CN107935943B - Ester-water amphiphilic hypocrellin derivative and preparation method and application thereof - Google Patents
Ester-water amphiphilic hypocrellin derivative and preparation method and application thereof Download PDFInfo
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- CN107935943B CN107935943B CN201610894400.0A CN201610894400A CN107935943B CN 107935943 B CN107935943 B CN 107935943B CN 201610894400 A CN201610894400 A CN 201610894400A CN 107935943 B CN107935943 B CN 107935943B
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- hypocrellin
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- 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 claims abstract description 158
- 238000002360 preparation method Methods 0.000 title claims abstract description 131
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 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 claims abstract description 145
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 39
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 29
- 229940079593 drug Drugs 0.000 claims abstract description 23
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 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 claims description 125
- -1 sulfocarboxyl ester Chemical class 0.000 claims description 104
- 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 claims description 63
- 125000001424 substituent group Chemical group 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 239000002202 Polyethylene glycol Substances 0.000 claims description 18
- 229920001223 polyethylene glycol Polymers 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 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 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 238000002428 photodynamic therapy Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 11
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 150000001450 anions Chemical class 0.000 claims description 8
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 229910006069 SO3H Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000002085 enols Chemical class 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003827 glycol group Chemical group 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 125000005647 linker group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 106
- 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 85
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract description 72
- 210000004027 cell Anatomy 0.000 abstract description 35
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 10
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 4
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- 239000000047 product Substances 0.000 description 162
- 238000010521 absorption reaction Methods 0.000 description 100
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 52
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 238000001308 synthesis method Methods 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000012512 characterization method Methods 0.000 description 33
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 14
- 239000004312 hexamethylene tetramine Substances 0.000 description 14
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 13
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical compound CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 12
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 239000012153 distilled water Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 9
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 230000031700 light absorption Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 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 7
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 5
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses an ester-water amphiphilic hypocrellin derivative and a preparation method and application thereof. Compared with a hypocrellin parent body, the hypocrellin derivative containing the condensed ethylene glycol, the quaternary ammonium salt and other group substitutions has the advantages that the absorption spectrum is obviously red-shifted, the molar extinction coefficient is greatly enhanced, and active oxygen species such as singlet oxygen can be efficiently generated under a photosensitive condition; the hydrophilic and hydrophobic properties of the derivatives are adjusted, so that the derivatives have different lipid-water amphiphilicities, and the biocompatibility of the derivatives with cells or tissues is increased; the lipid-water amphiphilic hypocrellin derivative can meet the requirements of different clinical medicines, and solves the contradiction between the requirements of different administration modes on the hydrophilicity and the lipophilicity of the medicine; under the same conditions, the ester-water amphiphilic hypocrellin derivative photosensitizer related to the invention has higher capacity of photodynamic inactivation of tumor cells than the first generation and second generation commercial photosensitizers.
Description
Technical Field
The invention relates to the technical field of photosensitizer medicines for photodynamic therapy. More particularly, relates to an ester-water amphiphilic hypocrellin derivative, and a preparation method and application thereof.
Background
Photodynamic Therapy (PDT) is a new selective treatment technology for vascular diseases, which is rapidly developed in recent years, and has a significant curative effect on various tumor diseases. Photodynamic therapy has become a fourth special type of tumor treatment method following surgery, radiotherapy and chemotherapy, and has the advantages of high efficiency and safety, continuous generation of reactive oxygen species under irradiation of light, resulting in damage or necrosis of diseased cells and tissues, and remarkable high efficiency compared with the conventional medicine which can only kill a single target molecule. The photodynamic therapy has drug targeting and bidirectional selectivity of illumination positioning, reduces the damage to normal cells, and ensures the safety of treatment. PDT has achieved a great achievement in clinical treatment of cancer, and is also used for treatment of non-tumor diseases, such as various angiopathies, condyloma acuminatum, psoriasis, nevus flammeus, rheumatoid arthritis, fundus macular degeneration and the like. In addition, photodynamic therapy also has a remarkable effect on laser beauty and the like.
Photosensitizers are key factors affecting the effectiveness of photodynamic therapy. Of the currently known photosensitizer drugs, the first generation of photosensitizer for clinical use is porphyrin-based photosensitizer, and the second generation is phthalocyanine-based photosensitizer. Among these photosensitizing drugs, the most prominent problem of porphyrin-based photosensitizers and phthalocyanine-based photosensitizers is that separation of geometric isomers is difficult, and it is difficult to obtain single-component pure compounds; and the relatively complex components are not beneficial to the evaluation of drug metabolism and toxicological analysis in the later period. Other photosensitizing drugs such as chlorins, chlorophylls, perylenequinones, and the like are also in development. At present, the photosensitive drugs clinically needed in China are still very deficient, and new high-efficiency photosensitive drugs are urgently needed to fill the vacancy.
Perylene quinone photosensitive drugs, such as cercosporin, hypericin, curcumol, hypocrellin, and the like, which have been successively discovered since the eighties of the last century, have been demonstrated to have anticancer activity. Wherein the hypocrellin is a natural photosensitizer extracted from hypocrellin which is a parasitic fungus on Yunnan plateau with altitude of 4000 m and arrowheads in China. The natural Hypocrellin mainly comprises Hypocrellin A (HA for short) and Hypocrellin B (HB for short). In recent years, people have more detailed researches on hypocrellin, which has basic conditions for becoming photosensitive drugs with excellent performance, such as strong absorption in a visible light region and large molar extinction coefficient, and can efficiently generate singlet oxygen under the photosensitive condition; belongs to a botanical drug, has good phototoxicity, low dark toxicity, fast metabolism in vivo and definite chemical structure, thereby having wide application prospect (Xushangjie, Zhang Xiaoxing, Chenshen and the like, research and development of a novel photodynamic drug-hypocrellin derivative, scientific notice, 2003, 48, 1005-fold 1015). However, the main absorption wavelength range of hypocrellin is 450-550nm, which is less than 1mm capable of tissue penetration, and the light absorption capacity in the photodynamic therapy window (600-900nm) is weak. Over the past decade there have been many chemical modifications to hypocrellins, among which ammonia-modified hypocrellins have a significant red shift of absorption wavelength to 600-700nm with a significant increase in molar extinction coefficient (Paul B., Babu M.S., Santhoskumar T.R., et al.Biophysic evaluation of two-shifted hypocrellins B derivatives as novel PDTs, J.Photochem.Photobiol.B:2009,94, 38-44). Amino-modified hypocrellins have shown superior photosensitizing drug properties, however, the water solubility and biocompatibility of such photosensitizers need further improvement. The target body of the microvascular disease is a xenogenic dense microvascular network in a focal zone and is sensitive to photodynamic action; in photodynamic therapy, the drug is usually delivered intravenously to the affected tissue through the blood circulation system. However, hypocrellin is a kind of lipophilic organic small molecule, and has very low solubility in water, and direct intravenous injection can spontaneously accumulate in blood to cause blood vessel blockage. Sulfonic acid substituted derivatives (Liu X, Xie J, Zhang L Y, et al. optimization of hypocrellin B derivative activity. Chinese Sci Bull,2009,54: 2045-. Therefore, the designed photosensitive drug molecule not only needs to satisfy the light absorption conditions as set forth above, but also needs to satisfy the optimized lipid-water amphiphilicity, which not only satisfies the concentration requirement required by intravenous injection, but also ensures high cell uptake rate to improve the photodynamic therapy effect.
Therefore, it is required to provide a lipid-water amphiphilic hypocrellin derivative which meets the light absorption condition and has optimized properties, and a preparation method and application thereof.
Disclosure of Invention
An object of the present invention is to provide an ester-water amphiphilic hypocrellin derivative; the second purpose of the invention is to provide a preparation method of ester-water amphiphilic hypocrellin derivative; the third purpose of the invention is to provide the application of the ester-water amphiphilic hypocrellin derivative. The invention provides the technical scheme aiming at the problems that the existing hypocrellin derivative can not only meet the light absorption condition, but also meet the optimized amphipathy of lipid and water. The applicant proposes that groups such as polyethylene glycol or long-chain quaternary ammonium salt and the like are used or groups such as polyethylene glycol and long-chain quaternary ammonium salt and the like are simultaneously introduced to modify hypocrellin, so that the biocompatibility of the hypocrellin is enhanced, and the hydrophilic and hydrophobic properties of a parent body of the hypocrellin are adjusted. The derivatives have different lipid-water amphiphilicities and are easily influenced by pH change. The photodynamic experiment proves that: the amphiphilic hypocrellin derivative can meet the requirements of different clinical medicines, and solves the contradiction between the requirements of different administration modes on the hydrophilicity and the lipophilicity of the medicine. This solution is disclosed for the first time in the present invention.
In order to achieve the first purpose, the invention adopts the following technical scheme:
an ester-water amphiphilic hypocrellin derivative, the structural general formula of the derivative is formula (1) or formula (2):
the formula (1) is piperazino hypocrellin derivative, and substituent R of the piperazino hypocrellin derivative1Is H or-COCH3(ii) a The R is1When it is H, the double bond is located at C indicated in formula (1)13、C14、C15C of three carbon atoms13＝C14Or C14＝C15(ii) a The R is1is-COCH3When the double bond is located at C as indicated in formula (1)13、C14、C15C of three carbon atoms13＝C14；
Substituent R of hypocrellin derivative of formula (2)1Is H, -COCH3or-C (CH)3) N-R; the R is1When it is H, the double bond is located at C indicated in formula (2)13、C14、C15Three areC of a carbon atom13＝C14Or C14＝C15(ii) a The R is1is-COCH3or-C (CH)3) When N-R, the double bond is located at C as indicated in formula (2)13、C14、C15C of three carbon atoms13＝C14；
R on the hypocrellin-pyrazine ring in formula (1)2-R7Are each dependent on substituent R; the substituent R is a hydrophobic group, a hydrophilic group or different combinations of the hydrophobic group and the hydrophilic group; the hydrophobic group contains alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocyclic group; the hydrophilic group contains hydroxyl, carboxyl, ester group, amide group, carboxylic acid group, sulfonic group, ethylene glycol group, quaternary ammonium salt or pyridinium; the structural general formula of the substituent R is shown as the formula (3):
in the formula (3), m is more than or equal to 0 and less than or equal to 12, n is more than or equal to 0 and less than or equal to 500, p is more than or equal to 0 and less than or equal to 12, and q is more than or equal to 0 and less than or equal to 12; m, n, p and q are zero or positive integers; y is a linking group; z is an end group; (OCH)2CH2)nIs a polyethylene glycol unit;
the connecting group Y in the formula (3) is NH, O, S, carboxylic ester, amide, sulfocarboxyl ester, aryl, heterocyclic aryl, alkyl of 3-12 carbon atoms or cycloalkyl of 3-12 carbon atoms;
the aryl is substituted or unsubstituted aryl; the heterocyclic aryl is substituted or unsubstituted heterocyclic aryl; hydrocarbyl of 3 to 12 carbon atoms comprising substituted or unsubstituted or heteroatom containing alkenes or alkynes; cycloalkyl of 3 to 12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing cycloalkane, cycloalkene or cycloalkyne, said heteroatom being an oxygen, nitrogen or sulfur atom; the substituent is halogen, hydroxyl, alkyl with 1-12 carbon atoms, alkenyl with 2-12 carbon atoms, alkynyl with 2-12 carbon atoms, cycloalkyl with 3-8 carbon atoms, aryl or aralkyl with 6-12 carbon atoms; or an alkyl group having a terminal group containing a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester; or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group of 1 to 12 carbon atom chain length containing a heteroatom which is an oxygen, nitrogen or sulfur atom; or different combinations of the above substituents;
the terminal group Z in the formula (3) is hydrogen, alkyl with 1-12 carbon atoms, alkoxy with 1-12 carbon atoms, phenyl, heterocycle, hydroxyl, sulfydryl, carboxylic acid group, sulfonic acid group, quaternary ammonium salt or pyridinium;
when the terminal group Z is quaternary ammonium salt, three substituents on the quaternary ammonium salt are respectively independent or simultaneously: alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 3 to 8 carbon atoms, aryl or aralkyl of 6 to 12 carbon atoms; or an alkyl group having a terminal group containing a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester; or an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group of 1 to 12 carbon atom chain length containing a heteroatom which is an oxygen, nitrogen or sulfur atom; or different combinations of the above substituents; the anion in the quaternary ammonium salt is the anion allowed by the pharmaceutical preparation;
when the terminal group Z is pyridinium, the substituent on the pyridine ring in the pyridinium is in ortho-position, meta-position or para-position; the pyridinium is prepared by quaternizing pyridine and halogenated hydrocarbon with different chain lengths and 1-12 carbon atoms; the anion in the pyridinium is the anion allowed by the pharmaceutical preparation;
a substituent R described in the formula (1)1is-COCH3The double bond being at C13＝C14When the piperazine ring marked by the formula (1) has at least one of the two carbon atoms a and b as a tertiary carbon atom; a substituent R described in the formula (1)1Is H, the double bond being at C14＝C15When the piperazine ring marked by the formula (1) has at least one of the two carbon atoms a and b as a tertiary carbon atom;
the R in the formula (2) is a substituent group, and the substituent group R is a hydrophobic group, a hydrophilic group or different combinations of the hydrophobic group and the hydrophilic group; the hydrophobic group contains alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocycle; the hydrophilic group contains hydroxyl, carboxyl, ester group, amide group, carboxylic group, sulfonic group, ethylene glycol group or quaternary ammonium salt; the structural general formula of the substituent R is shown as a formula (3);
a substituent R described in the formula (2)1is-COCH3The double bond being at C13＝C14When R is a substituent of formula (3), the following structure is not included: - (CH)2)m-NH-(CH2)p-Z; wherein m is more than or equal to 1 and less than or equal to 12, p is more than or equal to 0 and less than or equal to 12, and Z is hydroxyl, alkoxy, carboxylic acid or carboxylic ester;
the double bond of formula (2) being at C13＝C14Position, substituent R1is-COCH3or-C (CH)3) (iii) when N-R, the terminal group Z in said formula R does not contain a quaternary ammonium moiety.
The structural general formula of the piperazino hypocrellin derivative is shown as formula (4), (5) or (6):
in the formula (1), a substituent R of piperazino hypocrellin derivative1Is H, the double bond being at C13＝C14When the position is correct, the general structural formula is shown as a formula (4); substituent R of piperazino hypocrellin derivative1Is H, the double bond being at C14＝C15When the position is correct, the structural general formula is shown as a formula (5); substituent R of piperazino hypocrellin derivative1is-COCH3The double bond being at C13＝C14When the position is correct, the general structural formula is shown as a formula (6);
at least one of two carbon atoms a and b on the piperazine ring marked by the formula (5) is a tertiary carbon atom; at least one of two carbon atoms a and b on the piperazine ring marked by the formula (6) is a tertiary carbon atom;
the substituent R in the formula (4), the formula (5) and the formula (6)2-R7Are each as defined under substituent R in formula (3)2-R7Partially or totally identical, or totally different; substituent R2-R7Is a hydrophobic group, a hydrophilic group, or different combinations of hydrophobic and hydrophilic groups; the hydrophobic group contains alkyl, alkenyl, alkynyl, cycloalkyl or heterocycle; the hydrophilic group contains hydroxyl, carboxyl, ester group, ether group and acylAmino, sulfonic group, ethylene glycol unit or quaternary ammonium salt.
The general structural formula of the hypocrellin derivative in the formula (2) is formula (9) -formula (12):
in the formula (2), the substituent R of hypocrellin derivative1Is H, the double bond being at C13＝C14When the position is correct, the general structural formula is shown as a formula (9); substituent R of hypocrellin derivative1Is H, the double bond being at C14＝C15When the position is correct, the general structural formula is shown as a formula (10); substituent R of hypocrellin derivative1is-COCH3The double bond being at C13＝C14When the position is correct, the general structural formula is shown as a formula (11); substituent R of hypocrellin derivative1is-C (CH)3) N ═ R, double bond at C13＝C14When the position is correct, the general structural formula is shown as a formula (12);
the general structural formula of a substituent R in the formulas (9) and (12) is shown as a formula (3), and the substituent R is a hydrophobic group, a hydrophilic group or different combinations of the hydrophobic group and the hydrophilic group; the hydrophobic group contains alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocycle; the hydrophilic group contains hydroxyl, carboxyl, ester group, amide group, carboxylic group, sulfonic group, ethylene glycol group or quaternary ammonium salt;
in the formulas (10) and (11), the substituent R does not contain the following structure: - (CH)2)m-NH-(CH2)p-Z; wherein m is more than or equal to 1 and less than or equal to 12, p is more than or equal to 0 and less than or equal to 12, and Z is hydroxyl, alkoxy, carboxylic acid or carboxylic ester;
in the formulas (11) and (12), the substituent R does not contain a quaternary ammonium salt structure.
Preferably, the linker Y in the substituent R is: -NH-; -O-, -S-; -COO-; CONH-; -SO3-；-CH＝CH-；-C≡C-；-C6H4- (phenyl); -C6H3(CH3)-；-C6H3(C2H5)-；-C6H3(OH)-；-C6H3(F)-；-C6H3(Cl)-；-C6H3(Br)-；-C5H3N- (pyridyl); -C3H4- (cyclopropyl); -C4H6- (cyclobutyl); -C5H8- (cyclopentyl); -C5H7(CH3) - (methylcyclopentyl); -C5H7(OH) - (hydroxycyclopentyl); -C6H10- (cyclohexyl); -C6H9(CH3) - (methylcyclohexyl); -C6H9(C2H5) - (ethylcyclohexyl); -C6H9(C3H7) - (propylcyclohexyl); -C6H9(C4H9) - (butylcyclohexyl); -C6H8(CH3)2- (dimethylcyclohexyl); -C6H9(OH) - (hydroxycyclohexyl); -C7H12- (cycloheptyl);
(piperazinyl);
(1, 4-diazabicyclo [ 2.2.2)]An octyl group).
Preferably, the terminal group Z in the substituent R is: -H; -CH3；-C2H5；-C3H7；-C4H9；-C5H11；-C6H13；-OCH3；-OC2H5；-OC3H7；-OC4H9；-OC5H11；-OC6H13；-C6H5；-C5H4N；-OH,-NH2；-SH；-COOH；-COOCH3；-COOC2H5；-SO3H；-C5H4N+；-N+(CH3)3；-N+(C2H5)3；-N+(C3H7)3；-N+(C4H9)3；-N+(C5H11)3；-N+(C6H13)3；-N+(CH3)2(C2H5)；-N+(CH3)2(C3H7)；-N+(CH3)2(C4H9)；-N+(CH3)2(C5H11)；-N+(CH3)2(C6H13)；-N+(CH3)2(C7H15)；-N+(CH3)2(C8H17)；-N+(CH3)2(C9H19)；-N+(CH3)2(C10H23)；-N+(CH3)2(C11H23)；-N+(CH3)2(C12H25)；-N+(C2H5)2(C3H7)；-N+(C2H5)2(C4H9)；-N+(C2H5)2(C5H11)；-N+(C2H5)2(C6H13)；-N+(C2H5)2(C7H15)；-N+(C2H5)2(C8H17)；-N+(C2H5)2(C9H19)；-N+(C2H5)2(C10H23)；-N+(C2H5)2(C11H23)；-N+(C2H5)2(C12H25)；
(1, 4-diazabicyclo [ 2.2.2)]An octyl group); or isThe end group contains quaternary ammonium salt of hydroxyl, carboxylic acid group, sulfonic group or carboxylic ester.
Preferably, the substituents R are: -H; -CH3；-C2H5；-C3H7；-C4H9；-C5H11；-C6H13；-C3H6；-C5H9(cyclopentyl); -C6H11(cyclohexyl); -C6H10(CH3) (methylcyclohexyl); -C6H10(C2H5) (ethylcyclohexyl); -C6H10(C3H7) (propylcyclohexyl); -C6H10(C4H9) (butylcyclohexyl); -C6H9(CH3)2(dimethylcyclohexyl); -C6H10(OH) (hydroxycyclohexyl); -C7H12- (cycloheptyl); -C6H5；-CH2C6H5；-CH2CH2C6H5；-CH2CH2CH2C6H5；-C5H4N；-CH2C5H4N；-(CH2)2C5H4N；-(CH2)3C5H4N；-NH2；-NHC2H5；-NHC6H5；-NHC5H4N；-OH；-CH2CH2OH；-CH2CH2-OCH2CH2-OH；-CH2CH2-(OCH2CH2)2-OH；-CH2CH2-(OCH2CH2)3-OH；-CH2CH2-(OCH2CH2)4-OH；-CH2CH2-(OCH2CH2)5-OH；-CH2CH2-(OCH2CH2)6-OH；-CH2CH2-(OCH2CH2)7-OH；-CH2CH2-(OCH2CH2)8-OH；-CH2CH2-(OCH2CH2)9-OH；-CH2CH2-(OCH2CH2)10-OH；-CH2CH2-(OCH2CH2)11-OH；-CH2CH2-(OCH2CH2)12-OH；-CH2CH2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-CH2CH2-NH-CH2CH2-OCH2CH2OH；-CH2CH2-NH-CH2CH2-(OCH2CH2)2-OH；-CH2CH2-NH-CH2CH2-(OCH2CH2)3-OH；-CH2CH2-NH-CH2CH2-(OCH2CH2)4-OH；-CH2CH2-NH-CH2CH2-(OCH2CH2)6-OH；-CH2CH2-NH-CH2CH2-(OCH2CH2)n-OH; [ polyethylene glycol having a molecular weight of less than 3 million]；-(CH2)3-OH；-(CH2)3-OCH2CH2-OH；-(CH3)4-OCH2CH2-OH；-(CH2)3-(OCH2CH2)2-OH；-CH2CH2OCH3；-CH2CH2-OCH2CH2-OCH3；-CH2CH2-(OCH2CH2)2-OCH3；-CH2CH2-(OCH2CH2)4-OCH3；-CH2CH2-(OCH2CH2)6-OCH3；-CH2CH2-NH-CH2CH2-OCH2CH2OCH3；-CH2CH2-NH-CH2CH2-(OCH2CH2)2-OCH3；-CH2CH2-NH-CH2CH2-(OCH2CH2)3-OCH3；-CH2CH2-NH-CH2CH2-(OCH2CH2)4-OCH3；-CH2CH2-NH-CH2CH2-(OCH2CH2)6-OCH3；-CH2CH2-NHCH2CH2-NH2；-CH2CH2-(NHCH2CH2)2-NH2；-CH2CH2-(NHCH2CH2)3-NH2；-CH2CH2-NHCH2CH2-N(CH3)2；-CH2CH2-(NHCH2CH2)2-N(CH3)2；-CH2CH2-(NHCH2CH2)3-N(CH3)2；-CH2CH2-SH；-CH2CH2-S-CH2CH2OH；-CH2CH2-S-CH2CH2-OCH2CH2-OH；-CH2CH2-S-CH2CH2-(OCH2CH2)2-OH；-CH2CH2-S-CH2CH2-SH；-CH2CH2-(SCH2CH2)2-SH；-CH2CH2-(SCH2CH2)3-SH；-CH2CH2-(SCH2CH2)4-SH；-CH2CH2-SO3H；-(CH2CH2O)2-SO3H；-CH2CO2H；-CH2CH2CO2H；-CH2CH2CH2CO2H；-CH2CH2CH2CH2CO2H；-CH2-C(＝O)-OCH2CH2-OH；-CH2CH2-C(＝O)-OCH2CH2-OH；-CH2CH2-C(＝O)-(OCH2CH2)2-OH；-CH2CH2-C(＝O)-(OCH2CH2)3-OH；-CH2CH2-C(＝O)-(OCH2CH2)4-OH；-CH2CH2-C(＝O)-(OCH2CH2)6-OH；-CH2CH2-C(＝O)-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)3-C(＝O)-OCH2CH2-OH；-(CH2)3-C(＝O)-(OCH2CH2)2-OH；-(CH2)3-C(＝O)-(OCH2CH2)4-OH；-(CH2)3-C(＝O)-(OCH2CH2)6-OH；-(CH2)3-C(＝O)-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)4-C(＝O)-OCH2CH2-OH；-(CH2)4-C(＝O)-(OCH2CH2)2-OH；-(CH2)4-C(＝O)-(OCH2CH2)4-OH；-(CH2)4-C(＝O)-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)5-C(＝O)-OCH2CH2-OH；-(CH2)5-C(＝O)-(OCH2CH2)2-OH；-(CH2)5-C(＝O)-(OCH2CH2)4-OH；-(CH2)5-C(＝O)-(OCH2CH2)6-OH；-(CH2)5-C(＝O)-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-CH2CH2-SO2-OCH2CH2-OH；-CH2CH2-SO2-(OCH2CH2)2-OH；-CH2CH2-SO2-(OCH2CH2)4-OH；-CH2CH2-SO2-(OCH2CH2)6-OH；-CH2CH2-SO2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)3-SO2-OCH2CH2-OH；-(CH2)3-SO2-(OCH2CH2)2-OH；-(CH2)3-SO2-(OCH2CH2)4-OH；-(CH2)3-SO2-(OCH2CH2)6-OH；-(CH2)3-SO2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)4-SO2-OCH2CH2-OH；-(CH2)4-SO2-(OCH2CH2)2-OH；-(CH2)4-SO2-(OCH2CH2)4-OH；-(CH2)4-SO2-(OCH2CH2)6-OH；-(CH2)4-SO2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)5-SO2-OCH2CH2-OH；-(CH2)5-SO2-(OCH2CH2)2-OH；-(CH2)5-SO2-(OCH2CH2)4-OH；-(CH2)5-SO2-(OCH2CH2)6-OH；-(CH2)5-SO2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-CH2-C(＝O)NH-CH2CH2-OCH2CH2-OH；-(CH2)2-C(＝O)NH-CH2CH2-(OCH2CH2)2-OH；-(CH2)2-C(＝O)NH-CH2CH2-(OCH2CH2)3-OH；-(CH2)2-C(＝O)NH-CH2CH2-(OCH2CH2)6-OH；-(CH2)2-C(＝O)NH-CH2CH2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-(CH2)3-C(＝O)NH-CH2CH2-OCH2CH2-OH；-(CH2)3-C(＝O)NH-CH2CH2-(OCH2CH2)2-OH；-(CH2)3-C(＝O)NH-CH2CH2-(OCH2CH2)6-OH；-(CH2)3-C(＝O)NH-CH2CH2-(OCH2CH2)n-OH [ polyethylene glycol having a molecular weight of less than 3 ten thousand]；-CH2CH2-N+(CH3)3；-CH2CH2-N+(C2H5)3；-CH2CH2-N+(C3H7)3；-CH2CH2-N+(C4H9)3；-CH2CH2-N+(C5H11)3；-CH2CH2-N+(C6H13)3；-(CH2)3-N+(CH3)3；-(CH2)4-N+(CH3)3；-(CH2)5-N+(CH3)3；-(CH2)6-N+(CH3)3；-CH2CH2-N+(CH3)2(C2H5)；-CH2CH2-N+(CH3)2(C3H7)；-CH2CH2-N+(CH3)2(C4H9)；-CH2CH2-N+(CH3)2(C5H11)；-CH2CH2-N+(CH3)2(C6H13)；-CH2CH2-N+(CH3)2(C7H15)；-CH2CH2-N+(CH3)2(C8H17)；-CH2CH2-N+(CH3)2(C9H19)；-CH2CH2-N+(CH3)2(C10H21)；-CH2CH2-N+(CH3)2(C11H23)；-CH2CH2-N+(CH3)2(C12H25)；-(CH2)3-N+(CH3)3；-(CH2)3-N+(CH3)2(C2H5)；-(CH2)3-N+(CH3)2(C3H7)；-(CH2)3-N+(CH3)2(C4H9)；-(CH2)3-N+(CH3)2(C5H11)；-(CH2)3-N+(CH3)2(C6H13)；-(CH2)3-N+(CH3)2(C10H21)；-(CH2)3-N+(CH3)2(C12H25)；-(CH2)4-N+(CH3)3；-(CH2)4-N+(CH3)2(C2H5)；-(CH2)4-N+(CH3)2(C4H9)；-(CH2)4-N+(CH3)2(C6H13)；-(CH2)4-N+(CH3)2(C8H17)；-(CH2)4-N+(CH3)2(C10H21)；-(CH2)5-N+(CH3)3；-(CH2)5-N+(CH3)2(C2H5)；-(CH2)5-N+(CH3)2(C3H7)；-(CH2)5-N+(CH3)2(C4H9)；-(CH2)5-N+(CH3)2(C5H11)；-(CH2)5-N+(CH3)2(C6H13)；-(CH2)5-N+(CH3)2(C10H21)；-(CH2)5-N+(CH3)2(C12H25)；-(CH2)6-N+(CH3)3；-(CH2)6-N+(CH3)2(C2H5)；-(CH2)6-N+(CH3)2(C4H9)；-(CH2)6-N+(CH3)2(C6H13)；-(CH2)6-N+(CH3)2(C8H17)；-(CH2)6-N+(CH3)2(C10H21)；-(CH2)6-N+(CH3)2(C12H25)；-(CH2)4-N+(C2H5)3；-(CH2)4-N+(C2H5)2(C3H7)；-(CH2)4-N+(C2H5)2(C4H9)；-(CH2)4-N+(C2H5)2(C5H11)；-(CH2)4-N+(C2H5)2(C6H13)；-(CH2)4-N+(C2H5)2(C8H17)；-(CH2)4-N+(C2H5)2(C10H21)；-(CH2)4-N+(C2H5)2(C12H25)；
Preferably, the structural general formula of the piperazino hypocrellin derivative of formula (1) further comprises an enol tautomer represented by formula (1'); the general structural formula of the hypocrellin derivative of formula (2) also includes enol tautomer shown in formula (2'):
in order to achieve the second purpose, the invention adopts the following technical scheme:
a preparation method of an amphiphilic hypocrellin derivative comprises the following steps:
dissolving hypocrellin and corresponding substituted amine derivatives in an organic solvent, reacting in the dark under the protection of inert gas, and finally separating and purifying to obtain the ester water amphiphilic hypocrellin derivative. The hypocrellin is hypocrellin HB and deacetylated hypocrellin HC; the general formula of the substituent group structure of the substituted amine derivative is shown as a formula (3); the feeding molar ratio of the hypocrellin to the substituted amino derivative is 1: 5-1: 50, and specifically can be 1:5, 1:10, 1:15, 1:20, 1:30, 1:40 or 1: 50; the reaction temperature is 20-100 ℃; the reaction time is 6-18 hours. The organic solvent is acetonitrile, tetrahydrofuran, pyridine, N-dimethylformamide, methanol and ethanol; the reaction is carried out under the protection of inert gas such as argon or nitrogen, and the reaction is protected from light.
Preferably, the organic solvent is one of acetonitrile, tetrahydrofuran or pyridine; the feeding molar ratio of the hypocrellin to the substituted amine derivative is 1: 20; the reaction temperature is 60 ℃; the reaction time was 8 hours. Preferably, the separation and purification process is as follows: removing the reaction organic solvent to obtain a residue, and dissolving the residue with dichloromethane; washing with dilute hydrochloric acid solution and water in sequence; then drying, filtering and removing the solvent from the organic layer to obtain a crude product; and (3) carrying out chromatography on the crude product by using a silica gel plate to obtain the hypocrellin derivative containing the long-chain quaternary ammonium salt.
Preferably, the developing agent used in the silica gel plate chromatography is a mixed solution containing acetone, ethyl acetate, ethanol and diethylamine, and the volume ratio of the acetone, the ethyl acetate, the ethanol and the diethylamine in the mixed solution is 20:1:1 to 20:1:3: 1. Preferably, the separation and purification process is as follows: the reaction organic solvent was removed to give a blue-black solid residue which was dissolved in dichloromethane, washed three times with an equal volume of dilute aqueous hydrochloric acid (5%) and once with water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to give a crude product. The crude product was further separated by silica gel plate chromatography with acetone as developing agent: ethyl acetate: ethanol: and (3) diethylamine, wherein the preferable volume ratio is 20:1:1:1, so that the amino-substituted hypocrellin derivative is obtained, the yield is 5-20%, and the product is a blue-black solid.
In order to achieve the third purpose, the invention adopts the following technical scheme:
the application of the ester-water amphiphilic hypocrellin derivative as a photosensitizer medicine in photodynamic therapy is provided.
FIG. 1 shows the general structural formula of an amphiphilic hypocrellin designed by the present invention. Fig. 2 to 6 show the synthesis method of various hypocrellin derivatives according to the present invention. The hypocrellin derivative containing the condensed ethylene glycol or quaternary ammonium salt and other groups has very wide strong absorption in a phototherapy window, the maximum absorption spectrum wavelength is about 600-630nm and can reach 650nm maximally, the maximum absorption spectrum wavelength is more than 150nm than the maximum absorption peak (450nm) of a hypocrellin parent body, and the molar extinction coefficient is about 10000-40000M-1cm-1On the left and right sides, a very strong red light absorbing ability is shown (as shown in fig. 7); the water solubility is good, and the stock solution with the concentration range of 0.1 uM-1 mM can be prepared in the physiological saline. Its ability to generate reactive oxygen species is illustrated by FIG. 8: experiments show that the ester-water amphiphilic hypocrellin derivative can efficiently generate photosensitive active species mainly generating singlet oxygen (figure 8a) and also can generate a small amount of superoxide radical (figure 8b) when being measured by singlet oxygen and superoxide radical trapping agents respectively. Shown in FIG. 9Confocal fluorescence imaging experimental results show that phototherapy drug micromolecule HB-1 has good biocompatibility, can enter lysosomes of Hela cells, and can generate good red fluorescence imaging in the cells. HB-1 and Hela cells are incubated together, as shown in FIG. 10a, a cytotoxicity (dark toxicity) research experiment shows that the hypocrellin derivative HB-1 containing ethylene glycol synthesized in example 3 has small cytotoxicity, and similar to hypocrellin HB and a commercial photosensitive drug hematoporphyrin HpD, Hela cells are incubated for half an hour with a photosensitizer HB-1 with a concentration of 10uM, and no obvious death of Hela cells is seen, which indicates that the photosensitizer has no cytotoxicity basically. The cytotoxicity study experiment shown in FIG. 10b shows that HB-1 shows very strong killing power to Hela cells under red light irradiation. More than 90% of Hela cells can be killed by the hypocrellin B or the commercial photosensitizer hematoporphyrin derivative in the concentration range of 160nM, and only about 20% of Hela cells can be killed by the hypocrellin B or the commercial photosensitizer hematoporphyrin derivative under the same condition, which shows that the photodynamic effect of the amphiphilic hypocrellin B derivative is obviously superior to that of hypocrellin HB and the commercial photosensitizer hematoporphyrin HpD. FIG. 11 shows similar results in the dark cytotoxicity and phototoxicity tests of hypocrellin derivative HB-2 containing ethylene glycol synthesized in example 3. In addition, FIG. 12 shows the phototoxicity effect of the aminopropanol modified deacetylated hypocrellin HC-3 or HC-4 synthesized in example 4 for killing tumor cells; FIG. 13 is a graph showing the phototoxicity effect of the deacetylated hypocrellin HC-87 or HC-88 containing long-chain quaternary ammonium salt modification synthesized in example 46 on killing tumor cells; FIG. 14 is a graph showing the phototoxicity effect of piperazino hypocrellin HB-98 synthesized in example 52 on tumor killing cells; all the phototoxicity experimental results show that the photodynamic effect of the amphiphilic hypocrellin derivative is obviously superior to hypocrellin HB and a commercial photosensitizer hematoporphyrin HpD.
Compared with hypocrellin B parent substance, the ester-water amphiphilic hypocrellin derivative has the advantages that the water solubility is greatly enhanced by introducing the condensed glycol, the quaternary ammonium salt and other groups, and the oil-water ratio is adjusted by changing the chain length of the fatty chain, so that the derivative has good lipid-water amphiphilic property and good biocompatibility in cells or tissues; the compound exists in the form of ethylene glycol or quaternary ammonium salt, is not easily influenced by pH, and can be used in complex organisms; the hypocrellin with positive salt such as quaternary ammonium salt can effectively combine with negative charge species in organisms, and particularly has good nucleophilicity on tumor cells; the phototherapy effect is changed by adjusting the distance between the quaternary ammonium salt and the hypocrellin matrix; the condensed ethylene glycol is adopted, the hydrophilic and hydrophobic properties of photosensitive drug molecules can be adjusted at will by changing the unit number of the condensed ethylene glycol structure, so as to meet the requirements of different clinical drugs, and in addition, the condensed ethylene glycol structure is non-toxic, is also a drug component approved by the American FDA and has good biocompatibility. Therefore, the amphiphilic hypocrellin derivative can be directly dissolved in normal saline to prepare a preparation medicine, so that the medicinal effect is improved; and the compound is prepared from natural products, does not generate toxic or side effect, and lays a foundation for developing hypocrellin medicaments for treating cancers and anti-cancer viruses.
The invention discloses two types of ester-water amphiphilic hypocrellin derivatives, and a preparation method and application thereof. The hypocrellin is modified by ethylene glycol groups or quaternary ammonium salts with long chains, and the derivatives have different lipid-water amphiphilicities and are improved in biocompatibility with cells or tissues by adjusting the hydrophilic and hydrophobic properties of molecules. The maximum absorption wavelength of the compounds is in the range of 600-650nm, and the molar extinction coefficient reaches 10000-40000M-1cm-1Has strong light absorption capacity in the phototherapy window. Researches show that the derivatives can efficiently generate singlet oxygen and other active oxygen species under the photosensitive condition, have good photodynamic effect, and can be used as phototherapy drugs for treating diseases such as tumors and various microangiopathies.
In the prior art, research on preparation and extraction of the hypocrellin derivative modified by the ethylene glycol is not available, and related research on the high cell uptake rate is not found, wherein the compound can simultaneously meet the light absorption condition and also meet the optimized lipid-water amphipathy, namely the concentration requirement of intravenous injection.
It should be noted that the hypocrellin derivatives to be protected in this patent contain two enol tautomers (formula 1 and 1 ', formula 2 and 2'), and the chemical structures of both isomers are certainly within the protection scope. Further, unless otherwise specified, any range recited herein includes the endpoints and any number between the endpoints and any sub-range defined by the endpoints or any number between the endpoints.
The invention has the following beneficial effects:
1) the hypocrellin raw material is extracted from natural products, is easy to obtain, has low cost, can be prepared in a large scale, has small toxic and side effects and is easy to metabolize;
2) the synthesis and separation method is simple, and expensive reaction raw materials and complex separation means are not needed;
3) compared with a hypocrellin parent body, the absorption spectrum of the prepared hypocrellin derivative containing the condensed ethylene glycol, quaternary ammonium salt and other group substitution is obviously red-shifted, the molar extinction coefficient is greatly increased, and active oxygen can be efficiently generated under a photosensitive condition (singlet oxygen is taken as a main component, and active oxygen species such as superoxide radical and the like are taken as auxiliary components); the parent body of hypocrellin is introduced with a condensed ethylene glycol or quaternary ammonium salt and other group structures to adjust the hydrophilic and hydrophobic properties of the hypocrellin, so that the derivatives have different amphiphilicities of lipid and water and the biocompatibility of the derivatives with cells or tissues is improved; the derivatives of the lipo-hydro amphiphilic hypocrellin can meet the requirements of different clinical medicines and solve the contradiction between the requirements of different administration modes on the hydrophilicity and the lipophilicity of the medicines.
4) Compared with the first generation porphyrin photosensitizer and the second generation phthalocyanine photosensitizer which are clinically used, the ester-water amphiphilic hypocrellin derivative photosensitizer has obviously improved absorption wavelength and light absorption capacity, and importantly, the product is easy to separate and purify and has a definite structure, thereby overcoming the problems that the porphyrin and the phthalocyanine photosensitizer are difficult to separate and the composition of the porphyrin and phthalocyanine photosensitizer is difficult to determine. More importantly: under the same conditions, the ester-water amphiphilic hypocrellin derivative photosensitizer related to the invention has higher capacity of photodynamic inactivation of tumor cells than the first generation and second generation commercial photosensitizers.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 shows the general structural formula of an amphiphilic hypocrellin designed by the invention.
Fig. 2 shows a synthesis reaction scheme of a long-chain quaternary ammonium salt derivative in example 2 of the present invention.
FIG. 3 shows a scheme of synthesis reaction of hypocrellin B derivatives HB-1 and HB-2 containing ethylene glycol in example 3 of the present invention.
FIG. 4 shows a scheme of synthesis reaction of deacetylated hypocrellin HC and aminopropanol in example 4 of the present invention.
FIG. 5 shows a synthesis scheme of a deacetylated hypocrellin derivative containing a long-chain quaternary ammonium salt according to example 46 of the present invention.
FIG. 6 shows a scheme for synthesis reaction of piperazino hypocrellin derivatives HB-98 and HB-99 in example 52 of the present invention.
FIG. 7 is a graph showing the comparison of absorption spectra of hypocrellin B HB (a) extracted in example 1 of the present invention, hypocrellin B derivative HB-1(b) containing ethylene glycol prepared in example 3, and piperazino hypocrellin B derivative HB-98(c) prepared in example 52.
FIG. 8 is a graph showing the respective effects of hypocrellin derivative HB-1 containing ethylene glycol in example 3 of the present invention on a singlet oxygen scavenger (a) and a superoxide radical scavenger (b).
FIG. 9 is a confocal fluorescence image of hypocrellin derivative HB-1 containing ethylene glycol in Hela cells in example 3 of the present invention.
FIG. 10 shows dark toxicity patterns (a) and phototoxicity patterns (b) of hematoporphyrin derivative HpD, hypocrellin HB, and a derivative HB-1 containing ethylene glycol erythromycin in example 3 of the present invention against Hela cells at different concentrations.
FIG. 11 shows dark toxicity patterns (a) and phototoxicity patterns (b) of hematoporphyrin derivative HpD, hypocrellin HB, and a derivative HB-2 containing ethylene glycol erythromycin in example 3 of the present invention against Hela cells at different concentrations.
FIG. 12 is a graph showing phototoxicity of hematoporphyrin derivative HpD, hypocrellin HB and the deacetylated erythromycin derivative HC-3 or HC-4 modified with aminopropanol synthesized in example 4 of the present invention to Hela cells at different concentrations.
FIG. 13 shows phototoxicity profiles of hematoporphyrin derivative HpD, hypocrellin HB, and the deacetylated erythromycin derivative HC-87 or HC-88 modified with a long-chain quaternary ammonium salt in example 46 of the present invention against Hela cells at different concentrations.
FIG. 14 is a graph showing phototoxicity of hematoporphyrin derivative HpD, hypocrellin B HB, and piperazino-erythrocin-containing derivative HB-98 of example 52 of the present invention to Hela cells at different concentrations.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
Extracting Hypocrellin A (HA): crushing 100g hypocrellin by a crusher, placing the crushed hypocrellin in a Soxhlet extractor, continuously extracting for one day by using 1000mL of acetone as a solvent until an extracting solution is nearly colorless, filtering the extracting solution to remove a small amount of infiltrated solid insoluble substances, then removing the acetone by spinning, dissolving the acetone by using 500mL of dichloromethane, washing by using 4X 400mL of distilled water, separating an organic layer, spinning, washing a solid residue by using 5X 100mL of petroleum ether, spontaneously combusting the solid in air, air-drying, then recrystallizing twice by using chloroform-petroleum ether, and obtaining a crystal which is a target product Hypocrellin A (HA) with the purity of more than 98 percent. Thin layer silica gel plate chromatography is utilized, and the weight ratio of petroleum ether: ethyl acetate: the absolute ethyl alcohol (30:10:1) is used as a developing solvent, and can be further purified to obtain the hypocrellin A with high purity.
Preparation of Hypocrellin B (HB): the hypocrellin B is obtained by dehydrating oridonin under alkaline condition, and the preparation method is properly improved with reference to the reference book of Zhao Zhang organic chemistry, volume 252 and 254 pages of 1989. The specific method comprises the following steps: dissolving hypocrellin A1 g in KOH aqueous solution 1000 mL1.5%, stirring and reacting for 24 hr in dark place, neutralizing with slightly excessive dilute hydrochloric acid, extracting with chloroform, separating and purifying to obtain hypocrellin B0.98 g with yield of 98%.
Preparation of deacetylated Hypocrellin (HC): dissolving hypocrellin B200 mg in 100mL of 1.5% potassium hydroxide aqueous solution, refluxing for 8h in dark, cooling, neutralizing with slightly excessive dilute hydrochloric acid, extracting with dichloromethane, separating and purifying to obtain deacetylated hypocrellin B (HC) 110mg with a yield of 56%.1H NMR(CDCl3,δ,ppm):16.0(s,-OH,1H),15.9(s,-OH,1H),6.62(d,1H),6.35(s,2H),4.14,4.12(s,-OCH3,6H),4.02(s,-OCH3,3H),3.1(d,2H),2.25(s,-OCH3,3H)。
Example 2
The long-chain quaternary ammonium salt-containing derivative used in the invention is prepared by the following general method, and is represented by H2NCH2CH2-N+(CH3)2(C10H21) For column description.
Preparation of intermediate S1: n, N-dimethylethylenediamine (4.4g, 0.05mol) and diethyl carbonate (7.10g, 0.06mol) were mixed in a 100-ml round-bottomed flask, and the reaction mixture was reacted at 70 ℃ for 48 hours, followed by distillation under reduced pressure to give 7.20g of a pale yellow liquid in 89% yield.1H NMR(CDCl3,δ,ppm):5.45(s,-NH-,1H),4.10(d,J＝6.5Hz,-CH2O,2H),3.24(s,-NH-CH2-,2H),2.39(m,-CH2N,2H),2.22(d,J＝1.5Hz,CH3NCH3,6H),1.23(t,J＝6.5Hz,-CH2CH3,3H)。
Preparation of intermediate S2: intermediate S1 was reacted with 1-bromodecane (15.25g,0.05mol) at 100 ℃ for 48h for 72 h. The crude product was treated with acetone-ethyl ether (1:1) to give 15.83g total of white crystals 2 in about 68% yield.1H NMR(CDCl3,δ,ppm):6.73(s,CONH-,1H),4.10(q,J＝7.1Hz,-CH2O-,2H),3.77(s,-CH2N+,4H),3.53(s,CH3N+,6H),3.39(s,-NHCH2-,2H),1.78-1.67(m,-N+CH2CH2-,2H),1.31–1.20(m,-CH2-,29H),0.88(t,J＝6.8Hz,-CH3,3H).MS(ESI+):C23H50N2O2 +(M+H+),385.3788。
Preparation of long-chain quaternary ammonium salt derivative S3: to intermediate S2(10.60g,0.02mol), 50mL of 48% hydrobromic acid and 50mL of distilled water were added and the reaction was heated under reflux for 72 h. Hydrobromic acid was removed by rotary evaporation and the solid residue was purified by ethanol: recrystallization from ether (1:1) gave 13.62g of white flocculent crystals in 69% yield.1H NMR(D2O,δ,ppm):5.34(s,NH2,2H),3.65(m,NH2CH2CH2-,2H),3.48(m,-N+CH2CH2-,2H),3.38(m,NH2CH2-,2H),3.12(s,N+-CH3,6H),1.78(m,N+CH2CH2-,2H),1.37-0.99(m,-CH2-,26H),0.76(t,J＝6.5Hz,-CH3,3H).MS(ESI+):C20H46N2 +(M+H+),313.3590。
Example 3
Aminoethyl glycol modified hypocrellin B derivative (R ═ CH)2CH2OCH2CH2OH) preparation: the synthetic route is shown in the attached figure 4:
dissolving hypocrellin HB (100mg,0.18mmol) and aminoethyl glycol (0.40g,4mmol) in 20mL of anhydrous acetonitrile, mixing thoroughly, heating to 50 ℃ under the protection of nitrogen, stirring in the dark for 10h, and after the reaction, removing the solvent by rotary evaporation. The blue-black solid residue was dissolved in 200mL of dichloromethane, washed once with 100mL of dilute aqueous hydrochloric acid solution and twice with distilled water in this order, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was spin-dried to give a crude product. The obtained crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate (volume ratio 1:1) to give two blue-black solid products, RfValues of 0.80 and 0.24, respectively, where RfA product of 0.24 was identified as a product substituted at both positions 2 and 17, labeled HB-1, at a yield of 12.2%; rfThe 0.80 component was continued with acetone: separating with petroleum ether (volume ratio 1:1) plate chromatography to obtain Rf value of 0.85 (detected as 2-amino position extraction)Generation, labeled HB-2), yield 6.5%.
The characterization data of the 2, 17-amino substitution product HB-1 are as follows:1HNMR(CDCl3,δ,ppm):17.16(s,ArOH,1H),12.96(s,ArOH,1H),6.98(s,ArH,1H),6.55(s,ArH,1H),6.34(s,ArNH,1H),5.35(s,ArNH,1H),5.22(s,OH,1H),5.01(s,OH,1H),4.18(s,OCH3,3H),4.06(s,OCH3,3H),4.04(s,OCH3,3H),3.91-3.61(m,NHCH2CH2O,12H),3.56(d,CH,1H),3.25(d,CH,1H),2.27(s,COCH3,3H),2.19(m,CH2O,2H),2.02(m,CH2O,2H),1.57(s,CH3,3H),1.41-1.02(m,CH2-,19H),0.78(t,CH3,3H).MS(ESI):C37H40N2O11(M+H+) 689.0 ultraviolet maximum absorption wavelength: 468nm,630 nm.
The characterization data of the 2-amino substitution product HB-2 are as follows:1HNMR(CDCl3,δ,ppm):16.76(s,ArOH,1H),16.51(s,ArOH,1H),6.50(s,ArH,1H),6.47(s,ArH,1H),6.40(s,ArH,1H),5.80(s,CH2,1H),5.23(s,CH2,1H),4.18(s,OCH3,3H),4.08(s,OCH3,3H),4.02(s,OCH3,3H),3.83-3.76(m,NHCH2CH2,4H),3.67-3.62(m,OCH2CH2,4H),2.78(s,OH,1H),2.27(s,COCH3,3H),1.61(s,CH3,3H).MS(ESI):C33H31NO10,624.1(M+Na+) 600.5 (M-H). Maximum ultraviolet absorption wavelength: 464nm and 625 nm.
The structural formulas of the amino substitution products HB-1 and HB-2 are shown in the figure:
example 4
3-aminopropanol modified deacetylated hypocrellin derivative (R ═ CH)2CH2CH2OH), the synthetic route is shown as the attached figure 5:
dissolving deacetylated hypocrellin HC (100mg,0.20mmol) and aminoethyl glycol (0.30g,4mmol) in 20mL anhydrous tetrahydrofuranAnd after the mixture is fully mixed, heating the mixture to 60 ℃ under the protection of nitrogen, stirring the mixture for reaction for 12 hours in a dark place, and removing the solvent by rotary evaporation after the reaction is finished. The blue-black solid residue was dissolved in 200mL of dichloromethane, washed once with 100mL of dilute aqueous hydrochloric acid solution and twice with distilled water in this order, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was spin-dried to give a crude product. The obtained crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate (1:1 by volume) gave the product as a blue-black solid in 15.2% yield, RfThe value was 0.45, Mass Spectrometry MS (ESI +): 530.6. The amino substitution product HC-3 (double bond at C)13＝C14) Or HC-4 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 5
Aminoethyl diglycol modified hypocrellin B derivative (R ═ CH2CH2-(OCH2CH2)2-OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2-position and 17-position amino substitution products HB-5: yield 8.4%, RfIs 0.24. The characterization data are as follows: MS (ESI +): 777.5, respectively; maximum ultraviolet absorption wavelength: 468nm,632 nm.
2-amino substitution product HB-6: yield 5.8%, RfIs 0.55. The characterization data are as follows: MS (ESI +) 646.6; maximum ultraviolet absorption wavelength: 462nm,625 nm.
The structural formulas of the amino substitution products HB-5 and HB-6 are shown in the figure:
example 6
Aminoethyl triethylene glycol modified deacetylated hypocrellin derivative (R ═ CH2CH2-(OCH2CH2)3-OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product was obtained in a yield of 10.5%, RfIs 0.25. The characterization data are as follows: MS (ESI +): 648.5, respectively; maximum ultraviolet absorption wavelength: 468nm,632 nm. The amino substitution product HC-7 (double bond at C)13＝C14) Or HC-8 (double bond at C)14＝C15) The structural formula is shown as the figure:
example 7
Aminoethyl tetraketal modified hypocrellin B derivative (R ═ CH2CH2-(OCH2CH2)4-OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
The yield of the 2, 17-amino substituted product HB-9 is 12.4%, RfIs 0.30. The characterization data are as follows: MS (ESI +): 953.0. Maximum ultraviolet absorption wavelength: 475nm and 640 nm.
2-amino substitution product HB-10: yield 6.4%, RfIs 0.65. The characterization data are as follows: MS (ESI +): 734.3. Maximum ultraviolet absorption wavelength: 470nm,630 nm.
The structural formulas of the amino substitution products HB-9 and HB-10 are shown in the figure:
example 8
Aminoethyl polyethylene glycol modified bamboo deacetylation erythromycin derivative (R ═ CH2CH2-(OCH2CH2)n-OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product was obtained in a yield of 17.5％，RfIs 0.25; the characterization data are as follows: MS (ESI +) 560.0. Maximum ultraviolet absorption wavelength: 480nm and 635 nm. The amino substitution product HC-11 (double bond at C)13＝C14) HC-12 (double bond at C)14＝C15) The structural formula is shown in the figure:
example 9
3-aminopropyl glycol modified hypocrellin B derivative (R ═ CH2)3-OCH2CH2OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2, 17-amino substitution product HB-13: yield 6.5%, RfIs 0.16; mass Spectrometry MS (ESI +): 717.2; maximum ultraviolet absorption wavelength: 476nm,632 nm.
2-amino substitution product HB-14: yield 5.4%, RfIs 0.50; mass Spectrometry MS (ESI +): 615.6. Maximum ultraviolet absorption wavelength: 463nm,624 nm.
The structural formulas of the amino substitution products HB-13 and HB-14 are shown in the figure:
example 10
Deacetyl hypocrellin B derivative (R ═ CH) modified by ethylene glycol glycinate2COOCH2CH2OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product was obtained in 18.5% yield RfIs 0.18; mass Spectrometry MS (ESI +): 574.5; maximum ultraviolet absorption wavelength: 474nm,638 nm. The amino substitution product HC-15 (double bond at C)13＝C14) Or HC-16 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 11
Diethyleneglycol aminoacetate modified hypocrellin B derivative (R ═ CH)2CO(OCH2CH2)2OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2, 17-amino substitution product HB-17: yield 6.2%, RfIs 0.16; mass Spectrometry MS (ESI +): 805.5; maximum ultraviolet absorption wavelength: 468nm,635 nm.
2-amino substitution product HB-18: yield 3.4%, RfIs 0.60; mass Spectrometry MS (ESI +): 659.6. Maximum ultraviolet absorption wavelength: 462nm,624 nm.
The structural formulas of the amino substitution products HB-17 and HB-18 are shown in the figure:
example 12
Deacetyl hypocrellin derivative (R ═ CH) modified by triethylene glycol glycinate2CO(OCH2CH2)3OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product was obtained in a yield of 17.2%, RfIs 0.18; mass Spectrometry MS (ESI +): 662.3; maximum ultraviolet absorption wavelength: 466nm and 640 nm. The amino substitution product HC-19 (double bond at C)13＝C14) HC-20 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 13
Aminopropionic acid polyethylene glycol ester modified bamboo redMycoethyl derivative (R ═ CH2)2CO(OCH2CH2)nOH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2, 17-amino substitution product HB-21: yield 8.5%, RfIs 0.18; maximum ultraviolet absorption wavelength: 485nm and 645 nm.
2-amino substitution product HB-22: yield 4.5%, RfIs 0.50; maximum ultraviolet absorption wavelength: 465nm and 635 nm.
The structural formulas of the amino substitution products HB-21 and HB-22 are shown in the figure:
example 14
Triethylene glycol aminopentanoate modified deacetylated hypocrellin derivative (R ═ CH2)4CO(OCH2CH2)3OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product was obtained in 12.5% yield RfIs 0.21; mass Spectrometry MS (ESI +): 704.5; maximum ultraviolet absorption wavelength: 455nm and 642 nm. The amino substitution product HC-23 (double bond at C)13＝C14) HC-24 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 15
Hypocrellin derivative (R ═ CH) modified by ethylene glycol sulfamate2SO2-OCH2CH2-OH) preparation: dissolving hypocrellin HB (100mg,0.18mmol) and sulfamate monoethylene glycol ester (610mg,4mmol) in 20mL anhydrous acetonitrile, heating to 55 deg.C under nitrogen protection, stirring in dark for 8h, and rotary-evaporating to remove solvent. Blue and blackThe solid residue was dissolved in 200mL of dichloromethane, washed twice with dilute aqueous hydrochloric acid, washed once with distilled water, the organic layer was dried, filtered and the organic phase was spin-dried to give a crude product. Separating the obtained crude product by thin-layer silica gel chromatography, wherein the developing agent is acetone: petroleum ether (volume ratio of 2: 1) to obtain two blue-black solid products.
2, 17-amino substitution product HB-25: yield 9.2%, RfIs 0.18; mass Spectrometry MS (ESI +): 789.2; maximum ultraviolet absorption wavelength: 470nm and 640 nm.
2-amino substitution product HB-26: yield 4.4%, RfIs 0.55; mass Spectrometry MS (ESI +): 652.6. Maximum ultraviolet absorption wavelength: 465nm and 628 nm.
The structural formulas of the amino substitution products HB-25 and HB-26 are shown in the figure:
example 16
Diethylene glycol sulfamate modified bamboo deacetylation erythromycin derivative (R ═ CH)2SO2(OCH2CH2)2OH) preparation: the synthesis method is similar to the preparation of the hypocrellin derivative modified by diethylene glycol aminomethane sulfonate in example 15.
The product was obtained in 16.2% yield RfIs 0.16; mass Spectrometry MS (ESI +): 654.2; maximum ultraviolet absorption wavelength: 468nm,635 nm. The amino substitution product HC-27 (double bond at C)13＝C14) HC-28 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 17
Tetraethylsulfamate modified hypocrellin derivative (R ═ CH)2SO2(OCH2CH2)4OH) preparation: synthesis procedure is analogous to that of ammonia in example 15And preparing the hypocrellin derivative modified by diethylene glycol monomethanesulfonate.
2, 17-amino substitution product HB-29: yield 8.4%, RfIs 0.16; mass Spectrometry MS (ESI +): 1053.4; maximum ultraviolet absorption wavelength: 468nm,648 nm.
2-amino substitution product HB-30: yield 5.4%, RfIs 0.62; mass Spectrometry MS (ESI +): 784.6. Maximum ultraviolet absorption wavelength: 462nm,625 nm.
The structural formulas of the amino substitution products HB-29 and HB-30 are shown in the figure:
example 18
Hypocrellin derivative (R ═ CH) modified by triethylene glycol sulfamate2CH2CH2CH2SO2(OCH2CH2)3OH) preparation: the synthesis method is similar to the preparation of the hypocrellin derivative modified by diethylene glycol aminomethane sulfonate in example 15.
The product was obtained in 16.5% yield RfIs 0.21; mass Spectrometry MS (ESI +): 1036.5; maximum ultraviolet absorption wavelength: 455nm,638 nm. The amino substitution product HC-31 (double bond at C)13＝C14) Or HC-32 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 19
Ethylenediamine substituted diethylene glycol modified hypocrellin B derivative (R ═ CH2CH2-NHCH2CH2-OCH2CH2-OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2-position and 17-position amino substitution products HB-33: yield 9.4%, RfIs 0.18. The characterization data are as follows: MS (ESI +): 775.5, respectively; maximum ultraviolet absorption wavelength: 469nm and 635 nm.
2-amino substitution product HB-34: yield 8.8%, RfIs 0.58. The characterization data are as follows: MS (ESI +) 644.6; maximum ultraviolet absorption wavelength: 464nm and 626 nm.
The structural formulas of the amino substitution products HB-33 and HB-34 are shown in the figure:
example 20
Ethylenediaminediketal modified deacetylhypocrellin derivative (R ═ CH2CH2-NHCH2CH2-(OCH2CH2)2-OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product yield was 19.5%, RfIs 0.22. The characterization data are as follows: MS (ESI +): 646.5, respectively; maximum ultraviolet absorption wavelength: 468nm,631 nm. The amino substitution product HC-35 (double bond at C)13＝C14) Or HC-36 (double bond at C)14＝C15) The structure is shown as the figure:
example 21
Aminoethyl mercapto-substituted diethylene glycol modified hypocrellin B derivative (R ═ CH)2CH2-S-CH2CH2-OCH2CH2-OH) preparation: the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
The yield of the 2, 17-amino substituted product HB-37 is 11.4%, RfIs 0.35. The characterization data are as follows: MS (ESI +): 809.0. Maximum ultraviolet absorption wavelength: 475nm and 640 nm.
2-amino substitution product HB-38:yield 7.4%, RfIs 0.68. The characterization data are as follows: MS (ESI +): 662.3. Maximum ultraviolet absorption wavelength: 470nm,630 nm.
The structural formulas of the amino substitution products HB-37 and HB-38 are shown in the figure:
example 22
Aminoethyl mercapto-substituted tetraketal modified hypocrellin B derivative (R ═ CH2CH2-S-CH2CH2-(OCH2CH2)3-OH) preparation: the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product yield was 17.5%, RfIs 0.12; the characterization data are as follows: MS (ESI +): 709.0. Maximum ultraviolet absorption wavelength: 480nm and 635 nm. The amino substitution product HC-39 (double bond at C)13＝C14) Or HC-40 (double bond at C)14＝C15) The structure is shown in the figure:
example 23
Aminopropionamide tetraethylene glycol methyl ether modified hypocrellin B derivative (R ═ CH)2CH2CONH-CH2CH2–(OCH2CH2)3-OCH3) The preparation of (1): the synthesis method is similar to the preparation of the hypocrellin B derivative modified by aminoethyl glycol in example 3.
2, 17-amino substitution product HB-41: yield 7.8%, RfIs 0.15; mass Spectrometry MS (ESI +): 1035.2; maximum ultraviolet absorption wavelength: 461nm,643 nm.
2-amino substitution product HB-42: yield 5.4%, RfIs 0.54; mass Spectrometry MS (ESI +): 775.1. Maximum ultraviolet absorption wavelength: 458nm and 622 nm.
The structural formulas of the amino substitution products HB-41 and HB-42 are shown in the figure:
example 24
Aminopentanamide tetraethylene glycol ester modified hypocrellin B derivative (R ═ CH2)4CH2CONH-CH2CH2-(OCH2CH2)3-OCH3) The preparation of (1): the synthesis method is similar to the preparation of 3-aminopropanol modified deacetylated hypocrellin derivative in example 4.
The product yield was 16.5%, RfIs 0.21; mass Spectrometry MS (ESI +) 760.5; maximum ultraviolet absorption wavelength: 455nm and 642 nm. The amino substitution product HC-43 (double bond at C)13＝C14) Or HC-44 (double bond at C)13＝C14) The structural formula of (A) is shown in the figure:
example 25
Hexamine modified hypocrellin B derivative (R ═ CH)2CH2CH2CH2CH2CH3) The preparation of (1): dissolving hypocrellin HB (100mg,0.18mmol) and hexylamine (0.51g,5mmol) in 50mL anhydrous acetonitrile, heating to 55 deg.C under nitrogen protection, stirring in dark for 8h, and rotary evaporating to remove solvent. Dissolving the blue-black solid residue with 200mL of dichloromethane, washing with dilute hydrochloric acid aqueous solution twice and distilled water once in sequence, drying the organic layer, filtering, and spin-drying the organic phase to obtain a crude product. Separating the obtained crude product by thin-layer silica gel chromatography, wherein the developing agent is acetone: petroleum ether (volume ratio of 2: 1) to obtain two blue-black solid products.
2, 17-amino substitution product HB-45: yield 28.6%, RfIs 0.24; mass Spectrometry MS (ESI +): 695.4; maximum ultraviolet absorption wavelength: 455nm and 635 nm.
2-amino substitution product HB-46: yield 14.6%, RfIs 0.38; mass Spectrometry MS (ESI +): 598.2. Maximum ultraviolet absorption wavelength: 452nm,626 nm.
The structural formulas of the amino substitution products HB-45 and HB-46 are shown in the figure:
example 26
Butylamine modified hypocrellin B derivative (R ═ CH)2CH2CH2CH2) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-47: yield 32.6%, RfIs 0.26; mass Spectrometry MS (ESI +): 625.4; maximum ultraviolet absorption wavelength: 454nm,632 nm.
2-amino substitution product HB-48: yield 14.6%, RfIs 0.38; mass Spectrometry MS (ESI +): 570.2. Maximum ultraviolet absorption wavelength: 448nm and 624 nm.
The structural formulas of the amino substitution products HB-47 and HB-48 are shown in the figure:
example 27
Octylamine modified hypocrellin B derivative (R ═ CH)2CH2CH2CH2CH2CH2CH2CH2) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-49: yield 22.6%, RfIs 0.16; mass Spectrometry MS (ESI +): 737.4; maximum ultraviolet absorption wavelength: 452nm,632 nm.
2-amino substitution product HB-50: yield 18.6%, RfIs 0.60; mass Spectrometry MS (ESI +): 626.2. Maximum ultraviolet absorption wavelength: 445nm,621 nm.
The structural formulas of the amino substitution products HB-49 and HB-50 are shown in the figure:
example 28
Tetrahexylamine modified hypocrellin B derivative (R ═ CH)2CH2CH2CH2) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
The product was obtained in 38.6% yield RfIs 0.24; mass Spectrometry MS (ESI +) 528.4; maximum ultraviolet absorption wavelength: 455nm and 635 nm. The amino substitution product HC-51 (double bond at C)13＝C14) Or HC-52 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 29
Benzamido hypocrellin B derivative (R ═ CH)2C6H5) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-53: yield 25.4%, RfIs 0.22; mass Spectrometry MS (ESI +) 691.2; maximum ultraviolet absorption wavelength: 453nm and 642 nm.
2-amino substitution product HB-54: yield 14.5%, RfIs 0.45; mass Spectrometry MS (ESI +): 604.9. Maximum ultraviolet absorption wavelength: 453nm,622 nm.
The structural formulas of the amino substitution products HB-53 and HB-54 are shown in the figure:
example 30
Modification with phenylbutylamineHypocrellin B derivative (R ═ CH)2CH2CH2CH2C6H5) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-55: yield 17.5%, RfIs 0.23; mass Spectrometry MS (ESI +) 1037.5; maximum ultraviolet absorption wavelength: 452nm,636 nm.
2-amino substitution product HB-56: yield 14.8%, RfIs 0.36; mass Spectrometry MS (ESI +): 776.3. Maximum ultraviolet absorption wavelength: 452nm,619 nm.
The structural formulas of the amino substitution products HB-55 and HB-56 are shown in the figure:
example 31
2-methylpyridine hypocrellin B derivative (R ═ CH)2C5H4N) preparation: the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-57: yield 25.4%, RfIs 0.22; mass Spectrometry MS (ESI +): 693.2; maximum ultraviolet absorption wavelength: 453nm,634 nm.
2-amino substitution product HB-58: yield 14.5%, RfIs 0.45; mass Spectrometry MS (ESI +): 606.9. Maximum ultraviolet absorption wavelength: 450nm,622 nm.
The structural formulas of the amino substitution products HB-57 and HB-58 are shown in the figure:
example 32
Phenylbutylamine-modified deacetylated hypocrellin B derivative (R ═ CH)2CH2CH2CH2C5H4N) preparation: synthesis method of hypocrellin derivative modified with hexylamine similar to that in example 25And (4) preparation.
The product yield was 17.5%, RfIs 0.23; mass Spectrometry MS (ESI +): 605.5; maximum ultraviolet absorption wavelength: 452nm,636 nm. The amino substitution product HC-59 (double bond at C)13＝C14) Or HC-60 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 33
4-methylpyridinium salt butylamino hypocrellin B derivative (R ═ CH2)4C5H4N+(C6H11) Preparation of): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-61: yield 15.4%, RfIs 0.22; mass Spectrometry MS (ESI +): 984.2; maximum ultraviolet absorption wavelength: 453nm,634 nm.
2-amino substitution product HB-62: yield 14.5%, RfIs 0.45; mass Spectrometry MS (ESI +): 767.9. Maximum ultraviolet absorption wavelength: 450nm,622 nm.
The structural formulas of the amino substitution products HB-61 and HB-62 are shown in the figure:
example 34
Hypocrellin hydrazine (R ═ NH)2) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-63: yield 25.4%, RfIs 0.28; mass Spectrometry MS (ESI +): 543.8; maximum ultraviolet absorption wavelength: 455nm and 640 nm.
2-amino substitution product HB-64: yield 12.6%, RfIs 0.48; mass Spectrometry MS (ESI +): 529.9. Maximum ultraviolet absorption wavelength: 448nm and 625 nm.
The structural formulas of the amino substitution products HB-63 and HB-64 are shown in the figure:
example 35
Deacetyl hypocrellin hydrazine (R ═ NH)2) The preparation of (1): the synthesis method is similar to the preparation of the hypocrellin derivative modified by hexylamine in example 25.
The product yield was 28.5%, RfIs 0.30; mass Spectrometry MS (ESI +): 486.8; maximum ultraviolet absorption wavelength: 456nm and 642 nm. The amino substitution product HC-65 (double bond at C)13＝C14) Or HC-66 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 36
Preparation of hypocrellin hydrazine (R ═ OH): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, amino substitution product HB-67 at position 17: yield 28.6%, RfIs 0.22; mass Spectrometry MS (ESI +): 545.8; maximum ultraviolet absorption wavelength: 452nm,632 nm.
2-amino substitution product HB-68: yield 15.6%, RfIs 0.46; mass Spectrometry MS (ESI +): 531.9. Maximum ultraviolet absorption wavelength: 445nm,622 nm.
The structural formulas of the amino substitution products HB-67 and HB-68 are shown in the figure:
example 37
Preparation of deacetylated hypocrellin hydrazine (R ═ OH): the synthesis method was similar to the preparation of the hexylamine modified hypocrellin derivative in example 25.
The product yield was 21.5%, RfIs 0.28; mass Spectrometry MS (ESI +): 488.8; maximum ultraviolet absorption wavelength: 452nm and 640 nm. The amino substitution product HC-69 (double bond at C)13＝C14) Or HC-70 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 38
Cyclohexylamine modified hypocrellin (R ═ C)6H11) The preparation of (1): the synthesis method was similar to the preparation of the hexylamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-71: yield 58.6%, RfIs 0.58; mass Spectrometry MS (ESI +): 677.5; maximum ultraviolet absorption wavelength: 448nm and 626 nm.
2-amino substitution product HB-72: yield 12.6%, RfIs 0.82; mass Spectrometry MS (ESI +): 596.9. Maximum ultraviolet absorption wavelength: 446nm,618 nm.
The structural formulas of the amino substitution products HB-71 and HB-72 are shown in the figure:
example 39
Cyclohexylamine modified deacetylated hypocrellin (R ═ C)6H11) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
The product yield was 26.4%, RfIs 0.30; mass Spectrometry MS (ESI +): 553.8; maximum ultraviolet absorption wavelength: 450nm,638 nm. The amino substitution product HC-73 (double bond at C)13＝C14) Or HC-74 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 40
Cyclobutylamine modified hypocrellin (R ═ C)4H7) The preparation of (1): the synthesis method was similar to the preparation of the hexylamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-75: yield 35.6%, RfIs 0.52; mass Spectrometry MS (ESI +): 621.5; maximum ultraviolet absorption wavelength: 450nm and 630 nm.
2-amino substitution product HB-76: yield 15.6%, RfIs 0.80; mass Spectrometry MS (ESI +): 568.9. Maximum ultraviolet absorption wavelength: 448nm and 622 nm.
The structural formulas of the amino substitution products HB-75 and HB-76 are shown in the figure:
EXAMPLE 41
Cyclopentylamine modified hypocrellin (R ═ C)5H9) The preparation of (1): the synthesis method was similar to the preparation of the hexylamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-77: yield 25.8%, RfIs 0.56; mass Spectrometry MS (ESI +): 649.5; maximum ultraviolet absorption wavelength: 452nm,632 nm.
2-amino substitution product HB-78: yield 10.2%, RfIs 0.85; mass Spectrometry MS (ESI +): 581.9. Maximum ultraviolet absorption wavelength: 450nm,625 nm.
The structural formulas of the amino substitution products HB-77 and HB-78 are shown in the figure:
example 42
Cycloheptylamine modified hypocrellin (R ═ C)5H9) The preparation of (1): the synthesis method was similar to the preparation of the hexylamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-79: yield 28.1%, RfIs 0.58; mass Spectrometry MS (ESI +) 705.5; maximum ultraviolet absorption wavelength: 454nm,634 nm.
2-amino substitution product HB-80: yield 15.0%, RfIs 0.75; mass Spectrometry MS (ESI +): 610.2. Maximum ultraviolet absorption wavelength: 452nm and 627 nm.
The structural formulas of the amino substitution products HB-79 and HB-80 are shown in the figure:
example 43
P-methyl cyclohexylamine modified hypocrellin (R ═ C)6H10CH3) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-81: yield 46.6%, RfIs 0.52; mass Spectrometry MS (ESI +) 705.5; maximum ultraviolet absorption wavelength: 450nm,628 nm.
2-amino substitution product HB-82: yield 10.1%, RfIs 0.80; mass Spectrometry MS (ESI +): 610.4. Maximum ultraviolet absorption wavelength: 448nm and 621 nm.
The structural formulas of the amino substitution products HB-81 and HB-82 are shown in the figure:
example 44
4-aminopiperidine modified hypocrellin (R ═ C)5H10N) preparation: the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-83: yield 26.5%, RfIs 0.50; mass Spectrometry MS (ESI +): 679.5; maximum ultraviolet absorption wavelength: 452nm,630 nm.
2-amino substitution product HB-84: yield 20.1%, RfIs 0.82; mass Spectrometry MS (ESI +): 597.4. Ultraviolet lightMaximum absorption wavelength: 450nm,625 nm.
The structural formulas of the amino substitution products HB-81 and HB-82 are shown in the figure:
example 45
3-butenoic ammonia modified hypocrellin (R ═ C)4H7) The preparation of (1): the synthesis method is similar to the preparation of the hexamine modified hypocrellin derivative in example 25.
2, 17-amino substitution product HB-85: yield 16.5%, RfIs 0.52; mass Spectrometry MS (ESI +): 621.7; maximum ultraviolet absorption wavelength: 450nm and 632 nm.
2-amino substitution product HB-86: yield 28.1%, RfIs 0.84; mass Spectrometry MS (ESI +): 568.9. Maximum ultraviolet absorption wavelength: 451nm,628 nm.
The structural formulas of the amino substitution products HB-85 and HB-86 are shown in the figure:
example 46
N, N-dimethyl-N-decyl ammonium-ethanediamino deacetylation hypocrellin B (R ═ CH)2CH2-N+(CH3)2(C10H21) The synthetic route is shown in figure 4:
deacetylated hypocrellin HC (100mg,0.18mmol) and the long-chain quaternary ammonium salt derivative S3(224mg,0.72mmol) prepared in example 3 were dissolved in 20mL of anhydrous acetonitrile, mixed thoroughly, heated to 50 ℃ under nitrogen protection, stirred away from light for 10h, and after the reaction was complete, the solvent was removed by rotary evaporation. The blue-black solid residue was dissolved in 200mL of dichloromethane, washed once with 50mL of dilute aqueous hydrochloric acid solution and twice with distilled water in this order, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was suspended to obtain a crude product. Further separating the crude product with silica gel plate chromatography, developing with solventIs acetone: ethyl acetate: ethanol: diethylamine (volume ratio is 20:1:1:3) to respectively obtain two blue-black solid products. The product was obtained in 24.2% yield RfIs 0.37; mass Spectrometry MS (ESI +): 684.5; maximum ultraviolet absorption wavelength: 453nm,630 nm. The amino substitution product HC-87 (double bond at C)13＝C14) Or HC-88 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 47
N, N-dimethyl-N-12 alkylammonium-butanediamine hypocrellin B (R ═ CH)2CH2CH2CH2-N+(CH3)2(C12H23) Preparation of): the synthesis method is similar to the preparation of the quaternary ammonium salt-containing hypocrellin derivative in example 46.
The yield of the obtained product 2-amino substitution product is 15.4 percent, RfIs 0.36. The characterization data are as follows: MS (ESI +) 739.5; maximum ultraviolet absorption wavelength: 462nm,624 nm. The amino substitution product HC-89 (double bond at C)13＝C14) Or HC-90 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 48
N, N, N-trimethyl ammonium-sebacic diamido hypocrellin B (R ═ CH)2)10-N+(CH3)3) The preparation of (1): the synthesis method is similar to the preparation of the quaternary ammonium salt-containing hypocrellin derivative in example 46.
The yield of the obtained 2-amino-substituted product is 8.8 percent, RfIs 0.35. The characterization data are as follows: MS (ESI +) 791.2; maximum ultraviolet absorption wavelength: 464nm and 626 nm. The amino substitution product HC-91 (double bond at C)13＝C14) Or HC-92 (double bond)Is located at C14＝C15) The structural formula of (A) is shown in the figure:
example 49
N, N-dimethyl-N-decyl acetal amino hypocrellin B (R ═ CH)2CH2OCH2CH2OCH2CH2-N+(CH3)2(C10H21) Preparation of): the synthesis method is similar to the preparation of the quaternary ammonium salt-containing hypocrellin derivative in example 46.
The yield of the obtained 2-amino-substituted product was 15.5%, RfIs 0.28. The characterization data are as follows: MS (ESI +) 771.2; maximum ultraviolet absorption wavelength: 462nm,628 nm. The amino substitution product HC-93 (double bond at C)13＝C14) Or HC-94 (double bond at C)14＝C15) The structural formula of (A) is shown in the figure:
example 50
Preparation of piperazino deacetylated hypocrellin: dissolving deacetylated hypocrellin HC (100mg,0.20mmol) and ethylenediamine (421mg,2mmol) in 20mL anhydrous acetonitrile, mixing thoroughly, heating to 45 deg.C under nitrogen protection, stirring in dark place for 6h, and removing solvent by rotary evaporation after reaction. The blue-black solid residue was dissolved in 100mL of dichloromethane, washed three times with 50mL of dilute aqueous hydrochloric acid, washed once with distilled water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was suspended to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate: ethanol: diethylamine (volume ratio 20:1:1: 1) to give a blue-black solid product in 49.8% yield, RfIs 0.45. Product characterization data were as follows: ESI MS: m/z, 497.3. Maximum ultraviolet absorption wavelength: 462nm,650 nm. The structural formula of the product is shown inRespectively shown in the formula HC-95:
example 51
Preparation of methylpiperazine and deacetylated hypocrellin B: the preparation is similar to the preparation of piperazino-deacetylated hypocrellin in example 50. Yield 59.8%, RfIs 0.60. Product characterization data were as follows: ESI MS: m/z, 511.3. Maximum ultraviolet absorption wavelength: 465nm and 652 nm. The structural formula of the product is respectively shown as formula HC-96 or HC-97:
example 52
Preparation of dimethyl piperazino hypocrellin B: dissolving hypocrellin HB (100mg,0.18mmol) and dimethylethylenediamine (421mg,2mmol) in 20mL of anhydrous acetonitrile, mixing thoroughly, heating to 45 ℃ under the protection of nitrogen, stirring in the dark for 6h, and after the reaction is finished, removing the solvent by rotary evaporation. The blue-black solid residue was dissolved in 100mL of dichloromethane, washed three times with 50mL of dilute aqueous hydrochloric acid, washed once with distilled water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was suspended to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate: ethanol: diethylamine (volume ratio 20:1:1: 1) to give a blue-black solid product in 19.8% yield, RfIs 0.45. Product characterization data were as follows: ESI MS: m/z, 569.3. Maximum ultraviolet absorption wavelength: 462nm,650 nm. The structural formula of the product is respectively shown as HB-98 or HB-99:
example 53
Preparation of diethyl piperazino hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 18.8% and Rf was 0.38. Product characterization data were as follows: ESI MS: m/z, 596.8. Maximum ultraviolet absorption wavelength: 465nm and 655 nm. The structural formula of the product is respectively shown as HB-99 or HB-100:
example 54
Preparation of dipropyl piperazino hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 21.2% and Rf was 0.35. Product characterization data were as follows: ESI MS: m/z, 596.8. Maximum ultraviolet absorption wavelength: 462nm,652 nm. The structural formula of the product is respectively shown as the formula HB-101 or HB-102:
example 55
Preparing dibutyl piperazino hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 21.5% and Rf was 0.38. Product characterization data were as follows: ESI MS: m/z, 609.8. Maximum ultraviolet absorption wavelength: 468nm,657 nm. The structural formula of the product is respectively shown as formula HC-103 or HC-104:
example 56
Preparing dibutyl piperazino hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 18.8% and Rf was 0.38. Product characterization data were as follows: ESI MS: m/z, 665.8. Maximum ultraviolet absorption wavelength: 465nm and 655 nm. The structural formula of the product is respectively shown as formula HC-105 or HC-106:
example 57
Preparation of trimethylpiperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 23.4% and Rf was 0.48. Product characterization data were as follows: ESI MS: m/z, 569.3. Maximum ultraviolet absorption wavelength: 464nm and 652 nm. The structural formula of the product is respectively shown as HB-107 or HB-108:
example 58
Preparation of dibutyl-methylpiperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 18.8% and Rf was 0.38. Product characterization data were as follows: ESI MS: m/z, 596.8. Maximum ultraviolet absorption wavelength: 465nm and 655 nm. The structural formula of the product is respectively shown as HB-109 or HB-110:
example 59
Preparation of dihexyl-methylpiperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 18.8% and Rf was 0.38. Product characterization data were as follows: ESI MS: m/z, 596.8. Maximum ultraviolet absorption wavelength: 465nm and 655 nm. The structural formula of the product is respectively shown as HB-111 or HB-112:
example 60
Preparation of dimethyl-hydroxyethyl piperazino hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 12.5% and Rf was 0.35. Product characterization data were as follows: ESI MS: m/z, 611.6. Maximum ultraviolet absorption wavelength: 463nm,652 nm. The structural formula of the product is respectively shown as HB-113 or HB-114:
example 61
Preparation of dimethyl-diethylene glycol piperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 13.8% and Rf was 0.40. Product characterization data were as follows: ESI MS: m/z, 655.6. Maximum ultraviolet absorption wavelength: 460nm,655 nm. The structural formula of the product is respectively shown as the formula HB-115 or HB-116:
example 62
Preparation of dimethyl-triethylene glycol piperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 8.5% and Rf was 0.45. Product characterization data were as follows: ESI MS: m/z, 699.1. Maximum ultraviolet absorption wavelength: 462nm,658 nm. The structural formula of the product is respectively shown as the formula HB-117 or HB-118:
example 63
Preparation of dimethyl-triethylene glycol piperazine hypocrellin B: the synthesis was similar to the preparation of dimethylpiperazino hypocrellin b in example 52. The yield was 8.5% and Rf was 0.45. Product characterization data were as follows: ESI MS: m/z, 745.5. Maximum ultraviolet absorption wavelength: 462nm,658 nm. The structural formula of the product is respectively shown as the formula HB-119 or HB-120:
example 64
Preparing dihydroxyethyl piperazino hypocrellin B:
dissolving hypocrellin HB (100mg,0.18mmol) and dihydroxyethyl ethylenediamine (421mg,2mmol) in 20mL anhydrous acetonitrile, mixing thoroughly, heating to 45 deg.C under nitrogen protection, stirring in dark for 6h, and after reaction, rotary evaporating to remove solvent. The blue-black solid residue was dissolved in 100mL of dichloromethane, washed three times with 50mL of dilute aqueous hydrochloric acid, washed once with distilled water, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic phase was suspended to obtain a crude product. The obtained crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate: ethanol: diethylamine (volume ratio 20:1:1: 1) to give a blue-black solid product in 18.5% yield, RfIs 0.21. Product characterization data were as follows: ESI MS: m/z, 583.5. Maximum ultraviolet absorption wavelength: 463nm,650 nm. The structural formulas of the products are respectively shown as formulas HB-121 and HB-122:
example 65
Preparation of dihexyl-hydroxyethyl piperazino hypocrellin B: the synthesis was similar to the preparation of dihydroxyethyl piperazine and hypocrellin B in example 64. The yield was 25.5% and Rf was 0.41. Product characterization data were as follows: ESI MS: m/z, 596.8. Maximum ultraviolet absorption wavelength: 468nm,652 nm. The structural formulas of the products are respectively shown as formulas HB-123 and HB-124:
example 66
Preparing the derivative of the daubac quaternary ammonium salt modified hypocrellin B: the synthesis method is similar to the preparation of the quaternary ammonium salt-containing hypocrellin derivative in example 46. 2,17 positionAmino substitution product HB-125: yield 12.4%, RfIs 0.28; mass Spectrometry MS (ESI +): 941.2; maximum ultraviolet absorption wavelength: 455nm and 635 nm. 2-amino substitution product HB-126: yield 16.5%, RfIs 0.48; mass Spectrometry MS (ESI +): 746.9. Maximum ultraviolet absorption wavelength: 451nm,624 nm. The structural formulas of the amino substitution products HB-125 and HB-126 are shown in the figure:
example 67
Cell dark toxicity assay:
digesting the cultured Hela cells with 0.25% trypsin, beating to obtain single cell suspension, and adjusting cell number to about 2 × 104200 uL/mL of the culture medium was inoculated into 96-well plates at 37 ℃ in 5% CO2The incubator of (2) is used for culture. Removing supernatant culture solution after cell adherence, adding photosensitizer (hematoporphyrin derivative HpD, hypocrellin B, hypocrellin derivative HB-1) with different concentrations according to experimental design under the condition of keeping out of the sun, and standing at 37 deg.C and containing 5% CO2The incubator of (2) was incubated for 1 hour. The viability of the cells was examined by the MTT method. 20uL of MTT (in PBS, 5mg/m1) at 37 ℃ with 5% CO was added to each well2The incubation was terminated after 4 hours, the supernatant was carefully aspirated from the wells, and 150uL of dimethyl sulfoxide (DMSO) was added to each well and shaken in a micro shaker for 10 minutes to dissolve the purple crystals sufficiently. Selecting a wavelength of 570nm, detecting the optical density value (OD value) of each hole on a microplate reader, and calculating the cell survival rate according to the following formula: cell viability was defined as OD value in experimental group/OD value in blank group × 100%. The dark toxicity profile is shown in figure 10 a.
Example 68
Cytotoxicity experiments:
digesting the cultured Hela cells with 0.25% trypsin, beating, making into single cell suspension, and adjusting cell number to about 2 × 104200 uL/mL of the culture medium was inoculated into 96-well plates at 37 ℃ in 5% CO2In an incubator. Removing supernatant culture solution after cell adherence, adding photosensitizer (hematoporphyrin derivative HpD, hypocrellin B HB, hypocrellin derivative HB-1) with different concentrations according to experimental design under the condition of keeping out of the sun strictly, placing at 37 deg.C and containing 5% CO2The incubator of (2) was incubated for 1 hour. Then irradiating with semiconductor laser with wavelength of 635nm, and adjusting power density to 20mW/cm2The light beam is uniformly and vertically irradiated on a 96-well culture plate for 1000S, and each 96-well culture plate is provided with a blank group with 6 wells for each condition. After being irradiated, the mixture is placed at 37 ℃ and contains 5 percent of CO2The incubator of (1) was incubated for 24 hours and then the cell viability was examined. The viability of the cells was examined by the MTT method. 20uL of MTT (in PBS, 5mg/m1) at 37 ℃ with 5% CO was added to each well2The incubation was terminated after 4 hours, the supernatant was carefully aspirated from the wells, and 150uL of dimethyl sulfoxide (DMSO) was added to each well and shaken in a micro shaker for 10 minutes to dissolve the purple crystals sufficiently. Selecting a wavelength of 570nm, detecting the optical density value (OD value) of each hole on a microplate reader, and calculating the cell survival rate according to the following formula: cell viability was defined as OD value in experimental group/OD value in blank group × 100%. The phototoxicity profile is shown in figure 10 b.
Comparative example 1
The unmodified Hypocrellin B (HB) has a structural formula shown in FIG. 6, and an absorption spectrum shown in FIG. 7a, and has a maximum absorption wavelength of 450nm and weak absorption at 590nm of red light absorption. Hypocrellin B has weak light absorption capacity at 600-900nm of a phototherapy window, and is used for photodynamic therapy, and the photodynamic effect of killing tumor cells is much lower than that of the ester-water amphiphilic hypocrellin derivative in the invention (figures 10-14).
Comparative example 2
N, N-dimethyl-N-quinylhexanediamine salt-2, 17-diamino hypocrellin B25, substituted at 2 and 17 position; however, most of the whole molecules of the hypocrellin derivative are hydrophobic structures, and the hydrophilic part is mainly quaternary ammonium salt, so the effect of adjusting the hydrophilic and hydrophobic properties of the hypocrellin derivative is not good as that of the ester-water amphiphilic hypocrellin derivative containing ethylene glycol.
And (4) conclusion: the ester-water amphiphilic hypocrellin derivative prepared by the invention adopts a condensed glycol group or a quaternary ammonium salt with a long chain and other groups to modify hypocrellin, and the derivative has different lipid-water amphiphilicities by adjusting the hydrophilic and hydrophobic properties of molecules, and simultaneously improves the biocompatibility with cells or tissues. The lack of any substitution will result in the hypocrellin derivative being less effective in some respects to a varying degree.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.
Claims (5)
1. An ester-water amphiphilic hypocrellin derivative is characterized in that the structural general formula of the derivative is shown as a formula (2):
substituent R of hypocrellin derivative of formula (2)1is-H or-COCH3；
The structural general formula of the substituent R in the formula (2) is shown as the formula (3):
in the formula (3), m is more than or equal to 0 and less than or equal to 12, n is more than or equal to 0 and less than or equal to 500, p is more than or equal to 0 and less than or equal to 12, and q is more than or equal to 0 and less than or equal to 12; m, n, p and q are zero or positive integers; y is a linking group; z is terminalA group; (OCH)2CH2)nIs a polyethylene glycol unit;
the connecting group Y in the formula (3) is O, S, carboxylic ester, amide, sulfocarboxyl ester or cyclohexyl;
in the formula (3), the terminal group Z is hydrogen, alkyl with 1-12 carbon atoms, alkoxy with 1-12 carbon atoms, hydroxyl, sulfydryl, carboxylic acid group, sulfonic group, quaternary ammonium salt or pyridinium;
when the end group Z is quaternary ammonium salt, three substituent groups on the quaternary ammonium salt are respectively independent or are alkyl with 1-12 carbon atoms simultaneously; the anion in the quaternary ammonium salt is the anion allowed by the pharmaceutical preparation;
when the terminal group Z is pyridinium, the substituent on the pyridine ring in the pyridinium is in ortho-position, meta-position or para-position; the pyridinium is prepared by quaternizing pyridine and halogenated hydrocarbon with different chain lengths and 1-12 carbon atoms; the anion in the pyridinium is the anion allowed by the pharmaceutical preparation;
a substituent R described in the formula (2)1is-COCH3When said R formula is such that the terminal group Z does not contain a quaternary ammonium moiety.
2. The ester-water amphiphilic hypocrellin derivative according to claim 1, wherein the terminal group Z in the substituent R is: -H; -CH3；-C2H5；-C4H9；-C6H13；-OCH3；-OC2H5；-OC4H9；-OC6H13；-OH,-SH；-COOH；-SO3H；-C5H4N+；-N+(CH3)3；-N+(C2H5)3；-N+(C6H13)3；-N+(CH3)2(C2H5)；-N+(CH3)2(C6H13)；-N+(CH3)2(C8H17)。
3. The ester-hydrophilic amphiphilic hypocrellin derivative according to claim 1, wherein the general structural formula of the hypocrellin derivative of formula (2) further comprises enol tautomer represented by formula (2'):
4. the method for preparing an ester-water amphiphilic hypocrellin derivative according to any one of claims 1 to 3, comprising the steps of:
mixing hypocrellin B and corresponding substituted amino derivatives in a feeding molar ratio of 1: 5-50 in an organic solvent, wherein the organic solvent is one or more of acetonitrile, tetrahydrofuran, pyridine, methanol and ethanol, the reaction is carried out for 6-18 hours in a dark place under the protection of inert gas, the reaction temperature is 20-100 ℃, and the product is separated and purified to obtain the ester-water amphiphilic hypocrellin derivative.
5. Use of an esterilic amphiphilic hypocrellin derivative according to any one of claims 1 to 3 for the preparation of a photosensitizer drug in photodynamic therapy.
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| CN201610894400.0A CN107935943B (en) | 2016-10-13 | 2016-10-13 | Ester-water amphiphilic hypocrellin derivative and preparation method and application thereof |
| US15/769,789 US11154548B2 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, and preparation method and application thereof |
| CA3002695A CA3002695C (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
| EP16856928.3A EP3366669A4 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
| JP2018521084A JP2018536643A (en) | 2015-10-21 | 2016-10-21 | Mono- or poly-substituted oil-water amphiphilic hypocrellin derivatives and method for producing and using the same |
| PCT/CN2016/102832 WO2017067497A2 (en) | 2015-10-21 | 2016-10-21 | Monosubstituted or polysubstituted amphiphilic hypocrellin derivative, preparation method therefor, and uses thereof |
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