CN117658786A - Hypocrellin derivative, and preparation method and application thereof - Google Patents
Hypocrellin derivative, and preparation method and application thereof Download PDFInfo
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- CN117658786A CN117658786A CN202211013881.1A CN202211013881A CN117658786A CN 117658786 A CN117658786 A CN 117658786A CN 202211013881 A CN202211013881 A CN 202211013881A CN 117658786 A CN117658786 A CN 117658786A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- VANSZAOQCMTTPB-SETSBSEESA-N hypocrellin Chemical class C1[C@@](C)(O)[C@@H](C(C)=O)C2=C(OC)C(O)=C3C(=O)C=C(OC)C4=C3C2=C2C3=C4C(OC)=CC(=O)C3=C(O)C(OC)=C21 VANSZAOQCMTTPB-SETSBSEESA-N 0.000 title abstract description 72
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 239000003814 drug Substances 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 239000011261 inert gas Substances 0.000 claims description 10
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 238000005086 pumping Methods 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000005286 illumination Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229940125890 compound Ia Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 3
- 229940035437 1,3-propanediol Drugs 0.000 claims description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 3
- 238000001215 fluorescent labelling Methods 0.000 claims description 2
- KGHNSNSWRMJVND-UHFFFAOYSA-N Hypocrellin Natural products COC1=CC(=O)C2=C3C4C(C(C(=O)C)C(C)(O)Cc5c(OC)c(O)c6C(=O)C=C(OC)C(=C13)c6c45)C(=C2O)OC KGHNSNSWRMJVND-UHFFFAOYSA-N 0.000 abstract description 50
- BQJKVFXDDMQLBE-UHFFFAOYSA-N shiraiachrome A Natural products COC1=C2C3=C(OC)C=C(O)C4=C3C3=C5C(CC(C)(O)C(C(C)=O)C3=C(OC)C4=O)=C(OC)C(=O)C(C(O)=C1)=C25 BQJKVFXDDMQLBE-UHFFFAOYSA-N 0.000 abstract description 45
- 238000001953 recrystallisation Methods 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 239000007850 fluorescent dye Substances 0.000 abstract description 7
- 239000011159 matrix material Substances 0.000 abstract description 6
- 230000031700 light absorption Effects 0.000 abstract description 3
- 239000003550 marker Substances 0.000 abstract description 3
- 230000035515 penetration Effects 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
- 239000013078 crystal Substances 0.000 description 45
- APTUSGMALOMQQL-UHFFFAOYSA-N chembl2029624 Chemical compound O=C1C(OC)=C2C(C(C)=O)=C(C)CC3=C(OC)C(=O)C4=C(O)C=C(OC)C5=C4C3=C2C2=C1C(O)=CC(OC)=C25 APTUSGMALOMQQL-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- SBMXTMAIKRQSQE-UHFFFAOYSA-N Hypocrellin C Natural products O=C1C=C(OC)C2=C(C3=C45)C(OC)=CC(=O)C3=C(O)C(OC)=C4C(C(C)=O)=C(C)CC3=C5C2=C1C(O)=C3OC SBMXTMAIKRQSQE-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- -1 acetyl hypocrellin Chemical compound 0.000 description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 12
- YDLBDQPPRTYAIG-UHFFFAOYSA-N hypocrellin A Natural products COC1C2CC(C)(O)C(C(=O)C)C3=C(OC)C(=O)c4c(O)cc(OC)c5c6c(OC)cc(O)c(C1=O)c6c2c3c45 YDLBDQPPRTYAIG-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006862 quantum yield reaction Methods 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000002441 X-ray diffraction Methods 0.000 description 7
- 238000002189 fluorescence spectrum Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 238000002428 photodynamic therapy Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000005564 crystal structure determination Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000002211 ultraviolet spectrum Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000004435 EPR spectroscopy Methods 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001362 electron spin resonance spectrum Methods 0.000 description 2
- 229930184149 elsinochrome Natural products 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000005298 paramagnetic effect Effects 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- DETAHNVSLBCZAA-ARJGXJLFSA-N photo product Chemical compound C[C@@H]([C@]12O)[C@@H](OC(C)=O)[C@@]3(OC(C)=O)C(C)(C)C3[C@@H]2C2[C@]3(COC(C)=O)C[C@]4(O)[C@H]1C2[C@@]3(C)C4=O DETAHNVSLBCZAA-ARJGXJLFSA-N 0.000 description 2
- 238000001126 phototherapy Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002097 Lichenin Polymers 0.000 description 1
- 240000004971 Pseudosasa japonica Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- IYYMDGDZPDXTGT-UHFFFAOYSA-N perylene-1,2-dione Chemical group C1=CC(C2=C3C(=CC(C2=O)=O)C=CC=C32)=C3C2=CC=CC3=C1 IYYMDGDZPDXTGT-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009774 resonance method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to hypocrellin derivatives with hypocrellin parent eliminating substituent groups, and a preparation method and application thereof. The hypocrellin derivative provided by the invention is simple in post-treatment, and can be used for obtaining a product with high purity through simple recrystallization, so that the hypocrellin derivative is convenient to separate and purify, and the cost of the compound in the aspect of pharmaceutical application is greatly reduced. In addition, the hypocrellin derivative maintains the parent property of hypocrellin, the maximum ultraviolet light absorption wavelength is 400-600nm, the tissue penetration depth of absorbed light meets the depth requirement of focus of microvascular diseases, and belongs to a targeted photodynamic medicament for shallow phenotype diseases. The spectrum performance of the fluorescent dye is similar to that of a matrix, so that the fluorescent dye has the same excellent photodynamic performance as the matrix, and the fluorescent dye can be used as photodynamic medicine, photosensitizer, photodynamic antibacterial agent or tumor fluorescent marking agent together with the matrix.
Description
Technical Field
The invention belongs to the technical field of photodynamic phototherapy photosensitizers and photodynamic antibiosis of microvascular diseases, and particularly relates to hypocrellin derivatives with hypocrellin parent eliminating substituents, and a preparation method and application thereof.
Background
Photodynamic therapy (Photodynamic therapy, PDT for short) is a conventional clinical treatment of tumors following surgery, radiation therapy, chemotherapy, and the like. The principle of photodynamic therapy is: the photosensitizer is absorbed by focus tissue, and after being excited by light with correspondent wavelength, it can produce several active oxygen substances, in which singlet oxygen is produced 1 O 2 ) Is a main active substance and has therapeutic effect on killing pathological tissues. PDT has good effect in treating tumors of skin, oral cavity, digestive tract, respiratory tract and urinary system.
Many fungi of different species in nature are capable of metabolizing to produce natural pigments with perylenequinone backbone structures, including Hypocrellin (Hypocrellin), elsinochrome (elsinochrome), and lichenin (phaeophaerin), among others. Hypocrellin is obtained by separating and purifying hypocrellin, which is a parasitic fungus of the special species of China and is parasitic on the arrow bamboos of Yunnan and the like. Natural hypocrellins include two types: hypocrellin A (HA) and Hypocrellin B (HB) have the following structures:
the hypocrellin has relatively abundant natural resources, and 3-5% of natural hypocrellin A can be separated from dry hypocrellin meat. Researches for many years show that hypocrellin has high purity, single component and stable structure; low dark toxicity and quick in-vivo metabolism; high photo-killing property (singlet oxygen) 1 O 2 High yield), is an excellent photodynamic medicine. There have been reports on in vitro antiviral studies in the last two years.
However, how to develop hypocrellin derivatives with various structures, high yield in the preparation method, high purity of the product, and the same or similar photodynamic properties as the parent, and meeting different use requirements, is a great challenge at present.
Disclosure of Invention
In order to solve the technical problems, the invention firstly provides a compound shown in the following formula I:
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group; r is R 5 Methyl or H.
In one embodiment, R 1 、R 2 、R 3 、R 4 The same applies to methoxy groups.
As an example, the compound of formula I is compound H486:
in one embodiment, compound H486 is monoclinic with a space group of P21/c and a unit cell parameter ofα=90.00 (°), β= 96.9270 (10) (°), γ=90.00 (°), z=4, and a volume of +.>
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
wherein R is 1 、R 2 、R 3 、R 4 Having the definition as described above; r is R 5 Methyl or H.
And heating and refluxing the compound Ia in an aqueous solution of KOH in the absence of light under the protection of inert gas to obtain the compound shown in the formula I.
According to an embodiment of the invention, the mass fraction of KOH in the aqueous solution of KOH is 1 to 10%, for example 2.5 to 8.5%, for example 2 to 8%.
According to an embodiment of the invention, the molar ratio of compound Ia to KOH is 1 (0.1 to 0.7), for example 1 (0.3 to 0.5), for example 1:0.4.
According to an embodiment of the invention, the reaction time is 1 to 12 hours, such as 3 to 10 hours.
According to an embodiment of the invention, after the reaction is completed, hydrochloric acid is used for neutralization, dichloromethane extraction, water washing is carried out to neutrality, and reduced pressure distillation is carried out to obtain solid, and further chloroform and petroleum ether with the volume ratio of 1:5 are used for recrystallization.
In one embodiment, compound H486 is prepared using the following method: adding Hypocrellin B (HB) into KOH aqueous solution with the mass fraction of 2.5%, introducing argon, heating and refluxing for reaction in dark, detecting that the raw material is completely converted by mass spectrometry (MALDI-TOF), neutralizing by dilute hydrochloric acid, extracting by dichloromethane, washing by water to neutrality, distilling under reduced pressure to obtain solid, and recrystallizing by chloroform and petroleum ether with the volume ratio of 1:5.
In one embodiment, the single crystal of compound H486 is obtained by dissolving compound H486 in a mixed solvent of chloroform and acetone, and leaving the mixture at 0-10 ℃ in the dark for 1-4 weeks.
The invention also provides application of the compound shown in the formula I in preparing a compound shown in the formula II or the formula III as follows:
wherein R is 1 、R 2 、R 3 、R 4 Having the definition as described above.
The present invention also provides a compound of formula II as described above,
wherein R is 1 、R 2 Having the definition as described above.
In one embodiment, R 1 、R 2 Are methoxy groups.
As an example, the compound of formula II is compound H426:
in one embodiment, compound H426 is an orthorhombic system, the space group is Pbca, and the unit cell parameters areα=90 (°), β=90 (°), γ=90 (°), z=8, and volume +.>
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps:
and adding the compound shown in the formula I and KOH into a mixed solvent of tetrahydrofuran and 1, 3-propylene glycol, and heating and refluxing in an inert gas atmosphere in a dark place for reaction.
According to an embodiment of the invention, the volume ratio of tetrahydrofuran to 1, 3-propanediol is 1 (2-8), e.g. 1:5.
According to an embodiment of the invention, the molar ratio of the compound of formula I to KOH is 1 (800-1000), such as 1:951.
According to an embodiment of the invention, the reaction time is 0.1 to 5 hours, such as 0.5 to 1 hour.
According to an embodiment of the invention, the method further comprises the steps of neutralizing with a proper amount of diluted hydrochloric acid after the reaction is completed, extracting with chloroform, washing with water to be neutral, and distilling under reduced pressure to obtain a solid, wherein the volume ratio is further 1: 8. is recrystallized from chloroform and petroleum ether.
In one embodiment, compound H426 is prepared using the following steps: adding the compound H486 and KOH into a mixed solvent of tetrahydrofuran and 1, 3-propanediol in a volume ratio of 1:5, introducing argon, and heating and refluxing for reaction in dark place.
In one embodiment, a single crystal of compound H426 is prepared using the following steps: compound H426 was dissolved in a chloroform and acetone mixture and left to stand in the dark at 0-10 ℃ for 1-4 weeks.
The present invention also provides a compound of formula III as described above,
wherein R is 1 、R 2 、R 3 、R 4 Having the definition as described above.
In one embodiment, R 1 、R 2 、R 3 、R 4 The same applies to methoxy groups.
As an example, the compound of formula III is compound H970:
in one embodiment, the compound of formula III is monoclinic and the space group is P2 1 N, unit cell parameters areα=90.00 (°), β= 99.091 (2) (°), γ=90.00 (°), z=4, and a volume of +.>
The invention also provides a preparation method of the compound shown in the formula III, which comprises the following steps: adding the compound shown in the formula I and potassium carbonate into a mixed solvent of water and dimethyl sulfoxide, heating to 140-170 ℃ under the protection of inert gas for reaction, optionally further pumping out the solvent, adding a dilute hydrochloric acid aqueous solution, and reacting at 0-30 ℃.
According to an embodiment of the present invention, the reaction is carried out at 140 to 170℃for 1 to 12 hours.
According to an embodiment of the present invention, the reaction is carried out at 0 to 30℃for 12 to 36 hours.
According to an embodiment of the invention, the volume ratio of water to dimethyl sulfoxide is (5-15): 1, e.g. 10:1.
According to an embodiment of the invention, the molar ratio of the compound of formula I to potassium carbonate is 1 (170-370), for example 1 (200-350), such as 1:270.
In one embodiment, compound H970 is prepared using the following method: compound H486 and potassium carbonate were added to a volume ratio of 10:1 and dimethyl sulfoxide, heating to 150-160 ℃ under the protection of nitrogen, reacting for 4-8 hours, pumping the solvent, adding a proper amount of dilute hydrochloric acid aqueous solution, and stirring at room temperature for reacting for 12-48 hours.
According to an embodiment of the present invention, a single crystal of compound H970 is prepared by the following method: compound H970 is dissolved in a mixed solvent of chloroform and acetone and left in the dark at 0-10 ℃ for 1-4 weeks.
The present invention also provides a compound of formula IV,
wherein R is 1 、R 2 Identical or different, independently of one another, C 1-6 An alkoxy group.
In one embodiment, R 1 、R 2 Are methoxy groups.
By way of example, the compound of formula IV is compound H484,
in one embodiment, compound H484 is a triclinic system, the space group is P-1, and the unit cell parameters areα＝84.698(3)(°)，β＝86.783(3)
(°), γ= 86.783 (3) (°), z=2, volume
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps:
the compound shown in the formula Ib reacts with potassium hydroxide in glycol under the protection of inert gas, the temperature is heated to 150-200 ℃, the solvent is optionally pumped out further, the residue is dissolved by dilute hydrochloric acid aqueous solution, the water is washed to be neutral, and the reaction is carried out at 0-30 ℃.
According to an embodiment of the present invention, the reaction is carried out at 150 to 200℃for 1 to 12 hours.
According to an embodiment of the present invention, the reaction is carried out at 0 to 30℃for 1 to 24 hours.
According to an embodiment of the invention, the molar ratio of the compound of formula Ib to potassium hydroxide is from 1 (100 to 150), for example from 1 (120 to 130), for example from 1:125.
In one embodiment, compound H484 is prepared using the following method: hypocrellin A (HA) and potassium hydroxide are added into glycol, and after mixing, the mixture is heated to 170-180 ℃ under the protection of argon gas, reacted for 3-7 hours, the solvent is pumped out, the residue is dissolved by dilute hydrochloric acid aqueous solution, washed to be neutral, and reacted for 1-24 hours at room temperature.
In one embodiment, a single crystal of compound H484 is prepared using the following method: compound H484 was dissolved in a mixed solvent of ethyl acetate and chloroform and left at 0-10 ℃ protected from light for 1-4 weeks.
The present invention also provides a compound represented by the following formula V,
wherein R is 1 、R 2 、R 3 、R 4 Having the definition as described above.
In one embodiment, R 1 、R 2 、R 3 、R 4 The same applies to methoxy groups.
As an example, the compound of formula V is compound H528:
in one embodiment, compound H528 is triclinic, the space group is P-1, and the unit cell parameters areα= 82.221 (3), β= 69.007 (4), γ= 81.486 (3), z=2, volume +.>
The invention also provides a preparation method of the compound shown in the formula V, which comprises the following steps:
the compound shown in the formula Ib reacts with potassium carbonate in dimethylformamide under the protection of inert gas under the illumination of sodium lamp at 0-30 ℃ for 10-20 min, and then is heated to 150-180 ℃.
According to an embodiment of the present invention, the reaction is carried out at 150 to 180℃for 0.1 to 1 hour.
According to an embodiment of the invention, the molar ratio of the compound of formula Ib to potassium carbonate is 1 (15-40), for example 1 (18-38), for example 1:28.
In one embodiment, compound H528 is prepared using the following method: adding hypocrellin A HA and anhydrous potassium carbonate into dimethylformamide, fully mixing, illuminating for 10-20 min by a sodium lamp at room temperature under the protection of argon, rapidly heating to 160-170 ℃, and stirring for reaction for 0.2-0.7 h.
In one embodiment, a single crystal of compound H528 is prepared using the following method: dissolving the compound H528 in a mixed solvent of chloroform and acetone, and placing the mixture at 0-10 ℃ for 1-4 weeks in a dark place.
The invention also provides application of one, two or more of the compounds shown in the formula I, the formula II, the formula III, the formula IV or the formula V in preparing photodynamic medicaments, photosensitizers, photodynamic antibacterial agents or tumor fluorescent marking agents.
The invention also provides a pharmaceutical composition comprising one, two or more of the compounds shown in formula I, formula II, formula III, formula IV or formula V.
According to an embodiment of the invention, the pharmaceutical composition further optionally comprises at least one pharmaceutically acceptable excipient.
According to an embodiment of the invention, the pharmaceutical composition is a photodynamic drug.
According to an embodiment of the invention, the pharmaceutical composition is a photosensitizer.
According to an embodiment of the invention, the pharmaceutical composition is a photodynamic antibacterial agent.
According to an embodiment of the invention, the pharmaceutical composition is a tumor fluorescent labeling agent.
According to embodiments of the present invention, the pharmaceutical compositions of the present invention may be formulated by methods known in the art to include, but are not limited to, the following forms: liposomes, emulsions, and nanoparticles.
The invention has the following beneficial effects:
the hypocrellin derivative of the invention maintains the excellent characteristics of natural hypocrellin, and is specifically characterized in that:
1) The preparation method has the characteristics of mild reaction conditions and easiness in operation, and is convenient for industrial mass production. Wherein the compound of formula I can be obtained in very high yields (above 95%) and can be used as an intermediate for the further preparation of the compounds of formula II or III;the preparation method of the formula II is simple, and the yield is higher (more than 80 percent); after electromagnetic stirring is completed, a proper amount of dilute hydrochloric acid aqueous solution can be further added into the compound shown in the formula III, and stirring reaction is carried out at room temperature, so that the yield of a product is improved; after electromagnetic stirring, the compound shown in the formula IV can be further added with a proper amount of dilute hydrochloric acid aqueous solution, and stirred at room temperature for reaction, so that the yield of the product is improved, the yield is higher (more than 60 percent), and the relative ratio of the compound is higher 1 O 2 The quantum yield is higher and is more than 1;
in addition, the hypocrellin derivative is simple in post-treatment, and can obtain a product with high purity through simple recrystallization, so that the hypocrellin derivative is convenient to separate and purify, and the cost of the compound in the aspect of medicine application is greatly reduced.
2) The hypocrellin derivative maintains the parent property of hypocrellin, has the maximum ultraviolet light absorption wavelength of 400-600nm, has tissue penetration depth meeting the depth requirement of focus of microvascular diseases, and belongs to a targeted photodynamic medicament for shallow phenotype diseases. The spectrum performance of the fluorescent dye is similar to that of a matrix, so that the fluorescent dye has the same excellent photodynamic performance as the matrix, and the fluorescent dye can be used as photodynamic medicine, photosensitizer, photodynamic antibacterial agent or tumor fluorescent marking agent together with the matrix. The hypocrellin derivative can solve the problem of no scar treatment, avoid the absorption of visual pigment as far as possible, and selectively destroy the abnormal new blood of focus without damaging normal tissues or visual pigment, thereby exerting the photodynamic phototherapy effect to the greatest extent.
3) The hypocrellin derivative can efficiently generate singlet oxygen and active oxygen free radicals, and can be used for antibacterial photodynamic therapy.
4) The hypocrellin derivative prepared by the invention can be prepared into a series of hypocrellin derivative nano-preparations with better biocompatibility, namely liposome, emulsion and nanoparticles, so as to achieve the purpose of intravenous administration.
Definition and description of terms
“C 1-6 Alkoxy "includes C 1-6 Alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butylAnd O-linked groups such as t-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, and neopentyl.
It is well known to those skilled in the art that hypocrellin precursors have enol tautomerism, and thus, even if only one structure of a compound of formula I, or formula II, or formula III, or formula IV, or formula V is given in the present application, the enol tautomer thereof is within the scope of the present application, for example, the enol tautomer of formula I is of the structure shown below (other compound isomers are so deduced):
drawings
FIG. 1 is a diagram showing the structure of 15-position-eliminating acetyl hypocrellin (H486) crystal according to the present invention in example 1, which was measured by X-ray diffraction.
FIG. 2 is a diagram showing the crystal structure of the 2, 11-position-eliminated methoxy-15-position-eliminated acetyl hypocrellin derivative (H426) of example 2 of the present invention, which was measured by X-ray diffraction.
FIG. 3 (a) is a diagram (front) showing the crystal structure of the 15-position-H486 substituted hypocrellin derivative (H970) of example 3 of the present invention as measured by X-ray diffraction; (b) Crystal structure (side) of hypocrellin derivative (H970) was substituted at 15-position-H486 of example 3 of the present invention as measured by X-ray diffraction.
FIG. 4 is a diagram showing the structure of 15-position-ethyleneglycol cyclized substituted hypocrellin crystals of example 4 of the present invention as measured by X-ray diffraction.
FIG. 5 is a diagram showing the structure of 15-isopropyl substituted hypocrellin crystals of example 5 of the present invention as measured by X-ray diffraction.
FIG. 6 is a graph showing the ultraviolet absorption spectra of Hypocrellin B (HB), 15-position-eliminating acetyl hypocrellin (H486), 2, 11-position-eliminating methoxy-15-position-eliminating acetyl hypocrellin derivative (H426) in chloroform (each concentration of about 0.02 mg/ml).
FIG. 7 shows fluorescence spectra of Hypocrellin B (HB), 15-position-eliminating acetyl hypocrellin (H486), 2, 11-position-eliminating methoxy-15-position-eliminating acetyl hypocrellin (H426) in chloroform.
FIG. 8 shows the UV absorption spectra of 15-H486 substituted hypocrellin derivative (H970), photo-product 15-isopropyl substituted hypocrellin (H528) and 15-glycol cyclized substituted hypocrellin (H484) in chloroform (0.02 mg/ml).
FIG. 9 shows fluorescence spectra of 15-H486 substituted hypocrellin derivative (H970), 15-isopropyl substituted hypocrellin (H528) and 15-glycol cyclized substituted hypocrellin (H484) as a photo-product in chloroform.
FIG. 10 shows TEMP-in-chloroform solution of hypocrellin H426 and a capturing agent TEMP 1 O 2 The change of ESR signal with time of illumination, which demonstrates that hypocrellin H426 can be produced 1 O 2 And can calculate therefrom that it has a similarity to the parent 1 O 2 Efficiency is improved.
FIG. 11 shows TEMP-like production of hypocrellin H484 and Capture agent TEMP in oxygen saturated chloroform solution 1 O 2 The changes of ESR signal with time of illumination, which can prove that hypocrellin H484 can be produced 1 O 2 And can calculate therefrom that it has a similarity to the parent 1 O 2 Efficiency is improved.
FIG. 12 is a TEMP-like reaction of H484 (line 1), H426 (line 2), HB (line 3), H486 (line 4), H528 (line 5) and H970 (line 6) in an oxygen-saturated chloroform solution 1 O 2 The change of EPR signal intensity (same absorbance at 532 nm) with time of illumination shows that each hypocrellin derivative can be produced 1 O 2 And can calculate therefrom that each derivative has a similarity to the parent 1 O 2 Efficiency is improved; the inset shows the TEMP-like reaction of hypocrellin HB with capture agent TEMP in an oxygen saturated chloroform solution 1 O 2 Is a function of time of illumination.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
The crystal structure was determined by X-ray diffraction in the following examples, and the single crystal preparation and crystal structure test methods were:
dissolving the prepared compound in chloroform, chloroform and ethyl acetate or chloroform and acetone mixture, standing at 4deg.C in the dark for 1-4 weeks, and recrystallizing to obtain bulk or sheet monocrystal. The X-ray diffractometer model is Japanese science Synergy-R, the light source is copper micro focal spot turning target, the detector is Hybrid-CMOS 2D surface detection, the goniometer is fixed kappa type, the measurement temperature is 170K, and the analysis software is Olex2. The analytical data of single crystals of the compound are shown in tables 1 to 4.
Example 1
Preparation of 15-position-elimination acetyl hypocrellin b (H486): 80.3mg (1.52×10) -4 Molar) Hypocrellin B (HB) is added into 100ml of KOH aqueous solution with the mass fraction of 2.5%, argon is introduced after the mixture is fully mixed, the mixture is heated and refluxed in a dark place (the temperature is more than 100 ℃), electromagnetic stirring reaction is carried out for 5.5 hours, mass spectrum (MALDI-TOF) detection is carried out to detect that the raw material is completely converted, a proper amount of diluted hydrochloric acid is used for neutralization, dichloromethane is used for extraction for three times, water is used for washing to be neutral, and the solid is obtained through reduced pressure distillation. Recrystallization from chloroform-petroleum ether (1:5 by volume) gave 71.5mg of H486 as a reddish brown powder in 96.9% yield.
The structural detection data of the product are shown as follows:
lambda of ultraviolet spectrum max (CHCl 3 )：340.0nm，458.0nm,552.0nm
Fluorescence spectrum lambda max ：(CHCl 3 )：625.2nm
Infrared spectrum v max ：3433cm -1 ，2929cm -1 ，1608cm -1 ,1450cm -1 ,1220cm -1
Nuclear magnetic resonance (deuterated reagent is CDCl) 3 )：δ(1H):16.07(s,1H)，15.95(s,1H)， 6.5(s,1H)6.39(d,2H),5.46-5.42(2H)，4.17，4.15(s,6H)，4.04(m，-6H)， 2.32(m，3H)；
Mass spectrometry (MALDI-TOF): 487.1 (M+1); c (C) 28 H 22 O 8 : calculated value 486.48
Relative singlet oxygen Quantum yield 0.71
The structural formula of the product is as follows:
0.1mg of Compound H486 prepared in the above procedure was dissolved in 4mL of a mixture of chloroform and acetone (the volume ratio of both was 1:1), left at 4℃for 1 week in the absence of light (the procedure of this example was repeated, and single crystals were obtained by leaving for 2 weeks), and recrystallized to obtain a red bulk single crystal. Crystal structure determination Compound H486 has the molecular formula C 28 H 22 O 8 The single crystal is monoclinic, the space group is P21/c, and the unit cell parameter is α=90.00 (°), β= 96.9270 (10) (°), γ=90.00 (°), z=4, and a volume of +.>The crystal structure is shown in FIG. 1, and the single crystal parameters are shown in Table 1.
Table 1: single crystal parameters of Compound H486
/>
Note that: the molecular formula in the above table is C 56 H 44 O 16 The reason is that there are two identical H486 molecules in the unit cell, but not the aggregates.
Example 2
Preparation of 2, 11-elimination methoxy-15-elimination acetyl hypocrellin (H426): 23.0mg (4.73X10) -5 Molar) 15-position-eliminating acetyl hypocrellin (H486) prepared in example 1 and 1.8g KOH are added into 30ml mixed solvent of tetrahydrofuran and 1, 3-propylene glycol (volume ratio is 1:5), argon is introduced, heating reflux is carried out in a dark place, electromagnetic stirring reaction is carried out for 1.0 hour, mass spectrum (MALDI-TOF) detection is carried out for complete conversion of raw materials, a proper amount of diluted hydrochloric acid is used for neutralization, chloroform is used for extraction for three times, water washing is carried out until neutrality, and reduced pressure distillation is carried out to obtain solid. Chloroform-petroleum ether recrystallization (volume ratio 1:8) gave hypocrellin (H426) as a reddish brown powder 16.4mg, 81.4% yield.
The structural detection data of the product are shown as follows:
lambda of ultraviolet spectrum max (CHCl 3 )：448.0.0nm，531.0nm,561.0nm
Fluorescence spectrum lambda max ：(CHCl 3 )：621.2nm
Infrared spectrum v max ：3438cm -1 ，2924cm -1 ，1622cm -1 ,1452cm -1 ,1440cm -1
Nuclear magnetic resonance (deuterated reagent is CDCl) 3 )：δ(1H):15.10(s,1H)，14.99(s,1H)， 7.31(s,2H),7.22(s,1H)，6.50-6.35(d,2H)，4.03(s,6H)，2.27(m，2H)， 1.27(m，3H)；
Mass spectrometry (MALDI-TOF) 428.1 (M+1); c (C) 26 H 18 O 6 : calculated value 426.40
Relative singlet oxygen Quantum yield 0.78
The structural formula of the product is as follows:
0.1mg of compound H426 prepared in the above step is dissolved in 4mL of a mixed solution of chloroform and acetone (the volume ratio of the two is 1:1), and the mixture is placed in a dark place at 4 ℃ for 1 week, and the red blocky single crystal is obtained through recrystallization. The molecular formula of the crystal structure determination compound H426 is C 26 H 18 O 6 The crystal is orthorhombic, the space group is Pbca, and the unit cell parameter isα=90 (°), β=90 (°), γ=90 (°), z=8, and volume +.>The crystal structure is shown in FIG. 2, and the single crystal parameters are shown in Table 2.
Table 2: single crystal parameters of 2, 11-elimination methoxy-15-elimination acetyl hypocrellin (H426)
/>
Example 3: preparation of 15-H486 substituted hypocrellin derivative (H970)
27.0mg (5.56X10) of the 15-position-eliminating acetyl hypocrellin (H486) prepared in example 1 was reacted -5 Molar), 2.1g of solid potassium carbonate was added to 33mL of water and dimethyl sulfoxide (DMSO) (volume ratio 10: 1) Heating the mixed solvent to 155 ℃ under the protection of nitrogen, performing electromagnetic stirring reaction for 6.0 hours, pumping the solvent under reduced pressure, adding a proper amount of dilute hydrochloric acid aqueous solution, and performing stirring reaction at room temperatureExtracting with dichloromethane for 48 hr for 3 times, mixing, washing with water to neutrality, and draining to obtain brownish red solid, recrystallizing with dichloromethane/petroleum ether (volume ratio of 1:8) for 2 times to obtain brownish red solid 11.3mg, which is 15-H486 substituted double H486 hypocrellin derivative (H970), with yield of 42.1%.
The structural detection data of the product are shown as follows:
lambda of ultraviolet spectrum max (CHCl 3 )：340.0nm，463.0nm,555.0nm
Fluorescence spectrum lambda max ：(CHCl 3 )：619.2nm
Infrared spectrum v max ：3438cm -1 ，2930cm -1 ，1603cm -1 ,1452cm -1 ,1307cm -1
Nuclear magnetic resonance (deuterated reagent is CDCl) 3 )：δ(1H):16.07(s,2H)，15.95(s,2H)， 6.5(s,2H)6.39(d,4H),4.15-4.04(m，26H)，1.79(m，6H)；
Mass spectrometry (M/z): 972.3 (m+2); c (C) 56 H 42 O 16 : calculated value 970.25
Relative singlet oxygen quantum yield of 0.51
The structural formula of the product is as follows:
0.1mg of the 15-substituted double H486 derivative (H970) prepared in the above step is dissolved in a mixed solvent of 6mL of chloroform and acetone (volume ratio is 1:3), and the mixture is placed in a dark place at 4 ℃ for 2 weeks, and the red blocky monocrystal is obtained through recrystallization. Crystal structure determination the molecular formula of 15-position H486 substituted double H486 hypocrellin derivative (H970) is C 59 H 48 O 17 (C 56 H 42 O 16 .C 3 H 6 O) the single crystal was acetone based on the result of the single crystal, the single crystal was monoclinic system, and the space group was P2 1 N, unit cell parameters are α=90.00 (°), β= 99.091 (2) (°), γ=90.00 (°), z=4, and a volume of +.>The crystal structure is shown in FIG. 3, and the single crystal parameters are shown in Table 3.
Table 3: single crystal parameters of 15-H486 substituted hypocrellin (H970)
Example 4: preparation of 15-position-glycol cyclized substituted hypocrellin derivative 484 (H484)
Hypocrellin A (HA) 31.0mg (5.7X10) -5 Molar), adding 2.86g of solid potassium hydroxide into 20mL of glycol, fully mixing, heating to 175 ℃ under the protection of argon, carrying out electromagnetic stirring reaction for 5.0 hours, decompressing and pumping out a solvent, dissolving residues with a proper amount of dilute hydrochloric acid aqueous solution, washing with water to be neutral, reacting at room temperature for 24 hours, extracting with dichloromethane for 3 times, merging, pumping out to obtain black powder, recrystallizing with dichloromethane, and obtaining 16.3mg of 15-glycol cyclized substituted hypocrellin derivative 484 (H484) as brown crystals, wherein the yield is 62.9%.
The structural detection data of the product are shown as follows:
lambda of ultraviolet spectrum max (CHCl 3 )：444.0nm，566.0nm；
Fluorescence spectrum lambda max (CHCl 3 )：622.6nm；
Infrared spectrum v max ：3456cm -1 ，1609cm -1 ,1440cm -1 ,1229cm -1 ；
Nuclear magnetic resonance (deuterated reagent is CDCl) 3 )：δ(1H):15.20(s,1H)，14.97(s,1H)， 7.81(s,1H)，7.56(1H),6.72(s,2H)，6.35(1H)，4.27-4.02(4H),3.22(3H)，2.25(3H)；1.27(m，3H)
Mass spectrometry (M/z): 486.2 (m+2); calculated values: c (C) 28 H 20 O 8 : calculated value 484.46
Relative singlet oxygen quantum yield 1.01
The structural formula of the product is as follows:
0.5mg of Compound H484 prepared in the above procedure was dissolved in 6mL of a mixture of ethyl acetate and chloroform (the volume ratio of both of them was 1:5), left at 4℃for 1 week in the absence of light (the procedure of this example was repeated, and single crystals were obtained by leaving for 2 weeks), and recrystallized to obtain red bulk single crystals. Crystal structure determination Compound H484 has the molecular formula C 28 H 20 O 8 The crystal is triclinic, the space group is P-1, and the unit cell parameter is α= 84.698 (3) (°), β= 86.783 (3) (°), γ= 86.783 (3) (°), z=2, and a volume of +.>The crystal structure is shown in FIG. 4, and the single crystal parameters are shown in Table 4.
Table 4: single crystal parameters of 15-position-glycol cyclized substituted hypocrellin derivative (H484)
Example 5: preparation of 15-isopropyl substituted hypocrellin derivative (H528)
Hypocrellin A (HA) 22.3mg (4.1X10) -5 Molar), 1.58g of solid anhydrous potassium carbonate is added into 20mL of dimethylformamide, after being fully mixed, the mixture is irradiated by a sodium lamp at room temperature for 15min under the protection of argon, then the mixture is rapidly heated to 165 ℃ for electromagnetic stirring reaction for 0.5 hour, the product is photodecomposition, the reaction liquid turns light brown from green, the solvent is pumped down under reduced pressure, a proper amount of dilute hydrochloric acid aqueous solution is used for dissolving the residue, dichloromethane is extracted for 3 times and combined, water is used for washing to be neutral, brown powder is obtained after pumping, and the volume ratio of dichloromethane/petroleum ether is 1: 8) Recrystallization gave 3.8mg of a 15-isopropyl-substituted hypocrellin derivative (H528) as a brown powder in 17.6% yield.
The structural detection data of the product are shown as follows:
lambda of ultraviolet spectrum max (CHCl 3 )：338.0nm，464.0nm，556.0nm；
Fluorescence spectrum lambda max (CHCl 3 )：610.8nm；
Infrared spectrum v max ：3442cm -1 ，2936cm -1 ，1609cm -1 ,1452cm -1 ，1300cm -1 ；
Nuclear magnetic resonance (deuterated reagent is CDCl) 3 )：δ(1H):16.03(s，2H)，6.81(1H)， 6.36(s，2H)，4.14.-4.03(s,11H),2.38(s，4H)，1.79-1.71(s，2H)，0.87 (s，6H)；
Mass spectrometry (M/z): 529.34 (m+1); c (C) 31 H 28 O 8 : calculated value 528.56
Relative singlet oxygen Quantum yield 0.54
The structural formula of the product is as follows:
0.5mg of Compound H528 prepared in the above step was dissolved in 3mL of a mixture of chloroform and acetone (the volume ratio of both was 1:2), left at 4℃for 1 week in the absence of light (the procedure of this example was repeated, and single crystals were obtained by leaving for 2 weeks), and recrystallized to obtain a red bulk single crystal. The molecular formula of the crystal structure determination compound H528 is C 31 H 28 O 8 The crystal is triclinic, the space group is P-1, and the unit cell parameter is α= 82.221 (3), β= 69.007 (4), γ= 81.486 (3), z=2, volume +.>The crystal structure is shown in FIG. 5, and the single crystal parameters are shown in Table 5.
Table 5: single crystal parameters of 15-isopropyl substituted hypocrellin derivative (H528)
Example 6: the ESR spectrum of the compound singlet oxygen paramagnetic spectrum was measured by using Bruker-E500 and an electron spin resonance apparatus (X-band, microwave frequency: 9.418 GHz) at room temperature, and the irradiation light source was MGL-III-532nm (CLASS III-b LASER PRODUCT) LASER. The parameters of the measuring instrument are as follows: the microwave power is 10mW; microwave frequency 1.0X10 5 The method comprises the steps of carrying out a first treatment on the surface of the The sweeping width is 100G; a signal gain 40; adjusting the absorbance value of a sample to be detected at 532nm to be equal, carrying out light-shielding oxygenation for 5min, adding a capturing agent TEMPO (2, 6-tetramethyl-4-piperidone) of singlet oxygen to have final concentration of 100mM, carrying out laser in-situ irradiation at 532nm, detecting nitrogen-oxygen free radicals generated by the reaction of the singlet oxygen and the TEMPO by using a paramagnetic resonance method, and carrying out triple peak ESR spectrum of typical nitrogen-oxygen free radicals: the g factor and the fine coupling constant values are g= 2.0056 and a, respectively N ＝13.8G。
With Hypocrellin B (HB) 1 O 2 Quantum yield 0.76 (benzene) as a reference (DiWu, z.j., low j. W., photosensition with anticancer agents.12. Permene quinoniod pigment, anovel type of singlet oxygen sensitizer, j. Photochem. Photobiol. A: chem.,1992 64 273-287). The relative values of hypocrellin derivatives H486 and H426 prepared in examples 1 to 5 were calculated 1 O 2 Quantum yield 0.71,0.78; 15-substituted hypocrellin derivatives H970, H528, H484 1 O 2 The quantum yield was 0.51,0.54,1.01.
The hypocrellin derivative has high synthesis yield, simple post-treatment, and can obtain products with better purity by a simple recrystallization means, the maximum light absorption wavelength of each derivative is 400-600nm, the tissue penetration depth of absorbed light meets the focus depth requirement of microvascular diseases, the hypocrellin derivative has similar photodynamic property as a parent, and the hypocrellin derivative can be replaced to become a targeted photodynamic medicament suitable for shallow phenotype diseases.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (12)
1. A compound of formula I:
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group; r is R 5 Methyl or H.
2. A process for the preparation of a compound as claimed in claim 1, comprising the steps of:
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group;
heating and refluxing the compound Ia in KOH aqueous solution in the absence of light under the protection of inert gas to obtain a compound shown in a formula I;
preferably, the mass fraction of KOH in the aqueous solution of KOH is 1-10%;
preferably, the molar ratio of the compound Ia to KOH is 1 (0.1 to 0.7).
3. Use of a compound according to claim 1 for the preparation of a compound of formula II or formula III as shown below:
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group.
4. The compound of the formula II is shown in the specification,
wherein R is 1 、R 2 Identical or different, independently of one another, C 1-6 An alkoxy group.
5. The method for preparing the compound according to claim 4, comprising the steps of:
adding a compound shown in the formula I in claim 1 and KOH into a mixed solvent of tetrahydrofuran and 1, 3-propanediol, and heating and refluxing in an inert gas atmosphere in a dark place for reaction;
preferably, the volume ratio of tetrahydrofuran to 1, 3-propylene glycol is 1 (2-8);
preferably, the molar ratio of the compound of formula I to KOH is 1 (800-1000).
6. The compound of the formula III is shown in the specification,
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group.
7. A process for the preparation of a compound as claimed in claim 6, comprising the steps of:
adding a compound shown in a formula I and potassium carbonate into a mixed solvent of water and dimethyl sulfoxide, heating to 140-170 ℃ under the protection of inert gas to react for 1-12 hours, optionally further pumping the solvent, adding a dilute hydrochloric acid aqueous solution, and reacting at 0-30 ℃;
preferably, the volume ratio of water to dimethyl sulfoxide is (5-15): 1;
preferably, the molar ratio of the compound of formula I to potassium carbonate is 1 (170-370).
8. A compound of the formula (IV),
wherein R is 1 、R 2 Identical or different, independently of one another, C 1-6 An alkoxy group.
9. A process for the preparation of a compound as claimed in claim 8, comprising the steps of:
heating a compound shown in a formula Ib and potassium hydroxide in ethylene glycol under the protection of inert gas to react at 150-200 ℃, optionally further pumping out a solvent, dissolving the residue with a dilute hydrochloric acid aqueous solution, washing with water to be neutral, and reacting at 0-30 ℃;
preferably, the molar ratio of the compound of formula Ib to potassium hydroxide is 1 (100-150).
10. A compound represented by the formula V,
wherein R is 1 、R 2 、R 3 、R 4 Identical or different, independently of one another, C 1-6 An alkoxy group.
11. A process for the preparation of a compound as claimed in claim 10, comprising the steps of:
the compound shown in the formula Ib and potassium carbonate are subjected to sodium lamp illumination for 10-20 min at 0-30 ℃ under the protection of inert gas in dimethylformamide, and then heated to 150-180 ℃ for reaction;
preferably, the molar ratio of the compound of formula Ib to potassium carbonate is 1 (15-40).
12. Use of one, two or more of a compound of formula I according to claim 1, a compound of formula II according to claim 4, a compound of formula III according to claim 6, a compound of formula IV according to claim 8, or a compound of formula V according to claim 10 for the preparation of a photodynamic medicament, or a photosensitizer, or a photodynamic antibacterial agent, or a tumour fluorescence labelling agent.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211013881.1A CN117658786A (en) | 2022-08-23 | 2022-08-23 | Hypocrellin derivative, and preparation method and application thereof |
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| CN202211013881.1A CN117658786A (en) | 2022-08-23 | 2022-08-23 | Hypocrellin derivative, and preparation method and application thereof |
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