CN105343889A - Targeted fluorescent anti-cancer drug and preparation method thereof - Google Patents
Targeted fluorescent anti-cancer drug and preparation method thereof Download PDFInfo
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- CN105343889A CN105343889A CN201510763672.2A CN201510763672A CN105343889A CN 105343889 A CN105343889 A CN 105343889A CN 201510763672 A CN201510763672 A CN 201510763672A CN 105343889 A CN105343889 A CN 105343889A
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- glucosan
- sulfadiazine
- rhodamine
- bromoacetyl bromide
- ethylenediamine
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- 239000002246 antineoplastic agent Substances 0.000 title abstract description 13
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 49
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- 238000000034 method Methods 0.000 claims abstract description 43
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- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 174
- 229920001503 Glucan Polymers 0.000 claims description 172
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 172
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 140
- 229940043267 rhodamine b Drugs 0.000 claims description 120
- 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 119
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 117
- 229960004306 sulfadiazine Drugs 0.000 claims description 112
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 112
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 89
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 71
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 59
- 238000001291 vacuum drying Methods 0.000 claims description 48
- 238000004821 distillation Methods 0.000 claims description 47
- 238000001914 filtration Methods 0.000 claims description 47
- 238000001556 precipitation Methods 0.000 claims description 47
- JLDCNMJPBBKAHH-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-pyrimidin-2-ylazanide Chemical compound [Na+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 JLDCNMJPBBKAHH-UHFFFAOYSA-N 0.000 claims description 44
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Classifications
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- 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
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- 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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- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides a targeted fluorescent anti-cancer drug and a preparation method thereof. A structural formula of the anti-cancer drug is shown as the description. The targeted fluorescent anti-cancer drug has the advantages that the anti-cancer drug is highly targeted and fluorescent, so that stability of the anti-cancer drug in vivo can be improved and use ratio of the anti-cancer drug can be increased; since an anti-cancer drug and cancer cell acting process and drug efficacy in-situ imaging evaluation are achieved, early cancer diagnosis is achieved, and further, cancer treatment efficiency is improved while side effect is reduced.
Description
Technical field
The present invention relates to a kind of cancer therapy drug and preparation method thereof, particularly one and there is targeting and epipolic cancer therapy drug and preparation method thereof.
Background technology
Because the carcinogenic factor etc. of some E&H causes DNA to damage, thus activate proto-oncogene or deactivation tumor suppressor gene, target cell is transformed.To a certain degree will malignant diseases be formed when these target cells transformed are accumulated to, or even malignant tumor.This kind of disease often lacks specific symptoms in early days, manyly when being found belongs to middle and advanced stage, loses best occasion for the treatment.Therefore, early discovery, early diagnosis, early treatment are the keys reducing Malignant Tumor Recurrence rate, improve survival rate.
Traditional anticarcinogen generally passes through computer x-ray tomography (X-CT) to treatment of solid tumor method for estimating curative effect, positron emission tomography (PET), single photon emission tomography (SPECT), NMR (Nuclear Magnetic Resonance)-imaging (MRI), the means such as echography (US) realize.But these methods are just portrayed a kind of in tumor change procedure static state of state, be difficult to original position Real-Time Evaluation anticarcinogen to the situation of change of patient tumors and the kinetics studying anticarcinogen and carninomatosis stove mechanism on a molecular scale.
At present cancer patient is treated and mainly use chemicals, this kind anti-cancer drugs is in suppression or while killing tumor carcinoma cells, also easy some normal organ cell in body to be caused serious injury, and to some histoorgan as liver, kidney, the heart, lung etc. also cause serious harm.
Fluorescence imaging method has the advantage of harmless, non-intruding, highly sensitive and multi-target imaging, and especially targeting fluorescent probe has the advantage of tumour-specific targeted developing, and the early stage localization diagnosis for tumor provides a kind of new thinking and means.
Therefore, how tumor carcinoma cells focus targeted drug delivery system and fluorescent probe technique organically combine by research, realize simultaneously anticarcinogen to transmitting procedure in body of the targeting Delivery of carninomatosis stove and anticarcinogen and and the original position information sensing of cancerous cell effect, to realizing the announcement of electron transport essential laws of chemotherapeutic and cancerous cell effect, evaluating drug effect, raising chemotherapeutic curative effect to reduce patient's normal tissue injury all significant.
Summary of the invention
An object of the present invention is to provide one to have targeting and epipolic cancer therapy drug.
Two of object of the present invention there are provided the preparation method of this cancer therapy drug.
For achieving the above object, the present invention adopts following reaction mechanism to be:
1, bromoacetyl bromide glucosan is prepared:
2, sulfadiazine sodium is prepared:
3, ethylenediamine rhodamine B is prepared:
4, first sulfonyl carbanion is prepared:
5, on ethylenediamine rhodamine B, first sulfonyl carbanion is connect:
6, on bromoacetyl bromide glucosan, sulfadiazine is connect:
7, end product cancer therapy drug is prepared:
According to above-mentioned mechanism, the present invention adopts following technical scheme:
One has targeting and epipolic cancer therapy drug, it is characterized in that the structural formula of this 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)。
Prepare an above-mentioned method with targeting and epipolic cancer therapy drug, it is characterized in that the concrete steps of the method are:
A. beta glucan and bromoacetyl bromide are by 1:(0.5 ~ 0.8) mol ratio carry out condensation reaction, obtain bromoacetyl bromide glucosan, its structural formula is:
, wherein, x+y=1, (x+y): y=1:(0.5 ~ 0.8);
B. sulfadiazine and sodium hydroxide are fully reacted acquisition sulfadiazine sodium;
C. rhodamine B and ethylenediamine are obtained ethylenediamine rhodamine B through amidation process;
D. be dissolved in dimethyl sulfoxide by sodium hydride, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
E. dimethyl sulphoxide solution step c gained ethylenediamine rhodamine B and steps d gained being dissolved with first sulfonyl carbanion reacts under the catalytic action of dodecyl bromide, obtains the ethylenediamine rhodamine B of first sulfonyl carbanion grafting;
F. by step a gained bromoacetyl bromide glucosan and step b gained sulfadiazine sodium under the effect of catalyst TBAH, be obtained by reacting the bromoacetyl bromide glucosan of grafting sulfadiazine;
G. the ethylenediamine rhodamine B of step e gained first sulfonyl carbanion grafting and the bromoacetyl bromide glucosan of step f gained grafting sulfadiazine are reacted, obtain with bromoacetyl bromide glucosan be carrier, sulfadiazine is targeting group, rhodamine B is fluorophor has targeting and epipolic cancer therapy drug.
The concrete preparation method of above-mentioned steps a is as follows: by beta glucan, pyridine and bromoacetyl bromide according to mol ratio 1:1:(0.5 ~ 0.8) be dissolved in dimethyl sulfoxide, reaction 1 ~ 5d, then reactant liquor dehydrated alcohol is precipitated, sucking filtration obtains solid, after drying, product is dissolved in deionized water, second distillation is dialysed, and vacuum 40 ~ 80 DEG C of dryings obtain bromoacetyl bromide glucosan.
The concrete grammar of above-mentioned steps b is: be dissolved in deionized water by sulfadiazine and sodium hydroxide according to mol ratio 1:1 ~ 1:5, room temperature reaction 10 ~ 48h, then reactant liquor is poured under agitation in appropriate dehydrated alcohol, adularescent precipitation produces, and obtains sulfadiazine sodium with dehydrated alcohol cyclic washing, drying.
The concrete grammar of above-mentioned steps c is: be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, under an inert atmosphere, reacts 15 ~ 72h under room temperature, dries and obtain ethylenediamine rhodamine B under 40 ~ 70 DEG C of conditions.
The concrete grammar of above-mentioned steps e is: be added to by ethylenediamine rhodamine B in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, the mol ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B mol ratio are 0.01:1 ~ 0.1:1, then through the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
The concrete grammar of above-mentioned step f is: be 1:0.1:(0.1 ~ 0.7 by the sulfadiazine sodium of step a gained bromoacetyl bromide glucosan, TBAH and step b gained according to mol ratio) be dissolved in dimethyl sulphoxide solution, at room temperature react 1 ~ 5 day, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain the bromoacetyl bromide glucosan of grafting sulfadiazine, its structural formula is:
.
The concrete grammar of above-mentioned steps g is: be 1:(0.1 ~ 0.7 by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of step f gained grafting sulfadiazine and the grafting of step e gained first sulfonyl carbanion according to mol ratio) be dissolved in dimethyl sulphoxide solution, at room temperature react 1 ~ 5 day, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain that there is targeting and epipolic cancer therapy drug.
The structural formula of bromoacetyl bromide glucosan:
The structural formula of targeting fluorescent probe:
In formula 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 formula 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, described beta glucan be selected from glucosan 20,000, glucosan 100,000, glucosan 140,000 one or more, the molecular weight of glucosan 20,000 is 20000, and the molecular weight of glucosan 100,000 is 100000, the molecular weight of glucosan 140,000 is 140000.
Preferably, described beta glucan is selected from glucosan 20,000, and molecular weight is 20000.
Preferably, the preparation method of described bromoacetyl bromide glucosan is as follows: by beta glucan, pyridine and bromoacetyl bromide according to mol ratio 1:1:(0.5 ~ 0.8) be dissolved in dimethyl sulfoxide, reaction 1 ~ 5d, obtains bromoacetyl bromide glucosan.
Preferably, the molar concentration of described beta glucan glucosan in dimethyl sulfoxide is 0.1 ~ 1mol/L.
Preferably, the preparation method of described sulfadiazine sodium is as follows: be dissolved in deionized water by sulfadiazine and sodium hydroxide according to mol ratio 1:1, and reaction 10 ~ 48h, obtains sulfadiazine sodium.
Preferably, described sulfadiazine, sodium hydroxide molar concentration is in deionized water 0.1mol/L ~ 1mol/L.
Preferably, described sulfadiazine, sodium hydroxide molar concentration is in deionized water 0.4mol/L ~ 0.6mol/L.
Preferably, be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, under an inert atmosphere, reaction 15 ~ 72h, obtains ethylenediamine rhodamine B,
Preferably, described rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.01mol/L ~ 0.2mol/L.
Preferably, described rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L.
Preferably, the preparation method of the ethylenediamine rhodamine B of described first sulfonyl carbanion grafting is as follows:
Preferably, rhodamine B and ethylenediamine are dissolved in dehydrated alcohol according to mol ratio 1:1, under an inert atmosphere, reaction 15 ~ 72h, obtain ethylenediamine rhodamine B, described rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.01mol/L ~ 0.2mol/L;
Preferably, after being mixed according to mol ratio 10:1 ~ 2:1 with sodium hydride by dimethyl sulfoxide, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
Preferably, the mol ratio of described dimethyl sulfoxide and sodium hydride is 5:1 ~ 3:1.
Preferably, ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, finally by the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
Preferably, the mol ratio of described ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1.
Preferably, the mol ratio of described dodecyl bromide and ethylenediamine rhodamine B is 0.01:1 ~ 0.1:1.
Preferably, the mol ratio of the ethylenediamine rhodamine B of described sulfadiazine sodium and the grafting of first sulfonyl carbanion is (4 ~ 7): 1 ~ 1:(4 ~ 7).
Preferably, the mol ratio of the ethylenediamine rhodamine B of described sulfadiazine sodium and the grafting of first sulfonyl carbanion is 5:1 ~ 1:5.
Preferably, the preparation method of the bromoacetyl bromide glucosan of described grafting sulfadiazine is as follows: be 1:0.1:(0.1 ~ 0.7 by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio) be dissolved in dimethyl sulphoxide solution, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained.
Preferably, the molar concentration of described bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.1mol/L ~ 1mol/L.
Preferably, be 1:(0.1 ~ 0.7 by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio) be dissolved in dimethyl sulphoxide solution after mixing, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Preferably, the molar concentration of the bromoacetyl bromide glucosan of described grafting sulfadiazine in dimethyl sulphoxide solution is 0.1mol/L ~ 1mol/L.
Beta glucan is the bacterial polysaccharide that a class biocompatibility is good, has antiviral, defying age, blood sugar lowering, hemopoietic and immunomodulating and antineoplastic biological effectiveness.The acid resistance of beta glucan makes it by not being hydrolyzed utilization during stomach.A kind of stickum is had at intestinal tract surface---" fine hair ", fine hair has the receptor be combined with long chain polysaccharides.Wherein a kind of specific receptor can be combined with the polysaccharide specificity of this kind of tool special construction of beta glucan.After beta glucan is attached to specific receptor, eventually passes through enteric epithelium by pinocytosis and enter lymphsystem, and enter blood system from lymphsystem.
From pharmacodynamics angle, tumor cell has negative charge more more than normal cell surface, beta glucan has selective absorption and charge neutrality effect to tumor cell surface in sour environment, beta glucan also has the effect of direct inhibition tumor cell, show active anticancer by activated immune system, be combined with cancer therapy drug and can strengthen anticancer effect.In addition, beta glucan side chain contains abundant hydroxyl, more easily carries out chemical modification.Degradable in vivo, and catabolite is harmless, is suitable as very much the carrier of antitumor drug.
Sulfadiazine is that one has bioactive material, can tumor region selective enrichment in vivo, has the physiologically active of clear and definite close tumor characteristic, significantly antiviral and anticancer.This intelligent nano cancer therapy drug has good tumor-targeting and Co ntrolled release performance, has lower cytotoxicity, effectively can kill HeLa Cells to normal human's kidney embryo HEK293 cell, and can inducing apoptosis of tumour cell.Therefore sulfadiazine can be used as the cancer target group of medicine.
Rhodamine B (Rh-B) and derivant thereof are the important fluorescence probe materials of a class, can produce strong fluorescence under the effect of exciting light.Rhodamine B compound, after certain modification, its fluorescence emission wavelengths, fluorescent wavelength ranges, all effectively to be regulated and controled the sensitivity etc. of pH, thus can meet different application demands.In field of biomedical research, rhodamine B is because having good light stability and higher fluorescence quantum yield and being suitable as fluorescent tracer and fluorescent probe.But micromolecular rhodamine itself does not often possess some important Biofunctionals as tumor-targeting, rhodamine B compound often needs to be combined with other biological material.
Targeting fluorescent probe is that the material such as fluorescent dye and ligands specific, albumen, small-molecular peptides is combined into by chemical method, and target spot (as the receptor) specific binding that it can be special with cell surface, therefore has directivity.And target tumor can be divided into two kinds by mechanism: i.e. active targeting and passive target.Active targeting refers to the targeted delivery utilizing biologic specificity to interact as Ag-Ab combination or ligand-receptor combination etc. realize.Wherein conventional method is the receptor utilizing cancerous cell overexpression, is combined by the part corresponding with this receptor with functional molecular fragment, by active targeting by cancerous cell internalization.The receptor of this utilizable cancerous cell overexpression has tyrosine kinase receptor, folacin receptor, hormone receptor, polysaccharide receptor, lipoprotein receptor, TfR etc.
Design a desirable cancer target fluorescent probe, the following aspects be considered: the specific bond 1, with targeted molecular with height; 2, there is stable chemical constitution, be conducive to extending the probe half-life in vivo; 3, there is good fluorescence and harmless to health.
Compared with prior art, the invention provides a kind of is carrier with beta glucan, it is connected to the sulfadiazine of cancer target and epipolic rhodamine B macromole cancer therapy drug.This medicine has very strong targeting and fluorescence, by beta glucan support antitumor drug sulfadiazine, body endoenzyme can be reduced to the destruction of antitumor drug sulfadiazine and degraded, thus improve medicine stability in vivo and the utilization rate of antitumor drug, reduce the toxic and side effects of medicine; In addition, realizing while sulfadiazine kills cancerous cell, cancerous cell profile to be expressed by real-time fluorescence, realizing sulfadiazine and tumor carcinoma cells mechanism and curative effect of medication original position image evaluation, thus realize infantile tumour diagnosis, and then improve the therapeutic efficiency of tumor and reduce side effect.
Detailed description of the invention
The synthetic route of cancer therapy drug of the present invention is as follows:
In order to understand the present invention further; below in conjunction with embodiment, preparation method provided by the invention is described in detail; but should be appreciated that these describe just in order to further illustrate the features and advantages of the present invention, and they can not be interpreted as limiting the scope of the present invention.
Raw material used by following examples of the present invention is commercial goods.
Embodiment 1
Step one, synthetic bromide acetyl bromide glucosan:
Beta glucan 20,000, pyridine and bromoacetyl bromide are dissolved in dimethyl sulfoxide according to mol ratio 1:1:0.6, the molar concentration of beta glucan 20,000 in dimethyl sulfoxide is 0.1 ~ 1mol/L, 1 ~ 5d is reacted under room temperature, then reactant liquor dehydrated alcohol is precipitated, sucking filtration obtains solid, be dissolved in deionized water by product after drying, second distillation is dialysed, and vacuum 40 ~ 80 DEG C of dryings obtain bromoacetyl bromide glucosan.
Step 2, prepare sulfadiazine sodium:
Sulfadiazine and sodium hydroxide are dissolved in deionized water according to mol ratio 1:1, sulfadiazine, sodium hydroxide molar concentration is in deionized water 0.1mol/L ~ 1mol/L, room temperature reaction 10 ~ 48h, then reactant liquor is poured under agitation in appropriate dehydrated alcohol, adularescent precipitation produces, and obtains sulfadiazine sodium with dehydrated alcohol cyclic washing, drying.
The ethylenediamine rhodamine B of step 3, the grafting of synthesis first sulfonyl carbanion:
Be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.01mol/L ~ 0.2mol/L, and under an inert atmosphere, room temperature back flow reaction 15 ~ 72h, then uses CH
2cl
2extraction, last rotary evaporation drying obtains ethylenediamine rhodamine B;
After being mixed according to mol ratio 10:1 with sodium hydride by dimethyl sulfoxide, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, the mol ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B mol ratio are 0.01:1 ~ 0.1:1, then through the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
Step 4, synthesis cancer therapy drug:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
What obtain example 1 carries out infrared and nuclear-magnetism with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor and characterizes, and the glucosan carrier corresponding according to nuclear-magnetism, sulfadiazine targeting group, the integral area of rhodamine B fluorophor characteristic peak obtains sulfadiazine targeting group and the percent grafting of rhodamine B fluorophor on glucosan carrier.Sulfadiazine targeting group is 8 ~ 14% at the percent grafting of glucosan carrier, and the percent grafting of rhodamine B on glucosan carrier is 4 ~ 10%
Embodiment 2
According to method described in embodiment 1, prepare bromoacetyl bromide glucosan, difference, be beta glucan 100,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.5.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.2 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 3
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 1, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 5:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.1 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.5 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 4
According to method described in embodiment 1, prepare bromoacetyl bromide glucosan, difference, be beta glucan 100,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.56.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.2 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.36 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 5
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 1, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 2:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.5 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.1 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 6
According to method described in embodiment 1, prepare bromoacetyl bromide glucosan, difference, be beta glucan 100,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.68.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.38 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 7
Step one, synthetic bromide acetyl bromide glucosan:
Beta glucan 100,000, pyridine and bromoacetyl bromide are dissolved in dimethyl sulfoxide according to mol ratio 1:1:0.8, the molar concentration of beta glucan 100,000 in dimethyl sulfoxide is 0.1 ~ 1mol/L, 1 ~ 5d is reacted under room temperature, then reactant liquor dehydrated alcohol is precipitated, sucking filtration obtains solid, be dissolved in deionized water by product after drying, second distillation is dialysed, and vacuum 40 ~ 80 DEG C of dryings obtain bromoacetyl bromide glucosan.
Step 2, prepare sulfadiazine sodium:
Sulfadiazine and sodium hydroxide are dissolved in deionized water according to mol ratio 1:1, sulfadiazine, sodium hydroxide molar concentration is in deionized water 0.1mol/L ~ 1mol/L, room temperature reaction 10 ~ 48h, then reactant liquor is poured under agitation in appropriate dehydrated alcohol, adularescent precipitation produces, and obtains sulfadiazine sodium with dehydrated alcohol cyclic washing, drying.
The ethylenediamine rhodamine B of step 3, the grafting of synthesis first sulfonyl carbanion:
Be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.01mol/L ~ 0.2mol/L, and under an inert atmosphere, room temperature back flow reaction 15 ~ 72h, then uses CH
2cl
2after extraction, after rotary evaporation drying, obtain ethylenediamine rhodamine B;
After being mixed according to mol ratio 10:1 with sodium hydride by dimethyl sulfoxide, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, the mol ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B mol ratio 0.01:1 ~ 0.1:1, then through the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
Step 4, synthesis cancer therapy drug:
Be that 1:0.1:0.7 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.1 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 8
According to method described in embodiment 7, prepare bromoacetyl bromide glucosan, difference, be beta glucan 20,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.6.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 9
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 7, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 4:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.1 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.7 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 10
According to method described in embodiment 7, prepare bromoacetyl bromide glucosan, difference, be beta glucan 20,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.7.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.4 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 11
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 7, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 6:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.4 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 12
According to method described in embodiment 7, prepare bromoacetyl bromide glucosan, difference, be beta glucan 20,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.5.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.2 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 13
Step one, synthetic bromide acetyl bromide glucosan:
Beta glucan 20,000, pyridine and bromoacetyl bromide are dissolved in dimethyl sulfoxide according to mol ratio 1:1:0.5, the molar concentration of beta glucan 20,000 in dimethyl sulfoxide is 0.1 ~ 1mol/L, 1 ~ 5d is reacted under room temperature, then reactant liquor dehydrated alcohol is precipitated, sucking filtration obtains solid, be dissolved in deionized water by product after drying, second distillation is dialysed, and vacuum 40 ~ 80 DEG C of dryings obtain bromoacetyl bromide glucosan.
Step 2, prepare sulfadiazine sodium:
Sulfadiazine and sodium hydroxide are dissolved in deionized water according to mol ratio 1:1, sulfadiazine, sodium hydroxide molar concentration is in deionized water 0.1mol/L ~ 1mol/L, room temperature reaction 10 ~ 48h, then reactant liquor is poured under agitation in appropriate dehydrated alcohol, adularescent precipitation produces, and obtains sulfadiazine sodium with dehydrated alcohol cyclic washing, drying.
The ethylenediamine rhodamine B of step 3, the grafting of synthesis first sulfonyl carbanion:
Be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, rhodamine B, the ethylenediamine molar concentration in dehydrated alcohol is 0.01mol/L ~ 0.2mol/L, and under an inert atmosphere, room temperature back flow reaction 15 ~ 72h, then uses CH
2cl
2after extraction, after rotary evaporation drying, obtain ethylenediamine rhodamine B;
After being mixed according to mol ratio 5:1 with sodium hydride by dimethyl sulfoxide, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
Ethylenediamine rhodamine B is added in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, the mol ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B mol ratio are 0.01:1 ~ 0.1:1, then through the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
Step 4, synthesis cancer therapy drug:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.2 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 14
According to method described in embodiment 13, prepare bromoacetyl bromide glucosan, difference, be beta glucan 140,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.5.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.2 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 15
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 13, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 8:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.1 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.4 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 16
According to method described in embodiment 13, prepare bromoacetyl bromide glucosan, difference, be beta glucan 140,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.8.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.3 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.5 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 17
Bromoacetyl bromide glucosan and sulfadiazine sodium is prepared according to the method described in embodiment 13, difference is, rhodamine B in step 3, the ethylenediamine molar concentration in dehydrated alcohol is 0.1mol/L ~ 0.15mol/L, and the mol ratio of dimethyl sulfoxide and sodium hydride is 9:1.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.4 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 1mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.1 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 1mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
Embodiment 18
According to method described in embodiment 13, prepare bromoacetyl bromide glucosan, difference, be beta glucan 140,000, pyridine and bromoacetyl bromide according to mol ratio 1:1:0.7.
The building-up process of step 4 is as follows:
Be that 1:0.1:0.4 is dissolved in dimethyl sulphoxide solution by bromoacetyl bromide glucosan, TBAH and sulfadiazine sodium according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution is 0.5mol/L, at room temperature react 1 ~ 5d, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, the bromoacetyl bromide glucosan of grafting sulfadiazine is namely obtained;
Be be dissolved in dimethyl sulphoxide solution after 1:0.3 mixing by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of grafting sulfadiazine and the grafting of first sulfonyl carbanion according to mol ratio, the molar concentration of bromoacetyl bromide glucosan in dimethyl sulphoxide solution of grafting sulfadiazine is 0.5mol/L, at room temperature react 1 ~ 5d, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain with the cancer therapy drug that bromoacetyl bromide glucosan is carrier, sulfadiazine is targeting group, rhodamine B is fluorophor.
The explanation of above embodiment just understands method of the present invention and core concept thereof for helping.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improve and modify and also fall in the protection domain of the claims in the present invention.Be apparent for those skilled in the art to the multiple amendment of these embodiments, General Principle as defined herein can realize without departing from the spirit or scope of the present invention in other embodiments.Therefore, the present invention can not be restricted to these embodiments shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (8)
1. there is targeting and an epipolic cancer therapy drug, it is characterized in that the structural formula of this 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)。
2. prepare a method with targeting and epipolic cancer therapy drug according to claim 1, it is characterized in that the concrete steps of the method are:
A. beta glucan and bromoacetyl bromide are by 1:(0.5 ~ 0.8) mol ratio carry out condensation reaction, obtain bromoacetyl bromide glucosan, its structural formula is:
, wherein, x+y=1, (x+y): y=1:(0.5 ~ 0.8);
B. sulfadiazine and sodium hydroxide are fully reacted acquisition sulfadiazine sodium;
C. rhodamine B and ethylenediamine are obtained ethylenediamine rhodamine B through amidation process;
D. be dissolved in dimethyl sulfoxide by sodium hydride, under an inert atmosphere, temperature is react 10 ~ 20h under 40 ~ 60 DEG C of conditions, obtains the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion;
E. dimethyl sulphoxide solution step c gained ethylenediamine rhodamine B and steps d gained being dissolved with first sulfonyl carbanion reacts under the catalytic action of dodecyl bromide, obtains the ethylenediamine rhodamine B of first sulfonyl carbanion grafting;
F. by step a gained bromoacetyl bromide glucosan and step b gained sulfadiazine sodium under the effect of catalyst TBAH, be obtained by reacting the bromoacetyl bromide glucosan of grafting sulfadiazine;
G. the ethylenediamine rhodamine B of step e gained first sulfonyl carbanion grafting and the bromoacetyl bromide glucosan of step f gained grafting sulfadiazine are reacted, obtain with bromoacetyl bromide glucosan be carrier, sulfadiazine is targeting group, rhodamine B is fluorophor has targeting and epipolic cancer therapy drug.
3. preparation method according to claim 2, it is characterized in that the concrete preparation method of above-mentioned steps a is as follows: by beta glucan, pyridine and bromoacetyl bromide according to mol ratio 1:1:(0.5 ~ 0.8) be dissolved in dimethyl sulfoxide, reaction 1 ~ 5d, then reactant liquor dehydrated alcohol is precipitated, sucking filtration obtains solid, be dissolved in deionized water by product after drying, second distillation is dialysed, and vacuum 40 ~ 80 DEG C of dryings obtain bromoacetyl bromide glucosan.
4. preparation method according to claim 2, it is characterized in that the concrete grammar of above-mentioned steps b is: be dissolved in deionized water by sulfadiazine and sodium hydroxide according to mol ratio 1:1 ~ 1:5, room temperature reaction 10 ~ 48h, then reactant liquor is poured under agitation in appropriate dehydrated alcohol, adularescent precipitation produces, and obtains sulfadiazine sodium with dehydrated alcohol cyclic washing, drying.
5. preparation method according to claim 2, it is characterized in that the concrete grammar of above-mentioned steps c is: be dissolved in dehydrated alcohol by rhodamine B and ethylenediamine according to mol ratio 1:1, under an inert atmosphere, under room temperature, react 15 ~ 72h, dry under 40 ~ 70 DEG C of conditions and obtain ethylenediamine rhodamine B.
6. preparation method according to claim 2, it is characterized in that the concrete grammar of above-mentioned steps e is: be added to by ethylenediamine rhodamine B in the dimethyl sulphoxide solution being dissolved with first sulfonyl carbanion, the mol ratio of ethylenediamine rhodamine B and first sulfonyl carbanion is 1:1, be heated to 40 ~ 80 DEG C of reaction 2 ~ 10h, then add dodecyl bromide and continue reaction 2 ~ 10h, dodecyl bromide and ethylenediamine rhodamine B mol ratio are 0.01:1 ~ 0.1:1, then through the ethylenediamine rhodamine B of dialysing, namely vacuum drying obtains the grafting of first sulfonyl carbanion.
7. preparation method according to claim 2, it is characterized in that the concrete grammar of above-mentioned step f is: be 1:0.1:(0.1 ~ 0.7 by the sulfadiazine sodium of step a gained bromoacetyl bromide glucosan, TBAH and step b gained according to mol ratio) be dissolved in dimethyl sulphoxide solution, at room temperature react 1 ~ 5 day, then with dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain the bromoacetyl bromide glucosan of grafting sulfadiazine, its structural formula is:
.
8. preparation method according to claim 2, it is characterized in that the concrete grammar of above-mentioned steps g is: be 1:(0.1 ~ 0.7 by the ethylenediamine rhodamine B of the bromoacetyl bromide glucosan of step f gained grafting sulfadiazine and the grafting of step e gained first sulfonyl carbanion according to mol ratio) be dissolved in dimethyl sulphoxide solution, at room temperature react 1 ~ 5 day, then by reactant liquor dehydrated alcohol precipitation, sucking filtration, drying, second distillation dialysis, vacuum drying, namely obtain that there is targeting and epipolic cancer therapy drug.
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