CN105343889B - Cancer therapy drug with targeting and fluorescence and preparation method thereof - Google Patents
Cancer therapy drug with targeting and fluorescence and preparation method thereof Download PDFInfo
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- CN105343889B CN105343889B CN201510763672.2A CN201510763672A CN105343889B CN 105343889 B CN105343889 B CN 105343889B CN 201510763672 A CN201510763672 A CN 201510763672A CN 105343889 B CN105343889 B CN 105343889B
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- Prior art keywords
- glucan
- rhodamine
- bromoacetyl bromide
- ethylenediamine
- sulphadiazine
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- 239000003814 drug Substances 0.000 title claims abstract description 54
- 229940079593 drug Drugs 0.000 title claims abstract description 48
- 230000008685 targeting Effects 0.000 title claims abstract description 45
- 238000011275 oncology therapy Methods 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000002795 fluorescence method Methods 0.000 title abstract description 3
- 230000000694 effects Effects 0.000 claims abstract description 10
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 176
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 173
- 229920001503 Glucan Polymers 0.000 claims description 168
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 117
- 229940043267 rhodamine b Drugs 0.000 claims description 116
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 98
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 92
- 229960004306 sulfadiazine Drugs 0.000 claims description 92
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 89
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- PAVKBQLPQCDVNI-UHFFFAOYSA-N n',n'-diethyl-n-(9-methoxy-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-1-yl)propane-1,3-diamine Chemical compound N1C2=CC=C(OC)C=C2C2=C1C(C)=C1C=CN=C(NCCCN(CC)CC)C1=C2C PAVKBQLPQCDVNI-UHFFFAOYSA-N 0.000 claims description 43
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- FYGDTMLNYKFZSV-URKRLVJHSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](OC2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-URKRLVJHSA-N 0.000 claims description 27
- 229920002498 Beta-glucan Polymers 0.000 claims description 27
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides a kind of cancer therapy drug with targeting and fluorescence and preparation method thereof.The structural formula of the cancer therapy drug is：
Description
Technical field
The present invention relates to a kind of cancer therapy drug and preparation method thereof, particularly a kind of anticancer with targeting and fluorescence
Medicine and preparation method thereof.
Background technology
Carcinogenic factor due to some environment and genetics etc. causes DNA damage, so as to activate proto-oncogene or inactivation tumour
Suppressor, converts target cell.Malignant diseases will be formed to a certain extent when the target cell of these conversions accumulates, even
It is malignant tumour.This kind of disease is often lacking specific symptoms in early days, has belonged to middle and advanced stage when being found more, has lost optimal treatment
Opportunity.Therefore, early detection, early diagnosis, early treatment are to reduce Malignant Tumor Recurrence rate, improve the key of survival rate.
Traditional anticarcinogen generally passes through computer x-ray tomography to treatment of solid tumor method for estimating curative effect
(X-CT), positron emission tomography (PET), single photon emission tomography (SPECT), nuclear magnetic resonance into
As the means such as (MRI), echography (US) are realized.However, these methods are simply to a kind of state in tumour change procedure
Static state is portrayed, it is difficult to which Real-Time Evaluation anticarcinogen in situ is to the situations of change of patient tumors and studies anticarcinogen on a molecular scale
With the dynamics of carninomatosis stove mechanism.
At present cancer patient treat and mainly use chemicals, this kind anti-cancer drugs is suppressing or killing tumour cancer thin
While born of the same parents, also easily cause serious injury to some normal organ cells in body, and to some histoorgans such as liver,
Kidney, the heart, lung etc. also result in serious infringement.
Fluorescence imaging method has the advantages that harmless, non-intruding, highly sensitive and multi-target imaging, especially targets
Fluorescence probe has the advantage of fluorescent dye with tumour-specific targeting development, and a kind of new think of is provided for the early stage localization diagnosis of tumour
Road and means.
Therefore, how research organically combines tumor carcinoma cells lesion targeted drug delivery system and fluorescent probe technique,
Realize at the same time anticarcinogen to transmitting procedure in body of the targeting Delivery and anticarcinogen of carninomatosis stove and with cancer cell effect
Information sensing in situ, the announcement of the electron transport essential laws acted on cancer cell realizing chemotherapeutic, evaluating drug effect, raisingization
Treatment medication, which imitates and reduces patient's normal tissue injury, is respectively provided with significance.
The content of the invention
It is an object of the present invention to provide a kind of cancer therapy drug with targeting and fluorescence.
The second object of the present invention is the provision of the preparation method of the cancer therapy drug.
To achieve the above object, the present invention use following reaction mechanism for：
1st, bromoacetyl bromide glucan is prepared：
2nd, sodium sulfadiazine is prepared：
3rd, ethylenediamine rhodamine B is prepared：
4th, first sulfonyl carbanion is prepared：
5th, first sulfonyl carbanion is connect on ethylenediamine rhodamine B：
6th, sulphadiazine is connect on bromoacetyl bromide glucan：
7th, final product cancer therapy drug is prepared：
According to above-mentioned mechanism, the present invention adopts the following technical scheme that：
A kind of cancer therapy drug with targeting and fluorescence, it is characterised in that the structural formula of the cancer therapy drug is：
,
X+a+b=1,（x+a+b）：（a+b）=1：(0.5~0.8), a:B=(4~7):1~1:(4~7).
A kind of method for preparing the above-mentioned cancer therapy drug with targeting and fluorescence, it is characterised in that the tool of this method
Body step is：
A. beta glucan presses 1 with bromoacetyl bromide:（0.5~0.8）Molar ratio carry out condensation reaction, obtain bromoacetyl bromide
Glucan, its structural formula are：, wherein, x+y=1,（x+y）：y =1:（0.5~
0.8）；
B. sulphadiazine and sodium hydroxide are fully reacted into acquisition sodium sulfadiazine；
C. rhodamine B and ethylenediamine are obtained into ethylenediamine rhodamine B through amidation process；
D. sodium hydride is dissolved in dimethyl sulfoxide (DMSO), under an inert atmosphere, temperature be 40~60 DEG C under the conditions of reaction 10~
20h, obtains the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion；
E. the dimethyl sulfoxide (DMSO) by ethylenediamine rhodamine B obtained by step c with step d gained dissolved with first sulfonyl carbanion
Solution is reacted under the catalytic action of dodecyl bromide, obtains the ethylenediamine rhodamine B of first sulfonyl carbanion grafting；
F. by sodium sulfadiazine obtained by bromoacetyl bromide glucan obtained by step a and step b in catalyst tetrabutylammonium hydroxide
Under the action of ammonium, reaction obtains the bromoacetyl bromide glucan of grafting sulphadiazine；
G. it is grafting sulfanilamide (SN) obtained by the ethylenediamine rhodamine B of first sulfonyl carbanion grafting obtained by step e and step f is phonetic
The bromoacetyl bromide glucan of pyridine is reacted, and it is targeting group, Luo Dan to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Bright B is the cancer therapy drug with targeting and fluorescence of fluorophor.
The specific preparation method of above-mentioned steps a is as follows：By beta glucan, pyridine and bromoacetyl bromide according to molar ratio 1:1:
(0.5~0.8) is dissolved in dimethyl sulfoxide (DMSO), is reacted 1~5d, is then precipitated reaction solution with absolute ethyl alcohol, and suction filtration obtains solid,
Product is dissolved in deionized water after drying, second distillation dialysis, 40~80 DEG C of vacuum is dried to obtain bromoacetyl bromide glucan.
The specific method of above-mentioned steps b is：By sulphadiazine and sodium hydroxide according to molar ratio 1:1~1:5 be dissolved in from
In sub- water, 10~48h is reacted at room temperature, then pours into reaction solution in suitable absolute ethyl alcohol under agitation, there is white to sink
Form sediment and produce, washed repeatedly with absolute ethyl alcohol, be dried to obtain sodium sulfadiazine.
The specific method of above-mentioned steps c is：By rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol,
Under inert atmosphere, 15~72h is reacted at room temperature, is dried under the conditions of 40~70 DEG C and is obtained ethylenediamine rhodamine B.
The specific method of above-mentioned steps e is：Ethylenediamine rhodamine B is added to the dimethyl Asia dissolved with first sulfonyl carbanion
In sulfolane solution, the molar ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1,40~80 DEG C of 2~10h of reaction are heated to,
Then dodecyl bromide the reaction was continued 2~10h is added, dodecyl bromide is 0.01 with ethylenediamine rhodamine B molar ratio:1~
0.1:1, then through dialysing, being dried in vacuo the ethylenediamine rhodamine B for obtaining first sulfonyl carbanion and being grafted.
The specific method of above-mentioned step f is：By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and step obtained by step a
Suddenly the sodium sulfadiazine obtained by b is 1 according to molar ratio:0.1：（0.1~0.7）It is dissolved in dimethyl sulphoxide solution, at room temperature
Reaction 1~5 day, then precipitated, filtered with absolute ethyl alcohol, dry, second distillation dialysis, vacuum drying, that is, obtain be grafted sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine, its structural formula are：
。
The specific method of above-mentioned steps g is：By the bromoacetyl bromide glucan and step e of grafting sulphadiazine obtained by step f
The ethylenediamine rhodamine B of gained first sulfonyl carbanion grafting is 1 according to molar ratio：（0.1~0.7）It is molten to be dissolved in dimethyl sulfoxide (DMSO)
In liquid, react 1~5 day at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is filtered, is dried, second distillation is dialysed, true
Sky is dry, that is, obtains the cancer therapy drug with targeting and fluorescence.
The structural formula of bromoacetyl bromide glucan：
The structural formula of targeting fluorescence probe：
In Formulas I, x+y=1,（x+y）：y =1:（0.5~0.8）；
In Formula II, x+a+b=1,（x+a+b）:（a+b）=1：(0.5 ~ 0.8), a:b=(4~7):1~1:(4~7)
Preferably, in Formulas I, x+y=1,（x+y）：y =1:0.6；
Preferably, in Formula II, x+a+b=1,（x+a+b）:（a+b）=1:0.6, a:b=5:1~1:5.
Preferably, one or more of the beta glucan in glucan 20,000, glucan 100,000, glucan 140,000,
The molecular weight of glucan 20,000 is 20000, and the molecular weight of glucan 100,000 is 100000, the molecular weight of glucan 140,000 is
140000。
Preferably, the beta glucan is selected from glucan 20,000, molecular weight 20000.
Preferably, the preparation method of the bromoacetyl bromide glucan is as follows：By beta glucan, pyridine and bromoacetyl bromide according to
Molar ratio 1:1:（0.5~0.8）It is dissolved in dimethyl sulfoxide (DMSO), reacts 1 ~ 5d, obtain bromoacetyl bromide glucan.
Preferably, molar concentration of the beta glucan glucan in dimethyl sulfoxide (DMSO) is 0.1 ~ 1mol/L.
Preferably, the preparation method of the sodium sulfadiazine is as follows：By sulphadiazine and sodium hydroxide according to molar ratio 1:1
It is dissolved in deionized water, reacts 10 ~ 48h, obtain sodium sulfadiazine.
Preferably, the molar concentration of the sulphadiazine, sodium hydroxide in deionized water is 0.1mol/L ~ 1mol/L.
Preferably, the molar concentration of the sulphadiazine, sodium hydroxide in deionized water is 0.4mol/L ~ 0.6mol/
L。
Preferably, by rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, under an inert atmosphere, reaction
15 ~ 72h, obtains ethylenediamine rhodamine B,
Preferably, the molar concentration of the rhodamine B, ethylenediamine in absolute ethyl alcohol is the mol/L of 0.01mol/L ~ 0.2.
Preferably, the molar concentration of the rhodamine B, ethylenediamine in absolute ethyl alcohol is 0.1 mol/L ~ 0.15mol/
L。
Preferably, the preparation method of the ethylenediamine rhodamine B of the first sulfonyl carbanion grafting is as follows：
Preferably, by rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, under an inert atmosphere, reaction
15 ~ 72h, obtains ethylenediamine rhodamine B, the molar concentration of the rhodamine B, ethylenediamine in absolute ethyl alcohol for 0.01mol/L ~
0.2 mol/L；
Preferably, by dimethyl sulfoxide (DMSO) and sodium hydride according to molar ratio 10:1~2:After 1 mixing, under an inert atmosphere, temperature
To react 10 ~ 20h under the conditions of 40 ~ 60 DEG C, the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion is obtained；
Preferably, the molar ratio of the dimethyl sulfoxide (DMSO) and sodium hydride is 5:1~3:1.
Preferably, ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion, be heated to
40 ~ 80 DEG C of 2 ~ 10h of reaction, then add dodecyl bromide the reaction was continued 2 ~ 10h, most obtain first through dialysing, being dried in vacuo afterwards
The ethylenediamine rhodamine B of sulfonyl carbanion grafting.
Preferably, the molar ratio of the ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1.
Preferably, the molar ratio of the dodecyl bromide and ethylenediamine rhodamine B is 0.01:1~0.1:1.
Preferably, the molar ratio of the ethylenediamine rhodamine B of the sodium sulfadiazine and first sulfonyl carbanion grafting for (4 ~
7):1~1:(4~7)。
Preferably, the molar ratio of the sodium sulfadiazine and the ethylenediamine rhodamine B of first sulfonyl carbanion grafting is 5:1
~1:5。
Preferably, the preparation method of the bromoacetyl bromide glucan of the grafting sulphadiazine is as follows：Bromoacetyl bromide Portugal is gathered
Sugar, tetrabutylammonium hydroxide and sodium sulfadiazine are 1 according to molar ratio:0.1：（0.1~0.7）It is dissolved in dimethyl sulphoxide solution,
At room temperature react 1 ~ 5d, then precipitated, filtered with absolute ethyl alcohol, dry, second distillation dialysis, be dried in vacuo, that is, connect
The bromoacetyl bromide glucan of branch sulphadiazine.
Preferably, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.1mol/L ~ 1
mol/L。
Preferably, the bromoacetyl bromide glucan and the ethylenediamine Luo Dan of first sulfonyl carbanion grafting that sulphadiazine will be grafted
Bright B is 1 according to molar ratio：（0.1~0.7）It is dissolved in after mixing in dimethyl sulphoxide solution, reacts 1 ~ 5d at room temperature, then will
Reaction solution is precipitated with absolute ethyl alcohol, filtered, dried, second distillation dialysis, vacuum drying, that is, obtain using bromoacetyl bromide glucan as
Carrier, sulphadiazine are targeting group, the cancer therapy drug that rhodamine B is fluorophor.
Preferably, molar concentration of the bromoacetyl bromide glucan of the grafting sulphadiazine in dimethyl sulphoxide solution is
0.1mol/L~1 mol/L。
Beta glucan is the good bacterial polysaccharide of a kind of biocompatibility, has antiviral, anti-aging, hypoglycemic, thorn
Swash hematopoiesis and immunological regulation and antitumor biological effectiveness.The acid resistance of beta glucan can not be by water when being run through stomach
Solution utilizes.There is a kind of stickum in intestinal tract surface --- " fine hair ", has the acceptor combined with long chain polysaccharides on fine hair.Wherein one
Species specificity acceptor can be combined with the polysaccharide specificity of this kind of tool special construction of beta glucan.When beta glucan is attached to specificity
After acceptor, enteric epithelium is eventually passed through by pinocytosis and enters lymphatic system, and enters hematological system from lymphatic system.
In terms of pharmacodynamics angle, tumour cell has negative electrical charges more more than normal cell surface, and beta glucan is in acidity
There is selective absorption and charge neutrality to act on tumor cell surface in environment, beta glucan, which also has, directly suppresses tumour cell
Effect, by activated immune system show active anticancer, anticancer effect can be strengthened by being combined with cancer therapy drug.In addition, β-Portugal
Oligosaccharide side chains contain abundant hydroxyl, are easier to be chemically modified.It is degradable in vivo, and catabolite is harmless, it is non-
Often it is suitable as the carrier of antitumor drug.
Sulphadiazine is a kind of biologically active material, tumor region selective enrichment that can be in vivo, tool
There are clearly close knurl characteristic, physiological activity that is obvious antiviral and suppressing cancer cell.This intelligent nano cancer therapy drug has
Good tumor-targeting and control release performance, have relatively low cytotoxicity, energy to normal human kidney embryo HEK293 cells
HeLa Cells are effectively killed, and can induce apoptosis of tumor cells.Therefore sulphadiazine is used as the swollen of medicine
Knurl targets group.
Rhodamine B (Rh-B) and its derivative are a kind of important fluorescence probe materials, can be produced under the action of exciting light
Raw strong fluorescence.Rhodamine B compound after certain modification, its fluorescence emission wavelengths, fluorescent wavelength ranges,
Sensitiveness to pH etc. can effectively be regulated and controled, so as to meet different application demands.In field of biomedical research,
Rhodamine B is visited because being suitable as fluorescent tracer and fluorescence with preferable photostability and higher fluorescence quantum yield
Pin.But the rhodamine of small molecule does not often possess some important Biofunctional such as tumor-targetings, rhodamine Bization in itself
Compound generally requires to be used in combination with other biological material.
Targeting fluorescence probe is that the material such as fluorescent dye and ligands specific, albumen, small-molecular peptides passes through chemical method
It is combined into, target spot (such as acceptor) specific binding that it can be special with cell surface, therefore there is directionality.And target swollen
Knurl can be divided into two kinds again by mechanism：That is active targeting and passive target.Active targeting refers to utilize biologic specificity phase interaction
Combined with such as Ag-Ab or ligand-receptor combines etc. come the targeted delivery realized.The common method of one of which is to utilize cancer
The acceptor of cell overexpression, will be combined with the corresponding ligand of this receptor with functional molecular fragment, and pass through active targeting quilt
Cancer cell internalization.The acceptor of this utilizable cancer cell overexpression have tyrosine kinase receptor, folacin receptor, hormone by
Body, more saccharide acceptors, lipoprotein receptor, TfR etc..
A preferable cancer target fluorescence probe is designed, to consider the following aspects：1st, there is height with targeted molecular
The specific bond of degree；2nd, there is stable chemical constitution, be conducive to extend the half-life period of probe in vivo；3rd, there is well glimmering
Photosensitiveness and harmless to the body.
Compared with prior art, the present invention provides one kind using beta glucan as carrier, the sulphur of cancer target is connected to thereon
The rhodamine B macromolecular cancer therapy drug of amic metadiazine and fluorescence.The medicine has very strong targeting and fluorescence, passes through β-Portugal
Glycan support antitumor drug sulphadiazine, can reduce destruction and degraded of the internal enzyme to antitumor drug sulphadiazine, from
And medicine stability in vivo and the utilization rate of antitumor drug are improved, reduce the toxic side effect of medicine；In addition, realizing
While sulphadiazine kills cancer cell, cancer cell profile can be expressed with real-time fluorescence, realize sulphadiazine and tumour cancer
Cytosis process and curative effect of medication original position image evaluation, diagnose so as to fulfill infantile tumour, and then improve the treatment effect of tumour
Rate simultaneously reduces side effect.
Embodiment
The synthetic route of cancer therapy drug of the present invention is as follows：
In order to further appreciate that the present invention, preparation method provided by the invention is retouched in detail with reference to embodiment
State, but it is to be understood that these descriptions are intended merely to further illustrate the features and advantages of the present invention, and cannot understand them
For limiting the scope of the present invention.
Raw material used in following embodiments of the present invention is commercial goods.
Embodiment 1
Step 1: synthesis bromoacetyl bromide glucan：
By beta glucan 20,000, pyridine and bromoacetyl bromide according to molar ratio 1:1:0.6 is dissolved in dimethyl sulfoxide (DMSO), and β-Portugal gathers
Sugared 20,000 molar concentration in dimethyl sulfoxide (DMSO) be 0.1 ~ 1mol/L, at room temperature 1 ~ 5d of reaction, then by reaction solution with anhydrous second
Alcohol precipitates, and suction filtration obtains solid, and product is dissolved in deionized water after dry, second distillation dialysis, and 40 ~ 80 DEG C of vacuum is dry
To bromoacetyl bromide glucan.
Step 2: prepare sodium sulfadiazine：
By sulphadiazine and sodium hydroxide according to molar ratio 1:1 is dissolved in deionized water, and sulphadiazine, sodium hydroxide are being gone
Molar concentration in ionized water is 0.1mol/L ~ 1mol/L, reacts at room temperature 10 ~ 48h, then falls reaction solution under agitation
Enter in suitable absolute ethyl alcohol, there is white precipitate generation, washed repeatedly with absolute ethyl alcohol, be dried to obtain sodium sulfadiazine.
Step 3: the ethylenediamine rhodamine B of synthesis first sulfonyl carbanion grafting：
By rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, and rhodamine B, ethylenediamine are in absolute ethyl alcohol
In molar concentration be the mol/L of 0.01mol/L ~ 0.2, under an inert atmosphere, room temperature 15 ~ 72h of back flow reaction, then uses CH2Cl2
Extraction, last rotary evaporation are dried to obtain ethylenediamine rhodamine B；
By dimethyl sulfoxide (DMSO) and sodium hydride according to molar ratio 10:After 1 mixing, under an inert atmosphere, temperature is 40 ~ 60 DEG C of bars
10 ~ 20h is reacted under part, obtains the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion；
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion, ethylenediamine rhodamine B
Molar ratio with first sulfonyl carbanion is 1:1,40 ~ 80 DEG C of 2 ~ 10h of reaction are heated to, dodecyl bromide is then added and continues instead
2 ~ 10h is answered, dodecyl bromide is 0.01 with ethylenediamine rhodamine B molar ratio:1~0.1:1, then through dialysing, being dried in vacuo to obtain the final product
To the ethylenediamine rhodamine B of first sulfonyl carbanion grafting.
Step 4: synthesis cancer therapy drug：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Obtained to example 1 using bromoacetyl bromide glucan as carrier, sulphadiazine is that targeting group, rhodamine B are glimmering
The cancer therapy drug of light group carries out infrared and nuclear-magnetism characterization, and according to the corresponding glucan carrier of nuclear-magnetism, sulphadiazine targeting
Group, the integral area of rhodamine B fluorophor characteristic peak obtain sulphadiazine targeting group and rhodamine B fluorophor in Portugal
Grafting rate on glycan carrier.It is 8 ~ 14% that sulphadiazine, which targets group in the grafting rate of glucan carrier, and rhodamine B gathers in Portugal
Grafting rate on sugar carrier is 4 ~ 10%
Embodiment 2
According to 1 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 100,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.5.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1：0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.2 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 3
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 1, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO) with
The molar ratio of sodium hydride is 5:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.1 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.1mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.5 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.1mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 4
According to 1 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 100,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.56.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.2 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.36 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 5
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 1, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO) with
The molar ratio of sodium hydride is 2:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.5 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 1mol/L, at room temperature
React 1 ~ 5d, then precipitated, filtered with absolute ethyl alcohol, dry, second distillation dialysis, vacuum drying, that is, obtain be grafted sulfanilamide (SN) it is phonetic
The bromoacetyl bromide glucan of pyridine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.1 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 1 mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 6
According to 1 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 100,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.68.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.38 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 7
Step 1: synthesis bromoacetyl bromide glucan：
By beta glucan 100,000, pyridine and bromoacetyl bromide according to molar ratio 1:1:0.8 is dissolved in dimethyl sulfoxide (DMSO), and β-Portugal gathers
Sugared 100,000 molar concentration in dimethyl sulfoxide (DMSO) be 0.1 ~ 1mol/L, at room temperature 1 ~ 5d of reaction, then by reaction solution with anhydrous
Ethanol precipitation, suction filtration obtain solid, product are dissolved in deionized water after dry, second distillation dialysis, 40 ~ 80 DEG C of dryings of vacuum
Obtain bromoacetyl bromide glucan.
Step 2: prepare sodium sulfadiazine：
By sulphadiazine and sodium hydroxide according to molar ratio 1:1 is dissolved in deionized water, and sulphadiazine, sodium hydroxide are being gone
Molar concentration in ionized water is 0.1mol/L ~ 1mol/L, reacts at room temperature 10 ~ 48h, then falls reaction solution under agitation
Enter in suitable absolute ethyl alcohol, there is white precipitate generation, washed repeatedly with absolute ethyl alcohol, be dried to obtain sodium sulfadiazine.
Step 3: the ethylenediamine rhodamine B of synthesis first sulfonyl carbanion grafting：
By rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, and rhodamine B, ethylenediamine are in absolute ethyl alcohol
In molar concentration be the mol/L of 0.01mol/L ~ 0.2, under an inert atmosphere, room temperature 15 ~ 72h of back flow reaction, then uses CH2Cl2
After extraction, ethylenediamine rhodamine B is obtained after rotary evaporation drying；
By dimethyl sulfoxide (DMSO) and sodium hydride according to molar ratio 10:After 1 mixing, under an inert atmosphere, temperature is 40 ~ 60 DEG C of bars
10 ~ 20h is reacted under part, obtains the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion；
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion, ethylenediamine rhodamine B
Molar ratio with first sulfonyl carbanion is 1:1,40 ~ 80 DEG C of 2 ~ 10h of reaction are heated to, dodecyl bromide is then added and continues instead
Answer 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B molar ratio 0.01:1~0.1:1, then obtained through dialysing, being dried in vacuo
The ethylenediamine rhodamine B of first sulfonyl carbanion grafting.
Step 4: synthesis cancer therapy drug：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.7 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.1 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 8
According to 7 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 20,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.6.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 9
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 7, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO) with
The molar ratio of sodium hydride is 4:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.1 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.1mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.7 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.1mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 10
According to 7 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 20,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.7.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.4 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 11
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 7, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO) with
The molar ratio of sodium hydride is 6:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.4 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 1mol/L, at room temperature
React 1 ~ 5d, then precipitated, filtered with absolute ethyl alcohol, dry, second distillation dialysis, vacuum drying, that is, obtain be grafted sulfanilamide (SN) it is phonetic
The bromoacetyl bromide glucan of pyridine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 1 mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 12
According to 7 the method for embodiment, bromoacetyl bromide glucan is prepared, difference, is beta glucan 20,000, pyrrole
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.5.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.2 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 13
Step 1: synthesis bromoacetyl bromide glucan：
By beta glucan 20,000, pyridine and bromoacetyl bromide according to molar ratio 1:1:0.5 is dissolved in dimethyl sulfoxide (DMSO), and β-Portugal gathers
Sugared 20,000 molar concentration in dimethyl sulfoxide (DMSO) be 0.1 ~ 1mol/L, at room temperature 1 ~ 5d of reaction, then by reaction solution with anhydrous second
Alcohol precipitates, and suction filtration obtains solid, and product is dissolved in deionized water after dry, second distillation dialysis, and 40 ~ 80 DEG C of vacuum is dry
To bromoacetyl bromide glucan.
Step 2: prepare sodium sulfadiazine：
By sulphadiazine and sodium hydroxide according to molar ratio 1:1 is dissolved in deionized water, and sulphadiazine, sodium hydroxide are being gone
Molar concentration in ionized water is 0.1mol/L ~ 1mol/L, reacts at room temperature 10 ~ 48h, then falls reaction solution under agitation
Enter in suitable absolute ethyl alcohol, there is white precipitate generation, washed repeatedly with absolute ethyl alcohol, be dried to obtain sodium sulfadiazine.
Step 3: the ethylenediamine rhodamine B of synthesis first sulfonyl carbanion grafting：
By rhodamine B and ethylenediamine according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, and rhodamine B, ethylenediamine are in absolute ethyl alcohol
In molar concentration be the mol/L of 0.01mol/L ~ 0.2, under an inert atmosphere, room temperature 15 ~ 72h of back flow reaction, then uses CH2Cl2
After extraction, ethylenediamine rhodamine B is obtained after rotary evaporation drying；
By dimethyl sulfoxide (DMSO) and sodium hydride according to molar ratio 5:After 1 mixing, under an inert atmosphere, temperature is 40 ~ 60 DEG C of bars
10 ~ 20h is reacted under part, obtains the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion；
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion, ethylenediamine rhodamine B
Molar ratio with first sulfonyl carbanion is 1:1,40 ~ 80 DEG C of 2 ~ 10h of reaction are heated to, dodecyl bromide is then added and continues instead
2 ~ 10h is answered, dodecyl bromide is 0.01 with ethylenediamine rhodamine B molar ratio:1~0.1:1, then through dialysing, being dried in vacuo to obtain the final product
To the ethylenediamine rhodamine B of first sulfonyl carbanion grafting.
Step 4: synthesis cancer therapy drug：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.2 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 14
According to 13 the method for embodiment, prepare bromoacetyl bromide glucan, difference, be by beta glucan 140,000,
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.5.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.2 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 15
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 13, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in rapid three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO)
Molar ratio with sodium hydride is 8:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.1 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.1mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.4 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.1mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 16
According to 13 the method for embodiment, prepare bromoacetyl bromide glucan, difference, be by beta glucan 140,000,
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.8.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.3 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.5 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 17
Bromoacetyl bromide glucan and sodium sulfadiazine are prepared according to the method described in embodiment 13, difference is, step
The molar concentration of rhodamine B, ethylenediamine in absolute ethyl alcohol in rapid three is 0.1 mol/L ~ 0.15mol/L, dimethyl sulfoxide (DMSO)
Molar ratio with sodium hydride is 9:1.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.4 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 1mol/L, at room temperature
React 1 ~ 5d, then precipitated, filtered with absolute ethyl alcohol, dry, second distillation dialysis, vacuum drying, that is, obtain be grafted sulfanilamide (SN) it is phonetic
The bromoacetyl bromide glucan of pyridine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.1 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 1 mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
Embodiment 18
According to 13 the method for embodiment, prepare bromoacetyl bromide glucan, difference, be by beta glucan 140,000,
Pyridine and bromoacetyl bromide are according to molar ratio 1:1:0.7.
The building-up process of step 4 is as follows：
By bromoacetyl bromide glucan, tetrabutylammonium hydroxide and sodium sulfadiazine according to molar ratio be 1:0.1：0.4 is dissolved in
In dimethyl sulphoxide solution, molar concentration of the bromoacetyl bromide glucan in dimethyl sulphoxide solution is 0.5 mol/L, in room temperature
1 ~ 5d of lower reaction, then precipitated, filtered with absolute ethyl alcohol, dried, second distillation dialysis, vacuum drying, that is, obtain grafting sulfanilamide (SN)
The bromoacetyl bromide glucan of pyrimidine；
Will be grafted sulphadiazine bromoacetyl bromide glucan and first sulfonyl carbanion grafting ethylenediamine rhodamine B according to
Molar ratio is 1：It is dissolved in after 0.3 mixing in dimethyl sulphoxide solution, is grafted the bromoacetyl bromide glucan of sulphadiazine in dimethyl
Molar concentration in sulfoxide solution is 0.5mol/L, reacts 1 ~ 5d at room temperature, then reaction solution is precipitated with absolute ethyl alcohol, is taken out
Filter, dry, second distillation dialysis, vacuum drying, that is, it is targeting base to obtain by carrier, sulphadiazine of bromoacetyl bromide glucan
Group, the cancer therapy drug that rhodamine B is fluorophor.
The explanation of above example is only intended to help to understand method and its core concept of the invention.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvement and modification, these are improved and modification is also fallen into the protection domain of the claims in the present invention.To these embodiments
A variety of modifications are it will be apparent that the general principles defined herein can be not for those skilled in the art
Realized in other embodiments in the case of departing from the spirit or scope of the present invention.Therefore, the present invention is not intended to be limited to this
These embodiments shown in text, and it is to fit to the most wide scope consistent with the principles and novel features disclosed herein.
Claims (7)
1. a kind of preparation method of the cancer therapy drug with targeting and fluorescence, the structural formula of the cancer therapy drug are：
X+a+b=1, (x+a+b)：(a+b)=1：(0.5~0.8), a:B=(4~7):1~1:(4~7)；
It is characterized in that this method concretely comprises the following steps：
A. beta glucan presses 1 with bromoacetyl bromide:The molar ratio of (0.5~0.8) carries out condensation reaction, obtains bromoacetyl bromide Portugal and gathers
Sugar, its structural formula are：Wherein, x+y=1, (x+y)：Y=1:(0.5~0.8)；
B. sulphadiazine and sodium hydroxide are fully reacted into acquisition sodium sulfadiazine；
C. rhodamine B and ethylenediamine are obtained into ethylenediamine rhodamine B through amidation process；
D. sodium hydride is dissolved in dimethyl sulfoxide (DMSO), under an inert atmosphere, temperature reacts 10~20h under the conditions of being 40~60 DEG C,
Obtain the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion；
E. ethylenediamine rhodamine B obtained by step c is existed with step d gained dissolved with the dimethyl sulphoxide solution of first sulfonyl carbanion
Reacted under the catalytic action of dodecyl bromide, obtain the ethylenediamine rhodamine B of first sulfonyl carbanion grafting；
F. by sodium sulfadiazine obtained by bromoacetyl bromide glucan obtained by step a and step b in catalyst tetrabutylammonium hydroxide
Under effect, reaction obtains the bromoacetyl bromide glucan of grafting sulphadiazine；
G. by the bromine of grafting sulphadiazine obtained by the ethylenediamine rhodamine B of first sulfonyl carbanion grafting obtained by step e and step f
Acetyl bromide glucan is reacted, and it is that targeting group, rhodamine B are to obtain using bromoacetyl bromide glucan as carrier, sulphadiazine
The cancer therapy drug with targeting and fluorescence of fluorophor.
2. preparation method according to claim 1, it is characterised in that the specific preparation method of above-mentioned steps a is as follows：By β-
Glucan, pyridine and bromoacetyl bromide are according to molar ratio 1:1:(0.5~0.8) is dissolved in dimethyl sulfoxide (DMSO), reacts 1~5d, then
Reaction solution is precipitated with absolute ethyl alcohol, suction filtration obtains solid, and product is dissolved in deionized water after dry, second distillation dialysis,
40~80 DEG C of vacuum is dried to obtain bromoacetyl bromide glucan.
3. preparation method according to claim 1, it is characterised in that the specific method of above-mentioned steps b is：By sulphadiazine
With sodium hydroxide according to molar ratio 1:1~1:5 are dissolved in deionized water, react at room temperature 10~48h, are then stirring reaction solution
In the case of pour into suitable absolute ethyl alcohol, have white precipitate generation, washed repeatedly with absolute ethyl alcohol, be dried to obtain sulphadiazine
Sodium.
4. preparation method according to claim 1, it is characterised in that the specific method of above-mentioned steps c is：By rhodamine B with
Ethylenediamine is according to molar ratio 1:1 is dissolved in absolute ethyl alcohol, under an inert atmosphere, 15~72h is reacted at room temperature, in 40~70 DEG C of bars
Drying obtains ethylenediamine rhodamine B under part.
5. preparation method according to claim 1, it is characterised in that the specific method of above-mentioned steps e is：By ethylenediamine sieve
Red bright B is added in the dimethyl sulphoxide solution dissolved with first sulfonyl carbanion, ethylenediamine rhodamine B and first sulfonyl carbanion
Molar ratio is 1:1,40~80 DEG C of 2~10h of reaction are heated to, then add dodecyl bromide the reaction was continued 2~10h, dodecane
Bromide is 0.01 with ethylenediamine rhodamine B molar ratio:1~0.1:1, then obtain first sulfonyl carbon through dialysing, being dried in vacuo and bear
The ethylenediamine rhodamine B of ionic grafting.
6. preparation method according to claim 1, it is characterised in that the specific method of above-mentioned step f is：By step a institutes
It is 1 that the sodium sulfadiazine obtained by bromoacetyl bromide glucan, tetrabutylammonium hydroxide and step b, which is obtained, according to molar ratio:0.1：(0.1
~0.7) it is dissolved in dimethyl sulphoxide solution, reacts 1~5 day at room temperature, then precipitated, filtered with absolute ethyl alcohol, dried, two
Secondary distillation dialysis, vacuum drying, that is, obtain the bromoacetyl bromide glucan of grafting sulphadiazine, its structural formula is：
7. preparation method according to claim 1, it is characterised in that the specific method of above-mentioned steps g is：By obtained by step f
Be grafted the ethylenediamine rhodamine B of first sulfonyl carbanion grafting obtained by the bromoacetyl bromide glucan and step e of sulphadiazine according to
Molar ratio is 1：(0.1~0.7) is dissolved in dimethyl sulphoxide solution, is reacted 1~5 day at room temperature, then by reaction solution nothing
Water-ethanol precipitation, suction filtration, dry, second distillation dialysis, vacuum drying, that is, obtain the anticarcinogen with targeting and fluorescence
Thing.
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