CN108264514A - A kind of organic matter and its preparation method and application - Google Patents
A kind of organic matter and its preparation method and application Download PDFInfo
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- CN108264514A CN108264514A CN201611257470.1A CN201611257470A CN108264514A CN 108264514 A CN108264514 A CN 108264514A CN 201611257470 A CN201611257470 A CN 201611257470A CN 108264514 A CN108264514 A CN 108264514A
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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Abstract
The present invention provides a kind of organic matters, have Formulas I structure.Organic matter provided by the invention includes near-infrared fluorescent regiment headquarters point and efficient photosensitizing moiety with cancer target effect, the two bonding connection.This organic matter can be targeted in tumor locus to be accumulated, and pass through near-infrared living imaging and accurately detect knub position, after the organic matter reaches tumour, it is restored at bonding by thiol molecule high-caliber in tumour cell, releases photosensitizer, pass through laser irradiation, active oxygen is released, kills cancer cell.Organic matter provided by the invention has targeting, near-infrared fluorescence imaging and optical dynamic therapy effect simultaneously.The experimental results showed that organic matter provided by the invention can carry out targeted imaging and optical dynamic therapy to mouse interior tumor, be it is a kind of integrate tumor imaging, diagnosis, treatment multi-functional organic matter.Preparation method the present invention also provides above-mentioned organic matter and the application in treating cancer drug is prepared.
Description
Technical field
The present invention relates to bio-medical technology fields more particularly to a kind of organic matter and its preparation method and application.
Background technology
For fluorescent spectrometry due to its high sensitivity, selectivity is good, and the information of acquisition is intuitive, accurate, can Scientific Expression explanation
The problems such as structure, distribution, content and the physiological function of complex sample are widely used in terms of bioanalysis and radiography.But
That many organisms and tissue itself can emit fluorescence under the excitation of visible ray, the fluoroscopic examination of severe jamming biological sample and
Radiography, if the fluorescent wavelength ranges of haemocyanin in blood plasma is 325~350nm, reduced nicotinamide adenine dinucleotide phosphorus
The fluorescent wavelength ranges of sour enzyme (NADPH) and bilirubin be 430~470nm so that the sensitivity of visible region fluorescence analysis and
Accuracy receives very big influence.The study found that the fluoroscopic examination of near infrared spectrum than visible region fluoroscopic examination more
Add suitable biological tissue's Angiographic.The basis that living tissue carries out optics radiography is that luminous energy penetrates into organization internal, this
The depth of light infiltration and the wavelength of light are closely related.During using light more than 600nm, the depth of light infiltrating tissues is up to several lis
Rice, tissue that can be bigger to some volumes carries out radiography, so as to carry out medical diagnosis on disease.The maximum of near infrared fluorescent dye is inhaled
It is 600~900nm to receive wavelength and launch wavelength, can avoid background interference.Therefore, near-infrared fluorescent detection is in biological sample analysis
In have apparent superiority.
Modern medicine image technology is made that huge contribution for the development of modern medicine.MRI, CT, spiral CT, PET,
The methods of PET-CT, can obtain the multi-level information of tumor tissues.But the volume of above-mentioned imaging device is generally larger, imaging
Need to complete that (such as MRI needs have very high magnetic field, and PET and CT need have certain radioactivity spoke under given conditions
Penetrate), imaging time is usually in the time of a few minutes to dozens of minutes.These complicated factors determine that above-mentioned technology is difficult to realize
Real-time imaging is imaged to guide oncotherapy.And near-infrared spectroscopy can realize real time imagery, it is fast, clever with image taking speed
The advantages that sensitivity is high, imaging device relative volume is smaller has broad prospect of application in terms of image guides oncotherapy.
Photodynamic therapy is related to two key steps：Control photosensitizer first is formed in tumour cell in selectivity
It gulps down and is detained；Subsequent photosensitizer, which is excited by light, releases active oxygen (ROS) and singlet oxygen, guides apoptosis of tumor cells or bad
Extremely.It is mostly at present organic porphyrin, porphines, phthalocyanines derivates into photosensitizer workable for clinical or clinic, such as
Photofrin (haematoporphyrin), Visudyne (Verteporfin), Levulan (5-ALA), Foscan (Temoporfin, two
Hydrogen porphin photosensitizer), HPPH and ICG etc..
People are higher and higher to cancer diagnosis and the expectation for the treatment of at present, and present research focuses mostly in multifunctional nano medicine
Although the exploitation of objects system, Nano medication system achieve certain achievement, but in terms of safe and reliable and high-efficiency low-toxicity also
There are certain defects, limit its application in terms of clinical diagnosis and treatment.If quantum dot treatment is using inorganic heavy metal material
Material, is easy to be enriched in biological living and is difficult to degrade；To normal cell activity and in vivo, metabolism has very greatly nanogold/Argent grain
It influences, and particle size is affected by environment larger with pattern, considerably reduces its application in tumour diagnosis and treatment field；Nanometer
Carbon material complex distribution and is difficult to degrade in vivo, and there are potential bio-toxicities；The oxidation of magnetic nanoparticle such as four three
The pharmaceutical carrier of stability after the controllability of iron particle size is accurately positioned and is combined with to(for) its targeting has a significant impact；Fat
The size of class/polymer nano granules is difficult to control, and is easy to metabolic degradation in the living body and cancer target effect is poor；It is mesoporous to receive
The metabolic capability of rice material is poor, and the interaction mechanism between the diagnosis and treatment drug and mesoporous material loaded is difficult to analyze,
Influence to diagnosis and treatment process also not yet obtains comprehensively and in-depth study.Nanometer system is really applied to clinical diagnose and treat
It also needs further to study, verify, interaction and influence of the nanometer system on human body cell, tissue, cell, tissue, internal organs layer
The mechanism and mechanism in face, the biocompatibility of nanometer system and its influence to human immune system and the quantization of Nano medication
With standardized production and the problem of can not be ignored.Therefore, the transport of development reorganization drug targeting, vivo tracking, drug therapy and
The functions such as monitoring receive very big concern in the targeting diagnostic and therapeutic system of one more afterwards.Development collection cancer target, tumor imaging, drug
Oncotherapy and the functions such as monitoring are expected to solve the bottleneck that is faced of nano material in the multi-functional organic matter of one more afterwards.
Invention content
In view of this, the purpose of the present invention is to provide a kind of organic matter and its application, organic matter provided by the invention is
It is a kind of integrate tumor imaging, diagnosis, treatment multi-functional organic matter.
The present invention provides a kind of organic matters, have Formulas I structure：
In Formulas I,
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-；
Y is selected from halide ion, BF4 -Or metal cation；
Z is selected from-S- or-Se-；
R' is selected from C1-12Alkylidene；
R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
R5~R15Independently selected from H, phenyl, C1-18Alkyl, the C of halogen substitution1-18Alkyl, C1-18Alkylene, halogen atom
Or benzyl；
N is 1~5.
Preferably, the W is-NH-；R' is selected from C1-12Alkylidene；Z is-S-.
Preferably, the R' is selected from C1-5Alkylidene.
Preferably, the R1And R2Independently selected from C1-5Alkyl.
Preferably, the R3And R4For H.
Preferably, the R5、R6、R8、R9、R11、R12、R14And R15For H.
Preferably, the R7、R10And R13For phenyl.
Preferably, the W is-NH-；Y is Cl-、Br-Or I-；Z is-S-；R1And R2Independently selected from C1-3Alkyl；R3With
R4For H；R5~R15Independently selected from H or phenyl.
Preferably, the organic matter has Formula II structure：
The present invention provides a kind of preparation method of the compound described in above-mentioned technical proposal, including：
Formula A structural compounds and formula B structure compound are reacted, obtain Formulas I structural compounds：
Wherein, R5~R15Independently selected from H, phenyl, C1-18Alkyl, the C of halogen substitution1-18Alkyl, C1-18Alkylene, halogen
Plain atom or benzyl；
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-；
Y is selected from halide ion, BF4Or metal cation；
Z is selected from-S- or-Se-；
R' is selected from C1-12Alkylidene；
R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
N is 1~5.
Preferably, the preparation method of the compound of the formula B structure is：
The compound of the compound of formula C-structure and formula D structures is reacted, obtains the compound of formula B structure；
In formula C, R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
N is 1~5；
Y is selected from halide ion, BF4Or metal cation；
In formula D, R' is selected from C1-12Alkylidene；
Z is selected from-S- or-Se-；
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-.
Preferably, the preparation method of the compound is：
1 structural compounds of formula and 2 structural compounds of formula are reacted, obtain Formula II structural compounds；
Preferably, the reaction carries out in the presence of an activator.
Preferably, the activator is selected from dicyclohexylcarbodiimide, N, N- dimethyl -4- pyridines amine, 1- (3- diformazan ammonia
Base propyl) one or more of -3- ethyl-carbodiimide hydrochlorides (EDC) and n-hydroxysuccinimide (NHS).
Treating cancer medicine is being prepared the present invention provides above-mentioned organic matter or using the organic matter that the above method is prepared
Application in object.
Compared with prior art, organic matter provided by the invention includes the near-infrared fluorescent regiment headquarters with cancer target effect
Divide and efficient photosensitizing moiety, the two bonding connect.This organic matter can be targeted in tumor locus to be accumulated, and pass through near-infrared
Living imaging accurately detects knub position, after the organic matter reaches tumour, by mercaptan high-caliber in tumour cell at bonding
Molecule restores, and releases photosensitizer, by laser irradiation, releases active oxygen, kills cancer cell.Organic matter provided by the invention
There is targeting, near-infrared fluorescence imaging and optical dynamic therapy effect simultaneously.The experimental results showed that organic matter provided by the invention
Targeted imaging and optical dynamic therapy can be carried out to mouse interior tumor, be it is a kind of integrate tumor imaging, diagnosis, treatment it is more
Function organic matter.In addition, organic matter provided by the invention be organic molecule, be readily synthesized, structure clearly, construction of stable, control
System is simple.
Description of the drawings
In order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The embodiment of invention, for those of ordinary skill in the art, without creative efforts, can also basis
The attached drawing of offer obtains other attached drawings.
Fig. 1 is the mass spectrogram of 2 structural compounds of formula prepared by the embodiment of the present invention 2；
Fig. 2 is the mass spectrogram of organic matter prepared by the embodiment of the present invention 2；
Fig. 3 is organic matter cell survival rate test result prepared by the embodiment of the present invention；
Fig. 4 is organic matter prepared by the embodiment of the present invention to the test result of the fluorescence imaging of mouse in-vivo tumour；
Fig. 5 is the test result of organic matter optical dynamic therapy mouse in-vivo tumour prepared by the embodiment of the present invention.
Specific embodiment
Below in conjunction with the attached drawing in the embodiment of the present invention, the technical solution in the embodiment of the present invention is carried out clear, complete
Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, those of ordinary skill in the art are obtained every other without making creative work
Embodiment shall fall within the protection scope of the present invention.
The present invention provides a kind of organic matters, have Formulas I structure：
In Formulas I,
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-, preferably-NH-；
Y is selected from halide ion, BF4Or metal cation, preferably halide ion, BF4-, Na+Or K+, more preferably halogen
Plain ion, more preferably Cl-、Br-Or I-, most preferably I-；
Z is selected from-S- or-Se-, preferably-S-；
R' is selected from C1-12Alkylidene, preferably C1-5Alkylidene, more preferably C1-3Alkylidene, most preferably-
CH2-；
R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3, preferably C1-10Alkyl, more preferably C1-5
Alkyl, more preferably C1-3Alkyl, most preferably methyl；
R3And R4Independently selected from H, C1-18Alkyl or benzyl, preferably H；
R5~R15Independently selected from H, phenyl, C1-18Alkyl, the C of halogen substitution1-18Alkyl, C1-18Alkylene, halogen atom
Or benzyl；Preferably H or phenyl；R5、R6、R8、R9、R11、R12、R14And R15Preferably H；R7、R10And R13Preferably phenyl；
N is 1~5, preferably 1~3, more preferably 1.
In the present invention, the Formulas I is preferably：W is-NH-；Y is Cl-, Br-Or I-；Z is-S-；R1And R2Independently select
From C1-3Alkyl；R3And R4For H；R5~R15Independently selected from H or phenyl.
In the present invention, the organic matter more preferably has Formula II structure：
Near infrared fluorescent dye molecule (Cy.7.Cl) in Formula II structure of the present invention can be with other with cancer target effect
Nir dye molecule replace, intermediate linker cystamines molecule can replace with the short chain molecule of other disulfide bond, photosensitizer
(TPP) it can be replaced with other similar photosensitizers, to prepare the cancer target light power similarly guided with near-infrared fluorescence imaging
Treat small molecule.Other alternative scheme design philosophys and spirit are no different with this programme, are done according to spirit of the invention
Equivalent transformation or modification.
The present invention does not have special limitation to the preparation method of the Formulas I structure organic matter, according to those skilled in the art
The method of well known organic synthesis is prepared.In the present invention, the organic matter of the Formulas I structure is preferably according to following
It is prepared by method：
Formula A structural compounds and formula B structure compound are reacted, obtain Formulas I structural compounds：
R in formula A5~R15With W, Y, Z, R', R in formula B1、R2、R3、R4With the R in n and Formulas I5~R15、W、Y、Z、R'、
R1、R2、R3、R4Consistent with n, details are not described herein.
In the present invention, the preparation method of the compound of formula B structure is preferably：
The compound of the compound of formula C-structure and formula D structures is reacted, obtains the compound of formula B structure；
In the present invention, the preparation method of the compound of Formula II structure is preferably：
1 structural compounds of formula and 2 structural compounds of formula are reacted, obtain Formula II structural compounds；
In the present invention, the formula 1 and 2 structural compounds of formula are preferably reacted in the presence of an activator.In this hair
In bright, the activator is preferably dicyclohexylcarbodiimide, N, and N- dimethyl -4- pyridines amine, 1- (3- dimethylamino-propyls) -
One or more of 3- ethyl-carbodiimide hydrochlorides (EDC) and n-hydroxysuccinimide (NHS), more preferably two hexamethylenes
Base carbodiimide and N, N- dimethyl -4- pyridine amine.In the present invention, dicyclohexylcarbodiimide and N, N- dimethyl -4- pyrroles
The molar ratio of pyridine amine is preferably 1:(0.5~1.5), more preferably 1:(0.8~1.2), most preferably 1:1.
In the present invention, formula 1 and the temperature of 2 structural compounds of formula reaction are preferably 20~30 DEG C.In the present invention, formula 1
Time with the reaction of 2 structural compounds of formula is preferably 2~4 hours, more preferably 3 hours.In the present invention, 2 structure of formula 1 and formula
Compound is preferably reacted under nitrogen protection.
In the present invention, 1 structural compounds of formula are -10,15,2- triphenyl -21H, 23H porphines of 5- (4- carboxy phenyls)
(5-Mono (4-carboxyphenyl) -10,15,20-triphenylporphine, CAS:It 95051-10-8), can be by market
Purchase obtains.In the present invention, 2 structural compounds of formula are preferably prepared by the following method：
3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride are reacted, obtain 2 structural compounds of formula；
In the present invention, it is preferred under catalyst action, 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride in solvent and are helped
It is reacted in solvent, obtains 2 structural compounds of formula.The present invention is preferably by catalyst, 2-aminoethyl disulfide dihydrochloride, solvent and cosolvent
Mixing, obtains mixed liquor；3 structural compounds of formula are dissolved in a solvent, obtain lysate；Obtained lysate is added to mixed
It closes and is reacted in liquid, obtain 2 structural compounds of formula.In the present invention, it is preferred to mixed liquor is obtained under conditions of stirring.At this
In invention, the time of the stirring is preferably 0.5 hour.In the present invention, it is preferred to lysate is added to using dropping funel
In mixed liquor, the addition speed is preferably 1 drop/20s.In the present invention, 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride
The temperature of reaction is preferably 30~40 DEG C, more preferably 35 DEG C.In the present invention, 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride
The time of reaction is preferably 3~5 hours, more preferably 4 hours.In the present invention, 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride
It is preferred that it is reacted under the protection of nitrogen.
The present invention does not have special limitation to the source of 3 structural compounds of formula, using side well known to those skilled in the art
Method is prepared, and can also be bought and obtained by market.In the present invention, the catalyst is preferably triethylamine, pyridine, 4- bis-
Methylamino pyridine (DMAP), N, N- diisopropylethylamine (DIPEA), N, accelerine, sodium carbonate, sodium bicarbonate or acetic acid
Sodium, more preferably triethylamine.In the present invention, the cosolvent is preferably alcohol, more preferably methanol or ethyl alcohol.In the present invention
In, the solvent is preferably acetonitrile, dichloromethane, chloroform or dimethylformamide (DMF), more preferably acetonitrile.At this
In invention, the molar ratio of 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride is preferably 1:(1~1.5), more preferably 1:1.2.
In the present invention, after the completion of 3 structural compounds of formula and 2-aminoethyl disulfide dihydrochloride reaction, the reaction product that will preferably obtain
Rotation uses silica gel column purification after removing solvent, obtains 2 structural compounds of formula.In the present invention, it is molten in the silicagel column purification process
It is preferably dichloromethane or chloroform to solve agent.In the present invention, the silica gel column purification preferably uses wet method loading and gradient
Elution.In the present invention, the eluant, eluent is preferably the mixture of dichloromethane and methanol, preferably from 200:1 to 20:1 carries out
Gradient elution.
In the present invention, the molar ratio of 2 structural compounds of formula 1 and formula is preferably 1:(0.5~1.5), more preferably 1:
(0.8~1.2), most preferably 1:1.In the present invention, the molar ratio of 1 structural compounds of formula and activator is preferably 1:(1.5~
2.5), more preferably 1:2.
In the present invention, after the completion of formula 1 and 2 structural compounds of formula react, solvent preferably is removed into the rotation of obtained reaction product
Afterwards with silica gel column purification, Formula II structural compounds are obtained.In the present invention, the method for the silica gel column purification and above-mentioned technical side
The method of silica gel column purification is consistent described in case, and details are not described herein.
Organic matter described in above-mentioned technical proposal can be applied to prepare the drug for the treatment of cancer.In the present invention, it is described
Organic matter includes a fluorogen with cancer target effect, and fluorogen is near-infrared fluorescent group；It is efficiently photosensitive comprising one
Agent, centre are attached by disulfide bond (- S-S-), and this organic matter can be targeted in tumor locus to be accumulated, can be by near
Infrared living imaging accurately detects knub position；Simultaneously after the organic matter reaches tumour, disulfide bond (- S-S-) is by tumour cell
In the reduction of high-caliber thiol molecule, release photosensitizer, by laser irradiation, release active oxygen, kill cancer cell.This hair
In bright, the organic matter has targeting, near-infrared fluorescence imaging, optical dynamic therapy effect simultaneously, is a kind of collection tumor imaging, examines
The multi-functional organic matter that disconnected, treatment is integrated.Simultaneously as it is rolled into a ball containing near-infrared fluorescent in organic matter provided by the invention
It can be applied to the related fields such as photoacoustic imaging, diseased region imaging and sound dynamic therapy.
Raw material used in following embodiment of the present invention is commercial goods, and 1 structural compounds of formula used are CAS:
95051-10-8, the product identification that lark prestige company provides are the chemical products of M40615.
The preparation of 1 formula of embodiment, 3 structural compounds
2,3,3- dimethyl indole (5mL, 0.031mol) of compound and iodoethane (12,6mL, 0.16mol) are added in
In 50mL single necked round bottom flask, heating reflux reaction generates a large amount of solids in reaction process, monitors reaction end with TLC, about
Stop reaction after 24 hours.Reaction product is cooled to room temperature, then obtained native brown solid is poured out, is washed with dichloromethane
Wash, dry after obtain the solid of light purple powder shape, obtain intermediate product 1 (13.6g, 0.043mol), yield：68%.
The mixed liquor dropping funel of dichloromethane that phosphorus oxychloride (15mL, 0.16mol) and 18mL are dried under ice bath
It is added dropwise in the dichloromethane of 20mL dryings and the mixed liquor of dimethylformamide (DMF) (20mL, 0.26mol) composition, so
Cyclohexanone (5g, 0.051mol) is added dropwise into above-mentioned solution again afterwards, obtains reaction solution.Ice bath is removed, heating reaction solution is extremely
50 DEG C of reflux after reacting about 3 hours, stop reaction, are cooled down with ice-water bath, obtained product is then poured into 150g trash ices in batches
In.(- 20 DEG C) are stood overnight in refrigerator, and yellow orange solid is precipitated, and filter, solid is dried in vacuo, finally obtains intermediate production
Object 2 (2.1g, 0.012mol), yield：23%.
Intermediate product 1 (5g, 16mmol) and intermediate product 2 (1.4g, 8mmol) are added in the three-necked flask of 500mL, so
After add in n-butanol：Toluene (7:3, v/v) 150mL dissolves, bonus point hydrophone (injection toluene solvant) on one of bottleneck, in nitrogen
Under gas shielded, 130 DEG C of back flow reactions are heated to, a large amount of green matters are generated in reaction process, the reaction time is about 10 hours.
Stop reaction, vacuum rotary steam removes solvent, washed with ether, filter to obtain filter cake, is dried in vacuo, and obtains product as green solid i.e.
For 3 structural compounds of formula (4.7g, 7.42mmol), yield：94%.
Embodiment 2
At room temperature, 2-aminoethyl disulfide dihydrochloride (162mg, 0.72mmol), 1.5mL methanol, 416 μ L are added in 25mL round-bottomed flasks
Triethylamine, then add 2mL acetonitriles, quick stir about is after 0.5 hour, solution went clear, and 2-aminoethyl disulfide dihydrochloride all dissolves.Then
3 structural compounds of formula (38.4mg, 0.6mmol) prepared by embodiment 1 are dissolved in 4mL acetonitriles, are added drop-wise to dropping funel
It states in solution, general 1 drop/20s, heats, nitrogen is protected to react 4 hours at 35 DEG C.Solvent is removed into the rotation of obtained reaction product, is used
Silica gel column purification, sample are dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol is from 200:1 to 20:1 gradient
Elution, it is 2 structural compounds of formula (41.2mg, 0.055mmol) that rotation, which goes after solvent concentration to obtain indigo pulverulent solids, production
Rate is：9.1%.
Under ice bath, by 1 structural compounds of formula (5mmol, 3.29g), above-mentioned 2 structural compounds of formula being prepared
(5mmol, 3.77g), dicyclohexylcarbodiimide (5mmol, 1.03g), N, N- dimethyl -4- pyridines amine (5mmol,
It 610.86mg) is added in the round-bottomed flask of 100mL, nitrogen protection reaction 3 hours, stop reaction, the reaction that will be obtained at room temperature
Solvent is removed in product rotation, and with silica gel column purification, sample is dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol from
200:1 to 10:1 gradient elution, rotation go after solvent concentration to obtain cyan powders shape solid be organic matter (5.18g,
3.71mmol), yield：74%.
High resolution mass spectrum detection is carried out to 2 structural compounds of formula being prepared, testing result is as shown in Figure 1：HRMS
(EI)m/z C38H51N4S2 +(M+):577.2666, Found 577.2654, Fig. 1 are 2 structure of formula prepared by the embodiment of the present invention 2
The mass spectrogram of compound.As can be seen that method provided in an embodiment of the present invention can obtain the target product of 2 structure of formula.
High resolution mass spectrum detection is carried out to the organic matter being prepared, testing result is as shown in Figure 2：HRMS(EI)m/z
C83H79N8OS2 +(M+):1267.5813, Found 1267.5803, Fig. 2 are the mass spectrum of organic matter prepared by the embodiment of the present invention 2
Figure.As can be seen that method provided in an embodiment of the present invention can obtain the target product of Formula II structure.
Embodiment 3
At room temperature, 2-aminoethyl disulfide dihydrochloride (324mg, 1.44mmol), 3mL methanol, 832 μ L are added in 50mL round-bottomed flasks
Triethylamine, then add 4mL acetonitriles, quick stir about is after 0.5 hour, solution went clear, and 2-aminoethyl disulfide dihydrochloride all dissolves.Then
3 structural compounds of formula (76.8mg, 1.2mmol) that embodiment 1 is prepared are dissolved in 8mL acetonitriles, are added dropwise with dropping funel
Into above-mentioned solution, general 1 drop/20s, heating, nitrogen is protected to react 4 hours at 35 DEG C.The rotation of obtained reaction product is gone molten
Agent, with silica gel column purification, sample is dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol is from 200:1 to 20:
1 gradient elution, rotation go after solvent concentration to obtain indigo pulverulent solids be 2 structural compounds of formula (78.78mg,
0.105mmol), yield：8.7%.
Under ice bath, by 1 structural compounds of formula (50mmol, 32.94g), 2 structural compounds of formula (50mmol, 37.74g), two
Carbodicyclo hexylimide (50mmol, 10.32g), N, N- dimethyl -4- pyridines amine (50mmol, 6.11g) are added to the circle of 100mL
In the flask of bottom, nitrogen protection reaction 4 hours, stop reaction at room temperature, and the rotation of obtained reaction product is gone solvent, pure with silicagel column
Change, sample is dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol is from 200:1 to 10:1 gradient elution, rotation
It is organic matter (43.27g, 31.00mmol) to remove after solvent concentration to obtain cyan powders shape solid, yield：62.01%.
Embodiment 4
At room temperature, the addition 2-aminoethyl disulfide dihydrochloride (162mg, 0.72mmol) in 25mL round-bottomed flasks, 1.5mL methanol, 416
μ L triethylamines, then add 2mL acetonitriles, quick stir about is after 3 hours, solution went clear, and 2-aminoethyl disulfide dihydrochloride all dissolves.Then
3 structural compounds of formula (38.4mg, 0.6mmol) prepared by embodiment 1 are dissolved in 4mL acetonitriles, are added drop-wise to dropping funel
It states in solution, general 1 drop/20s, heats, nitrogen is protected to react 6 hours at 40 DEG C.Solvent is removed into the rotation of obtained reaction product, is used
Silica gel column purification, sample are dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol is from 200:1 to 20:1 gradient
Elution, rotation obtain the compound (95.98mg, 0.13mmol) that indigo pulverulent solids are 2 structure of formula after removing solvent concentration,
Yield：10.6%.
Under ice bath, by the compound (100mmol, 3.29g) of 1 structure of formula, the above-mentioned compound of 2 structure of formula being prepared
(100mmol, 3.77g), dicyclohexylcarbodiimide (100mmol, 1.03g), N, N- dimethyl -4- pyridines amine (100mmol,
It 610.86mg) is added in the round-bottomed flask of 1000mL, at room temperature nitrogen protection reaction 10 hours, stops reaction, it is anti-by what is obtained
Product rotation is answered to remove solvent, with silica gel column purification, sample is dissolved with dichloromethane, wet method loading, eluant, eluent dichloromethane：Methanol
From 200:1 to 10:1 gradient elution, rotation go after solvent concentration to obtain cyan powders shape solid be organic matter (74.38g,
53.30mmol), yield：53.30%.
Cell survival rate under the different organic concentrations of embodiment 5
The Hela cells of logarithmic phase growth are collected, individual cells suspension is made into culture solution is obtained containing 10% tire calf serum,
Per 100 μ L of hole, on 96 orifice plate upper berth, 6 row × 7 arrange, and cell concentration is 5000/ hole (remaining edge hole fills sterile PBS).It is placed on
37 DEG C, 5%CO2Cell incubator in cultivate, until cell monolayer is paved with bottom hole.Add in the probe organic matter of 7 groups of various concentrations
Molecule (embodiment 1 is prepared)：0.1st, 2,10,30,60,80,100 μM, every group sets 5 multiple holes, and masking foil package is placed on thin
It is cultivated 1 day or so in born of the same parents' incubator and 96 orifice plates is taken out after cell adherent growth, suck supernatant, added in PBS and gently wash, then
Suck supernatant.Fresh 180 μ L of RPMI 1640 culture mediums are added in per hole, add 20 μ of MTT solution of the 5mg/mL prepared in advance
L continues to be placed on 37 DEG C, 5%CO2Cell incubator in culture 4h after carefully suck liquid in hole.150 μ L are added in per hole
DMSO, 5~15min of low-speed oscillation on shaking table, Shi formazans fully dissolve.Simultaneously set control wells (refinement born of the same parents, culture medium,
MTT, dimethyl sulfoxide (DMSO)), zeroing hole (adds culture medium, MTT, dimethyl sulfoxide (DMSO)).Finally, at enzyme-linked immunosorbent assay instrument 490nm
The light absorption value in each hole is measured, records the testing result per hole, cell survival rate is calculated, with a concentration of horizontal stroke of probe organic molecule
Axis is drawn a diagram by the longitudinal axis of cell survival rate, observes the toxicity of probe, and testing result is as shown in figure 3, Fig. 3 is real for the present invention
The organic matter cell survival rate test result of example preparation is applied, from the figure 3, it may be seen that when probe molecule concentration is up to 100 μM, Hela is thin
The survival rate of born of the same parents still be up to 70%, illustrate that probe molecule cytotoxicity is very low, this advantage allow its deeper into should
For biological field..
6 organic matter of embodiment is to the fluorescence imaging of mouse in-vivo tumour
In living imaging experiment, big using 6~8 weeks bought by Shenzhen Xianjin Technology Academe of Chinese Academy of Sciences animal center
For homotype combination female BAl BIc/C nude mices as experimental subjects, weight is naked with the animal isolator raising of shielding between 15~20g
Mouse, temperature control is at about 28 DEG C, and humid control 40% or so, in strict accordance with the feeding standard of nude mice raised by feeding standard
It supports.The cell transplanted is MCF7 (human breast cancer cell).
It cultivates MCF7 cells and (with the DMEM culture mediums containing 10% fetal calf serum, is placed on 37 DEG C, 5%CO2Cell incubator
Middle culture), the MCF7 cells grown in logarithmic phase are taken, are digested with 0.25% trypsase (0.25%), in digestion gently
Culture dish is shaken, when visually seeing that cell comes off in bulk, at once plus DMEM and 10%FBS terminates digestion, blows and beats, centrifugation,
Supernatant is abandoned, physiological saline is added in, shakes up, 20 μ L is taken to look into number under an optical microscope, calculates the cell concentration in suspension, and with this
Corresponding extension rate is calculated, then adds physiological saline by cell liquid concentration dilution to 2 × 106A/0.2mL, is placed in ice chest
It preserves.It is sterilized with 75% alcohol to mouse skin, in the abdomen face in-situ injection transplanting 2 × 10 of nude mice6A MCF7 cells, three days
The line of apsides of the weight of record mouse and tumour daily afterwards, whole tumours are grown and accessible fixed hard tumour after 1 week
Tubercle, the knurl line of apsides is 1~2cm or so after 3~4 weeks, and experiment modeling is successful.
With yellow Jackets, (a concentration of 1%) intraperitoneal anesthesia is into knurl mouse (50mg/kg dosage).By the mouse after stupor
It is put into small animal living body imaging system rapidly to take pictures, obtains picture before cancer target label.Later, by organic solution
(embodiment 1 is prepared) is injected intravenously by tail bone in injection mouse body (dosage 0.2mg/kg).By 0~for 24 hours after,
The different periods carries out optical imaging experiments with small animal imaging instrument, and different time carries out imaging observation.Living imaging process
In, excitation light source be 615nm~665nm feux rouges, collected in the range of 680nm~800nm, setting the time for exposure be
400msec.Testing result as shown in figure 4, the organic matter that Fig. 4, which is the embodiment of the present invention, to be prepared to the fluorescence of mouse in-vivo tumour into
The test result of picture, as shown in Figure 4, after tail vein injection probe, probe molecule carries out in mouse body via blood circulation
Distribution, arrives first at heart and liver, at 3 hours, reaches maximum in the fluorescence intensity of cardia, it is already possible to by internal
Imaging system is clearly observed fluorescence very strong in mouse body, and with the cycle of blood, probe CP molecules are non-in mouse body
It is often promptly distributed, the fluorescence of cardia gradually weakens, and the fluorescence of tumor locus gradually enhances, and at 13 hours, swells
The fluorescence intensity that knurl position is launched is significantly larger than other positions, very clearly, has reached our expection, has successfully detected small
Mouse tumor locus, and after 3 hours, the fluorescence signal of tumor locus is still very strong.Illustrate probe molecule can be well
Targeted imaging is carried out to tumour, very solid reference is provided for successive treatment.
7 organic matter of embodiment is to the optical dynamic therapy effect of mouse in-vivo tumour
24 tumor-bearing mices are randomly divided into 4 groups, every group 6, blank group is without any processing, light group 808nm
(100mW cm-2) laser according to 30 minutes, what the 150 μ L embodiments 1 of every tail vein injection of mouse of probe groups were prepared has
Machine object (40 μ g/ are only), the organic matter (40 that 150 μ L embodiments 1 of every mouse tail vein injection of probe and light group is added to be prepared
μ g/ are only), and with 808nm (100mW cm-2) laser according to 30 minutes, measure record mouse tumorous size every three days, and calculate and control
After treatment with the mouse tumor volume ratio (V/V before treatment0).Testing result is as shown in figure 5, Fig. 5 is prepared by the embodiment of the present invention
The test result of organic matter optical dynamic therapy mouse in-vivo tumour as shown in Figure 5, adds probe and illumination increases mouse tumor
Apparent inhibiting effect has been arrived, and has significantly been subsided after 2 weeks, and has added mouse and blank control group mouse of the probe without illumination
Tumor growth rate is basically identical, illustrates, probe has tumour after laser initiation apparent optical dynamic therapy effect.
As seen from the above embodiment, organic matter provided by the invention has Formulas I structure, comprising with cancer target effect
Near-infrared fluorescent regiment headquarters point and efficient photosensitizing moiety, the two bonding connection.This organic matter can be targeted in tumor locus to be stored
Product, and pass through near-infrared living imaging and accurately detect knub position, after the organic matter reaches tumour, by tumour cell at bonding
In the reduction of high-caliber thiol molecule, release photosensitizer, by laser irradiation, release active oxygen, kill cancer cell.This hair
The organic matter of bright offer has targeting, near-infrared fluorescence imaging and optical dynamic therapy effect simultaneously.The experimental results showed that this hair
The organic matter of bright offer can carry out targeted imaging and optical dynamic therapy to mouse interior tumor, be a kind of collection tumor imaging, diagnosis,
Treat the multi-functional organic matter being integrated.In addition, organic matter provided by the invention be organic molecule, be readily synthesized, structure it is bright
Really, construction of stable, control are simple.
Above-described embodiment only technical concept and feature to illustrate the invention, its object is to allow person skilled in the art
Scholar can understand present disclosure and implement according to this, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done should all be covered within protection scope of the present invention.
Claims (15)
1. a kind of organic matter has Formulas I structure：
In Formulas I,
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-；
Y is selected from halide ion, BF4 -Or metal cation；
Z is selected from-S- or-Se-；
R' is selected from C1-12Alkylidene；
R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
R5~R15Independently selected from H, phenyl, C1-18Alkyl, the C of halogen substitution1-18Alkyl, C1-18Alkylene, halogen atom or benzyl
Base；
N is 1~5.
2. organic matter according to claim 1, which is characterized in that the W is-NH-；R' is selected from C1-12Alkylidene；Z for-
S-。
3. organic matter according to claim 2, which is characterized in that the R' is selected from C1-5Alkylidene.
4. organic matter according to claim 1, which is characterized in that the R1And R2Independently selected from C1-5Alkyl.
5. organic matter according to claim 1, which is characterized in that the R3And R4For H.
6. organic matter according to claim 1, which is characterized in that the R5、R6、R8、R9、R11、R12、R14And R15For H.
7. organic matter according to claim 1, which is characterized in that the R7、R10And R13For phenyl.
8. organic matter according to claim 1, which is characterized in that the W is-NH-；Y is Cl-、Br-Or I-；Z is-S-；R1
And R2Independently selected from C1-3Alkyl；R3And R4For H；R5~R15Independently selected from H or phenyl.
9. organic matter according to claim 8, which is characterized in that the organic matter has Formula II structure：
10. a kind of preparation method of compound described in claim 1, including：
Formula A structural compounds and formula B structure compound are reacted, obtain Formulas I structural compounds：
Wherein, R5~R15Independently selected from H, phenyl, C1-18Alkyl, the C of halogen substitution1-18Alkyl, C1-18Alkylene, halogen are former
Son or benzyl；
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-；
Y is selected from halide ion, BF4 -Or metal cation；
Z is selected from-S- or-Se-；
R' is selected from C1-12Alkylidene；
R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
N is 1~5.
11. according to the method described in claim 10, it is characterized in that, the preparation method of the compound of the formula B structure is：
The compound of the compound of formula C-structure and formula D structures is reacted, obtains the compound of formula B structure；
In formula C, R1And R2Independently selected from H, C1-10Alkyl ,-COOH or-HSO3；
R3And R4Independently selected from H, C1-18Alkyl or benzyl；
N is 1~5；
Y is selected from halide ion, BF4 -Or metal cation；
In formula D, R' is selected from C1-12Alkylidene；
Z is selected from-S- or-Se-；
W is selected from-CH2,-O- ,-S- ,-Se- or-NH-.
12. according to the method described in claim 10, it is characterized in that, the preparation method of the compound is：
1 structural compounds of formula and 2 structural compounds of formula are reacted, obtain Formula II structural compounds；
13. according to the method for claim 12, which is characterized in that the reaction carries out in the presence of an activator.
14. according to the method for claim 13, which is characterized in that the activator is selected from dicyclohexylcarbodiimide, N,
N- dimethyl -4- pyridines amine, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC) and N- hydroxysuccinimidyl acyls
One or more of imines (NHS).
15. the method in the organic matter or claim 10~14 in claim 1~9 described in any one described in any one
Application of the organic matter being prepared in treating cancer drug is prepared.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109422758A (en) * | 2017-08-22 | 2019-03-05 | 中国科学院深圳先进技术研究院 | A kind of near-infrared fluorescent ratio fluorescent probe and its preparation method and application |
| CN109954140A (en) * | 2017-12-26 | 2019-07-02 | 深圳先进技术研究院 | One organic molecular species are in the application for preparing cancer target, diagnosis and therapeutic reagent |
| WO2023040089A1 (en) * | 2021-09-14 | 2023-03-23 | 中国科学院深圳先进技术研究院 | Fluorescent compound and probe |
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2016
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109422758A (en) * | 2017-08-22 | 2019-03-05 | 中国科学院深圳先进技术研究院 | A kind of near-infrared fluorescent ratio fluorescent probe and its preparation method and application |
| CN109422758B (en) * | 2017-08-22 | 2020-09-22 | 中国科学院深圳先进技术研究院 | Near-infrared fluorescence ratio fluorescence probe and preparation method and application thereof |
| CN109954140A (en) * | 2017-12-26 | 2019-07-02 | 深圳先进技术研究院 | One organic molecular species are in the application for preparing cancer target, diagnosis and therapeutic reagent |
| WO2023040089A1 (en) * | 2021-09-14 | 2023-03-23 | 中国科学院深圳先进技术研究院 | Fluorescent compound and probe |
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