CN106589000B - 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex - Google Patents
2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex Download PDFInfo
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- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 title claims abstract description 32
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 title claims abstract description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 101710128901 Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
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- 239000013078 crystal Substances 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 8
- 238000012360 testing method Methods 0.000 claims abstract description 8
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- 229910052763 palladium Inorganic materials 0.000 claims description 8
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- 238000005660 chlorination reaction Methods 0.000 claims description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
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- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
- C07F15/0066—Palladium compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention discloses a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex, complex molecule formula is Pd (L) Cl or [Pd (C13H11N4O2) Cl], wherein HL is 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone.The invention also discloses the preparation methods of complex, step includes: that the aqueous solution of palladium salt is added drop-wise to the methanol solution for setting 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone in a round bottom flask, it stirs 10-12 hours at room temperature, filtering, crocus precipitating is obtained, yield is up to 70%；Dry powder is dissolved in n,N-Dimethylformamide (DMF) and forms supersaturated solution, filtering puts the filtrate into test tube, spreads in ether, obtains yellow bulk crystals.The complex passes through half-inhibitory concentration (IC50) measurement prove that it has good inhibiting effect to the activity of Protein-tyrosine-phosphatase (PTP1B, TCPTP and SHP-1), can be used as the inhibitor application of Protein-tyrosine-phosphatase (PTP1B, TCPTP and SHP-1).
Description
Technical field
The present invention relates to metal complex more particularly to a kind of 2- hydroxy-n ' the-(Asia 1- (pyrazine -2-yl) second
Base) benzoyl hydrazone palladium chloride complex and its preparation method and application.
Background technique
Protein-tyrosine-phosphatase (PTPs) is one of the phosphate radical on the tyrosine residue of energy specific for hydrolysis phosphorylation
Fermentoid.Protein tyrosine phosphatase is the main path of organism inner cell signal transduction, this reversible protein-tyrosine
Phosphorylation events are regulated and controled jointly by PTPs and protein tyrosine kinase (PTKs).The former catalytic tyrosine dephosphorylation, after
Person's catalytic tyrosine phosphorylation.Research shows that the exception of protein tyrosine phosphatase level and diabetes, obesity, autoimmune
The morbidity of the diseases such as defect, leukaemia and cancer has close connection.At present it is found that PTPs type existing 107
Kind, such as PTP1B, TCPTP, SHP-1, SHP-2.
PTP1B can make the dephosphorylations such as insulin receptor, insulin receptor substrate and leptin, thus to insulin and
The signal transduction of leptin carries out negative regulator.The mouse for knocking out PTP1B gene significantly improves the sensibility of insulin, draws to diet
The fat tolerance enhancing risen, and mouse physically well develops, and does not influence ordinary life.Therefore, the screening of PTP1B inhibitor is
Develop the important channel of antidiabetic object.
TCPTP is a kind of non-receptor type Protein-tyrosine-phosphatase intracellular, is played in cell signal goes to procedure important
Negative regulation effect.TCPTP is the key gene to control inflammation, and the mouse of TCPTP gene knockout can be within three to five weeks
Death, and the symptoms such as short and small, enlargement of lymph nodes, lymphopoiesis and hematopoietic defect with appearance, or even cause myocarditis, close
Save inflammation, gastritis etc..Therefore TCPTP plays an important role to the control of inflammation, is expected to develop into anti-inflammatory drug.
SHP-1 is expressed in hematopoietic cell, and down regulation is played in cell signaling pathway, its exception can cause
Serious immune system disorder.The mouse of SHP-1 gene delection shows various immunologic derangements, finally in 2-3 weeks
It is dead.SHP-1 has been considered as the tumor suppressor gene in lymthoma, leukaemia and other tumours.So SHP-1 inhibitor is ground
Study carefully the anti-cancer drugs object for being expected to filter out high-efficiency low-toxicity.
Summary of the invention
The first object of the present invention is to provide a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl
Hydrazone palladium chloride complex.
The second object of the present invention is to provide above-mentioned 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzene first
The preparation method of acylhydrazone palladium chloride complex.
The third object of the present invention is to provide above-mentioned 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzene first
A kind of application of the acylhydrazone palladium chloride complex as Protein-tyrosine-phosphatase PTP1B activity inhibitor.
The fourth object of the present invention is to provide above-mentioned 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzene first
A kind of application of the acylhydrazone palladium chloride complex as Protein-tyrosine-phosphatase TCPTP activity inhibitor.
The fifth object of the present invention is to provide above-mentioned 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzene first
A kind of application of the acylhydrazone palladium chloride complex as Protein-tyrosine-phosphatase SHP-1 activity inhibitor.
A kind of 2- hydroxy-n provided by the invention '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride is matched
Object is closed, molecular formula is Pd (L) Cl or [Pd (C13H11N4O2) Cl], wherein HL is 2- hydroxy-n '-(1- (pyrazine -2-yl)
Ethylidene) benzoyl hydrazone, molecular weight 397.11, complex structure formula are as follows:
A kind of 2- hydroxy-n provided by the invention '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride is matched
The preparation method for closing object, includes the following steps:
(1) by PdCl2It is dissolved in the water to form Na by the molar ratio of 1:2 with NaCl2PdCl4Solution；
(2) by above-mentioned Na2PdCl4Solution is added drop-wise to 2- hydroxy-n ' the-(Asia 1- (pyrazine -2-yl) of equimolar amounts
Ethyl) benzoyl hydrazone methanol solution in, at room temperature stir 10-12 hours, filter to obtain crocus powder；
(3) dry powder is dissolved in n,N-Dimethylformamide (DMF) and forms supersaturated solution, filtering, by filtrate
It is put into test tube, is spread in ether, obtains yellow bulk crystals after two weeks, it is the complex of structure formula (I) after measured.
The reaction equation of above-mentioned synthesis are as follows:
PdCl2+ 2NaCl=Na2PdCl4 (1)
2- hydroxy-n prepared by the present invention '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex
The crystal diffused out from DMF belongs to the P 2 of monoclinic system1/ c space group, cell parameter: α=90 °, β=98.86 (3) °, γ=90 °.In complex
The molar ratio of palladium ion and ligand and chlorine is 1:1:1, and ligand is with three tooth chelating ligands to palladium ion, while palladium ion and a chlorine
Ion coordination reaches electroneutral.
Beneficial effects of the present invention:
Complex of the invention is 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone and Metal Palladium
The new palladium complex of one kind that ion obtains under room temperature reaction.The synthetic method of the complex is simple, lower production costs, mistake
Journey is easy to control, and yield is up to 70%.Complex of the invention is to Protein-tyrosine-phosphatase (PTP1B, TCPTP and SHP-1)
Activity has good inhibiting effect, to the half-inhibitory concentration (IC of PTP1B50) it is 0.35 μM, dense is inhibited to the half of TCPTP
Spend (IC50) it is 0.30 μM, to the half-inhibitory concentration (IC of SHP-150) it is 0.57 μM, it can be used as Protein-tyrosine-phosphatase
The inhibitor application of (PTP1B, TCPTP and SHP-1).
Detailed description of the invention
Fig. 1 is complex of the present invention [Pd (C13H11N4O2) Cl] and crystal structure figure.
Fig. 2 is complex of the present invention [Pd (C13H11N4O2) Cl] and electrospray ionization mass spectrum figure.
Fig. 3 is complex of the present invention [Pd (C13H11N4O2) Cl] inhibit the active IC of PTP1B50Value measurement curve.
Fig. 4 is complex of the present invention [Pd (C13H11N4O2) Cl] inhibit the active IC of TCPTP50Value measurement curve.
Fig. 5 is complex of the present invention [Pd (C13H11N4O2) Cl] inhibit the active IC of SHP-150Value measurement curve.
Specific embodiment
With reference to the accompanying drawings and examples, invention is further described in detail.
1 2- hydroxy-n of embodiment '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex [Pd
(C13H11N6S) Cl] preparation method.
Weigh 0.1mmol (0.0177g) PdCl2It is dissolved in 5mL water and is formed with 0.2mmol (0.0116g) NaCl
Na2PdCl4Solution, by above-mentioned Na2PdCl4Solution is added drop-wise in the 10mL methanol solution of 0.1mmol (0.0256g) HL, at room temperature
Stirring 12 hours, filters to obtain crocus powder, is respectively washed three times with water, methanol and ether respectively, vacuum drying.Yellow powder weight
0.0291g, yield 70%.
Complex infrared spectroscopy characteristic absorption (cm-1): 1664 (C=O)；1618 (C=N)；528(Pd-N)；468(Pd-
O)。
Complex determination of elemental analysis: [Pd (C13H11N4O2)Cl]·H2O, theoretical value: C 37.61, H 3.16, N
13.50；Experiment value: C 37.43, H 3.12, N 13.36.
The cooperation of the 2- hydroxy-n of the present invention of embodiment 2 '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N6S) Cl] crystal cultural method.
By dry powdered 2- hydroxy-n of the present invention '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone chlorination
Palladium complex, which is dissolved in n,N-Dimethylformamide (DMF), forms supersaturated solution, and filtering puts the filtrate into test tube, in ether
Middle diffusion obtains yellow bulk crystals after two weeks.Crystal structure analysis is [Pd (C13H11N4O2)Cl]。
The cooperation of the 2- hydroxy-n of the present invention of embodiment 3. '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N4O2) Cl] and crystal structure determination and result.
Crystal, picking rule, transparent yellow bulk-shaped monocrystal particle are observed under high magnification microscope.Use synchrotron radiation light source
(Beijing Synchrotron Radiation 3W1A line station), the operating voltage of 2.5GeV, MARCCD-165 detector collect sample and are to wavelengthDiffraction data, during this, with protection of liquid nitrogen sample, temperature is 100 (2) K.With HKL200 and SHELXL-
2014/7 program bag handles data, and parsing obtains the crystal structure of complex.Detailed crystal structure information is listed in table 1.
1 complex of table [Pd (C13H11N4O2) Cl] crystallographic data
The cooperation of the 2- hydroxy-n of the present invention of embodiment 4. '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N4O2) Cl] and electrospray ionization mass spectrum.
In order to study the existence form of complex in the solution, by a small amount of 2- hydroxy-n '-(1- (pyrazine -2-
Yl) ethylidene) benzoyl hydrazone palladium chloride complex solid powder is dissolved in methanol, and oscillation, which makes it dissolve, reaches saturation, and is centrifuged
Clear transparent solutions are obtained, electrospray mass spectrometer is loaded to, using electric spray ion source, with positive ion mode test sample and are remembered
Record mass spectrometric data.Fig. 2 is the positive ionization electrospray mass spectrogram of complex.It is observed that complex is corresponding in electrospray ionization mass spectrum figure
Molecular ion peak.Table 2 is the positive ionization electrospray mass spectrum ownership of complex.The result shows that experiment value is consistent with theoretical value, table
The structure type that bright complex is designed in the solution with us is stabilized.
2 palladium complex of table [Pd (C13H11N4O2) Cl] and positive ionization electrospray mass spectrum ownership
The cooperation of the 2- hydroxy-n of the present invention of embodiment 5. '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N4O2) Cl] Protein-tyrosine-phosphatase PTP1B inhibitory effect is detected.
IC50Measuring principle:
Six hydration 4-NPP salt (pNPP) under the catalytic action of PTPs, can be analyzed to yellow to nitro
Benzoic acid (pNP), the product have very strong UV absorption at 405nm, after terminating reaction, detect pNP at 405nm by microplate reader
The variation of absorbance value to detect the situation of change of enzymatic activity indirectly, egg as catalyst can be learnt by then carrying out analysis
The reacted amount of white tyrosine phosphatase (PTPs).
IC50The meaning of value:
IC50That is half-inhibitory concentration, refer to causing enzymatic activity when dropping to original enzyme activity half required inhibitor it is dense
Degree, IC50Value is the standard for judging inhibitor rejection ability size.Its numerical value is lower, shows that inhibitor inhibits albumen junket ammonia
Acid phosphoric acid enzyme (PTPs) active effect is better.
IC50Measuring method:
The measurement of inhibition of enzyme activity experiment is MOPS buffer system [the 30mM morpholinepropanesulfonic acid for being 7.20 in pH
(MOPS), 50mM NaCl] in carry out.
Inhibitor is configured to 10 first-3Then the DMSO mother liquor of M is diluted to a series of various concentration gradients with DMSO
Solution keeps its concentration suitable with the buffer solution soluble protein tyrosine phosphatase (PTPs) now matched, spare.Inhibitor inhibits
The activity experiment of PTPs is carried out in 96 orifice plates, and MOPS buffer solution of the 83 μ L containing enzyme is added in first three row, last row is added
MOPS buffer solution without enzyme is as control.Again to arrange the inhibitor for sequentially adding 10 μ L various concentration gradients for unit, set
After 37 DEG C of thermostat water baths react 30 minutes, 2 μ L pNPP (0.1M) are added to above-mentioned solution and are reacted to start, after 15 minutes,
It is terminated and is reacted with 5 μ L (2M) NaOH, the UV absorption in each hole at 405nm decomposition product pNP of substrate is measured by microplate reader
Value.It is mapped with Origin program, is fitted these concentration-gradient curves to acquire IC50Value.
All continuous modes are designed with blank and control experiment, to exclude the interference of solvent, complex intrinsic colour.Every time
All with the complex solution newly prepared, and the above parallel laboratory test in triplicate.
Testing result: when above-mentioned Protein-tyrosine-phosphatase (PTPs) is PTP1B, 2- hydroxy-n '-(1- is (to phenodiazine
Miscellaneous benzene -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex [Pd (C13H11N4O2) Cl] to the half-inhibitory concentration of PTP1B
(IC50) are as follows: 0.35 μM (see Fig. 3).
The cooperation of the 2- hydroxy-n of the present invention of embodiment 6. '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N4O2) Cl] Protein-tyrosine-phosphatase TCPTP inhibitory effect is detected.
Detection method, principle and step are the same as embodiment 5.
Testing result: when above-mentioned Protein-tyrosine-phosphatase (PTPs) is TCPTP, 2- hydroxy-n '-(1- is (to phenodiazine
Miscellaneous benzene -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex [Pd (C13H11N4O2) Cl] to the half-inhibitory concentration of TCPTP
(IC50) are as follows: 0.30 μM (see Fig. 4).
The cooperation of the 2- hydroxy-n of the present invention of embodiment 7. '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
Object [Pd (C13H11N4O2) Cl] Protein-tyrosine-phosphatase SHP-1 inhibitory effect is detected.
Detection method, principle and step are the same as embodiment 5.
Testing result: when above-mentioned Protein-tyrosine-phosphatase (PTPs) is SHP-1 2- hydroxy-n '-(1- is (to phenodiazine
Miscellaneous benzene -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex [Pd (C13H11N4O2) Cl] to the half-inhibitory concentration of SHP-1
(IC50) are as follows: 0.57 μM (see Fig. 5).
Claims (6)
1. a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride complex, feature exist
In structural formula are as follows:
2. 2- hydroxy-n according to claim 1 '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone palladium chloride
The preparation method of complex, which comprises the steps of:
(1) in molar ratio 1:2 by PdCl2It is dissolved in the water to form Na with NaCl2PdCl4Solution；
(2) by above-mentioned Na2PdCl4Solution be added drop-wise to equimolar amounts 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene)
In the methanol solution of benzoyl hydrazone, stirs 10-12 hours at room temperature, filter to obtain crocus powder；
(3) dry powder is dissolved in n,N-Dimethylformamide (DMF) and forms supersaturated solution, filtering is put the filtrate into
Test tube is spread in ether, obtains yellow bulk crystals after two weeks.
3. a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone chlorination as claimed in claim 2
The preparation method of palladium complex, which is characterized in that the mixing time is 12 hours.
4. a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone chlorination as described in claim 1
Palladium complex is preparing the application in PTP1B inhibitor.
5. a kind of 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone chlorination as described in claim 1
Palladium complex is preparing the application in TCPTP inhibitor.
6. a kind of seat 2- hydroxy-n '-(1- (pyrazine -2-yl) ethylidene) benzoyl hydrazone chlorine as described in claim 1
Change palladium complex and prepares the application in SHP-1 inhibitor.
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