CN106749343A - A kind of acylhydrazone schiff bases copper complex human serum albumins compound and its application - Google Patents
A kind of acylhydrazone schiff bases copper complex human serum albumins compound and its application Download PDFInfo
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- CN106749343A CN106749343A CN201611055528.4A CN201611055528A CN106749343A CN 106749343 A CN106749343 A CN 106749343A CN 201611055528 A CN201611055528 A CN 201611055528A CN 106749343 A CN106749343 A CN 106749343A
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- hsa
- copper complex
- schiff bases
- acylhydrazone
- human serum
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Links
- 239000002262 Schiff base Substances 0.000 title claims abstract description 60
- 102000009027 Albumins Human genes 0.000 title claims abstract description 41
- 108010088751 Albumins Proteins 0.000 title claims abstract description 41
- 210000002966 serum Anatomy 0.000 title claims abstract description 41
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- -1 schiff bases copper complex Chemical class 0.000 title claims abstract description 35
- 229910052802 copper Inorganic materials 0.000 claims abstract description 39
- 150000004753 Schiff bases Chemical group 0.000 claims abstract description 32
- 239000002105 nanoparticle Substances 0.000 claims abstract description 29
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229940002612 prodrug Drugs 0.000 claims abstract description 20
- 239000000651 prodrug Substances 0.000 claims abstract description 20
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- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 12
- 239000010949 copper Substances 0.000 claims description 47
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 32
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 30
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/08—Copper compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of acylhydrazone schiff bases copper complex and its composite nanoparticles constituted with human serum albumins, the acylhydrazone schiff bases copper complex chemical formula is [CuBr (BA) (L)] or [CuBr (DMF) (L)], wherein BA=quinoline, L is the compound with three tooth acylhydrazone schiff base structures, DMF=N, N dimethylformamide）, the Br in the complex−, quinoline or DMF are coordinated as part and copper center.Acylhydrazone schiff bases copper complex of the present invention and its with human serum albumins constitute composite nanoparticles as prodrug, pharmaceutical activity is not only increased, additionally it is possible to reduce drug toxicity, with fine clinical value.
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of acylhydrazone schiff bases copper complex, a kind of acylhydrazone schiff bases copper are matched somebody with somebody
Compound-human serum albumins compound and its application in prodrug is prepared.
Background technology
Estimated according to GLOBOCAN, the whole world in 2012 there are about 1,700,000 new breast cancer cases and 521, and 900 breast cancer are dead
Die, 21,400,000 new cases of cancers and about 13,200,000 cancer mortality cases will be increased to the year two thousand thirty whole world is estimated.Although conventional cancer
Chemotherapy is quite beneficial in the past few decades in terms of survival rate is improved, but it also shows that many adverse effects, includes
The efficiency of limit, without specificity, multidrug resistance and adverse side effect.In order to overcome these obstacles, various methods are developed,
Including prodrug strategies and nanoparticulate drug delivery strategies.
At present, there is the geometry and ligancy and kinetic property of wide spectrum due to metal complex, will metallizes
Compound exploitation is increasingly becoming the interest of Pharmaceutical Chemist for cancer therapy drug.In Metal Substrate anticancer compound of future generation, Cu conducts
The indispensable element of human body, with specific bioactivity and oxidizing property, therefore Cu anticancer compounds have huge potentiality.It is special
Not, cancer cell absorbs more Cu than normal cell.The main method of design HSA- Metal Substrate prodrugs is by HSA at present
Special amino acid is coupled with Metal Substrate pharmaceutical chemistry.But, this conventional chemical conjugation methods have the shortcomings that many.Example
Such as, excessive chemical bonds agent can cause HSA to precipitate.And Cys34 is difficult to connect medicine in being in the zanjon of HSA.Additionally, in body
Interior HSA carriers delivery metal prodrug reach cancer cell also exist two it is possible the drawbacks of.Firstth, metal prodrug is connected to HSA tables
Face, causes medicine to be exposed to other internal albumen, so that these albumen may cause gold with HSA competition binding medicines
Category prodrug is escaped from HSA carriers and being attached to other albumen may cause side effect.Secondth, because metal prodrug and HSA are tied
Close too weak, metal prodrug may too early discharge and can not reach cancer cell.
The content of the invention
The present invention is in view of the shortcomings of the prior art, synthesized two kinds of Cu complexs with leaving group, such complex can
Not use any chemical linking agent to covalently bind in the IIA calmodulin binding domain CaMs of HSA, it is to avoid problems of the prior art.Enter
One step, the acylhydrazone schiff bases copper complex-human serum albumins compound of formation can be made human serum by removing solvent method
Albumin copper (II) prodrug nano particle (HSA-Cu (II)), medicaments uniformity is dispersed in nanosphere body, it is to avoid prodrug is prominent to be released.
Concrete technical scheme of the present invention is as follows：
A kind of acylhydrazone schiff bases copper complex, chemical formula is as follows：
[CuBr (BA) (L)] or [CuBr (DMF) (L)], wherein BA=quinoline, L is with three tooth acylhydrazone schiff base structures
Compound, DMF=N, dinethylformamide), the Br in the complex-, quinoline or DMF match somebody with somebody as part with copper center
Position.
Preferably, the L is the compound of aroyl hydrazone schiff base structure, more preferably O, N, O-three tooth aroyl hydrazone Schiff
The compound of alkali structure.A preferred scheme of the invention, L has below formula structure：
Or
Wherein
Or-CH3,
R2=-H ,-F ,-Cl ,-Br or-CH3。
A preferred scheme of the invention, L is (E)-N'- (5- chlorine-2-hydroxyls benzal) benzoyl hydrazine.The acylhydrazone seat
Husband's alkali copper complex is preferably as follows：
Compound another object of the present invention is to provide above-mentioned acylhydrazone schiff bases copper complex and human serum albumins, it is above-mentioned
Acylhydrazone schiff bases copper complex can not need chemical linking agent, and directly be formed with human serum albumins covalent bond.X- is penetrated
The research of line mono-crystalline structures shows that Lys199 the and His242 amino acid of HSA IIA calmodulin binding domain CaMs replaces the quinoline in C1 complexs respectively
Quinoline and Br-Part is coordinated with copper center；And the DMF groups of C2 complexs keep inertia, the His242 ammonia of HSA IIA calmodulin binding domain CaMs
The Br of base acid substitution axial direction-Part is coordinated with copper center.
Above-mentioned acylhydrazone schiff bases copper complex-human serum albumins is compound can not to use chemical linking agent, by acylhydrazone seat
Husband's alkali copper complex is directly incubated 24h with human serum albumins and prepares at room temperature, comprises the following steps that：
(1) take 2g Powdered Activated Carbons, the medical human serum albumins of 5ml ultra-pure waters and 10ml 20% in 50ml beakers, by this
Beaker is placed in frozen water, adjusts pH to 2.8, stirs 2h, then adjusts pH to 7.5.Be then centrifuged for and dialyse removal except activated carbon,
Dimer and polymer in HSA obtain the monomer HAS used by follow-up test；
(2) concentration of the monomer HSA obtained after being dialysed with determined by ultraviolet spectrophotometry；
(3) with 1：3 ratio mixes HSA (100mg/mL) in the cushioning liquid of 20mM potassium phosphates (pH 7.5) and copper coordinates
Thing, then normal temperature be incubated 24h, excessive copper complex is by being centrifuged wash-out removal.
Another object of the present invention is to provide above-mentioned acylhydrazone schiff bases copper complex-human serum albumins compound nanometer
Particle, can by acylhydrazone schiff bases copper complex-human serum albumins compound by go solvent technology be made size it is homogeneous and
The prodrug nanosphere being dispersed in nano particle of medicaments uniformity.
In order to further improve targeting and reduce side effect, above-mentioned acylhydrazone schiff bases copper complex-human serum albumins
Composite nanoparticles can further connect folic acid (FA) targeting small molecule.
Match somebody with somebody another object of the present invention is to provide acylhydrazone schiff bases copper complex of the present invention, acylhydrazone schiff bases copper
Compound-human serum albumins compound, acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles and connection
There is the acylhydrazone schiff bases copper complex-application of the human serum albumins composite nanoparticles in prodrug is prepared of folic acid.
Aforementioned prodrugs are antineoplastic or treatment Fe supply disease medicament.
Preferably, the antineoplastic can be used to treat the cancers such as cervical carcinoma, lung cancer, breast cancer, liver cancer.
Advantage of the present invention：
(1) benzoyl hydrazine schiff base ligand has good active anticancer, and the present invention keeps main pharmacophore part (L) constant, if
Ligands (quinoline or DMF) of the meter with different coordination atoms, preferably Br, as leaving group, does not make as the 3rd part
In the case of chemical linking agent, His242 the or Lys199 amino acid of HSA can replace acylhydrazone schiff bases of the present invention
The leaving group Er Yutong centers coordination of copper complex, is closely adhered to the IIA subdomains of HSA, improves HSA delivery copper prodrugs
Efficiency.
(2) acylhydrazone schiff bases copper complex of the present invention-human serum albumins composite nanoparticles (HSA-C1/C2
) and acylhydrazone schiff bases copper complex-human serum albumins compound-folic acid nano particle (FA-HSA-C1/C2 NPs) point NPs
Not Ju You about 162nm diameter and about 220nm diameters, be not easy to be swallowed both with narrow size distribution, after injection, and
And with good biocompatibility.
(3) acylhydrazone schiff bases copper complex (C1/C2) of the present invention has higher antitumor compared to main pharmacophore ligand L
Activity.
(4) acylhydrazone schiff bases copper complex of the present invention-human serum albumins composite nanoparticles (HSA-C1/C2
NPs) and it is connected with the acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles (FA-HSA-C1/ of folic acid
C2 NPs) compare with proto-drug C1/C2 with more high anti-tumor activity.
(5) acylhydrazone schiff bases copper complex of the present invention-human serum albumins composite nanoparticles (HSA-C1/C2
NPs) and it is connected with the acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles (FA-HSA-C1/ of folic acid
C2 NPs) compare with proto-drug C1/C2 to normal cell with lower toxicity.
(6) acylhydrazone schiff bases copper complex of the present invention-human serum albumins composite nanoparticles (HSA-C1/C2
NPs) and it is connected with the acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles (FA-HSA-C1/ of folic acid
C2 NPs) can substantially reduce liver, renal toxicity and the good tolerance of acylhydrazone schiff bases copper complex, with it is good it is clinical should
Use prospect.
Brief description of the drawings
Fig. 1 acylhydrazone schiff bases copper complexes of the present invention [CuBr (BA) (L)] (complex C1) and [CuBr (DMF)
(L)] the chemical constitution of (complex C2).
The exercising result of the N-HBr of Fig. 2 complexs C1 and complex C2.(A) it is the N- of complex C1
HBr acts on the polymeric bonds to be formed (symmetrical code：(i)x,0.5-y,-0.5+z)；(B) it is the N- of complex C2
HBr acts on the dimer to be formed (symmetrical code：(i)1-x,1-y,1-z).
The fluorescence quenching spectrum of HSA under Fig. 3 (A) complex C1 and C2 various concentrations, T=298K, arrow is represented to be increased
Fluorescent quenching during complex concentration (0-4 μM).(B) the MALDI-TOF-MS mass spectrograms of HSA-C1/C2 compounds.
The electrospray ionization mass spectrometry (ESI-MS) of Fig. 4 .HSA-C1 compounds (A) and HSA-C2 compounds (B) releasing product,
Black fine rule is the spectrum observed, Nogata gray line is the m/z signal peaks of simulation.
The 2F of Fig. 5 (A) HSA-C1 compounds and HSA-C2o-FcElectron-density map.(B) entirety of HSA-C1/C2 compounds
Structure.(C) local combining environmental figure of the copper complex in HSA IIA calmodulin binding domain CaMs.
Scanning electron microscope image (B) HSA-C1/ of Fig. 6 (A) HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs
The particle diameter of C2 NPs and FA-HSA-C1/C2 NPs and distribution.
Fig. 7 (A) C1/C2 (5 μM), HSA-C1/C2 NPs (5 μM) and FA-HSA-C1/C2 NPs (5 μM) act on red thin
Hemolytic reaction analysis after born of the same parents 1h.(B) phase microscope observes C1/C2 (5 μM), HSA-C1/C2 NPs (5 μM) and FA-HSA-C1/
The aggegation situation that C2 NPs (5 μM) are acted on after the h of red blood cell compares.Each value represents average value ± SD (n=3).
The gross tumor volume of Fig. 8 (A) each administration group of Bel-7402 tumor mouse models compares.(B) Bel-7402 mice with tumor
The knurl weight average value of each administration group of model compares.(C) weight ratio of each administration group of Bel-7402 tumor mouse models is compared with (* P<
0.05；**P<0.01；***P<0.001).
The tumour of each treatment group of Fig. 9 intracorporeal active experiments and h and E dyeing (H＆E) group of other slices of organs
Knit inspection result (multiplication factor × 400).
In each treatment group's ground tumor tissues of Figure 10 .C2 complexs, HSA-C2 NPs and FA-HSA-C2 NPs and major organs
(each value represents average value ± SD (n=3) to copper content：*P<0.05；**P<0.01.).
Specific embodiment
Specific steps of the invention are illustrated by the following examples, but are not limited by the example.
The term for being used in the present invention, unless otherwise indicated, typically there are those of ordinary skill in the art generally to manage
The implication of solution.
The present invention is described in further detail with reference to specific embodiment and with reference to data.It should be understood that the embodiment is
In order to demonstrate the invention, rather than by any way the scope of the present invention is limited.
In the examples below, the various processes and method not described in detail are conventional methods as known in the art.
With reference to specific embodiment, the present invention is further described.
Medical human serum albumins is bought from U.S. Ztel Belling biological products Co., Ltd.Other chemical drugs for being used
Product and solvent are commercial source and are high-purities.Water used is all distilled water in the reaction.Elementary analysis (C, N and H) exists
Carried out on the analyzer of Perkin-Elmer companies 2400.Infrared (IR) is determined and is used Nexus870 FT-IR spectrophotometers
(4000-400-1) and KBr compressing tablets.
The acylhydrazone schiff bases copper complex of the present invention of embodiment 1 [CuBr (BA) (L)] (compound C1) and [CuBr
(DMF) (L)] (compound C2) preparation and sign
Benzoyl hydrazine schiff bases (can with (E)-N'- (5- chlorine-2-hydroxyls benzal) for acylhydrazone schiff base ligand L used by the present invention
Bibliography：Ali HM,Puvaneswary S,Ng SW.5-Chlorosalicylaldehyde
benzoylhydrazone.Acta Crystallogr.,Sect.E:Struct.Rep.Online 2005,61, o2415. system
) as a example by, prepare acylhydrazone schiff bases copper complex.
The synthetic method of [CuBr (BA) (L)] (C1) is as follows：L (0.55g, 2mmol) and heterocycle nitrogen ligand quinoline (BQAL；
0.26g, 2mmol) it is dissolved in 15mL methyl alcohol, in stirring at normal temperature 1h, obtain orange-yellow liquid.It is subsequently adding and is dissolved in methyl alcohol
CuBr2(0.44g, 2mmol) solution.Above-mentioned mixed solution continues to be stirred for 1h at room temperature, obtains blackish green solution, then mistake
Filter mixed solution, collects filtrate.The filtrate keeps slow volatilization 7 days or so in atmosphere, and black-and-blue crystalline substance is slowly separated out in solution
Body.Crystal is separated, with distillation water washing three times, and is dried in the vacuum desiccator containing anhydrous calcium chloride.Yield：
C23H17BrClCuN3O2(546.30) 776mg (71%).Elementary analysis：C, 50.56 (50.53)；H, 3.13 (3.14) and N,
7.69(7.70)。IR(KBr,cm-1)：1616 ν (C=N)；581,549,487,468,443 ν (Cu-N/Cu-O).
The above method is can refer to, DMF is replaced into the quinoline in the above method, prepared [CuBr (DMF) (L)] (C2).Yield：
C17H17BrClCuN3O3(490.24) 764mg (78%).Elementary analysis：C, 41.65 (41.53)；H, 3.49 (3.52) and N,
8.57(8.58)。IR(KBr,cm-1)：1619 ν (C=N)；548,505,458,436,422 ν (Cu-N/Cu-O).
Reaction equation is as follows：
Mono-crystalline structures are characterized：The crackless single crystal of selected shape rule, determines in 292-298K.With graphite monochromator
Mo-Kα(The scan mode of ω -2 θ) radiation ray collect crystal data, then using Bruker APEX
Visit diffractometer record diffraction data in SMART CCD faces.Data correction is carried out using SADABS programs.Structure by heavy-atom method and
Direct method is parsed, and uses the complete matrix least square method of SHELXTL5.1 to F2Refined.All of non-hydrogen atom enters
Row anisotropy refine.And all of hydrogen atom is placed on preferable geometric position and constrains on the atom belonging to it.Change
The crystallographic data of compound C1 and C2 is as shown in table 1.The part bond distance of selection and bond angle are as shown in table 2.For structural analysis
Crystallographic data by Cambridge crystallographic data center (Cambridge Crystallographic Data Centre) receive
Collection, No. CCDC of C1 No. CCDC for 1011410, C2 is 967408.Corresponding crystal data can also freely from Cambridge crystal
Data center obtains.
The crystal data of table 1. complex C1 and C2
The part bond distance of table 2. complex C1 and C2With bond angle [°].
X-ray single crystal diffraction shows that complex C1 belongs to monoclinic system, and space group is P21/c.As shown in figure 1, not
Contain a three tooth schiff base ligands, Cu (II) center, a quinoline part and a terminal Br atom in symmetrical cell.
A nitrogen-atoms and two oxygen atoms on Cu (II) centers and schiff base ligand, a nitrogen-atoms from quinoline part and
Axial terminal Br is coordinated, and forms the common pentacoordinate structure of copper compound.All of Cu-N/O distances exist 's
It is consistent with the similar structure bond distance for having reported in scope.Can be described as one around Cu1 centers coordination polyhedrom slightly to distort
Square pyramid (τ=0.004).In the solid state, the monomeric unit of C1 passes through coordination bromine atoms (Br1) and neighbouring list
N2 on body schiff base ligandiComposition N-HBr weak interactions (Br1···N1i-
H4iAngle is 158.7 °；Symmetrical code：(i) x, 0.5-y, -0.5+z, as shown in Figure 2 A), form 1D polymerizations and connect.
The crystal structure of complex C2 is as shown in Figure 1.X-ray single crystal diffraction shows that complex C2 belongs to anorthic system,
Space group is P-1.Coordination configuration around copper center is quite similar with C1, except ligand molecule DMF in the plane is different.
And in the solid state, the monomeric unit of C2 is by the bromine atoms (Br1) being coordinated and the N5 on monomer schiff base ligandiStructure
Into N-HBr weak interactions (Symmetrical code：(i) 1-x, 1-y, 1-z, such as Fig. 2 B institutes
Show), form dimeric structure.
The preparation of the acylhydrazone schiff bases copper complex of embodiment 2-human serum albumins compound (HSA-C1/C2) and sign
The 20% of 10ml medical human serum albumins, 2g Powdered Activated Carbons and 5ml ultra-pure waters are taken in 50ml beakers, this is burnt
Cup is placed in frozen water, adjusts pH to 2.8, stirs 2h, then adjusts pH to 7.5.Be then centrifuged for and dialyse removal except activated carbon,
Dimer and polymer in HSA obtain the monomer HSA used by follow-up test.
The single crystal diffraction of HSA compounds：Aliphatic acid (PA) is diluted with 20mM potassium phosphates (pH 7.5) arrive 2.5mM.In experiment
In, to make C1 and C2 and HSA be combined into prodrug compound, first by the PA (2.5mmol) of 380 μ L, the HSA (100mg/ of 100 μ L
ML) and 90 μ L Cu complexs (5mmol) mixing, then normal temperature be incubated 24h, finally mixture is placed in concentration tube and is added water
Washing and filtering is concentrated into 100mg/ml (micropore spin filterings (cut-off of 10,000 dalton).Expanded by sitting drop steam at room temperature
Dissipate and crystallized, the solution in the present drop plate of the compound of isometric HSA and storage is mixed, this solution is by 28-32% (weights
Amount/volume) PEG3350,50mM potassium phosphates (pH 7.5), 5% glycerine and 5% DMSO mix.The crystal grown
Directly select to take out from dropping liquid and and then refrigerated in liquid nitrogen.The data of X-ray diffraction are to use SSRF,
(100K) collects what is completed under cryogenic.Diffraction data HKL2000 treatment.The structure of HSA compounds passes through AMORE journeys
The molecule of sequence puts method (HSA-MYR is model, PDB code 1BJ5) and builds model.The preliminary cast of structure uses CNS program rigidity first
Refine, then increases the refine wheel number refine B- factors, until obtaining original Fo-FcAnd 2Fo-FcElectron-density map.These electronics
Density map is used to refer to the position of aliphatic acid and copper compound, and manually adjustment structure and increase refine wheel number are further
Refine protein structure.PyMOL softwares are used for accompanying drawing and describe and process.The details and cell parameter of Data Collection are given in table 3.
The crystal data of table 3.HSA-C1/C2 compounds
a Values for the outermost resolution shell are given in parentheses.
bRmerge=100 × ΣhΣj|Ihj-Ih|/ΣhΣj Ihj where Ih is the weighted mean
intensity of the symmetry-related refractions Ihj.
cRmodel=100 × Σhkl|Fobs-Fcalc|/ΣhklFobs where Fobs and Fcalc are the observed
and calculated structure factors,respectively.
dRfree is the RmodelCalculated using a randomly selected 5%sample of
reflection data omitted from the refinement.。
Fluorescence spectrum experiments result shows, as complex C1 or C2 concentration increase, human serum albumins in wavelength about
There is strong fluorescent quenching in 346nm, this shows that these copper complexes combine the IIA subdomains in HSA and have strong binding ability
(as shown in Figure 3A).Substance assistant laser desorpted/ionization time (MALDI-TOF-MS) display HSA and C1 or C2 of flight mass spectrum
After effect, molecular weight increases about 400Da than single HSA, shows that about copper complex is attached to HSA (as shown in Figure 3 B).
Additionally, under conditions of pH 5, electrospray ionization mass spectrometry (ESI-MS) table for the copper compound discharged from HSA-C1 compounds
It is bright, when energy is 0 volt in source, there is m/z=335.97, this is [Cu (L)]+(fit:335.97) isotopic peak, this meaning
Taste Br and BA parts and is lost (as shown in Figure 4 A).And under similarity condition, the copper compound discharged from HSA-C2 compounds
Electrospray ionization mass spectrometry (ESI-MS) peak in m/z=409.03, this is [(L) Cu (DMF)]+(fit:409.03) isotope
Peak, shows that DMF parts are present in HSA-C2 compounds (as shown in Figure 4 B).
The mono-crystalline structures analysis result of HSA-C1/C2 compounds shows there is a copper compound point in the IIA subdomains of HAS
Sub (as shown in Figure 5A).The general structure of HSA-C1/C2 is still heart shape.In IIA subdomains, copper chemical combination be attached to one by
Arg222, Arg218, His242, Lys199, Trp214, Leu219, Ala291, Phe223, Leu238, Arg257, Leu260,
In the hydrophobic cavity that Ile264, Ser287 and Ile290 are constituted (as shown in Figure 5 B).HSA-C1 structures show, Lys199 and
His242 distinguishes substd quinolines part and Br parts, is coordinated with copper center.And HSA-PA-C2 structures show, His242 substitution axles
To Br parts, and Lys199 does not replace the DMF parts in plane.
The acylhydrazone schiff bases copper complex-human serum albumins compound-of embodiment 3 folic acid nano particle (FA-HSA-C1/
C2 preparation) and sign
(1) system of acylhydrazone schiff bases copper complex-human serum albumins compound-folic acid nano particle (HSA-C1/C2 NPs)
It is standby
In order to obtain HSA- metals prodrug and constant load medicine ratio, first by acylhydrazone schiff bases of the present invention obtained in embodiment 1
Copper complex is incubated (mol ratio 1 at room temperature with HSA：3) 24h, excessive acylhydrazone schiff bases copper complex spin dialysis removal.
Then, solvent method is removed according in document, under conditions of room temperature and constant agitation, by the acylhydrazone schiff bases of the above-mentioned incubations of 4mL
Copper complex adjusts pH to 8 with HSA mixtures (1.5mM), is continuously added to 15.0mL ethanol solutions (1mL/min), gradually forms
HSA-C1/C2 NPs.After protein denaturation, 8% 450 microlitres of glutaraldehyde water solution is added to be crosslinked to realize nano-particle.So
Said mixture is centrifuged 10 minutes with 40,000rpm afterwards, isolated HSA-C1/C2 NPs.[Weber C,Kreuter J,
Langer K.Desolvation process and surface characteristics of HSA-
nanoparticles.Int J Pharm.2000；196(2):197-200；Sebak S,Mirzaei M,Malhotra M,
Kulamarva A,Prakash S.Human serum albumin nanoparticles as an efficient
noscapine drug delivery system for potential use in breast cancer:preparation
and in vitro analysis.Int J Nanomedicine.2010；5:525-32.].
(2) acylhydrazone schiff bases copper complex-human serum albumins compound-folic acid nano particle (FA-HSA-C1/C2
NPs preparation)
The NaOH (0.1N) FA solution (20mg/mL) of 2.5mL, in N- (3- dimethylaminopropyls)-N- ethyls of 50mg
The lower lucifuge stirring 30min of N-hydroxy-succinamide (NHS) catalysis of carbodiimide (EDC) and 20mg.Then, by HSA-C1/
C2 NPs suspensions (content 15mg/mL) is added, and continues lucifuge stirring 3 hours.Unreacted FA by differential centrifugation (40,
000rpm, 10min) said mixture removes.The FA-HSA-C1/C2 NPs water redisperses of bottom will be deposited in, be carried out follow-up
Experiment.The content of copper compound is by cracking nano particle into solution state in FA-HSA-C1/C2 NPs, then uses graphite furnace
Atomic Absorption Spectrometer (GF-AAS) determines the content of wherein copper.
(3) sign of FA-HSA-C1/C2 NPs and hemolytic are determined
Scanning electron microscope image shows that HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs have spherical and smooth table
Face (as shown in Figure 6A).The average diameter and size distribution of the nano-particle of preparation are determined by laser light scattering.HSA-C1/C2
NPs and FA-HSA-C1/C2 NPs have the diameter and about 220nm diameters of about 162nm respectively, and both have narrow granularity
Distribution is (as shown in Figure 6B).In this particle size range, compared to larger nano particle, will after the nano particle injection of this particle diameter
It is not easy phagocytosis.
One of NPs necessary conditions for intravenously administrable are with excellent blood compatibility.Therefore, to above-mentioned nano particle
Hemolysis rate be estimated by Haemolytic Assay.The hemolytic performance of FA-HSA-C1/C2 NPs passes through spectrophotometry.
For the research of RCA, each sample (5 μM of Cu (II) compounds, 5 μM of HSA-C1/C2 NPs and 5 μM of FA-HSA-
C1/C2 NPs) 1h is acted on blood, it is placed on slide, it is analyzed with phasecontrast microscope.Shown in result figure 7A, relatively
In single C1/C2 complexs, HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs are substantially reduced to erythrocyte hemolysis destruction,
Even if in 5 μM of high concentration.Additionally, individually Cu (II) compounds and red blood cell are acted on 1 hour, there is agglutination phenomenon, and
Red blood cell is not observed agglutination phenomenon (as shown in Figure 7 B) in HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs.
The determination of activity of embodiment 4 C1/C2, HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs
(1) active determination in vitro
SMMC-7721 Bel-7402 and normal lung fibroblasts WI-38 are (from the American Type Culture
Collection and the German Collection of Microorganisms and Cell Cultures buy)
Cultivated in DMEM (Glu having) culture medium.The culture medium contains 10% hyclone (FBS), the green grass or young crops of 50U/mL
Mycin, 50mg/mL streptomysins.Then, the cell containing culture medium is placed in 37 DEG C of steam humidity and 5%CO2Incubator training
Support.
Density is about 3 × 104Cell/mL, is inoculated into 96 orifice plates (per the μ L of hole 180).In 37 DEG C and 5%CO of temperature2's
CO224h is cultivated in incubator.Be subsequently adding with various concentrations gradient candidate drug (C1/C2, HSA-C1/C2 NPs and
FA-HSA-C1/C2 NPs, drug concentration is in terms of copper), then at 37 DEG C and 5%CO2Under conditions of be incubated 48h.Absorbance enzyme
Mark instrument is surveyed under the dual wavelength of 570/630nm.Final IC50(when survivaling cell number is control group half, drug concentration)
Value is drawn (n=5) by classical Bliss methods.At least 3 times independent repetitions of all test experiments.
Result as shown in table 4, as a result shows that in vitro, FA-HSA-C1/C2 NPs are than C1/C2 and HSA-C1/C2 NPs couple
Folacin receptor secretes more Bel-7402 cells shows and goes out cell toxicant higher and lives, and secretes little normal to folacin receptor
Similar effect is not observed in WI-38 lung fibroblasts.
Table 4 C1/C2, HSA-C1/C2 NPs and FA-HSA-C1/C2 NPs are to the Bel-7402 and IC of WI -38 cell50 a
(μM) value.
aIC50 values are presented as the mean±SD from three separated
experiments。
(2) activity in vivo is determined
External activity research shows C2 series (C2, HSA-C2 NPs and FA-HSA-C2 NPs) than C1 series (C1, HSA-C1
NPs and FA-HSA-C1 NPs) there is more preferable active anticancer.Therefore, in order to further assess the HSA nano-carriers of FA- functionalizations
Whether more preferable anticancer property is shown in vivo with prodrug strategies, by taking active preferably C2 series as an example, using heterograft
Bel-7402 mouse liver cancer models are further studied.
All experimental animals observe People's Republic of China's administration of health regulations (reference number of a document NO.55,2001).
Kunming (KM) mouse are provided by the Chinese Academy of Sciences (Shanghai).
All experiments are repeated 3 to 5 times.Student's t-test check the significance of difference for assessing measured value.Survey
Measure result to be represented with mean+SD (SD), work as p<0.05, it is believed that with significant difference.
(1) studies on acute toxicity
Method in acute toxicity testing bibliography of C2, HSA-C2 NPs and the FA-HSA-C2 NPs in mouse body.32
The KM mouse (3~4 weeks ages weighed 18~22g, the female and male of equivalent) of health, are divided into 4 groups, control group, C2 groups, HSA-
C2 NPs groups and FA-HSA-C2 NPs groups, every group 8.C2 groups, HSA-C2 NPs and FA-HSA-C2 NPs groups injection equivalent
Dose (15 μm of ol Cu/kg body weight), control group injects 0.9% isometric physiological saline.After effect 7 days, blood sample is analyzed
In day (door) winter propylhomoserin transaminase (aspartate aminotransferase, AST), alanine aminotransferase (alanine
Aminotransferase, ALT), creatine kinase (creatinine kinase, CK) and blood urine nitrogen (blood urea
Nitrogen, BUN) index.
After determining dosing 7 days, day (door) winter propylhomoserin transaminase (aspartate aminotransferase, AST),
Alanine aminotransferase (alanine aminotransferase, ALT), creatine kinase (creatinine kinase, CK) and blood
Urinary nitrogen (blood urea nitrogen, BUN) level, assessment is to the toxicity of the heart, liver and kidney of normal rat (such as the institute of table 5
Show).All dosing group CK value levels are similar to control group, show C2, and HSA-C2 NPs and FA-HSA-C2 NPs are almost without the heart
Dysentery.BUN values correspondence high Toxicity of Kidney high.The BUN values (18.4 ± 2.4mmol/L) of C2 groups are apparently higher than control group
(NaCl, 7.3 ± 1.1mmol/L).And HSA-C2 NPs and FA-HSA-C2 NPs groups, particularly FA-HSA-C2 NPs groups, it is bright
It is aobvious to have relatively low renal toxicity.AST the and ALT levels of C2 groups are apparently higher than control group, and HSA-C2 NPs and FA-HSA-C2 NPs
AST the and ALT levels of group are suitable with control group, show that HSA-C2 NPs and FA-HSA-C2 NPs have very low hepatotoxicity wind agitation.
The serological analysis result of table 5.NaCl, C2, HSA-C2 NPs and FA-HSA-C2 NPs administration group mouse
(2) internal antitumor activity
Bel-7402 cells and high concentration matrigel are mixed into (matrigel：PBS=1：3).Because matrigel condenses at 10 DEG C,
Therefore, all processes all should be operated on ice.Adjustment cell density, every nude mice/0.2mL, in order to ensure every nude inoculation
Cell number it is uniform, in cell point to the EP pipes of precooling that 0.2mL is mixed, cell number is 5 × 106Individual, every nude mice connects
One is planted to manage.1mL syringes used during inoculation also answer precooling.After inoculating cell, the shapes and sizes of observation and record tumour.
When tumour is about 100mm3, select 32 nude mices that knurl body is uniform, size is relatively uniform and be randomly divided into 4 groups, every group 8
Only (control group, C2 groups, HSA-C2 NPs groups and FA-HSA-C2 NPs groups).Control group 0.9% physiological saline of injection, C2 groups,
HSA-C2 NPs groups and FA-HSA-C2 NPs groups inject 3.5 μm of medicines of ol Cu/kg body weight to be injected intravenously administering mode.Often
A medicine is given within 3 days, nude mice body weight is claimed before administration and gross tumor volume (gross tumor volume (mm is recorded with slide measure3)=1/2 × (L ×
W2), L is the major diameter of tumour, and W is the minor axis of tumour), it is administered 14 times altogether.
Bel-7402 mice with tumor is injected intravenously C2, HSA-C2 NPs and FA-HSA-C2 NPs, NaCl injection conduct respectively
Control.The change of an every 3 days gross tumor volumes of monitoring and mouse body weight.After experiment periods terminate within 24 days, FA-HSA-C2 NPs treatments
The tumour of group is significantly less than C2 and HSA-C2 NPs groups (result is as shown in Figure 8 A).Compared to control group, after treatment in 24 days, C2 groups swell
Knurl volume for control group volume 65.3 ± 5.9%, HSA-C2 NPs be control group 47.6 ± 5.1%, FA-HSA-C2 NPs
Only the 29.9 ± 3.1% of control group, show that FA-HSA-C2 NPs have more preferable Hepetoma than C2 and HSA-C2 NPs groups.Together
When, 24 days after treatment, put to death mouse and harvest tumour, weigh and take pictures (as shown in Fig. 8 B and C).Tumor control rate (TIR) is used
Tumor weight is calculated.Compared to control group, the TIR of FA-HSA-C2 NPs is 78.2% (P<0.001), hence it is evident that swollen higher than C2
Knurl inhibiting rate (34.2%, P<0.01) with inhibiting rate (54.4%, the P of HSA-C2 NPs<0.001).
In order to further assess active anticancer, tumor tissues carry out section and h and E dyes (H＆E) histology
Check.H＆E dyeing displays, medicine group is substantially different (such as Fig. 9 institutes with the tumor tissues morphology of the histotomy of control group
Show).Have the big core of spindle in NaCl groups, in tumour cell, and do not have in tumor tissues visible Apoptosis or
Necrosis, represents tumour fast-growth.However, the tumour cell shown in each field of microscope, in C2, HSA-C2 NPs and
Average cell quantity declines in FA-HSA-C2 NPs groups, the contraction of fragment and core, particularly FA-HSA-C2 NPs treatments occurs
Tumour it is more obvious.
(3) side effect in vivo is compared
Fig. 8 C are shown in therapeutic process, control group, the change of C2, HSA-C2 NPs and FA-HSA-C2 NPs group mouse body weight.
HSA-C2 NPs and FA-HSA-C2 NPs group mouse body heavy phases have dropped 11.8% and 8.1% respectively for first body weight, hence it is evident that low
In the decline (16.5%) of control group mouse body weight.And the decline of C2 group mouse body weight reaches 18.4%.These results show,
HSA-C2 NPs and FA-HSA-C2 NPs reduce the side effect of C2.Additionally, H＆E dyeing is also used for observing the related pair of medicine
Act on and to the toxicity (as shown in Figure 9) of major organs.It is worth mentioning, all groups have little to no effect to heart.However, it is possible to
It is clearly observed C2 and induces serious liver damage (liver cell atrophy and mild fatty lesion) and kidney damage (focus exception
With the hyalina of renal tubule).In contrast, HSA-C2 NPs and FA-HSA-C2 NPs it is smaller to liver and kidney injury-it is light
Micro milling and cellular atrophy.Changes of weight and pathological study result show that HSA-C2 NPs and FA-HSA-C2 NPs can be effective
Reduce the side effect of C2 inductions and the HSA-C2 NPs of toxicity, particularly folic acid functionalization in ground.
(4) Journal of Sex Research is targetted in vivo
In Bel-7402 tumor tissues can effectively being run up to for the HSA NPs carriers for determining folic acid functionalization in vivo,
We determine C2, copper content in tumor tissues and major organs in HSA-C2 NPs and FA-HSA-C2 NPs treatment groups.To protect
- 80 DEG C of hearts of the mice with tumor of refrigerator, liver, kidney and tumor tissues are stored in be homogenized respectively.Then 0.5g samples are taken respectively adds 1mL
30% hydrogen peroxide (H2O2) and 7mL dense HNO3, the mineralising in polytetrafluoroethylene (PTFE) pressure vessel.The Cu in sample after mineralising
Ion concentration is determined with inductively coupled plasma atomic emission spectrometry (ICP-AES).
The result of ICP-AES (ICP-AES) shows, HSA-C2 NPs and FA-HSA-
The content of copper is respectively 1.5 and 2.1 times (as shown in Figure 10) of C2 groups in C2 NPs group tumours.These conclusions show that folic acid is received
The intracellular village effect of body mediation selectively runs up to Bel-7402 tumour cells and plays to the HSA NPs carriers of folic acid functionalization
Important effect.Result data also shows, HSA-C2 NPs and FA-HSA-C2 NPs advantageously reduce C2 run up to hepatic tissue and
In renal tissue.
Claims (10)
1. a kind of acylhydrazone schiff bases copper complex, it is characterised in that chemical formula is as follows：
[CuBr (BA) (L)] or [CuBr (DMF) (L)], wherein BA=quinoline, L is with three tooth acylhydrazone schiff base structures
Compound, DMF=N, dinethylformamide, the Br in the complex-, quinoline or DMF are coordinated as part and copper center.
2. acylhydrazone schiff bases copper complex as claimed in claim 1, it is characterised in that L is the change of aroyl hydrazone schiff base structure
Compound.
3. acylhydrazone schiff bases copper complex as claimed in claim 2, it is characterised in that L is O, N, O-three tooth aroyl hydrazone Schiff
The compound of alkali structure.
4. acylhydrazone schiff bases copper complex as claimed in claim 3, it is characterised in that L has below formula structure：
Or
Wherein
Or-CH3,
R2=-H ,-F ,-CI ,-Br or-CH3。
5. a kind of acylhydrazone schiff bases copper complex-human serum albumins compound, it is characterised in that by claim any one of 1-4
Described acylhydrazone schiff bases copper complex is formed with human serum albumins covalent bond.
6. acylhydrazone schiff bases copper complex-human serum albumins compound as claimed in claim 5, it is characterised in that do not use
Chemical linking agent, is directly incubated 24h and prepares at room temperature by acylhydrazone schiff bases copper complex with human serum albumins.
7. a kind of acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles, it is characterised in that acylhydrazone schiff bases
Copper complex-human serum albumins compound is as described in claim 5 or 6.
8. acylhydrazone schiff bases copper complex-human serum albumins composite nanoparticles as claimed in claim 7, its feature exists
Folic acid is connected with the nano grain surface.
9. the acylhydrazone schiff bases copper complex as described in claim any one of 1-4, the acylhydrazone seat as described in claim 5 or 6
Husband's alkali copper complex-human serum albumins compound and acylhydrazone schiff bases copper complex-people as claimed in claim 7 or 8
Application of the seralbumin composite nanoparticles in prodrug is prepared.
10. application as claimed in claim 9, it is characterised in that the prodrug is antineoplastic or treatment Fe supply disease medicine
Thing.
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| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
| CN108558914A (en) * | 2018-04-08 | 2018-09-21 | 广西师范大学 | Copper complex and its synthetic method based on biotin o-vanillin acyl hydrazone derivative and application |
| CN109908364A (en) * | 2019-03-28 | 2019-06-21 | 广西师范大学 | Using human serum albumins as the synthetic method and application of gold (III) metal composite of carrier |
| CN109970770A (en) * | 2019-04-10 | 2019-07-05 | 陕西理工大学 | A kind of preparation method and applications of the Schiff base complex of double-core copper |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107698609A (en) * | 2017-09-15 | 2018-02-16 | 广西师范大学 | Method and application based on human serum albumins IB subdomain synthesizing antitumor metal prodrugs |
| CN107698609B (en) * | 2017-09-15 | 2020-01-31 | 广西师范大学 | Method for synthesizing anti-tumor metal prodrug based on human serum albumin IB subdomain and application |
| CN107936044A (en) * | 2017-11-22 | 2018-04-20 | 广西师范大学 | It is a kind of using pyridyl ketone contracting thiocarbohydrazone as the copper complex and its synthetic method of ligand and application |
| CN108558914A (en) * | 2018-04-08 | 2018-09-21 | 广西师范大学 | Copper complex and its synthetic method based on biotin o-vanillin acyl hydrazone derivative and application |
| CN108558914B (en) * | 2018-04-08 | 2019-06-28 | 广西师范大学 | Copper complex and its synthetic method and application based on biotin o-vanillin acyl hydrazone derivative |
| CN109908364A (en) * | 2019-03-28 | 2019-06-21 | 广西师范大学 | Using human serum albumins as the synthetic method and application of gold (III) metal composite of carrier |
| CN109908364B (en) * | 2019-03-28 | 2021-09-14 | 广西师范大学 | Synthetic method and application of gold (III) metal complex with human serum albumin as carrier |
| CN109970770A (en) * | 2019-04-10 | 2019-07-05 | 陕西理工大学 | A kind of preparation method and applications of the Schiff base complex of double-core copper |
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