CN107935943A - 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 PDF

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CN107935943A
CN107935943A CN201610894400.0A CN201610894400A CN107935943A CN 107935943 A CN107935943 A CN 107935943A CN 201610894400 A CN201610894400 A CN 201610894400A CN 107935943 A CN107935943 A CN 107935943A
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hypocrellin
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double bond
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CN107935943B (en
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汪鹏飞
吴加胜
郑秀丽
顾瑛
刘卫敏
葛介超
张洪艳
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Technical Institute of Physics and Chemistry of CAS
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Priority to PCT/CN2016/102832 priority patent/WO2017067497A2/en
Priority to US15/769,789 priority patent/US11154548B2/en
Priority to JP2018521084A priority patent/JP2018536643A/en
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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

Amphiphilic hypocrellin derivant of ester water and its preparation method and application
Technical field
The present invention relates to the photosensitizer drug technical field of optical dynamic therapy.It is amphiphilic more particularly, to a kind of ester water Hypocrellin derivant and its preparation method and application.
Background technology
Photodynamic therapy (Photodynamic Therapy, abbreviation PDT) is that the one kind developed rapidly in recent years is directed to blood The selective therapy new technology that pipe venereal disease becomes, it also has the effect of notable to various tumor diseases.Photodynamic therapy has become After operation, the tumor therapeuticing method of the 4th kind of specific type of radiation and chemotherapy then, it is advantageous that its high efficiency and peace Quan Xing, can continuously generate active oxygen species under light illumination, cause the damage or necrosis of sick cell and tissue, and traditional Medicine, which can only kill single target molecule and compare, has significant high efficiency.There is photodynamic therapy target-oriented drug and illumination to determine The two-way choice of position, reduces the damage to normal cell, so that the security for the treatment of is guaranteed.PDT not only exists Significant achievement is achieved in clinical anticancer, while is also used for non-tumorous type disease, such as various vascular lesions, condyloma acuminatum, The treatment of the diseases such as psoriasis, nevus flammeus, rheumatoid arthritis, fundus flavimaculatus lesion.In addition, photodynamic therapy is for laser Beauty etc. also has significant effect.
Photosensitizer is the key factor for influencing optical dynamic therapy effect.It is currently known in the photosensitizer drug of application, is used for Clinical first generation photosensitizer is porphyrin photosensitive drug, and the second generation is phthalocyanines photosensitive drug.In these photosensitive drugs, porphyrin The most outstanding problem of class photosensitizer and phthalocyanines photosensitizer is that the separation of geometric isomer is difficult, it is difficult to obtains the purifying of one pack system Compound；And its relative complex component is also unfavorable for the drug metabolism in later stage, the assessment of toxicity test.Other photosensitive drugs Such as dihydro porphin, chlorophyll class, quinones are also for development phase.At present, the photosensitive drug that China's clinic needs is still It is very deficient, it is badly in need of new efficient photosensitive drug and fills a vacancy.
Quinones photosensitive drug is found in succession from last century the eighties, such as cercosporin, hypericin, Jia Rang chambers Rhzomorph, hypocrellin etc., have all had been found active anticancer.Wherein hypocrellin be by 4000 meters of Yunnan Province of China plateau elevation, The natural photosensitizer extracted in a kind of red bacterium of parasitical fungi-bamboo on arrow bamboo.Natural hypocrellin mainly includes the red fungus beetle of bamboo Plain (Hypocrellin A, abbreviation HA) and hypocrelline B (Hypocrellin B, abbreviation HB).In recent years, people are red to bamboo Rhzomorph has more to be studied in detail, and hypocrellin possesses the primary condition of the photosensitive drug as superior performance, such as visible region Domain have it is strong absorb and molar extinction coefficient it is big, it is photosensitive under the conditions of can efficiently produce creating singlet oxygen；Belong to autonomic drug, it has light Toxicity is good, dark toxicity is low, internal metabolism is fast, chemical constitution is clear and definite, thus be with a wide range of applications (Xu Shangjie, Zhang Xiaoxing, Chen Shen etc., the research of new photo-dynamical medicine-hypocrellin derivant and progress, Science Bulletin, 2003,48,1005-1015). But the main absorbing wavelength scope of hypocrellin, in 450-550nm, this wavelength energy tissue penetration is also less than 1 millimeter, in light It is weaker that dynamic therapy window (600-900nm) absorbs light ability.There have been many changes for being directed to hypocrellin in past more than ten years Modification is learned, the obvious red shift of its absorbing wavelength of hypocrellin to 600-700nm, the molar extinction coefficient of wherein ammonia modification significantly increases (Paul B.,Babu M.S.,Santhoshkumar T.R.,et al.Biophysical evaluation of two red-shifted hypocrellin B derivatives as novel PDT agents, J.Photochem.Photobiol.B:2009,94,38-44).Amido modified hypocrellin has shown preferable photosensitive Pharmaceutical properties, but the water solubility and biocompatibility of this kind of photosensitizer also need to further improve.The target of capilary class disease Body is the intensive microvessel network of heteroplasia of focal zone, sensitive to photodynamic action；During optical dynamic therapy, medicine is usually noted with vein The mode penetrated transports to pathological tissues by blood circulation system.However, hypocrellin is a kind of lipophilicity organic molecule, in water In solubility it is very low, directly intravenous injection can in blood self-assemble and cause blood vessel blockage.The derivative of sulfonic acid substitution (Liu X,Xie J,Zhang L Y,et al.Optimization of hypocrellin B derivative amphiphilicity and biological activity.Chinese Sci Bull,2009,54:2045-2050) energy Solve the problems, such as well water miscible, but since its is negatively charged, and substantial amounts of negative electrical charge is mutually exclusive in cell and tissue, carefully Born of the same parents' uptake ratio is relatively low, greatly reduces Photodynamic activity.Therefore, the photosensitive drug molecule of design will not only meet as proposed above Light absorbs condition, also to meet that the fat water of optimization is amphiphilic-both meet to be injected intravenously required concentration requirement, ensure again high Cellular uptake rate to improve optical dynamic therapy effect.
Accordingly, it is desirable to provide a kind of not only met that light absorbs condition, but also the amphiphilic hypocrellin of fat water with optimization derived Thing and its preparation method and application.
The content of the invention
It is an object of the present invention to provide a kind of amphiphilic hypocrellin derivant of ester water；Second mesh of the present invention Be a kind of preparation method of the amphiphilic hypocrellin derivant of ester water is provided；Third object of the present invention is to provide one The application of the kind amphiphilic hypocrellin derivant of ester water.The present invention can not only meet at the same time for existing hypocrellin derivant Light absorbs condition, and meet the amphiphatic problem of fat water of optimization, it is proposed that technical scheme.Applicant is proposed with poly- The groups such as the quaternary ammonium salt of ethylene glycol or long-chain introduce the base group modification hypocrellin such as polyethylene glycol and long chain quaternary at the same time, Strengthen its biocompatibility, adjust hypocrellin parent hydrophobe property.The analog derivative is amphiphilic with different fat water, and The advantages that easily being influenced by pH changes.Light dynamic experiment proves：Such amphiphilic hypocrellin derivant can meet different clinics Requirement needed for medication, solves different modes of administration to the contradiction between medicine hydrophily and lipophilicity requirement.The technical side Case discloses first in the present invention.
To reach above-mentioned first purpose, the present invention uses following technical proposals：
A kind of amphiphilic hypocrellin derivant of ester water, the general structure of the derivative is formula (1) or formula (2)：
Formula (1) is the substituent R of piperazine and hypocrellin derivant, the piperazine and hypocrellin derivant1For H or- COCH3；The R1For H when, double bond is located at the C marked in formula (1)13、C14、C15The C of three carbon atoms13=C14Or C14= C15；The R1For-COCH3When, double bond is located at the C marked in formula (1)13、C14、C15The C of three carbon atoms13=C14；
The substituent R of formula (2) described hypocrellin derivant1For H ,-COCH3Or-C (CH3)=N-R；The R1For H when, Double bond is located at the C marked in formula (2)13、C14、C15The C of three carbon atoms13=C14Or C14=C15；The R1For-COCH3Or- C(CH3During)=N-R, double bond is located at the C marked in formula (2)13、C14、C15The C of three carbon atoms13=C14；
Hypocrellin described in formula (1) and the R in pyridine ring2-R7It is subordinated to substituent R；The substituent R is hydrophobic The various combination of group, hydrophilic radical or hydrophobic grouping and hydrophilic radical；The hydrophobic grouping is containing alkyl, alkenyl, alkynyl, ring Alkyl, cycloalkenyl group, cycloalkynyl radical, phenyl or heterocyclic radical；The hydrophilic radical hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulphur Acidic group, condensed ethandiol base, quaternary ammonium salt or pyridiniujm；Shown in the general structure of the substituent R such as formula (3)：
In formula (3), 0≤m≤12,0≤n≤500,0≤p≤12,0≤q≤12；Described m, n, p, q are zero or positive integer； Y is linking group；Z is end group；(OCH2CH2)nFor polyethylene glycol unit；
Linking group Y is NH, O, S, carboxylate, acid amides, sulphur carboxylic ester, aryl, heterocyclic aryl, 3-12 carbon atoms in formula (3) Alkyl or 3-12 carbon atoms cyclic hydrocarbon radical；
The aryl is substituted or non-substituted aryl；Heterocyclic aryl is substituted or non-substituted heterocyclic aryl；3-12 carbon The alkyl of atom includes substituted or non-substituted or contains heteroatomic alkene or alkynes；The cyclic hydrocarbon radical of 3-12 carbon atoms includes substitution Or it is non-substituted or containing heteroatomic cycloalkane, cycloolefin or cycloalkyne, the hetero atom is oxygen, nitrogen or sulphur atom；It is described to take Dai Jiwei halogens, hydroxyl, the alkyl of 1-12 carbon atoms, alkenyl, alkynyl, the 3-8 of 2-12 carbon atom of 2-12 carbon atom are a The aralkyl of the cycloalkyl of carbon atom, aryl or 6-12 carbon atoms；Either end group contains hydroxyl, carboxylic acid group, sulfonic group or carboxylic The alkyl of acid esters；Or alkyl, alkenyl, alkynyl, cycloalkanes containing hetero atom for the 1-12 carbon atom chain lengths of oxygen, nitrogen or sulphur atom Base, aryl or aralkyl；The either various combination of above-mentioned substituent；
End group Z is alkoxy, phenyl, heterocycle, the hydroxyl of hydrogen, the alkyl of 1-12 carbon atoms, 1-12 carbon atom in formula (3) Base, sulfydryl, carboxylic acid group, sulfonic group, quaternary ammonium salt or pyridiniujm；
When the end group Z is quaternary ammonium salt, three substituents are independently or at the same time on the quaternary ammonium salt：1-12 carbon atoms Alkyl, the alkenyl of 2-12 carbon atom, the alkynyl of 2-12 carbon atom, the cycloalkyl of 3-8 carbon atom, 3-8 carbon atom Cycloalkenyl group, the aralkyl of aryl or 6-12 carbon atoms；Either end group contains hydroxyl, carboxylic acid group, sulfonic group or carboxylate Alkyl；Or alkyl, alkenyl, alkynyl, cycloalkyl, aryl containing hetero atom for the 1-12 carbon atom chain lengths of oxygen, nitrogen or sulphur atom Or aralkyl；The either various combination of above-mentioned substituent；Anion in quaternary ammonium salt is the permitted anion of pharmaceutical preparation；
When the end group Z is pyridiniujm, the substituent in the pyridiniujm on pyridine ring is in ortho position, meta or para position；Pyrrole Pyridine salt is by pyridine and the carbon atom containing 1-12 of different chain length halogenated hydrocarbons is quaternized forms；Anion in pyridiniujm is medicine system The permitted anion of agent；
Formula (1) described substituent R1For-COCH3, double bond be located at C13=C14When, formula (1) mark piperazine ring on a, b two At least one carbon atom is tertiary carbon atom；Formula (1) described substituent R1It is located at C for H, double bond14=C15When, the piperazine of formula (1) mark It is tertiary carbon atom that two carbon atoms of a, b are at least one on piperazine ring；
Formula (2) described R is substituent, and the substituent R is hydrophobic grouping, hydrophilic radical or hydrophobic grouping and hydrophilic group The various combination of group；The hydrophobic grouping contains alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, phenyl or heterocycle；Institute State hydrophilic radical hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulfonic group, condensed ethandiol base or quaternary ammonium salt；The substituent Shown in the general structure of R such as formula (3)；
Formula (2) described substituent R1For-COCH3, double bond be located at C13=C14When, the substituent R in formula (3) does not include following Structure：-(CH2)m-NH-(CH2)p-Z；Wherein 1≤m≤12,0≤p≤12, Z are hydroxyl, alkoxy, carboxylic acid or carboxylate；
Formula (2) described double bond is located at C13=C14Position, substituent R1For-COCH3Or-C (CH3During)=N-R, the R general formulas Middle end group Z does not include quaternary ammonium moiety.
The general structure of the piperazine and hypocrellin derivant is formula (4), (5) or (6)：
In formula (1), the substituent R of piperazine and hypocrellin derivant1It is located at C for H, double bond13=C14During position, its structure is led to Shown in formula such as formula (4)；The substituent R of piperazine and hypocrellin derivant1It is located at C for H, double bond14=C15During position, its general structure As shown in formula (5)；The substituent R of piperazine and hypocrellin derivant1For-COCH3, double bond be located at C13=C14During position, its structure Shown in general formula such as formula (6)；
It is tertiary carbon atom that two carbon atoms of a, b are at least one on the piperazine ring that formula (5) is marked；The piperazine that formula (6) is marked It is tertiary carbon atom that two carbon atoms of a, b are at least one on piperazine ring；
Substituent R in the formula (4), formula (5), formula (6)2-R7The definition of substituent R in formula (3) is subordinated to, is substituted Base R2-R7It is partly or entirely identical or entirely different；Substituent R2-R7For hydrophobic grouping, hydrophilic radical or hydrophobic grouping With the various combination of hydrophilic radical；The hydrophobic grouping contains alkyl, alkenyl, alkynyl, cycloalkyl or heterocycle；The hydrophilic radical contains Hydroxyl, carboxyl, ester group, ether, amide groups, sulfonic group, condensed ethandiol unit or quaternary ammonium salt.
The general structure of hypocrellin derivant is formula (9)-formula (12) in the formula (2)：
In formula (2), the substituent R of hypocrellin derivant1It is located at C for H, double bond13=C14During position, its general structure such as formula (9) shown in；The substituent R of hypocrellin derivant1It is located at C for H, double bond14=C15During position, its general structure such as formula (10) institute Show；The substituent R of hypocrellin derivant1For-COCH3, double bond be located at C13=C14During position, its general structure such as formula (11) institute Show；The substituent R of hypocrellin derivant1For-C (CH3) N=R, double bond be located at C13=C14During position, its general structure such as formula (12) shown in；
In the formula (9)-formula (12) shown in substituent R general structure such as formula (3), the substituent R is hydrophobic grouping, parent Water base group or the various combination of hydrophobic grouping and hydrophilic radical；The hydrophobic grouping is containing alkyl, alkenyl, alkynyl, cycloalkyl, ring Alkenyl, cycloalkynyl radical, phenyl or heterocycle；The hydrophilic radical hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulfonic group, contracting second Glycol-based or quaternary ammonium salt；
In the formula (10), formula (11), substituent R does not include with lower structure：-(CH2)m-NH-(CH2)p-Z；Wherein 1≤m ≤ 12,0≤p≤12, Z are hydroxyl, alkoxy, carboxylic acid or carboxylate；
In the formula (11), formula (12), substituent R does not include the structure of quaternary ammonium salt.
Preferably, the connector 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- (pyridine radicals)；-C3H4- (cyclopropyl)；-C4H6- (cyclobutyl)；-C5H8- (cyclopenta)；-C5H7 (CH3)-(methylcyclopentyl)；-C5H7(OH)-(hydroxycyclopent base)；-C6H10- (cyclohexyl)；-C6H9(CH3)-(methyl cyclohexane Base)；-C6H9(C2H5)-(ethylcyclohexyl)；-C6H9(C3H7)-(propylcyclohexyl)；-C6H9(C4H9)-(butylcyclohexyl)；- C6H8(CH3)2- (Dimethylcyclohexyl)；-C6H9(OH)-(hydroxy-cyclohexyl)；-C7H12- (suberyl)；(piperazinyl)；(1,4- diazabicylos [2.2.2] octyl).
Preferably, the end 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- diazabicylos [2.2.2] octyl)；Either end group Quaternary ammonium salt containing hydroxyl, carboxylic acid group, sulfonic group or carboxylate.
Preferably, the substituent R is：-H；-CH3；-C2H5；-C3H7；-C4H9；-C5H11；-C6H13；-C3H6；-C5H9(ring Amyl group)；-C6H11(cyclohexyl)；-C6H10(CH3) (methylcyclohexyl)；-C6H10(C2H5) (ethylcyclohexyl)；-C6H10(C3H7) (propylcyclohexyl)；-C6H10(C4H9) (butylcyclohexyl)；-C6H9(CH3)2(Dimethylcyclohexyl)；-C6H10(OH) (hydroxyl ring Hexyl)；-C7H12- (suberyl)；-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 [molecular weight is less than 30,000 polyethylene glycol]；-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；[molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；- (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 [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-CH2CH2-SO2- OCH2CH2-OH；-CH2CH2-SO2-(OCH2CH2)2-OH；-CH2CH2-SO2-(OCH2CH2)4-OH；-CH2CH2-SO2- (OCH2CH2)6-OH；-CH2CH2-SO2-(OCH2CH2)n- OH [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-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 [molecular weight is less than 30,000 polyethylene glycol]；-(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 [molecular weight is less than 30,000 polyethylene glycol]；-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, enol of the general structure of formula (1) piperazine and hypocrellin derivant shown in also comprising formula (1 ') Dynamic isomer；The general structure of formula (2) described hypocrellin derivant is also comprising the enol tautomer shown in formula (2 ')：
To reach above-mentioned second purpose, the present invention uses following technical proposals：
A kind of preparation method of amphiphilic hypocrellin derivant, includes the following steps：
Hypocrellin and corresponding substituted amine derivatives are dissolved in organic solvent, are carried out in the dark under inert gas shielding anti- Should, most afterwards through isolating and purifying, you can obtain the amphipathic hypocrellin derivant of ester water.The hypocrellin is hypocrelline B HB With deacetylation hypocrellin HC；Shown in the substituent structure general formula such as formula (3) of the substituted amine derivatives；The hypocrellin Molar ratio with substituted amino derivant is 1:5~1:50, concretely 1:5、1:10、1:15、1:20、1:30、1:40 Or 1:50；The temperature of reaction is 20-100 DEG C；When the time of reaction is 6-18 small.The organic solvent for acetonitrile, tetrahydrofuran, Pyridine, N,N-dimethylformamide, methanol, ethanol；Reaction needs inert gas such as argon gas or nitrogen to protect lower progress, and will Lucifuge is reacted.
Preferably, the organic solvent is one kind in acetonitrile, tetrahydrofuran or pyridine；The hypocrellin and substitution amine The molar ratio of derivative is 1:20；The temperature of reaction is 60 DEG C；When the time of reaction is 8 small.Preferably, the separation is pure The process of change is：Except dereaction organic solvent obtains residue, residue is dissolved with dichloromethane；It is water-soluble with dilute hydrochloric acid successively Liquid and water washing；Organic layer drying, filtering, removing solvent are then obtained into crude product；By crude product purified by silica gel plate layer chromatography, i.e., Obtain the hypocrellin derivant containing long chain quaternary.
Preferably, solvent used during silica gel plate layer chromatography is the mixing containing acetone, ethyl acetate, ethanol and diethylamine Liquid, acetone in the mixed liquor, ethyl acetate, the volume ratio of ethanol and diethylamine are 20:1:1:1~20:1:3:1.Preferably, The process that isolates and purifies is：Except dereaction organic solvent, obtain black-and-blue solid residue and dissolved with dichloromethane, with etc. Diluted hydrochloric acid aqueous solution (5%) washing of volume three times, washing once, organic layer is with anhydrous magnesium sulfate is dry, filtering, removes solvent Obtain crude product.Gained crude product purified by silica gel plate layer chromatography method further separates, and solvent is acetone：Ethyl acetate：Ethanol：Diethyl Amine, preferred volume ratio are 20:1:1:1, the hypocrellin derivant of amino substitution is obtained, yield 5~20%, product is blue-black Color solid.
To reach above-mentioned 3rd purpose, the present invention uses following technical proposals：
A kind of amphiphilic hypocrellin derivant of ester water as described above is as the photosensitizer drug in optical dynamic therapy Using.
Fig. 1 is a kind of general structure of amphiphilic hypocrellin designed by the present invention.Fig. 2~Fig. 6 be the present invention relates to All kinds of hypocrellin derivants synthetic method.Hypocrellin of the present invention containing the group such as condensed ethandiol or quaternary ammonium salt spreads out Biology, has the strong of non-constant width to absorb, its maximum absorption spectrum wavelength is reachable in 600-630nm or so, maximum in phototherapy window 650nm, than maximum absorption band (450nm) more than red shift 150nm of hypocrellin parent, molar extinction coefficient about 10000- 40000M-1cm-1Left and right, shows extremely strong red light absorption ability (as shown in Figure 7)；It is water-soluble preferably, can in physiological saline To configure storing solution in 0.1uM~1mM concentration ranges.It produces the ability of active oxygen and passes through shown in Fig. 8：Experiment shows, distinguishes Measured with creating singlet oxygen and superoxide radical capturing agent, such amphipathic hypocrellin derivant of ester water can efficiently produce photosensitive Active specy, to produce based on creating singlet oxygen (Fig. 8 a), can also produce a small amount of superoxide radical (Fig. 8 b).Being total to shown in Fig. 9 Confocal fluorescence imaging experiment the result shows that, phototherapy medicament small molecule HB-1 has preferable biocompatibility, can enter Hela The lysosome of cell, and good feux rouges fluorescence imaging can be produced in cell.HB-1 and Hela cells are incubated together, are such as schemed Shown in 10a, cytotoxicity (dark toxicity) development test shows, synthesized hypocrellin containing condensed ethandiol derives in embodiment 3 The cytotoxicity of thing HB-1 is smaller, and the hypocrelline B HB and photosensitive drug haematoporphyrin HpD of commercialization similar, and Hela cells are used The photosensitizer HB-1 of 10uM concentration is incubated half an hour, has no that Hela cells have obvious death, illustrates that such photosensitizer does not have substantially There is cytotoxicity.Cell phototoxicity research experiment as shown in fig. lob shows that HB-1 is under red light irradiation, to Hela cell tables Reveal very strong lethality.160nM concentration ranges with regard to can kill more than 90% Hela cells, and the red bacterium of bamboo under the same terms B prime or commercial photosensitizer hematoporphyrin derivative, can only kill 20% or so Hela cells, illustrate that such amphiphilic bamboo is red The light power effect of streptozotocin derivative is substantially better than hypocrelline B HB and commercial photosensitizer haematoporphyrin HpD.Figure 11 is to implementing The cell dark toxicity of the synthesized HB-2 of hypocrellin derivant containing condensed ethandiol has also obtained similar with phototoxicity experiments in example 3 Result.In addition, Figure 12 shows deacetylation the hypocrellin HC-3 or HC-4 of the aminopropanol modification synthesized by embodiment 4 The phototoxicity design sketch of tumor killing cell；Figure 13 shows the deacetylation of the modification containing long chain quaternary synthesized by embodiment 46 The phototoxicity design sketch of hypocrellin HC-87 or HC-88 tumor killing cell；Figure 14 shows piperazine synthesized by embodiment 52 simultaneously The phototoxicity design sketch of hypocrelline B HB-98 tumor killing cells；Above all of phototoxicity experiments result illustrates such double The light power effect of parent's property hypocrellin derivant is substantially better than hypocrelline B HB and commercial photosensitizer haematoporphyrin HpD.
Compared with hypocrelline B parent, contracting second two is introduced in the amphiphilic hypocrellin derivant of ester water of the invention The groups such as alcohol, quaternary ammonium salt greatly strengthen that its is water-soluble, and oil-water ratio is adjusted by varying the chain length of aliphatic chain so that such Derivative has good fat water amphiphilic, also has good biological compatibility in cell or tissue；Such compound with Condensed ethandiol or quaternary ammonium form exist, and are not easy to be influenced by pH, available in complicated organism；This kind of band normal salt of quaternary ammonium salt Hypocrellin can be effectively combined negative electrical charge species in organism, especially there is good nucleophilicity to tumour cell； Change phototherapy effect by adjusting the distance between quaternary ammonium salt and hypocrellin parent；, can be by changing using condensed ethandiol Become the unit number of condensed ethandiol structure, any hydrophobe property for adjusting photosensitive drug molecule, to meet different clinical medicines Demand, condensed ethandiol structure is nontoxic in addition, and U.S. FDA approval drug component, there is good biocompatibility.Cause This, such amphiphilic hypocrellin derivant can be directly dissolved in physiological saline and make preparation medicine, improve medicinal effects；And it is natural Product is made, and will not produce toxic side effect, and the medicine for exploitation hypocrellin treating cancer and anti-cancer virus is laid a good foundation.
The present invention discloses two amphiphilic hypocrellin derivants of class ester water and its preparation method and application.Using condensed ethandiol The group such as group or quaternary ammonium salt with long-chain modifies hypocrellin, by adjusting the hydrophobe property of molecule, such is spread out Biology is amphiphilic with different fat water, while improves the biological compatibility with cell or tissue.Such compound absorption maximum Wavelength reaches 10000-40000M in 600-650nm scopes, molar extinction coefficient-1cm-1, there is very strong extinction in phototherapy window Ability.Research shows that this analog derivative can efficiently produce creating singlet oxygen isoreactivity oxygen species under the conditions of photosensitive, has good Photodynamic effect, can be used as the phototherapy medicament treatment disease such as tumour and all kinds of microangiopathies.
In the prior art, there is not the research of preparation and the extraction of the hypocrellin derivant of the modification containing condensed ethandiol also, also Do not find that such compound can meet light absorbs condition at the same time, also meet optimization fat water it is amphiphilic-meet vein note The concentration requirement of injection is penetrated, to ensure the correlative study of high cellular uptake rate.
It is furthermore noted that hypocrellin derivant to be protected is needed to contain two kinds of tautomerisms involved in this patent Isomers (such as formula 1 and 1 ', formula 2 and 2 '), the chemical constitution of two kinds of isomers is certainly within protection domain.Do not have for another fruit Special instruction, any scope described in the present invention is including any numerical value between end value and end value and with end value or end Any subrange that any number between value is formed.
Beneficial effects of the present invention are as follows：
1) from natural product extraction, raw material is easy to get the hypocrellin raw material in the present invention, cost is low, can largely prepare, poison Small side effects, be easy to be metabolized；
2) synthesis and separation method are simple, the reaction raw materials of no costliness and complicated separation means；
3) hypocrellin derivant of the substitution containing groups such as condensed ethandiol, quaternary ammonium salts prepared by is female compared to hypocrellin Body, the notable red shift of its absorption spectrum and molar extinction coefficient greatly increases can efficiently produce active oxygen (singlet state under the conditions of photosensitive Based on oxygen, supplemented by superoxide radical isoreactivity oxygen species)；The bases such as condensed ethandiol or quaternary ammonium salt are introduced in hypocrellin parent Unity structure adjusts its hydrophobe property, and having the analog derivative, different fat water are amphiphilic, at the same increase its with cell or The biological compatibility of tissue；This amphiphilic hypocrellin derivant of lipoid water can meet the requirement needed for different clinical applications, Different modes of administration is solved to the contradiction between medicine hydrophily and lipophilicity requirement.
4) first generation porphyrin light of the amphiphilic hypocrellin derivant photosensitizer of ester water in the present invention and Clinical practice Quick dose is compared with second generation phthalocyanines photosensitizer, its absorbing wavelength and absorbing ability are obviously improved, it is important that product is easy to point From, purifying, structure it is clear and definite, overcome porphyrin and phthalocyanines photosensitizer be not readily separated and form labyrinth and is difficult to definite ask Topic.More importantly：Under the same terms, the amphiphilic hypocrellin derivant photosensitizer of ester water involved in the present invention compares the first generation There is the ability of the light power killing tumor cells of higher with second generation commercialization photosensitizer.
Brief description of the drawings
The embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 shows a kind of general structure of amphiphilic hypocrellin designed by the present invention.
Fig. 2 shows the synthetic reaction route map of the long chain quaternary ammonium salt derivative in the embodiment of the present invention 2.
Fig. 3 shows the synthesis of the hypocrellin B derivatives HB-1 and HB-2 containing condensed ethandiol in the embodiment of the present invention 3 Reaction scheme figure.
Fig. 4 shows the synthetic reaction route map of the deacetylation hypocrellin HC and aminopropanol in the embodiment of the present invention 4.
Fig. 5 shows that the synthesis of the deacetylation hypocrellin derivant containing long chain quaternary in the embodiment of the present invention 46 is anti- Answer route map.
Fig. 6 shows the synthetic reaction of the piperazine and hypocrellin B derivatives HB-98 and HB-99 in the embodiment of the present invention 52 Route map.
Fig. 7 shows the bamboo containing condensed ethandiol prepared by the hypocrelline B HB (a) of the extraction of the embodiment of the present invention 1, embodiment 3 Piperazine and the absorption spectrum of hypocrellin B derivatives HB-98 (c) are prepared in red bacterium B prime derivative HB-1 (b) and embodiment 52 Comparison diagram.
Fig. 8 show the hypocrellin derivant HB-1 containing condensed ethandiol in the embodiment of the present invention 3 respectively with creating singlet oxygen The action diagram of capturing agent (a), superoxide radical capturing agent (b).
Fig. 9 shows the hypocrellin derivant HB-1 containing condensed ethandiol in the embodiment of the present invention 3 respectively in Hela cells In confocal fluorescent image.
Figure 10 shows containing in the hematoporphyrin derivative HpD, hypocrelline B HB and the embodiment of the present invention 3 of various concentrations Dark toxicity figures (a) and phototoxicity figure (b) of the red streptozotocin derivative HB-1 of condensed ethandiol to Hela cells.
Figure 11 shows containing in the hematoporphyrin derivative HpD, hypocrelline B HB and the embodiment of the present invention 3 of various concentrations Dark toxicity figures (a) and phototoxicity figure (b) of the red streptozotocin derivative HB-2 of condensed ethandiol to Hela cells.
Figure 12 is shown synthesized by the hematoporphyrin derivative HpD, hypocrelline B HB and the embodiment of the present invention 4 of various concentrations Aminopropanol modify the red streptozotocin derivative HC-3 or HC-4 of deacetylation to the phototoxicity figures of Hela cells.
Figure 13 is shown in the hematoporphyrin derivative HpD, hypocrelline B HB and the embodiment of the present invention 46 of various concentrations Phototoxicity figures of the red streptozotocin derivative HC-87 or HC-88 of deacetylation of the modification containing long chain quaternary to Hela cells.
Figure 14 is shown in the hematoporphyrin derivative HpD, hypocrelline B HB and the embodiment of the present invention 52 of various concentrations Phototoxicity figure containing piperazine and red bacterium B prime derivative HB-98 to Hela cells.
Embodiment
In order to illustrate more clearly of the present invention, the present invention is done further with reference to preferred embodiments and drawings It is bright.Similar component is indicated with identical reference numeral in attached drawing.It will be appreciated by those skilled in the art that institute is specific below The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Embodiment 1
The extraction of hypocrellin A (HA)：The red bacterium of 100g bamboos is crushed with pulverizer, is placed in apparatus,Soxhlet's, with 1000mL Acetone as solvent continuously extraction one day it is closely colourless to extracting solution, extracting solution is filtered to remove the solid insoluble penetrated on a small quantity, then It is spin-dried for removing acetone, is dissolved with 500mL dichloromethane, 4 × 400mL distillation water washings, isolates organic layer and be spin-dried for, solid residues Thing 5 × 100mL petroleum ethers, spontaneous combustion air-dries the solid in atmosphere, then with chloroform-petroleum ether recrystallization twice, institute It is target product hypocrellin A (HA) to obtain crystal, and purity is more than 98%.Using thin-layer silicon offset plate chromatography, with petroleum ether： Ethyl acetate：Absolute ethyl alcohol (30:10:1) make solvent, can be further purified to obtain the hypocrellin A of high-purity.
The preparation of hypocrelline B (HB)：Hypocrelline B is dehydrated by A prime and is obtained in alkaline conditions, preparation method ginseng Examine 252-254 pages of Zhao of volume 9 in 1989 and open the reference book of great organic chemistry, be suitably modified.Specific method is as follows：1 gram of bamboo is red Fungus beetle element is dissolved in the KOH aqueous solutions of 1000mL1.5%, lucifuge stirring reaction 24 it is small when after, with slightly excessive dilute hydrochloric acid neutralize, With chloroform recovery product, hypocrelline B 0.98g, yield 98% are obtained after isolating and purifying.
The preparation of deacetylation hypocrellin (HC)：200mg hypocrelline Bs are dissolved in 1.5% potassium hydroxide of 100mL In aqueous solution, lucifuge back flow reaction 8h, is neutralized after cooling with slightly excessive dilute hydrochloric acid, extracts product with dichloromethane, separation carries 110mg deacetylations hypocrelline B (HC), yield 56% are obtained after pure.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)。
Embodiment 2
Salt derivative containing long chain quaternary ammonium used of the invention is made by following universal method, with H2NCH2CH2-N+(CH3)2 (C10H21) it is row explanation.
The preparation of intermediate S1：N, N- dimethyl-ethylenediamine (4.4g, 0.05mol) and diethyl carbonate (7.10g, 100 milliliters of round-bottomed flasks 0.06mol) are mixed in, reaction solution reacts 48h at 70 DEG C, and then vacuum distillation obtains flaxen Liquid 7.20g, yield 89%.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)。
The preparation of intermediate S2：Intermediate S1 and 1- bromine certain herbaceous plants with big flowers alkane (15.25g, 0.05mol) reacts anti-under 48h at 100 DEG C Answer 72h.Crude product acetone-diethyl ether (1:1) 2 common 15.83g of white crystal, yield about 68% are obtained.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。
The preparation of long chain quaternary ammonium salt derivative S3：48% hydrogen bromines of 50mL are added in intermediate S2 (10.60g, 0.02mol) Acid and 50mL distilled water, heating reflux reaction 72h.Revolving removes hydrobromic acid, solid residue ethanol：Ether (1:1) tie again Crystalline substance obtains white flock crystal 13.62g, yield 69%.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。
Embodiment 3
Hypocrellin B derivatives (the R=-CH of aminoethyl ethylene glycol modification2CH2OCH2CH2OH preparation)：Synthetic route As shown in Figure 4：
By hypocrelline B HB (100mg, 0.18mmol) and aminoethyl ethylene glycol (0.40g, 4mmol) be dissolved in 20mL without In water-acetonitrile, after being sufficiently mixed, 50 DEG C are heated under nitrogen protection, lucifuge stirring reaction 10h, after completion of the reaction, revolving removes Solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, and washed once, distills with 100mL diluted hydrochloric acid aqueous solutions successively Twice, organic layer is spin-dried for obtaining crude product water washing with anhydrous magnesium sulfate drying, filtering, organic phase.Gained crude product silica gel plate Chromatography further separates, and solvent is acetone：Ethyl acetate (volume ratio 1:1) two kinds of blue-black solids, are respectively obtained Product, RfValue is respectively 0.80 and 0.24, wherein RfFor 0.24 product by being accredited as while in 2 and 17 substitution products, Labeled as HB-1, yield 12.2%；RfContinue to use acetone for 0.80 component：Petroleum ether (volume ratio 1:1) plate layer chromatography separates, It is 0.85 (2 bit amino substitution products being detected as, labeled as HB-2) to obtain Rf values, yield 6.5%.
2,17- bit amino substitution product HB-1 characterize datas 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 wavelengths：468nm,630nm.
2- bit amino substitution product HB-2 characterize datas 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).Ultraviolet maximum absorption wavelength：464nm,625nm.
The structural formula of above-mentioned amino substitution product HB-1, HB-2 are as shown in the figure：
Embodiment 4
3- aminopropanols modification deacetylation hypocrellin derivant (R=-CH2CH2CH2OH preparation), synthetic route is such as Shown in attached drawing 5：
Deacetylation hypocrellin HC (100mg, 0.20mmol) and aminoethyl ethylene glycol (0.30g, 4mmol) are dissolved in In 20mL anhydrous tetrahydro furans, after being sufficiently mixed, 60 DEG C are heated under nitrogen protection, lucifuge stirring reaction 12h, reaction finishes Afterwards, revolving removes solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, and is washed successively with 100mL diluted hydrochloric acid aqueous solutions Wash once, distilled water washes twice, organic layer is with anhydrous magnesium sulfate is dry, filtering, organic phase are spin-dried for obtaining crude product.Gained is thick Product are further separated with silica gel plate chromatography, and solvent is acetone：Ethyl acetate (volume ratio 1:1), obtain blue-black solid Body product, yield 15.2%, RfIt is worth for 0.45, mass spectrum MS (ESI+):530.6.The amino substitution product HC-3 (double bond positions In C13=C14) or HC-4 (double bond is located at C14=C15) structural formula scheme shown in：
Embodiment 5
Aminoethyl tirethylene glycol modification hypocrellin B derivatives (R=- (CH2CH2-(OCH2CH2)2- OH) preparation： The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3.
2 and 17 while amino substitution product HB-5：Yield is 8.4%, RfFor 0.24.Characterize data is as follows：MS (ESI+)：777.5；Ultraviolet maximum absorption wavelength：468nm,632nm.
2- bit amino substitution products HB-6：Yield is 5.8%, RfFor 0.55.Characterize data is as follows：MS(ESI+): 646.6；Ultraviolet maximum absorption wavelength：462nm,625nm.
The structural formula of described amino substitution product HB-5, HB-6 are as shown in the figure：
Embodiment 6
Aminoethyl triethylene Glycol modification deacetylation hypocrellin derivant (R=- (CH2CH2-(OCH2CH2)3- OH) Prepare：The preparation of 3- aminopropanols modification deacetylation hypocrellin derivant in synthetic method similar embodiment 4.
Products therefrom yield is 10.5%, RfFor 0.25.Characterize data is as follows：MS(ESI+)：648.5；Ultraviolet maximum suction Receive wavelength：468nm,632nm.(double bond is located at C to the amino substitution product HC-713=C14) or HC-8 (double bond is located at C14= C15) structural formula is as shown in the figure：
Embodiment 7
Four condensed ethandiol of aminoethyl modification hypocrellin B derivatives (R=- (CH2CH2-(OCH2CH2)4- OH) preparation： The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3.
2,17 bit amino substitution product HB-9:Yield is 12.4%, RfFor 0.30.Characterize data is as follows：MS(ESI+): 953.0.Ultraviolet maximum absorption wavelength：475nm,640nm.
2- bit amino substitution products HB-10：Yield is 6.4%, RfFor 0.65.Characterize data is as follows：MS(ESI+): 734.3.Ultraviolet maximum absorption wavelength：470nm,630nm.
Shown in the structural formula of described amino substitution product HB-9, HB-10 are schemed：
Embodiment 8
The red bacterium B prime derivative (R=- (CH of the polyethyleneglycol modified bamboo deacetylation of aminoethyl2CH2-(OCH2CH2)n- OH) Prepare：The preparation of 3- aminopropanols modification deacetylation hypocrellin derivant in synthetic method similar embodiment 4.
Products therefrom yield is 17.5%, RfFor 0.25；Characterize data is as follows：MS(ESI+):560.0.Ultraviolet maximum suction Receive wavelength：480nm,635nm.(double bond is located at C to the amino substitution product HC-1113=C14), (double bond is located at C to HC-1214= C15) shown in structural formula schemes：
Embodiment 9
3- aminopropyls ethylene glycol modification hypocrellin B derivatives (R=- (CH2)3-OCH2CH2OH preparation)：Synthesis The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in method similar embodiment 3.
2,17 bit amino substitution product HB-13：Yield is 6.5%, RfFor 0.16；Mass spectrum MS (ESI+):717.2；It is ultraviolet Maximum absorption wavelength：476nm,632nm.
2- bit amino substitution products HB-14：Yield is 5.4%, RfFor 0.50；Mass spectrum MS (ESI+):615.6.It is ultraviolet most Big absorbing wavelength：463nm,624nm.
Shown in the structural formula of described amino substitution product HB-13, HB-14 are schemed：
Embodiment 10
Amion acetic acid glycol ester modification deacetylation hypocrellin B derivatives (R=-CH2COOCH2CH2OH system) It is standby：The preparation of 3- aminopropanols modification deacetylation hypocrellin derivant in synthetic method similar embodiment 4.
Products therefrom yield is 18.5%, RfFor 0.18；Mass spectrum MS (ESI+):574.5；Ultraviolet maximum absorption wavelength： 474nm,638nm.(double bond is located at C to the amino substitution product HC-1513=C14) or HC-16 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 11
Amion acetic acid binaryglycol ester modification hypocrellin B derivatives (R=-CH2CO(OCH2CH2)2OH preparation)：Close The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified into method similar embodiment 3.
2,17 bit amino substitution product HB-17：Yield is 6.2%, RfFor 0.16；Mass spectrum MS (ESI+):805.5；It is ultraviolet Maximum absorption wavelength：468nm,635nm.
2- bit amino substitution products HB-18：Yield is 3.4%, RfFor 0.60；Mass spectrum MS (ESI+):659.6.It is ultraviolet most Big absorbing wavelength：462nm,624nm.
Shown in the structural formula of described amino substitution product HB-17, HB-18 are schemed：
Embodiment 12
Amion acetic acid triglycol ester modification deacetylation hypocrellin derivant (R=-CH2CO(OCH2CH2)3OH) Prepare：The preparation of 3- aminopropanols modification deacetylation hypocrellin derivant in synthetic method similar embodiment 4.
Products therefrom yield is 17.2%, RfFor 0.18；Mass spectrum MS (ESI+):662.3；Ultraviolet maximum absorption wavelength： 466nm,640nm.(double bond is located at C to the amino substitution product HC-1913=C14) (double bond is located at C to HC-2014=C15) structure Shown in formula is schemed：
Embodiment 13
Alanine macrogol ester modification hypocrellin B derivatives (R=- (CH2)2CO(OCH2CH2)nOH preparation)： The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3.
2,17 bit amino substitution product HB-21：Yield is 8.5%, RfFor 0.18；Ultraviolet maximum absorption wavelength：485nm, 645nm。
2- bit amino substitution products HB-22：Yield is 4.5%, RfFor 0.50；Ultraviolet maximum absorption wavelength：465nm, 635nm。
Shown in the structural formula of described amino substitution product HB-21, HB-22 are schemed：
Embodiment 14
Aminovaleric acid triglycol ester modification deacetylation hypocrellin derivant (R=- (CH2)4CO(OCH2CH2)3OH) Preparation：The preparation of 3- aminopropanols modification deacetylation hypocrellin derivant in synthetic method similar embodiment 4.
Products therefrom yield is 12.5%, RfFor 0.21；Mass spectrum MS (ESI+):704.5；Ultraviolet maximum absorption wavelength： 455nm,642nm.(double bond is located at C to the amino substitution product HC-2313=C14) (double bond is located at C to HC-2414=C15) structure Shown in formula is schemed：
Embodiment 15
NSC 209983 glycol ester modification hypocrellin derivant (R=-CH2SO2-OCH2CH2- OH) preparation：By bamboo Red bacterium B prime HB (100mg, 0.18mmol) and NSC 209983 monoethylene glycol ester (610mg, 4mmol) are dissolved in the anhydrous second of 20mL In nitrile, 55 DEG C are heated under nitrogen protection, after 8h is reacted in lucifuge stirring, revolving removes solvent.Black-and-blue solid residue is used 200mL dichloromethane dissolves, and is washed twice successively with diluted hydrochloric acid aqueous solution, distilled water washed once, organic layer is dry, filtering, Organic phase is spin-dried for obtaining crude product.Gained crude product is separated with thin layer of silicone analysis method, and solvent is acetone：Petroleum ether (volume ratio For 2：1) two kinds of black-and-blue solid products, are obtained.
2,17 bit amino substitution product HB-25：Yield is 9.2%, RfFor 0.18；Mass spectrum MS (ESI+):789.2；It is ultraviolet Maximum absorption wavelength：470nm,640nm.
2- bit amino substitution products HB-26：Yield is 4.4%, RfFor 0.55；Mass spectrum MS (ESI+):652.6.It is ultraviolet most Big absorbing wavelength：465nm,628nm.
Shown in the structural formula of described amino substitution product HB-25, HB-26 are schemed：
Embodiment 16
Red streptozotocin derivative (the R=-CH of NSC 209983 binaryglycol ester modification bamboo deacetylation2SO2(OCH2CH2)2OH) Preparation：The preparation of NSC 209983 binaryglycol ester modification hypocrellin derivant in synthetic method similar embodiment 15.
Products therefrom yield is 16.2%, RfFor 0.16；Mass spectrum MS (ESI+):654.2；Ultraviolet maximum absorption wavelength： 468nm,635nm.(double bond is located at C to the amino substitution product HC-2713=C14) (double bond is located at C to HC-2814=C15) structure Shown in formula is schemed：
Embodiment 17
NSC 209983 tetraethylene glycol ester modification hypocrellin derivant (R=-CH2SO2(OCH2CH2)4OH preparation)：Close The preparation of NSC 209983 binaryglycol ester modification hypocrellin derivant into method similar embodiment 15.
2,17 bit amino substitution product HB-29：Yield is 8.4%, RfFor 0.16；Mass spectrum MS (ESI+):1053.4；It is ultraviolet Maximum absorption wavelength：468nm,648nm.
2- bit amino substitution products HB-30：Yield is 5.4%, RfFor 0.62；Mass spectrum MS (ESI+):784.6.It is ultraviolet most Big absorbing wavelength：462nm,625nm.
Shown in the structural formula of described amino substitution product HB-29, HB-30 are schemed：
Embodiment 18
Amino fourth sulfonic acid triglycol ester modification hypocrellin derivant (R=-CH2CH2CH2CH2SO2(OCH2CH2)3OH) Preparation：The preparation of NSC 209983 binaryglycol ester modification hypocrellin derivant in synthetic method similar embodiment 15.
Products therefrom yield is 16.5%, RfFor 0.21；Mass spectrum MS (ESI+):1036.5；Ultraviolet maximum absorption wavelength： 455nm,638nm.(double bond is located at C to the amino substitution product HC-3113=C14) or HC-32 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 19
Ethylenediamine base substitution tirethylene glycol modification hypocrellin B derivatives (R=- (CH2CH2-NHCH2CH2- OCH2CH2- OH) preparation：The system for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3 It is standby.
2 and 17 while amino substitution product HB-33：Yield is 9.4%, RfFor 0.18.Characterize data is as follows：MS (ESI+)：775.5；Ultraviolet maximum absorption wavelength：469nm,635nm.
2- bit amino substitution products HB-34：Yield is 8.8%, RfFor 0.58.Characterize data is as follows：MS(ESI+): 644.6；Ultraviolet maximum absorption wavelength：464nm,626nm.
The structural formula of described amino substitution product HB-33, HB-34 are as shown in the figure：
Embodiment 20
Ethylenediamine base tirethylene glycol modification deacetylation hypocrellin derivant (R=- (CH2CH2-NHCH2CH2- (OCH2CH2)2- OH) preparation：3- aminopropanols modify deacetylation hypocrellin derivant in synthetic method similar embodiment 4 Preparation.
The products collection efficiency is 19.5%, RfFor 0.22.Characterize data is as follows：MS(ESI+)：646.5；Ultraviolet maximum suction Receive wavelength：468nm,631nm.(double bond is located at C to the amino substitution product HC-3513=C14) or HC-36 (double bond is located at C14= C15) structure is as shown in the figure：
Embodiment 21
Aminoethyl sulfydryl substitution diethylene glycol modification hypocrellin B derivatives (R=-CH2CH2-S-CH2CH2-OCH2CH2- OH preparation)：The preparation for the hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3.
2,17 bit amino substitution product HB-37:Yield is 11.4%, RfFor 0.35.Characterize data is as follows：MS(ESI+): 809.0.Ultraviolet maximum absorption wavelength：475nm,640nm.
2- bit amino substitution products HB-38：Yield is 7.4%, RfFor 0.68.Characterize data is as follows：MS(ESI+): 662.3.Ultraviolet maximum absorption wavelength：470nm,630nm.
Shown in the structural formula of described amino substitution product HB-37, HB-38 are schemed：
Embodiment 22
Aminoethyl sulfydryl substitutes the red bacterium B prime derivative (R=- (CH of four condensed ethandiols modification bamboo deacetylation2CH2-S- CH2CH2-(OCH2CH2)3- OH) preparation：3- aminopropanols modify deacetylation hypocrellin in synthetic method similar embodiment 4 The preparation of derivative.
The products collection efficiency is 17.5%, RfFor 0.12；Characterize data is as follows：MS(ESI+):709.0.Ultraviolet maximum suction Receive wavelength：480nm,635nm.(double bond is located at C to the amino substitution product HC-3913=C14) or HC-40 (double bond is located at C14= C15) shown in structure schemes：
Embodiment 23
Amino propionamide tetraethylene glycol methyl ether modification hypocrellin B derivatives (R=-CH2CH2CONH-CH2CH2– (OCH2CH2)3-OCH3) preparation：The hypocrellin B derivatives that aminoethyl ethylene glycol is modified in synthetic method similar embodiment 3 Preparation.
2,17 bit amino substitution product HB-41：Yield is 7.8%, RfFor 0.15；Mass spectrum MS (ESI+):1035.2；It is ultraviolet Maximum absorption wavelength：461nm,643nm.
2- bit amino substitution products HB-42：Yield is 5.4%, RfFor 0.54；Mass spectrum MS (ESI+):775.1.It is ultraviolet most Big absorbing wavelength：458nm,622nm.
Shown in the structural formula of described amino substitution product HB-41, HB-42 are schemed：
Embodiment 24
Amino valeramide tetraethylene glycol ester modification hypocrellin B derivatives (R=- (CH2)4CH2CONH-CH2CH2- (OCH2CH2)3-OCH3) preparation：3- aminopropanols modification deacetylation hypocrellin derives in synthetic method similar embodiment 4 The preparation of thing.
The products collection efficiency is 16.5%, RfFor 0.21；Mass spectrum MS (ESI+):760.5；Ultraviolet maximum absorption wavelength： 455nm,642nm.(double bond is located at C to the amino substitution product HC-4313=C14) or HC-44 (double bond is located at C13=C14) knot Shown in structure formula is schemed：
Embodiment 25
Hexylamine modification hypocrellin B derivatives (R=-CH2CH2CH2CH2CH2CH3) preparation：By hypocrelline B HB (100mg, 0.18mmol) and own ammonia (0.51g, 5mmol) are dissolved in 50mL anhydrous acetonitriles, and 55 DEG C are heated under nitrogen protection, After lucifuge stirring reaction 8h, revolving removes solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, successively with dilute salt Aqueous acid washes twice, distilled water washed once, and organic layer is dry, filter, organic phase is spin-dried for obtaining crude product.Gained crude product Separated with thin layer of silicone analysis method, solvent is acetone：Petroleum ether (volume ratio 2：1) two kinds of black-and-blue solids that obtain, are obtained to produce Thing.
2,17 bit amino substitution product HB-45：Yield is 28.6%, RfFor 0.24；Mass spectrum MS (ESI+):695.4；It is ultraviolet Maximum absorption wavelength：455nm,635nm.
2- bit amino substitution products HB-46：Yield is 14.6%, RfFor 0.38；Mass spectrum MS (ESI+):598.2.It is ultraviolet most Big absorbing wavelength：452nm,626nm.
Shown in the structural formula of described amino substitution product HB-45, HB-46 are schemed：
Embodiment 26
Butylamine modification hypocrellin B derivatives (R=-CH2CH2CH2CH2) preparation：Synthetic method similar embodiment 25 The preparation of middle hexylamine modification hypocrellin derivant.
2,17 bit amino substitution product HB-47：Yield is 32.6%, RfFor 0.26；Mass spectrum MS (ESI+):625.4；It is ultraviolet Maximum absorption wavelength：454nm,632nm.
2- bit amino substitution products HB-48：Yield is 14.6%, RfFor 0.38；Mass spectrum MS (ESI+):570.2.It is ultraviolet most Big absorbing wavelength：448nm,624nm.
Shown in the structural formula of described amino substitution product HB-47, HB-48 are schemed：
Embodiment 27
Octylame modification hypocrellin B derivatives (R=-CH2CH2CH2CH2CH2CH2CH2CH2) preparation：Synthetic method class Like the preparation of hexylamine modification hypocrellin derivant in embodiment 25.
2,17 bit amino substitution product HB-49：Yield is 22.6%, RfFor 0.16；Mass spectrum MS (ESI+):737.4；It is ultraviolet Maximum absorption wavelength：452nm,632nm.
2- bit amino substitution products HB-50：Yield is 18.6%, RfFor 0.60；Mass spectrum MS (ESI+):626.2.It is ultraviolet most Big absorbing wavelength：445nm,621nm.
Shown in the structural formula of described amino substitution product HB-49, HB-50 are schemed：
Embodiment 28
Fourth hexylamine modification hypocrellin B derivatives (R=-CH2CH2CH2CH2) preparation：Synthetic method similar embodiment The preparation of hexylamine modification hypocrellin derivant in 25.
Products therefrom yield is 38.6%, RfFor 0.24；Mass spectrum MS (ESI+):528.4；Ultraviolet maximum absorption wavelength： 455nm,635nm.(double bond is located at C to the amino substitution product HC-5113=C14) or HC-52 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 29
Benzyl amino hypocrellin B derivatives (R=-CH2C6H5) preparation：Hexylamine is repaiied in synthetic method similar embodiment 25 Adorn the preparation of hypocrellin derivant.
2,17 bit amino substitution product HB-53：Yield is 25.4%, RfFor 0.22；Mass spectrum MS (ESI+):691.2；It is ultraviolet Maximum absorption wavelength：453nm,642nm.
2- bit amino substitution products HB-54：Yield is 14.5%, RfFor 0.45；Mass spectrum MS (ESI+):604.9.It is ultraviolet most Big absorbing wavelength：453nm,622nm.
Shown in the structural formula of described amino substitution product HB-53, HB-54 are schemed：
Embodiment 30
Phenyibutylamine modification hypocrellin B derivatives (R=-CH2CH2CH2CH2C6H5) preparation：Synthetic method is similar real Apply the preparation of hexylamine modification hypocrellin derivant in example 25.
2,17 bit amino substitution product HB-55：Yield is 17.5%, RfFor 0.23；Mass spectrum MS (ESI+):1037.5；It is purple Outer maximum absorption wavelength：452nm,636nm.
2- bit amino substitution products HB-56：Yield is 14.8%, RfFor 0.36；Mass spectrum MS (ESI+):776.3.It is ultraviolet most Big absorbing wavelength：452nm,619nm.
Shown in the structural formula of described amino substitution product HB-55, HB-56 are schemed：
Embodiment 31
2- picoline amido hypocrellin B derivatives (R=-CH2C5H4N preparation)：Synthetic method similar embodiment The preparation of hexylamine modification hypocrellin derivant in 25.
2,17 bit amino substitution product HB-57：Yield is 25.4%, RfFor 0.22；Mass spectrum MS (ESI+):693.2；It is ultraviolet Maximum absorption wavelength：453nm,634nm.
2- bit amino substitution products HB-58：Yield is 14.5%, RfFor 0.45；Mass spectrum MS (ESI+):606.9.It is ultraviolet most Big absorbing wavelength：450nm,622nm.
Shown in the structural formula of described amino substitution product HB-57, HB-58 are schemed：
Embodiment 32
Phenyibutylamine modification deacetylation hypocrellin B derivatives (R=-CH2CH2CH2CH2C5H4N preparation)：Synthesis The preparation of hexylamine modification hypocrellin derivant in method similar embodiment 25.
The products collection efficiency is 17.5%, RfFor 0.23；Mass spectrum MS (ESI+):605.5；Ultraviolet maximum absorption wavelength： 452nm,636nm.(double bond is located at C to the amino substitution product HC-5913=C14) or HC-60 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 33
4- picoline salt fourth amino hypocrellin B derivatives (R=- (CH2)4C5H4N+(C6H11)) preparation：Synthesis side The preparation of hexylamine modification hypocrellin derivant in method similar embodiment 25.
2,17 bit amino substitution product HB-61：Yield is 15.4%, RfFor 0.22；Mass spectrum MS (ESI+):984.2；It is ultraviolet Maximum absorption wavelength：453nm,634nm.
2- bit amino substitution products HB-62：Yield is 14.5%, RfFor 0.45；Mass spectrum MS (ESI+):767.9.It is ultraviolet most Big absorbing wavelength：450nm,622nm.
Shown in the structural formula of described amino substitution product HB-61, HB-62 are schemed：
Embodiment 34
Hypocrelline B hydrazine (R=-NH2) preparation：Hexylamine modification hypocrellin spreads out in synthetic method similar embodiment 25 The preparation of biology.
2,17 bit amino substitution product HB-63：Yield is 25.4%, RfFor 0.28；Mass spectrum MS (ESI+):543.8；It is ultraviolet Maximum absorption wavelength：455nm,640nm.
2- bit amino substitution products HB-64：Yield is 12.6%, RfFor 0.48；Mass spectrum MS (ESI+):529.9.It is ultraviolet most Big absorbing wavelength：448nm,625nm.
Shown in the structural formula of described amino substitution product HB-63, HB-64 are schemed：
Embodiment 35
Deacetylation hypocrelline B hydrazine (R=-NH2) preparation：25 hexylamine of synthetic method similar embodiment modification bamboo is red It is prepared by streptozotocin derivative.
The products collection efficiency is 28.5%, RfFor 0.30；Mass spectrum MS (ESI+):486.8；Ultraviolet maximum absorption wavelength： 456nm,642nm.(double bond is located at C to the amino substitution product HC-6513=C14) or HC-66 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 36
The preparation of hypocrelline B hydrazine (R=-OH)：Hexylamine modification hypocrellin derives in synthetic method similar embodiment 25 The preparation of thing.
2,17 bit amino substitution product HB-67：Yield is 28.6%, RfFor 0.22；Mass spectrum MS (ESI+):545.8；It is ultraviolet Maximum absorption wavelength：452nm,632nm.
2- bit amino substitution products HB-68：Yield is 15.6%, RfFor 0.46；Mass spectrum MS (ESI+):531.9.It is ultraviolet most Big absorbing wavelength：445nm,622nm.
Shown in the structural formula of described amino substitution product HB-67, HB-68 are schemed：
Embodiment 37
The preparation of deacetylation hypocrelline B hydrazine (R=-OH)：Hexylamine modification bamboo is red in synthetic method similar embodiment 25 It is prepared by streptozotocin derivative.
The products collection efficiency is 21.5%, RfFor 0.28；Mass spectrum MS (ESI+):488.8；Ultraviolet maximum absorption wavelength： 452nm,640nm.(double bond is located at C to the amino substitution product HC-6913=C14) or HC-70 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 38
Amine-modified hypocrellin (the R=-C of hexamethylene6H11) preparation：Hexylamine modification bamboo is red in synthetic method similar embodiment 25 It is prepared by streptozotocin derivative.
2,17 bit amino substitution product HB-71：Yield is 58.6%, RfFor 0.58；Mass spectrum MS (ESI+):677.5；It is ultraviolet Maximum absorption wavelength：448nm,626nm.
2- bit amino substitution products HB-72：Yield is 12.6%, RfFor 0.82；Mass spectrum MS (ESI+):596.9.It is ultraviolet most Big absorbing wavelength：446nm,618nm.
Shown in the structural formula of described amino substitution product HB-71, HB-72 are schemed：
Embodiment 39
The amine-modified deacetylation hypocrellin (R=-C of hexamethylene6H11) preparation：Hexylamine in synthetic method similar embodiment 25 Modify the preparation of hypocrellin derivant.
The products collection efficiency is 26.4%, RfFor 0.30；Mass spectrum MS (ESI+):553.8；Ultraviolet maximum absorption wavelength： 450nm,638nm.(double bond is located at C to the amino substitution product HC-7313=C14) or HC-74 (double bond is located at C14=C15) knot Shown in structure formula is schemed：
Embodiment 40
Ring butylamine modification hypocrellin (R=-C4H7) preparation：Hexylamine modification bamboo is red in synthetic method similar embodiment 25 It is prepared by streptozotocin derivative.
2,17 bit amino substitution product HB-75：Yield is 35.6%, RfFor 0.52；Mass spectrum MS (ESI+):621.5；It is ultraviolet Maximum absorption wavelength：450nm,630nm.
2- bit amino substitution products HB-76：Yield is 15.6%, RfFor 0.80；Mass spectrum MS (ESI+):568.9.It is ultraviolet most Big absorbing wavelength：448nm,622nm.
Shown in the structural formula of described amino substitution product HB-75, HB-76 are schemed：
Embodiment 41
Cyclopentamine modification hypocrellin (R=-C5H9) preparation：Hexylamine modification bamboo is red in synthetic method similar embodiment 25 It is prepared by streptozotocin derivative.
2,17 bit amino substitution product HB-77：Yield is 25.8%, RfFor 0.56；Mass spectrum MS (ESI+):649.5；It is ultraviolet Maximum absorption wavelength：452nm,632nm.
2- bit amino substitution products HB-78：Yield is 10.2%, RfFor 0.85；Mass spectrum MS (ESI+):581.9.It is ultraviolet most Big absorbing wavelength：450nm,625nm.
Shown in the structural formula of described amino substitution product HB-77, HB-78 are schemed：
Embodiment 42
Amine-modified hypocrellin (the R=-C of cycloheptyl5H9) preparation：Hexylamine modification bamboo is red in synthetic method similar embodiment 25 It is prepared by streptozotocin derivative.
2,17 bit amino substitution product HB-79：Yield is 28.1%, RfFor 0.58；Mass spectrum MS (ESI+):705.5；It is ultraviolet Maximum absorption wavelength：454nm,634nm.
2- bit amino substitution products HB-80：Yield is 15.0%, RfFor 0.75；Mass spectrum MS (ESI+):610.2.It is ultraviolet most Big absorbing wavelength：452nm,627nm.
Shown in the structural formula of described amino substitution product HB-79, HB-80 are schemed：
Embodiment 43
P-methyl-cyclohexylamine modification hypocrellin (R=-C6H10CH3) preparation：In synthetic method similar embodiment 25 oneself The preparation of amine-modified hypocrellin derivant.
2,17 bit amino substitution product HB-81：Yield is 46.6%, RfFor 0.52；Mass spectrum MS (ESI+):705.5；It is ultraviolet Maximum absorption wavelength：450nm,628nm.
2- bit amino substitution products HB-82：Yield is 10.1%, RfFor 0.80；Mass spectrum MS (ESI+):610.4.It is ultraviolet most Big absorbing wavelength：448nm,621nm.
Shown in the structural formula of described amino substitution product HB-81, HB-82 are schemed：
Embodiment 44
4- amino piperidines modification hypocrellin (R=-C5H10N preparation)：Hexylamine is repaiied in synthetic method similar embodiment 25 Adorn the preparation of hypocrellin derivant.
2,17 bit amino substitution product HB-83：Yield is 26.5%, RfFor 0.50；Mass spectrum MS (ESI+):679.5；It is ultraviolet Maximum absorption wavelength：452nm,630nm.
2- bit amino substitution products HB-84：Yield is 20.1%, RfFor 0.82；Mass spectrum MS (ESI+):597.4.It is ultraviolet most Big absorbing wavelength：450nm,625nm.
Shown in the structural formula of described amino substitution product HB-81, HB-82 are schemed：
Embodiment 45
3- butylene ammonia modification hypocrellin (R=-C4H7) preparation：Hexylamine modifies bamboo in synthetic method similar embodiment 25 The preparation of red streptozotocin derivative.
2,17 bit amino substitution product HB-85：Yield is 16.5%, RfFor 0.52；Mass spectrum MS (ESI+):621.7；It is ultraviolet Maximum absorption wavelength：450nm,632nm.
2- bit amino substitution products HB-86：Yield is 28.1%, RfFor 0.84；Mass spectrum MS (ESI+):568.9.It is ultraviolet most Big absorbing wavelength：451nm,628nm.
Shown in the structural formula of described amino substitution product HB-85, HB-86 are schemed：
Embodiment 46
N, N- dimethyl-N-certain herbaceous plants with big flowers base ammonium-second diaminourea deacetylation hypocrelline B (R=-CH2CH2-N+(CH3)2 (C10H21)) preparation, its synthetic route is as shown in Figure 4：
Long chain quaternary ammonium salt derivative S3 prepared by deacetylation hypocrellin HC (100mg, 0.18mmol) and embodiment 3 (224mg, 0.72mmol) is dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, 50 DEG C is heated under nitrogen protection, lucifuge stirring 10h is reacted, after completion of the reaction, revolving removes solvent.Black-and-blue solid residue 200mL dichloromethane dissolves, and uses successively 50mL diluted hydrochloric acid aqueous solutions washed once, distilled water washes twice, and organic layer is hanged with anhydrous magnesium sulfate drying, filtering, organic phase It is dry to obtain crude product.Gained crude product is further separated with silica gel plate chromatography, and solvent is acetone：Ethyl acetate：Ethanol：Diethyl Amine (volume ratio 20:1:1:3) two kinds of black-and-blue solid products, are respectively obtained.Products therefrom yield is 24.2%, RfFor 0.37；Mass spectrum MS (ESI+):684.5；Ultraviolet maximum absorption wavelength：453nm,630nm.The amino substitution product HC-87 is (double Key mapping is in C13=C14) or HC-88 (double bond is located at C14=C15) structural formula scheme shown in：
Embodiment 47
12 alkylammoniums of N, N- dimethyl-N-- butanediamine amino hypocrelline B (R=-CH2CH2CH2CH2-N+(CH3)2 (C12H23)) preparation：The preparation of the hypocrellin derivant containing quaternary ammonium salt in synthetic method similar embodiment 46.
Products therefrom 2- bit amino substitution products yield is 15.4%, RfFor 0.36.Characterize data is as follows：MS(ESI+): 739.5；Ultraviolet maximum absorption wavelength：462nm,624nm.(double bond is located at C to the amino substitution product HC-8913=C14) or (double bond is located at C to HC-9014=C15) structural formula as shown in the figure：
Embodiment 48
Two amido hypocrelline B (R=- (CH of N, N, N- trimethyl ammonium-certain herbaceous plants with big flowers2)10-N+(CH3)3) preparation：Synthetic method The preparation of the hypocrellin derivant containing quaternary ammonium salt in similar embodiment 46.
Gained 2- bit amino substitution products yield is 8.8%, RfFor 0.35.Characterize data is as follows：MS(ESI+):791.2； Ultraviolet maximum absorption wavelength：464nm,626nm.(double bond is located at C to the amino substitution product HC-9113=C14) or HC-92 it is (double Key mapping is in C14=C15) structural formula as shown in the figure：
Embodiment 49
N, N- dimethyl-N-certain herbaceous plants with big flowers base condensed ethandiol amino hypocrelline B (R=- (CH2CH2OCH2CH2OCH2CH2-N+ (CH3)2(C10H21)) preparation：The preparation of the hypocrellin derivant containing quaternary ammonium salt in synthetic method similar embodiment 46.
Gained 2- bit amino substitution products yield is 15.5%, RfFor 0.28.Characterize data is as follows：MS(ESI+): 771.2；Ultraviolet maximum absorption wavelength：462nm,628nm.(double bond is located at C to the amino substitution product HC-9313=C14) or (double bond is located at C to HC-9414=C15) structural formula as shown in the figure：
Embodiment 50
The preparation of piperazine and deacetylation hypocrellin：By deacetylation hypocrellin HC (100mg, 0.20mmol) and second Diamines (421mg, 2mmol) is dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, is heated to 45 DEG C under nitrogen protection, lucifuge is stirred Reaction 6h is mixed, after completion of the reaction, revolving removes solvent.Black-and-blue solid residue 100mL dichloromethane dissolves, dilute with 50mL Aqueous hydrochloric acid solution washs three times, then is washed with distilled water once, and organic layer is hanged dry with anhydrous magnesium sulfate drying, filtering, organic phase Obtain crude product.Gained crude product is further separated with silica gel plate chromatography, and solvent is acetone：Ethyl acetate：Ethanol：Diethylamine (volume ratio 20：1：1：1) black-and-blue solid product, yield 49.8%, R, are obtainedfFor 0.45.Characterization of The Products data are such as Under：ESI MS：m/z,497.3.Ultraviolet maximum absorption wavelength：462nm,650nm.The structural formula of the product is respectively such as formula HC- Shown in 95：
Embodiment 51
The preparation of methyl piperazine and deacetylation hypocrelline B：Preparation method is similar to piperazine and de- second in embodiment 50 The preparation of acyl group hypocrellin.Yield is 59.8%, RfFor 0.60.Characterization of The Products data are as follows：ESI MS：m/z,511.3.It is purple Outer maximum absorption wavelength：465nm,652nm.The structural formula of the product is respectively as shown in formula HC-96 or HC-97：
Embodiment 52
The preparation of lupetazin and hypocrelline B：By hypocrelline B HB (100mg, 0.18mmol) and dimethyl second Diamines (421mg, 2mmol) is dissolved in 20mL anhydrous acetonitriles, after being sufficiently mixed, is heated to 45 DEG C under nitrogen protection, lucifuge is stirred Reaction 6h is mixed, after completion of the reaction, revolving removes solvent.Black-and-blue solid residue 100mL dichloromethane dissolves, dilute with 50mL Aqueous hydrochloric acid solution washs three times, then is washed with distilled water once, and organic layer is hanged dry with anhydrous magnesium sulfate drying, filtering, organic phase Obtain crude product.Gained crude product is further separated with silica gel plate chromatography, and solvent is acetone：Ethyl acetate：Ethanol：Diethylamine (volume ratio 20：1：1：1) black-and-blue solid product, yield 19.8%, R, are obtainedfFor 0.45.Characterization of The Products data are such as Under：ESI MS：m/z,569.3.Ultraviolet maximum absorption wavelength：462nm,650nm.The structural formula of the product is respectively such as formula HB- Shown in 98 or HB-99：
Embodiment 53
The preparation of diethyl piperazine and hypocrelline B：Lupetazin and the red bacterium of bamboo in synthetic method similar embodiment 52 The preparation of B prime.Yield is 18.8%, Rf 0.38.Characterization of The Products data are as follows：ESI MS：m/z,596.8.Ultraviolet maximum suction Receive wavelength：465nm,655nm.The structural formula of the product is respectively as shown in formula HB-99 or HB-100：
Embodiment 54
The preparation of dipropyl piperazine and hypocrelline B：Lupetazin and the red bacterium of bamboo in synthetic method similar embodiment 52 The preparation of B prime.Yield is 21.2%, Rf 0.35.Characterization of The Products data are as follows：ESI MS：m/z,596.8.Ultraviolet maximum suction Receive wavelength：462nm,652nm.The structural formula of the product is respectively as shown in formula HB-101 or HB-102：
Embodiment 55
The preparation of dibutyl piperazine and hypocrelline B：Lupetazin and the red bacterium of bamboo in synthetic method similar embodiment 52 The preparation of B prime.Yield is 21.5%, Rf 0.38.Characterization of The Products data are as follows：ESI MS：m/z,609.8.Ultraviolet maximum suction Receive wavelength：468nm,657nm.The structural formula of the product is respectively as shown in formula HC-103 or HC-104：
Embodiment 56
The preparation of dibutyl piperazine and hypocrelline B：Lupetazin and the red bacterium of bamboo in synthetic method similar embodiment 52 The preparation of B prime.Yield is 18.8%, Rf 0.38.Characterization of The Products data are as follows：ESI MS：m/z,665.8.Ultraviolet maximum suction Receive wavelength：465nm,655nm.The structural formula of the product is respectively as shown in formula HC-105 or HC-106：
Embodiment 57
The preparation of tri methyl piperazine and hypocrelline B：Lupetazin and the red bacterium of bamboo in synthetic method similar embodiment 52 The preparation of B prime.Yield is 23.4%, Rf 0.48.Characterization of The Products data are as follows：ESI MS：m/z,569.3.Ultraviolet maximum suction Receive wavelength：464nm,652nm.The structural formula of the product is respectively as shown in formula HB-107 or HB-108：
Embodiment 58
The preparation of dibutyl-methyl piperazine and hypocrelline B：Lupetazin is simultaneously in synthetic method similar embodiment 52 The preparation of hypocrelline B.Yield is 18.8%, Rf 0.38.Characterization of The Products data are as follows：ESI MS：m/z,596.8.It is ultraviolet Maximum absorption wavelength：465nm,655nm.The structural formula of the product is respectively as shown in formula HB-109 or HB-110：
Embodiment 59
The preparation of dihexyl-methyl piperazine and hypocrelline B：Lupetazin is simultaneously in synthetic method similar embodiment 52 The preparation of hypocrelline B.Yield is 18.8%, Rf 0.38.Characterization of The Products data are as follows：ESI MS：m/z,596.8.It is ultraviolet Maximum absorption wavelength：465nm,655nm.The structural formula of the product is respectively as shown in formula HB-111 or HB-112：
Embodiment 60
The preparation of dimethyl-hydroxyethyl piperazine and hypocrelline B：Lupetazin in synthetic method similar embodiment 52 And the preparation of hypocrelline B.Yield is 12.5%, Rf 0.35.Characterization of The Products data are as follows：ESI MS：m/z,611.6.It is purple Outer maximum absorption wavelength：463nm,652nm.The structural formula of the product is respectively as shown in formula HB-113 or HB-114：
Embodiment 61
The preparation of dimethyl-diethylene glycol base piperazine and hypocrelline B：Dimethyl in synthetic method similar embodiment 52 The preparation of piperazine and hypocrelline B.Yield is 13.8%, Rf 0.40.Characterization of The Products data are as follows：ESI MS：m/z, 655.6.Ultraviolet maximum absorption wavelength：460nm,655nm.The structural formula of the product is respectively such as formula HB-115 or HB-116 institutes Show：
Embodiment 62
The preparation of dimethyl-triethylene glycol base piperazine and hypocrelline B：Dimethyl in synthetic method similar embodiment 52 The preparation of piperazine and hypocrelline B.Yield is 8.5%, Rf 0.45.Characterization of The Products data are as follows：ESI MS：m/z, 699.1.Ultraviolet maximum absorption wavelength：462nm,658nm.The structural formula of the product is respectively such as formula HB-117 or HB-118 institutes Show：
Embodiment 63
The preparation of dimethyl-triethylene glycol base piperazine and hypocrelline B：Dimethyl in synthetic method similar embodiment 52 The preparation of piperazine and hypocrelline B.Yield is 8.5%, Rf 0.45.Characterization of The Products data are as follows：ESI MS：m/z, 745.5.Ultraviolet maximum absorption wavelength：462nm,658nm.The structural formula of the product is respectively such as formula HB-119 or HB-120 institutes Show：
Embodiment 64
The preparation of dihydroxy ethyl piperazine and hypocrelline B：
Hypocrelline B HB (100mg, 0.18mmol) and dihydroxy ethyl ethylenediamine (421mg, 2mmol) are dissolved in 20mL In anhydrous acetonitrile, after being sufficiently mixed, 45 DEG C are heated under nitrogen protection, lucifuge stirring reaction 6h, after completion of the reaction, revolving removes Solvent.Black-and-blue solid residue with 100mL dichloromethane dissolve, wash three times with 50mL diluted hydrochloric acid aqueous solutions, then with distill Once, organic layer is with anhydrous magnesium sulfate is dry, filtering, organic phase hang and dry obtain crude product for water washing.Gained crude product silica gel plate Chromatography further separates, and solvent is acetone：Ethyl acetate：Ethanol：Diethylamine (volume ratio 20：1：1：1) blue-black, is obtained Color obtains solid product, yield 18.5%, RfFor 0.21.Characterization of The Products data are as follows：ESI MS：m/z,583.5.Ultraviolet maximum Absorbing wavelength：463nm,650nm.The structural formula of the product is respectively as shown in formula HB-121 and HB-122：
Embodiment 65
The preparation of dihexyl-hydroxyethyl piperazine and hypocrelline B：Dihydroxy ethyl piperazine in synthetic method similar embodiment 64 The preparation of piperazine and hypocrelline B.Yield is 25.5%, Rf 0.41.Characterization of The Products data are as follows：ESI MS：m/z,596.8. Ultraviolet maximum absorption wavelength：468nm,652nm.The structural formula of the product is respectively as shown in formula HB-123 and HB-124：
Embodiment 66
DABACO quaternary ammonium salts modify the preparation of hypocrellin B derivatives：Contain quaternary ammonium salt in synthetic method similar embodiment 46 The preparation of hypocrellin derivant.2,17 bit amino substitution product HB-125：Yield is 12.4%, RfFor 0.28；Mass spectrum MS (ESI+):941.2；Ultraviolet maximum absorption wavelength：455nm,635nm.2- bit amino substitution products HB-126：Yield is 16.5%, RfFor 0.48；Mass spectrum MS (ESI+):746.9.Ultraviolet maximum absorption wavelength：451nm,624nm.The amino substitution Shown in the structural formula of product HB-125, HB-126 are schemed：
Embodiment 67
Cell dark toxicity is tested：
By Trypsin Induced of the Hela cells of culture with 0.25%, piping and druming, single cell suspension is made, adjusts cell number About 2x104A/mL, is seeded in 96 well culture plates per hole 200uL and is placed in 37 DEG C and contains 5%CO2Incubator in cultivate.Treat cell Supernatant discarding nutrient solution after adherent, strictly empirically design adds the photosensitizer (haematoporphyrin of various concentrations under conditions of lucifuge Derivative HpD, hypocrelline B HB, the red bacterium derivative HB-1 of bamboo), it is placed in 37 DEG C and contains 5%CO2Incubator in continue culture and incubate Educate 1 it is small when.With the survival rate of mtt assay detection cell.Addition 20uL MTT (being prepared with PBS, concentration 5mg/m1) in per hole, 37 DEG C contain 5%CO2Incubator in continue culture 4 it is small when after terminate culture, it is careful to inhale the supernatant abandoned in hole, then per Kong Zhongjia Enter 150uL dimethyl sulfoxide (DMSO)s (DMSO), shaken 10 minutes with micro vibrator, purple crystal thing is fully dissolved.Select 570nm Wavelength, detects the OD value (OD values) in each hole in microplate reader, and cell survival rate is calculated according to the following formula：Cell survival rate =experimental group OD values/blank group OD value × 100%.Dark toxicity figure is shown in figure loa.
Embodiment 68
Cell phototoxicity experiments：
By the Hela cells of culture with 0.25% Trypsin Induced, piping and druming, is made single cell suspension, adjusts cell number About 2x104A/mL, is seeded in 96 well culture plates per hole 200uL and is placed in 37 DEG C and contains 5%CO2Incubator in cultivate.Treat cell Supernatant discarding nutrient solution after adherent, strictly empirically (haematoporphyrin spreads out design addition various concentrations photosensitizer under conditions of lucifuge Biological HpD, hypocrelline B HB, the red bacterium derivative HB-1 of bamboo), it is placed in 37 DEG C and contains 5%CO2Incubator in continue culture be incubated 1 it is small when.Then it is irradiated using wavelength 635nm semiconductor lasers, adjustment power density is 20mW/cm2, with making homogenizer Vertical irradiation is on 96 well culture plates, irradiation time 1000S, while every piece of 96 well culture plates are all provided with blank group, each condition If 6 holes.Irradiation is placed on 37 DEG C and contains 5%CO2Incubator in continue culture be incubated 24 it is small when, then detect cell survival rate. With the survival rate of mtt assay detection cell.20uL MTT (being prepared with PBS, concentration 5mg/m1) are added in per hole, 37 DEG C contain 5% CO2Incubator in continue culture 4 it is small when after terminate culture, it is careful to inhale the supernatant abandoned in hole, then per hole in add 150uL Dimethyl sulfoxide (DMSO) (DMSO), is shaken 10 minutes with micro vibrator, purple crystal thing is fully dissolved.570nm wavelength is selected, The OD value (OD values) in each hole is detected in microplate reader, cell survival rate is calculated according to the following formula：Cell survival rate=experiment Group OD values/blank group OD value × 100%.Phototoxicity figure is shown in figure 10b.
Comparative example 1
The structural formula of unmodified hypocrelline B (HB) as shown in fig. 6, absorption spectrum as shown in Figure 7a, its maximum is inhaled Wavelength is received in 450nm, has weak absorbing at red light absorption 590nm in addition.Hypocrelline B is inhaled at phototherapy window 600-900nm Light ability is weaker, it is used for optical dynamic therapy, and light power kills the ability of tumour cell than the amphiphilic bamboo of ester water in the present invention Red streptozotocin derivative effect is (Figure 10-14) far short of what is expected.
Comparative example 2
N, N- dimethyl-N-Kui Ji hexamethylene diamine salt -2,17- diaminourea hypocrelline B S25, substitute at the same time at 2,17； But it is all hydrophobic structure that the whole molecule of the hypocrellin derivant is most of, hydrophilic segment is mainly quaternary ammonium salt, therefore it is adjusted The effect of hydrophobe property is saved not as the amphiphilic hypocrellin derivant of ester water containing condensed ethandiol in the present invention.
Conclusion：The amphiphilic hypocrellin derivant of ester water produced by the present invention, using condensed ethandiol group or with long-chain The group such as quaternary ammonium salt modify hypocrellin, by adjusting the hydrophobe property of molecule, there is the analog derivative different Fat water is amphiphilic, while improves the biological compatibility with cell or tissue.Hypocrellin derivant can all be made by lacking any substitution Effect have different degrees of decrease in some aspects.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is every to belong to this hair Row of the obvious changes or variations that bright technical solution is extended out still in protection scope of the present invention.

Claims (8)

1. a kind of amphiphilic hypocrellin derivant of ester water, it is characterised in that the general structure of the derivative is formula (1) or formula (2)：
Formula (1) is the substituent R of piperazine and hypocrellin derivant, the piperazine and hypocrellin derivant1For H or-COCH3； The R1For H when, double bond is located at the C marked in formula (1)13、C14、C15The C of three carbon atoms13=C14Or C14=C15；It is described R1For-COCH3When, double bond is located at the C marked in formula (1)13、C14、C15The C of three carbon atoms13=C14；
The substituent R of formula (2) described hypocrellin derivant1For H ,-COCH3Or-C (CH3)=N-R；The R1For H when, double bond The C marked in formula (2)13、C14、C15The C of three carbon atoms13=C14Or C14=C15；The R1For-COCH3Or-C (CH3During)=N-R, double bond is located at the C marked in formula (2)13、C14、C15The C of three carbon atoms13=C14；
Hypocrellin described in formula (1) and the R in pyridine ring2-R7It is subordinated to substituent R；The substituent R for hydrophobic grouping, The various combination of hydrophilic radical or hydrophobic grouping and hydrophilic radical；The hydrophobic grouping containing alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl group, cycloalkynyl radical, phenyl or heterocyclic radical；The hydrophilic radical hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulfonic group, Condensed ethandiol base, quaternary ammonium salt or pyridiniujm；Shown in the general structure of the substituent R such as formula (3)：
In formula (3), 0≤m≤12,0≤n≤500,0≤p≤12,0≤q≤12；Described m, n, p, q are zero or positive integer；Y is Linking group；Z is end group；(OCH2CH2)nFor polyethylene glycol unit；
Linking group Y is NH, O, S, carboxylate, acid amides, sulphur carboxylic ester, aryl, heterocyclic aryl, the hydrocarbon of 3-12 carbon atoms in formula (3) The cyclic hydrocarbon radical of base or 3-12 carbon atoms；
The aryl is substituted or non-substituted aryl；Heterocyclic aryl is substituted or non-substituted heterocyclic aryl；3-12 carbon atoms Alkyl include substituted or non-substituted or contain heteroatomic alkene or alkynes；The cyclic hydrocarbon radical of 3-12 carbon atoms includes substitution or non- Substitute or containing heteroatomic cycloalkane, cycloolefin or cycloalkyne, the hetero atom is oxygen, nitrogen or sulphur atom；The substituent Alkynyl, 3-8 carbon for halogen, hydroxyl, the alkyl of 1-12 carbon atoms, the alkenyl of 2-12 carbon atom, 2-12 carbon atom is former The cycloalkyl of son, the aralkyl of aryl or 6-12 carbon atoms；Either end group contains hydroxyl, carboxylic acid group, sulfonic group or carboxylate Alkyl；Or alkyl, alkenyl, alkynyl, cycloalkyl, virtue containing hetero atom for the 1-12 carbon atom chain lengths of oxygen, nitrogen or sulphur atom Base or aralkyl；The either various combination of above-mentioned substituent；
End group Z is alkoxy, phenyl, heterocycle, hydroxyl, the mercapto of hydrogen, the alkyl of 1-12 carbon atoms, 1-12 carbon atom in formula (3) Base, carboxylic acid group, sulfonic group, quaternary ammonium salt or pyridiniujm；
When the end group Z is quaternary ammonium salt, three substituents are independently or at the same time on the quaternary ammonium salt：The alkane of 1-12 carbon atoms Base, the alkenyl of 2-12 carbon atom, the alkynyl of 2-12 carbon atom, the cycloalkyl of 3-8 carbon atom, the ring of 3-8 carbon atom The aralkyl of alkenyl, aryl or 6-12 carbon atoms；Either end group contains the alkyl of hydroxyl, carboxylic acid group, sulfonic group or carboxylate； Or alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl containing hetero atom for the 1-12 carbon atom chain lengths of oxygen, nitrogen or sulphur atom Base；The either various combination of above-mentioned substituent；Anion in quaternary ammonium salt is the permitted anion of pharmaceutical preparation；
When the end group Z is pyridiniujm, the substituent in the pyridiniujm on pyridine ring is in ortho position, meta or para position；Pyridiniujm It is by pyridine and the carbon atom containing 1-12 of different chain length halogenated hydrocarbons is quaternized forms；Anion in pyridiniujm is pharmaceutical preparation institute The anion of permission；
Formula (1) described substituent R1For-COCH3, double bond be located at C13=C14When, formula (1) mark piperazine ring on two carbon originals of a, b At least one son is tertiary carbon atom；Formula (1) described substituent R1It is located at C for H, double bond14=C15When, the piperazine ring of formula (1) mark At least one upper two carbon atoms of a, b are tertiary carbon atom；
Formula (2) described R is substituent, and the substituent R is hydrophobic grouping, hydrophilic radical or hydrophobic grouping and hydrophilic radical Various combination；The hydrophobic grouping contains alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, phenyl or heterocycle；The parent Water base hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulfonic group, condensed ethandiol base or quaternary ammonium salt；The substituent R Shown in general structure such as formula (3)；
Formula (2) described substituent R1For-COCH3, double bond be located at C13=C14When, the substituent R in formula (3) does not include following knot Structure：-(CH2)m-NH-(CH2)p-Z；Wherein 1≤m≤12,0≤p≤12, Z are hydroxyl, alkoxy, carboxylic acid or carboxylate；
Formula (2) described double bond is located at C13=C14Position, substituent R1For-COCH3Or-C (CH3During)=N-R, end group in the R general formulas Z does not include quaternary ammonium moiety.
2. a kind of amphipathic hypocrellin derivant of ester water according to claim 1, it is characterised in that the piperazine and bamboo Shown in the general structure of red streptozotocin derivative such as formula (4), (5) or (6)：
In formula (1), the substituent R of piperazine and hypocrellin derivant1It is located at C for H, double bond13=C14During position, its general structure is such as Shown in formula (4)；The substituent R of piperazine and hypocrellin derivant1It is located at C for H, double bond14=C15During position, its general structure such as formula (5) shown in；The substituent R of piperazine and hypocrellin derivant1For-COCH3, double bond be located at C13=C14During position, its general structure As shown in formula (6)；
It is tertiary carbon atom that two carbon atoms of a, b are at least one on the piperazine ring that formula (5) is marked；The piperazine ring that formula (6) is marked At least one upper two carbon atoms of a, b are tertiary carbon atom；
Substituent R in the formula (4), formula (5), formula (6)2-R7It is subordinated to the definition of substituent R in formula (3), substituent R2- R7It is partly or entirely identical or entirely different；Substituent R2-R7For hydrophobic grouping, hydrophilic radical or hydrophobic grouping and hydrophilic The various combination of group；The hydrophobic grouping contains alkyl, alkenyl, alkynyl, cycloalkyl or heterocycle；The hydrophilic radical hydroxyl, Carboxyl, ester group, ether, amide groups, sulfonic group, condensed ethandiol unit or quaternary ammonium salt.
3. a kind of amphiphilic hypocrellin derivant of ester water according to claim 1, it is characterised in that in the formula (2) The general structure of hypocrellin derivant is formula (9)-formula (12)：
In formula (2), the substituent R of hypocrellin derivant1It is located at C for H, double bond13=C14During position, its general structure such as formula (9) It is shown；The substituent R of hypocrellin derivant1It is located at C for H, double bond14=C15During position, shown in its general structure such as formula (10)；Bamboo The substituent R of red streptozotocin derivative1For-COCH3, double bond be located at C13=C14During position, shown in its general structure such as formula (11)；Bamboo is red The substituent R of streptozotocin derivative1For-C (CH3) N=R, double bond be located at C13=C14During position, shown in its general structure such as formula (12)；
In the formula (9)-formula (12) shown in the general structure such as formula (3) of substituent R, the substituent R is hydrophobic grouping, hydrophilic The various combination of group or hydrophobic grouping and hydrophilic radical；The hydrophobic grouping is containing alkyl, alkenyl, alkynyl, cycloalkyl, cyclenes Base, cycloalkynyl radical, phenyl or heterocycle；The hydrophilic radical hydroxyl, carboxyl, ester group, amide groups, carboxylic acid group, sulfonic group, contracting second two Alcohol radical or quaternary ammonium salt；
In the formula (10), formula (11), substituent R does not include with lower structure：-(CH2)m-NH-(CH2)p-Z；Wherein 1≤m≤12, 0≤p≤12, Z are hydroxyl, alkoxy, carboxylic acid or carboxylate；
In the formula (11), formula (12), substituent R does not include the structure of quaternary ammonium salt.
A kind of 4. amphiphilic hypocrellin derivant of ester water according to claim 1, it is characterised in that the substituent R In connector Y be：-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- (pyridine radicals)；- C3H4- (cyclopropyl)；-C4H6- (cyclobutyl)；-C5H8- (cyclopenta)；-C5H7(CH3)-(methylcyclopentyl)；-C5H7(OH)-(hydroxyl Cyclopentyl)；-C6H10- (cyclohexyl)；-C6H9(CH3)-(methylcyclohexyl)；-C6H9(C2H5)-(ethylcyclohexyl)；-C6H9 (C3H7)-(propylcyclohexyl)；-C6H9(C4H9)-(butylcyclohexyl)；-C6H8(CH3)2- (Dimethylcyclohexyl)；-C6H9 (OH)-(hydroxy-cyclohexyl)；-C7H12- (suberyl)；(piperazinyl)；(1,4- diazabicylos [2.2.2] Octyl).
A kind of 5. amphiphilic hypocrellin derivant of ester water according to claim 1, it is characterised in that the substituent R In end group Z be：-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- diazabicylos [2.2.2] octyl)；Either end group contains hydroxyl, carboxylic acid group, sulfonic group Or the quaternary ammonium salt of carboxylate.
6. according to a kind of amphiphilic hypocrellin derivant of ester water described in claim 1, it is characterised in that formula (1) is described Enol tautomer of the general structure of piperazine and hypocrellin derivant shown in also comprising formula (1 ')；Formula (2) described bamboo is red The general structure of streptozotocin derivative is also comprising the enol tautomer shown in formula (2 ')：
7. a kind of preparation method of amphiphilic hypocrellin derivant of ester water as described in claim 1-6 is any, its feature exist In the preparation method includes the following steps：
It is 1 by molar ratio:5~50 hypocrelline B and corresponding substituted amino derivant are mixed in organic solvent, The organic solvent is the one or more in acetonitrile, tetrahydrofuran, pyridine, methanol and ethanol, lucifuge under inert gas shielding Carry out reaction for 6-18 it is small when, the temperature of reaction is 20-100 DEG C, and product is through isolating and purifying, you can the red bacterium of the amphiphilic bamboo of ester water Plain derivative.
8. a kind of amphiphilic hypocrellin derivant of ester water as described in claim 1-6 is any is as the light in optical dynamic therapy The application of quick dose of medicine.
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