toxicity 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 229940011871 estrogen Drugs 0.000 description 5
- 239000000262 estrogen Substances 0.000 description 5
- 230000003637 steroidlike Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000003098 androgen Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical group OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 3
- 229960005471 androstenedione Drugs 0.000 description 3
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 2
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
- 235000005811 Viola adunca Nutrition 0.000 description 2
- 240000009038 Viola odorata Species 0.000 description 2
- 235000013487 Viola odorata Nutrition 0.000 description 2
- 235000002254 Viola papilionacea Nutrition 0.000 description 2
- 229940030486 androgens Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000006225 natural substrate Substances 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- VIKNJXKGJWUCNN-FOEMKWDFSA-N (10R,13S,17R)-17-ethynyl-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound O=C1CC[C@@H]2C3CC[C@](C)([C@](CC4)(O)C#C)C4C3CCC2=C1 VIKNJXKGJWUCNN-FOEMKWDFSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010057654 Breast cancer female Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000003278 haem Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and a preparation method thereof. The present invention utilizes the modified carboxyl group of exemestane and connects it to the hydroxyl group of phthalocyanine derivative by means of esterification reaction. The targeting function of the aromatase inhibitor exemestane is utilized, the targeting agent can be accurately positioned in breast cancer cells, so that the accurate targeting of the drug is realized, and the photodynamic effect of phthalocyanine is combined, so that the more efficient killing effect on breast cancer is realized. The compound has the advantages of simple synthesis method, easily obtained raw materials, low cost, less side reaction, higher yield, easy purification and contribution to industrial production.
Description
Technical Field
The invention belongs to the field of design and synthesis of antitumor drugs, and particularly relates to a phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and a preparation method thereof.
Background
Breast cancer (Breast cancer) is the most common cancer in women worldwide and is also the leading cause of cancer-related death. Of all the different breast tumor subtypes, the most common is estrogen receptor positive (ER +) breast cancer (70% of all diagnosed cases), and such tumors account for approximately 60% of pre-menopausal breast cancer and 75% of post-menopausal breast cancer. Meanwhile, studies have shown that estrogen plays a key role in tumor development and survival. More importantly, endogenous estrogen in postmenopausal women is converted by aromatase from androgens produced by the adrenal glands, breast tissue and adipocytes. Therefore, prevention and treatment of postmenopausal breast cancer is more challenging, and aromatase has gradually become a target enzyme for drug design.
At present, Aromatase Inhibitors (AIs) are one of the major clinical endocrine therapies for breast cancer. By inhibiting aromatase activity, estrogen levels can be reduced by more than 90% without interfering with the production of other steroids. Aromatase inhibitors can be divided into two subtypes, depending on their chemical structure: steroid type I and non-steroid type II. Steroidal AIs are analogs of the aromatase natural substrate Androstenedione (ASD) and therefore compete directly with androgens. These AIs bind covalently to the active site of aromatase, leading to its irreversible inactivation. Thus, steroidal AIs are also known as "suicide inhibitors". On the other hand, non-steroidal AIs have triazole functionality that interacts reversibly and non-covalently with the heme moiety of aromatase, saturating the enzyme binding site and preventing androgen binding to aromatase and the electron transfer chain.
In which exemestane is a third generation steroidal aromatase inhibitor, structurally similar to the natural substrate androstenedione of aromatase. Since estrogen in postmenopausal women is mainly produced by the conversion of androgen from adrenal and ovarian glands by aromatase in peripheral tissues, exemestane is inactivated by irreversible binding to the active site of aromatase, thereby reducing estrogen levels in the blood circulation of postmenopausal women. Exemestane has therefore been used clinically in post-menopausal women for hormone-dependent breast cancer treatment. Furthermore, exemestane is a neutral compound, not only having a steroidal structure, but also having a high lipophilicity. However, despite the remarkable therapeutic effect of exemestane on postmenopausal breast cancer, its further clinical use is limited due to problems such as inevitable drug resistance and side effects.
Based on the above, on the basis of the research of small molecule targeted photosensitizer, the invention combines aromatase inhibitor and photodynamic therapy, thereby solving the problems of exemestane in the treatment of postmenopausal breast cancer and the limitations of photodynamic therapy. At present, no aromatase inhibitor mediated PDT strategy for the treatment of postmenopausal breast cancer has been reported. The invention utilizes amphiphilic tetraethylene glycol to covalently connect exemestane and zinc phthalocyanine (ZnPc) to obtain a novel conjugated photosensitizer EX-Pc, which is expected to have high selectivity on tumor cells over-expressed by aromatase, thereby realizing the purpose of photodynamic targeted therapy of breast cancer.
Disclosure of Invention
The invention aims to provide a preparation method of phthalocyanine derivatives for targeted photodynamic therapy of postmenopausal breast cancer, which is characterized in that an aromatase inhibitor exemestane and a phthalocyanine photosensitizer modified by a triethylene glycol chain are covalently connected, so that the photosensitizer can specifically kill breast cancer cells, and a novel medicament with high biocompatibility, good targeting property and small toxic and side effects is obtained; the compound synthesized by the invention has a single structure, no isomer exists, and the product is easy to purify; the synthesis method is simple, has less side reaction, higher yield, easily obtained raw materials and low cost, and is beneficial to industrial production.
In order to realize the purpose, the technical scheme of the invention is as follows:
a method for preparing a phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer, comprising the following steps:
(1) sodium borohydride (0.063mg,1.66mmol) was added to a stirred mixture of trifluoroacetic acid (0.4mL), glacial acetic acid (0.4mL) and acetonitrile (0.4mL) in an ice bath and mixed well. Then accurately weighing
(0.10mg,0.34mmol, CAS:107868-30-4), then dissolved in dry dichloromethane (8mL) and added slowly to the mixture. After this time, the reaction was stirred at room temperature for 12h under nitrogen blanket. Then with 10% NaHCO3The reaction mixture was neutralized with aqueous solution and extracted with dichloromethane (3X 100 mL). The collected organic layer was washed with water (3X 100mL) and anhydrous MgSO4Dried, filtered and concentrated to give a white solid mixture. Finally purifying the mixture by silica gel column chromatography to obtain EX-OH with a chemical structure:
(2) will be provided with
(0.97g,3.27mmol), DMAP (0.04g,0.33mmol) and succinic anhydride (0.37g,3.70mmol) were added sequentially to a 100mL two-necked flask, then 15mL anhydrous DMF was added to the reaction flask, stirred and mixed well, and triethylamine (0.70g,6.90mmol) was added slowly to the reaction in a dropwise manner. Subsequently, stirring reaction was started for 48h under room temperature conditions and nitrogen protection. After the reaction is finished, performing vacuum rotary evaporation on the reaction system to remove DMF, and purifying by adopting column chromatography to obtain a light yellow solid compound EX-COOH, wherein the chemical structure of the light yellow solid compound EX-COOH is as follows:
(3) Will be provided with
(CAS:51762-67-5)0.87g and 2.75g of anhydrous potassium carbonate were dissolved in 15mL of anhydrous acetonitrile, and the reaction was heated to 70 ℃ to prepare a solution
(CAS:112-60-7)0.97g was added to the reaction system, followed by heating to 85 ℃ and refluxing for 7h, N2Protection; after the reaction is finished, the solvent is dried in vacuum, dichloromethane is used for dissolution, saturated saline solution is used for extraction, an organic layer is collected and dried in vacuum, dichloromethane-methanol is used as an eluent, and silica gel column chromatography is carried out to separate, so as to obtain a light white solid compound Pn-OH, wherein the chemical structure of the light white solid compound Pn-OH is as follows:
(4) the Pn-OH obtained in the step (3),
(CAS:91-15-6) is added into 10mL of anhydrous N-amyl alcohol according to the molar ratio of 1:10, the solution is heated to 100 ℃ and stirred to be dissolved until the solution becomes clear, then 5 equivalents of anhydrous zinc acetate is added, the temperature is heated to 130 ℃, when the solution becomes light green, 0.8mL of DBU (CAS number: 6674-22-2) is added into the reaction system, the reaction is continued for 7h, and N is added during the reaction process2Protecting, and performing decompression spin-drying after reaction; then using dichloromethane-methanol as eluent to separate by silica gel column chromatography to obtain a green solid compound ZnPc-OH with a chemical structure of
(5) Adding EX-COOH obtained in the step (2) and EDCI (CAS number: 25952-53-8) into anhydrous DMF according to the molar ratio of 1:1, reacting and stirring for 20min, then dropwise adding 1 equivalent of ZnPc-OH dissolved in DMF and 0.01 equivalent of DMAP, reacting for 24h at normal temperature, wherein N is N during the reaction 2Protecting, and performing decompression spin-drying after reaction; then using dichloromethane-methanol as eluent to separate by silica gel column chromatography to obtain green solid EX-Pc, namely the green solid EX-Pc for the targeted photodynamic therapy of the postmenopausal breast cancerA phthalocyanine derivative.
Photodynamic Therapy (PDT) is a novel, minimally invasive method of tumor Therapy. The basic elements of the method comprise a photosensitizer, light with certain wavelength and molecular oxygen. Photosensitizers, as catalysts for photodynamic therapy, are central to photodynamic therapy. The ideal photosensitizer preferably satisfies the following: the components are single, the structure is clear, and the properties are stable; the specific targeting property is strong; weak dark toxicity and strong phototoxicity; the photosensitization capability is strong, and the yield of singlet oxygen quantum is high; the longest excitation wavelength is in the near infrared region, and has stronger absorption in the photodynamic therapy window (650-800 nm). The phthalocyanine derivative is one of ideal photosensitizers because of excellent photophysical and photochemical properties (higher molar extinction coefficient and fluorescence quantum yield, less sensitivity to chemical environment, etc.). The invention synthesizes the phthalocyanine derivative with strong absorption in the near infrared region, and the solubility of the phthalocyanine derivative is increased by modifying the tetraethylene glycol so as to enhance the singlet oxygen quantum yield and phototoxicity.
According to the invention, exemestane is carboxylated, and then a tetraethylene glycol and trinitrophthalonitrile monomer are synthesized and then reach a phthalocyanine matrix, and then a target drug modified phthalocyanine derivative EX-Pc is obtained through an esterification reaction. The invention takes a small molecule targeted drug and a phthalocyanine photosensitizer modified by a triethylene glycol chain as a research object, takes a human breast cancer cell MCF-7 cell and a murine breast cancer cell 4T1 cell as test cell strains, and develops the research on the in vitro and in vivo anti-breast cancer activity of the invention.
The invention has the remarkable advantages that:
(1) the tetraglycol trisection chain can enhance the amphipathy of phthalocyanine photosensitizer molecules, and when the tetraglycol trisection chain is modified on the phthalocyanine photosensitizer, the uptake of cancer cells to the phthalocyanine photosensitizer can be effectively enhanced, so that the photodynamic therapy effect is improved; meanwhile, the maximum absorption of the photosensitizer is in a red light region, the exciting light has strong capability of penetrating tissues, and skin phototoxicity is not easy to cause during photodynamic therapy, so that the photosensitizer is an ideal photosensitizer.
(2) The phthalocyanine derivative modified by the aromatase inhibitor has stronger targeting on breast cancer cells, shows a certain chemotherapy effect on the breast cancer cells, and has no obvious killing effect on normal tissues.
(3) The target compound has a single structure, no isomer exists, and the product is easy to purify.
(4) The synthesis method is simple, has less side reactions, easily obtained raw materials and low cost, and is beneficial to industrial production.
Drawings
FIG. 1A) killing effect of different drugs on three cells in the absence of light; B) under light irradiation (λ 670nm, 0.48J. cm)-2) Killing effect of different medicines on three cells;
fig. 2 is a graph of tumor volume changes for different drug groups.
Detailed Description
The invention is further illustrated but not limited by the following examples in connection with comparative examples.
Example 1
A method for preparing phthalocyanine derivatives for targeted photodynamic therapy of acute lymphocytic leukemia, comprising the steps of:
(1) sodium borohydride (0.063mg,1.66mmol) was added to a stirred mixture of trifluoroacetic acid (0.4mL), glacial acetic acid (0.4mL) and acetonitrile (0.4mL) in an ice bath, and mixed well. Then accurately weighing
(0.10mg,0.34mmol) and then dissolved in anhydrous dichloromethane (8mL) and added slowly to the mixture. After this time, the reaction was stirred at room temperature for 12h under nitrogen. Then with 10% NaHCO3The reaction mixture was neutralized with aqueous solution and extracted with dichloromethane (3X 100 mL). The collected organic layer was washed with water (3X 100mL) and anhydrous MgSO 4Dried, filtered and concentrated to give a white solid mixture. The mixture was finally purified by silica gel column chromatography to give EX-OH in 39% yield, which has the chemical structure:
(2) will be provided with
(0.97g,3.27mmol), DMAP (0.04g,0.33mmol) and succinic anhydride (0.37g,3.70mmol) were added sequentially to a 100mL two-necked flask, then 15mL anhydrous DMF was added to the reaction flask, stirred and mixed well, and triethylamine (0.70g,6.90mmol) was added slowly to the reaction in a dropwise manner. Subsequently, stirring reaction was started for 48h under room temperature conditions and nitrogen protection. After the reaction is finished, performing vacuum rotary evaporation on the reaction system to remove DMF, and purifying by adopting column chromatography to obtain a light yellow solid compound EX-COOH with the yield of 47 percent, wherein the chemical structure is as follows:
(3) will be provided with
0.87g and 2.75g of anhydrous potassium carbonate in 15mL of anhydrous acetonitrile, and heating the mixture to 70 ℃ for reaction
0.97g of the mixture is added into the reaction system, and then the temperature is increased to 85 ℃ for refluxing for 7h, N2Protection; after the reaction is finished, the solvent is dried in vacuum, dichloromethane is used for dissolution, saturated saline solution is used for extraction, an organic layer is collected and dried in vacuum, dichloromethane-methanol is used as an eluent, silica gel column chromatography is carried out for separation, and a light white solid compound Pn-OH is obtained, the yield is 65%, and the chemical structure is as follows:
(4) The Pn-OH obtained in the step (3),
Adding the mixture into 10mL of anhydrous N-amyl alcohol according to a molar ratio of 1:10, heating to 100 ℃, stirring and dissolving until the solution becomes clear, then adding 5 equivalents of anhydrous zinc acetate, heating to 130 ℃, adding 0.8mL of DBU into the reaction system when the solution becomes light green, continuing to react for 7 hours, protecting by N2 in the reaction process, and carrying out reduced pressure spin drying after the reaction; then using dichloromethane-methanol as eluent to make silica gel column chromatography separation to obtain green solid compound ZnPc-OH with yield of 12%, its chemical structure is
1H NMR(400MHz,DMSO-d6)δ＝9.25(dd,J＝9.8,6.6Hz,4H),9.20(d,J＝6.1Hz,1H),9.11(d,J＝7.2Hz,1H),8.75(d,J＝7.4Hz,1H),8.16(dt,J＝16.8,5.8Hz,6H),7.97(t,J＝7.6Hz,1H),7.58(d,J＝7.9Hz,1H),4.82(m,2H),4.53(t,J＝5.5Hz,1H),4.37(m,2H),4.07(t,J＝5.0Hz,2H),3.76(t,J＝5.0Hz,2H),3.59(m,2H),3.49(dd,J＝5.6,4.1Hz,2H),3.42(m,2H),3.38(s,2H).13C NMR(101MHz,DMSO-d6):δ＝174.96,169.25,167.95,156.11,153.38,153.28,153.20,153.14,140.93,138.91,138.61,138.56,138.51,138.48,136.87,131.01,129.61,129.56,129.46,125.57,122.66,120.05,115.45,114.15,72.79,70.99,70.57,70.40,70.22,69.38,69.16,60.65,34.17,31.73,29.42,29.13,24.98,22.53,14.39.HRMS(ESI):m/z calcd for C40H33N8 O5Zn[M+H]+:769.184；found,769.1884。
(5) Adding EX-COOH and EDCI obtained in the step (2) into anhydrous DMF according to the molar ratio of 1:1, reacting and stirring for 20min, then dropwise adding 1 equivalent of ZnPc-OH dissolved in DMF and 0.01 equivalent of DMAP, reacting for 24h at normal temperature, wherein N is N in the reaction process2Protecting, and performing decompression spin-drying after reaction; then using dichloromethane-methanol as eluent, separating by silica gel column chromatography to obtain green solid EX-Pc, namely the phthalocyanine derivative used for the targeted photodynamic therapy of the postmenopausal breast cancer, wherein the yield is 10%, and the chemical structure is as follows:
1H NMR(600MHz,DMSO-d6)δ＝9.42(s,6H),9.07(d,J＝7.4Hz,1H),8.23(s,6H),8.16(t,J＝7.5Hz,1H),7.81(d,J＝21.1Hz,2H),7.43–7.33(m,1H),5.90(dd,J＝10.1,1.9Hz,1H),5.82(d,J＝2.0Hz,1H),4.96–4.92(m,2H),4.78(dt,J＝35.0,2.1Hz,2H),4.44(t,J＝4.6Hz,2H),4.15(t,J＝8.4Hz,1H),4.10(t,J＝4.9Hz,2H),4.07–4.02(m,2H),3.79(t,J＝4.9Hz,2H),3.60(dd,J＝5.9,3.7Hz,4H),3.50(s,4H),3.40(d,J＝30.1Hz,2H),2.44(s,2H),2.36(t,J＝6.9Hz,2H),2.18(d,J＝7.5Hz,1H),2.07(dd,J＝13.5,4.0Hz,1H),1.99(dt,J＝26.6,7.0Hz,2H),1.78–1.75(m,1H),1.73–1.64(m,2H),1.47(q,J＝7.8Hz,2H),0.69(s,3H),0.33(s,3H)。13C NMR(151MHz,DMSO-d6)δ＝185.45,172.35,171.73,167.85,156.39,155.33,153.78,153.67,153.61,145.75,141.32,139.18,138.74,138.71,131.26,130.09,129.77,129.69,129.60,127.00,125.99,122.84,122.78,122.69,121.88,115.71,114.50,112.15,81.87,71.02,70.65,70.33,69.65,68.61,63.88,49.20,43.48,42.34,35.78,34.95,34.90,31.74,31.61,30.29,29.46,29.01,27.05,25.57,23.01,22.55,21.74,19.50,14.41,11.71。HRMS(ESI)m/z calcd for C64H60N8O9Zn[M+H]+:1149.3847,found:1149.3801。
preparation of control drug M:
the compound
(references: chem. Commun.,2013,49, 9570-9572),
Adding the mixture into 10mL of anhydrous N-amyl alcohol according to the molar ratio of 1:10, heating to 100 ℃, stirring and dissolving until the solution becomes clear, then adding 5 equivalents of anhydrous zinc acetate, heating to 130 ℃, adding 0.8mL of DBU into the reaction system when the solution becomes light green, continuing to react for 7 hours, wherein N is N in the reaction process 2And (5) protecting. After reaction, decompression and spin-drying; then, taking dichloromethane-methanol as an eluent, and separating by silica gel column chromatography to obtain a green solid compound M, wherein the chemical structure of the green solid compound M is as follows:
application example 1
The in vitro photodynamic activity of phthalocyanine derivatives prepared in example 1 for targeted photodynamic therapy of postmenopausal breast cancer was studied. Cytotoxicity assays for photosensitizers typically involve both phototoxicity and dark toxicity, as measured by the MTT method. The detection principle is that the chemical name of MTT is 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazole brom azole blue. The detection principle of this experimental method is that mitochondria of living cells contain succinate dehydrogenase, which is a reductive enzyme, and can reduce exogenous MTT to insoluble blue-violet crystalline Formazan (Formazan) and deposit it in the cells, whereas mitochondria of dead cells do not contain succinate dehydrogenase and cannot reduce MTT, so blue-violet crystalline Formazan does not appear. Related experiments showed that Dimethylsulfoxide (DMSO) organic solvent was able to solubilize formazan deposited in cells. At this time, the light absorption (OD value) was measured at a wavelength of 490nm or 570nm using an enzyme-linked immunosorbent assay. The number of living cells was judged from the measured OD value, and the larger the OD value, the stronger the cell activity (the less the drug toxicity if the drug toxicity was measured).
MTT test:
a. cell plating: selecting MCF-7 and 4T1 cells with good growth state, and diluting the cells to make the cell density 8 × 104Cells were added evenly to 96-well plates using a row gun, 6 replicates per concentration data were set, and 100L cell suspension was added per well.
b. Adding medicine: DMF stock solution (containing 5% CEL) was prepared at drug concentrations of 1mM, 0.5mM, 0.25mM, 0.125mM, 0.0625mM, and 0.03125mM, respectively. Measuring 1L of mother liquor and diluting the mother liquor into 1mL of DMEM culture medium to finally obtain the product with logarithmic concentration of 1M, 0.5M, 0.25M, 0.125M, 0.0625M and 0.03125M in sequence. To the corresponding drug wells, 20L of the corresponding drug concentration was added, resulting in a drug gradient of 0.1M, 0.05M, 0.025M, 0.0125M, 0.00625M, 0.003125M. The 96-well plate was placed in a cell incubator for overnight incubation to allow uptake of the drug into the cells.
c. Light toxicity and dark toxicity test: the old medium was aspirated, washed three times with sterile saline, and 100L of fresh medium was added. In the phototoxicity experiment, 670nm LED light is used for 2min and then placed in an incubator overnight. In contrast group dark toxicity experiment, after replacing new culture medium, without illumination, placing in incubator to culture overnight.
detection of OD value: after the culture is finished, 10L of the prepared MTT solution is added into each well by using a pipette, the well is shaken on a shaking table for 5min, and then the 96-well plate is continuously placed into an incubator to be cultured for 4 h.
e. The medium was decanted from the 96-well plate, 100L DMSO solution was added to each well and shaken on a shaker for 40min, and then OD at 570nm of the solution was measured with a microplate reader.
The phthalocyanine derivative for the targeted photodynamic therapy of the postmenopausal breast cancer is determined by adopting an MTT method, under the conditions of illumination and no illumination, the phthalocyanine derivative has the killing effect on breast cancer cells MCF-7 and 4T1 and normal liver cells LO2, the illumination wavelength is 670nm, and the illumination energy density is 0.48J cm-2。
From the experimental data it can be seen that: as shown in fig. 1, the phthalocyanine derivative used for the targeted photodynamic therapy of postmenopausal breast cancer has no obvious killing effect on cells under the condition of no illumination and at the drug concentration of 0.1 mu M; under the condition of light, the drug group and the control group showed strong phototoxicity to cells at 0.1. mu.M, and half Inhibitory Concentration (IC) thereof50Values) are shown in table 1.
TABLE 1 IC of Tetraethylene glycol trisubstituted phthalocyanine derivatives and control drugs50Value of
Application example 2
The in vivo photodynamic activity of the phthalocyanine derivative prepared in example 1 for targeted photodynamic therapy of postmenopausal breast cancer was investigated. The in vivo photodynamic activity of the photosensitizer is reflected by the tumor inhibition effect of the drug on a mouse breast cancer 4T1 tumor model.
Tumor inhibition rate experiment:
(1) 4T1 cells in good growth state were harvested, resuspended by centrifugation and adjusted to a cell density of 1X 107One per mL. After the right side of hind limb of the mouse is disinfected by 75 percent alcohol, 200L of cell suspension is inoculated subcutaneously until the average size of tumor reaches 100mm3The experiment was then performed.
(2) The mice were divided into 4 groups (EX-Pc group, M group, EXE group, normal saline group), and 5 mice per group. Before administration, nude mice were weighed and tumor sizes were measured, and then each mouse was intravenously injected with the corresponding drug (75M, 200. mu.L) and physiological saline solution, respectively, in groups, and after 8 hours of administration, the tumor area was irradiated with a 670nm laser for 10min while each timeBody weights were weighed and tumor volumes were measured at fixed time points of day. (V is 0.5 XL.times.W2(ii) a L, W for the length and width of the tumor, respectively).
The prepared phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer is used for testing the inhibition effect of a mouse breast cancer 4T1 tumor model under the condition of illumination, so that the photodynamic activity of the medicine in vivo is reflected.
From experimental data it can be seen that: as shown in FIG. 2, under the condition of illumination, EX-Pc drug showed strong phototoxicity, the tumor volume showed slow and weak increase, and the tumor volume was 180mm after 14 days 3. The contrast medicine M group, contrast medicine EXE group and blank Control group have poor photodynamic effect on the tumor, the tumor volume increases in an uncontrollable way, and the tumor volume is 670mm after 14 days3、1080mm3And 1350mm3. The experimental results show that: the phthalocyanine derivative used for the targeted photodynamic therapy of the postmenopausal breast cancer has stronger photodynamic effect on tumor tissues in a mouse body.
Since the-OH of tetraethylene glycol in the target drug EX-PC is used as a reaction site for attaching EX-COOH molecules, but triethylene glycol thereof does not participate in any reaction, the M compound containing triethylene glycol can better reflect the comparative effect thereof. Therefore, we selected M compounds as control drugs in the present invention to perform experiments.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (3)
1. A phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer, comprising: the chemical structural formula of the phthalocyanine derivative is as follows:
2. a method of preparing a phthalocyanine derivative according to claim 1 for targeted photodynamic therapy of postmenopausal breast cancer, wherein: the phthalocyanine derivative is obtained by covalently connecting phthalocyanine molecules and an aromatase inhibitor through tetraethylene glycol trimer, and is used for targeted photodynamic therapy of postmenopausal breast cancer.
3. The production method according to claim 2, characterized in that: the method specifically comprises the following steps:
(1) adding sodium borohydride into a mixture of trifluoroacetic acid, glacial acetic acid and acetonitrile stirred in an ice bath environment, fully stirring and uniformly mixing, and then slowly adding a dissolved compound
Is stirred at room temperature for 12 h under the protection of nitrogen, and then NaHCO is used3The reaction mixture was neutralized with an aqueous solution and extracted with dichloromethane, and the collected organic layer was washed with water and anhydrous MgSO4Drying, filtering, concentrating and purifying to obtain white solid EX-OH with a chemical structure as follows:
(2) sequentially adding EX-OH, DMAP and succinic anhydride into a reaction container, adding anhydrous DMF, stirring and mixing uniformly, then dropwise and slowly adding triethylamine into a reaction system, then starting stirring and reacting for 48 hours under the room temperature condition and the protection of nitrogen, after the reaction is finished, carrying out vacuum rotary evaporation on the reaction system to remove DMF, then purifying by adopting column chromatography, and finally obtaining a light yellow solid compound EX-COOH, wherein the chemical structure of the compound is as follows:
(3) will be provided with
Dissolving anhydrous potassium carbonate in anhydrous acetonitrile, reacting and heating to 70 ℃, and reacting and heating 
Added to the reaction system, N2Heating to 85 ℃ under protection and refluxing for 7 h; after the reaction is finished, the solvent is dried in vacuum, dichloromethane is used for dissolution, saturated saline solution is used for extraction, an organic layer is collected and dried in vacuum, dichloromethane-methanol is used as an eluent, silica gel column chromatography is carried out for separation, and a light white solid compound Pn-OH is obtained, and the chemical structure of the compound is as follows:
(4) mixing Pn-OH obtained in the step (3) with
Adding into anhydrous N-amyl alcohol, heating to 100 deg.C, stirring for dissolving until the solution becomes clear, adding anhydrous zinc acetate, heating to 130 deg.C, adding DBU into the reaction system when the solution becomes light green, continuing to react for 7h, wherein N is N in the reaction process2Protecting, and performing decompression spin-drying after reaction; then taking dichloromethane-methanol as an eluent, and separating by silica gel column chromatography to obtain a green solid compound ZnPc-OH, wherein the chemical structure is as follows:
(5) adding EX-COOH and EDCI obtained in the step (2) into anhydrous DMF, reacting and stirring for 20 min, then dropwise adding a DMF solution dissolved with ZnPc-OH and DMAP, reacting at normal temperature for 24 h, wherein N is N in the reaction process2Protecting, and performing decompression spin-drying after reaction; and then separating by silica gel column chromatography with dichloromethane-methanol as eluent to obtain green solid EX-Pc, namely the phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210372800.0A CN114751953A (en) | 2022-04-11 | 2022-04-11 | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210372800.0A CN114751953A (en) | 2022-04-11 | 2022-04-11 | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114751953A true CN114751953A (en) | 2022-07-15 |
Family
ID=82328737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210372800.0A Pending CN114751953A (en) | 2022-04-11 | 2022-04-11 | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114751953A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160326A (en) * | 2022-07-30 | 2022-10-11 | 福州大学 | Phthalocyanine complex of targeted IDO enzyme and preparation method and application thereof |
-
2022
- 2022-04-11 CN CN202210372800.0A patent/CN114751953A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| GANKUN YUAN ET AL.: ""An aromatase inhibitor in combination with Zinc(II) phthalocyanine for targeted therapy of post-menopausal breast cancer"", 《DYES AND PIGMENTS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160326A (en) * | 2022-07-30 | 2022-10-11 | 福州大学 | Phthalocyanine complex of targeted IDO enzyme and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104387412B (en) | Fluorine boron two pyrrole derivative that erlotinib is modified and Synthesis and applications thereof | |
| CN104039796B (en) | 1-oxo/acylated Oridonin derivative acylated for-14-, and its preparation method and application | |
| CN105418643B (en) | A kind of bilateral biotin Phthalocyanine Zinc conjugates and its preparation and application | |
| PL188811B1 (en) | Synthetic metal-substituted bacteriochlorophilic derivatives and their application | |
| CN109575061B (en) | Water-soluble anticancer photosensitizer and preparation and application thereof | |
| JP7043260B2 (en) | A novel dihydroporphyrin e6 derivative and a pharmaceutically acceptable salt thereof, a method for preparing the same and a use thereof. | |
| CN108440586A (en) | Two azole derivatives of fluorine boron of cumarin modification and its preparation and application | |
| CN113943304B (en) | Pim-1 kinase targeted phthalocyanine-5-bromo-1-benzofuran-2-carboxylic acid complex, and preparation method and application thereof | |
| CN111662333A (en) | Bis-terpyridyl iridium (III) complex and synthetic method thereof | |
| CN109912607A (en) | Porphyrin-Chrysin compound and its anti-tumor activity | |
| CN114751953A (en) | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof | |
| CN109456352B (en) | Phenylboronic acid ester modified hydrogen peroxide activated type boron dipyrromethene photosensitizer and preparation thereof | |
| CN106046008A (en) | Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative | |
| Zhou et al. | Novel glycosylation zinc (II)–cryptolepine complexes perturb mitophagy pathways and trigger cancer cell apoptosis and autophagy in SK-OV-3/DDP cells | |
| CN104311566A (en) | Preparation method and application of water soluble cationic zinc phthalocyanine photosensitizer | |
| Uruma et al. | Design, synthesis, and biological evaluation of a highly water-soluble psoralen-based photosensitizer | |
| CN107789623B (en) | Piperazine substituted silicon phthalocyanines and their use in photothermal therapy | |
| CN106083872B (en) | Purpurin 18 ether derivative and its preparation method and application | |
| CN113603698A (en) | Phthalocyanine-perphenazine conjugate with type I photosensitive reaction and photothermal synergistic effect and application in pharmaceutical field | |
| CN104447769A (en) | Molecularly targeted anticancer photosensitizer erlotinib-phthalocyanine conjugate | |
| CN113683602A (en) | Heptamethine cyanine small molecule for multi-modal treatment of hypoxic tumors, and preparation method and application thereof | |
| CN113717183B (en) | Phthalocyanine modified by pericyclic asymmetric arginine, preparation thereof and application thereof in pharmaceutical field | |
| RU2707754C1 (en) | Fluorinated porphyrin derivatives exhibiting anti-tumor activity | |
| CN111057063B (en) | Phthalocyanine derivative for targeted photodynamic therapy of acute lymphocytic leukemia and preparation method thereof | |
| CA2988030C (en) | Dihydropyrene derivatives, processes for preparing the same and their uses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220715 |
|
| RJ01 | Rejection of invention patent application after publication |