CN103232486B - Vanadium oxide complex as well as preparation method and application thereof - Google Patents
Vanadium oxide complex as well as preparation method and application thereof Download PDFInfo
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- CN103232486B CN103232486B CN201310165627.8A CN201310165627A CN103232486B CN 103232486 B CN103232486 B CN 103232486B CN 201310165627 A CN201310165627 A CN 201310165627A CN 103232486 B CN103232486 B CN 103232486B
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- sulfydryl
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Abstract
The invention provides a vanadium oxide complexa and a preparation method thereof and an application of the complex as a protein tyrosine phosphatase 1B (PTP1B) inhibitor. The vanadium oxide complex provided by the invention is 5-chloro-salicyladehyde condens-4-amino-5-sulfydryl-1, 2, 4- triazole Schiff base vanadium oxide. The preparation method of the vanadium oxide complex comprises steps of: dissolving a 5-chloro-salicyladehyde condens-4-amino-5-sulfydryl-1, 2, 4- triazole Schiff base ligand into absolute ethyl alcohol; dripping triethylamine of the same molar weight; heating and stirring the ligand to be dissolved; and then adding the absolute ethyl alcohol solution with the dissolved triethylamine the molar weight of which is the same as that of absolute ethyl alcohol solution, stirring, refluxing, cooling, filtering, collecting a mother liquid and separating yellow massive crystals out. The complex is simple in synthesizing method, is prepared by easily obtained raw materials, and has an obvious inhibition function on the activity of PTP1B with nanomolar concentration; and the prepared complex can be used as the protein tyrosine phosphatase 1B inhibitor.
Description
Technical field
The present invention relates to transition metal complex, be specifically related to a kind of vanadyl title complex and preparation method thereof, and this title complex is as the application of protein-tyrosine phosphatase 1B inhibitor.
Background technology
Protein-tyrosine-phosphatase (PTPs) is the metal-free enzyme of a class be extensively present in organism, it and this reversible dynamic process of protein kinase common modulin tyrosine phosphorylation, wherein, protein-tyrosine makes protein phosphorylation, and protein kinase then makes albumen dephosphorylation.In human body, more than 100 kind of PTPs is had to be considered to relevant with the approach of various enhancer or inhibitor signal transduction.PTPs can the transduction of cell cycle regulation and signal, and in the response of cell signal, it can by combining to come the effect degree of modulin tyrosine phosphorylation with protein tyrosine phosphatase kinases.The Abnormal regulation path of these signalling systems is found relevant with numerous disease.Abnormal PTPs activity can cause the generation of the numerous disease comprising cancer, diabetes and rheumatic arthritis etc.
PTP 1B (PTP1B) is a classical non-receptor type tyrosine Phosphoric acid esterase in PTPs family, important negative regulation effect is played in insulin signaling pathway, current in vivo and in vitro finds, in insulin target tissue in the type ii diabetes patient body caused by insulin resistant, the expression of PTP1B increases greatly, the overexpression of PTP1B has blocked the activation of insulin receptor tyrosine and the intracellular signaling of Regular Insulin, so PTP1B has become the therapy target that diabetes and obesity are generally acknowledged, also the focus of a lot of R&D institution and drugmaker's research and development new drug is in the world become, and find the small molecules carrying out specific binding and effect with PTP1B, research small molecules and PTP1B interact, then become the basis that research and development take PTP1B as the new drug of target spot.In recent years, the research of PTP1B inhibitor causes people's interest widely, and the domestic and international report about PTP1B inhibitor much at present, but major part all concentrates on organic micromolecule compound aspect.Due to the distinctive biological activity of metal ion, the inorganic molecules compound of PTP1B effectively can be suppressed more and more to cause the concern of people, some are efficient, low toxicity, specific inorganic molecules compound be expected to become novel antidiabetic medicine.
People were the most active to VO (IV) the vanadyl class Study on Complexes with insulin activity in recent years, development is also the fastest, and every country also is all stepping up to develop this type of antidiabetic medicine.At present except BMOV, some coordination modes are VO (N2O2), the title complex of VO (O2S2), VO (N2S2), VO (N4), VO (S4) also has para-insulin character, but the title complex para-insulin character that coordination mode is VO2 (NSO) have not been reported, so we prepare and have studied the Schiff's base vanadyl title complex with para-insulin character based on PTP1B target spot, the treatment for diabetes provides a kind of new drug development approach.
Summary of the invention
The object of the present invention is to provide a kind of vanadyl title complex and preparation method thereof, and this title complex is as the application of inhibitors of protein tyrosine phosphatase.
A kind of vanadyl title complex provided by the invention, be 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole Schiff's base vanadyl, its molecular formula is C
9h
6clN
4o
3sV, molecular weight is 336.63, and structural formula is:
The preparation method of a kind of vanadyl title complex provided by the invention, comprises the steps:
(1) (as: chemical reagent, 2009,31 (10), 785-788) 4-amino-5-sulfydryl-1,2,4-triazole is synthesized;
(2) 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand is synthesized: by equimolar amount 4-amino-5-sulfydryl-1,2,4-triazole and 5-chloro-salicylic aldehyde are dissolved in dehydrated alcohol, under stirring respectively, the ethanol solution of 5-chloro-salicylic aldehyde is added drop-wise in the ethanol solution of 4-amino-5-sulfydryl-1,2,4-triazole, then the vitriol oil of 1-2 times of molar weight is dripped, there is pale yellow precipitate, reflux after 4 hours, cooling, filter, solid is recrystallization in dehydrated alcohol;
(3) vanadyl title complex of the present invention is synthesized: by the vanadyl acetylacetonate of equimolar amount and 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand is dissolved in dehydrated alcohol respectively, heated and stirred 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2, the ethanol solution of 4-triazole schiff base ligand, the triethylamine dripping equimolar amount makes part dissolve, then, then add the ethanol solution of vanadyl acetylacetonate, stirring and refluxing is after 4 hours, cooling, filter, collect mother liquor, separate out yellow bulk crystals.
The reaction formula of above-mentioned synthetic method is:
The title complex that the present invention obtains can be used as protein-tyrosine phosphatase 1B inhibitor.This title complex is 78nm to the half-inhibition concentration of PTP1B.Suppress type to be competitive type inhibitor, suppress constant K
ivalue is 109nM, and title complex and the interactional bonding ratio of PTP1B are 0.95082, and binding constants is: 1.06 × 10
6m
-1.
Advantage of the present invention and effect
Title complex synthetic method of the present invention is simple, raw material is easy to get, just remarkable restraining effect is had to the activity of PTP 1B (PTP1B) when nanomolar concentrations, therefore, title complex of the present invention has para-insulin activity, and the treatment for diabetes provides a kind of new drug development approach.
Accompanying drawing explanation
The crystalline structure figure of Fig. 1 vanadyl title complex of the present invention;
Fig. 2 vanadyl title complex of the present invention suppresses the IC of PTP1B activity
50pH-value determination pH curve;
Fig. 3 vanadyl title complex of the present invention is to the suppression type curve of PTP1B;
Fig. 4 vanadyl title complex of the present invention is to the suppression constant curve of PTP1B;
Fig. 5 vanadyl title complex of the present invention is to the fluorescent quenching collection of illustrative plates of PTP1B;
Binding constants and the bonding of Fig. 6 vanadyl title complex of the present invention and PTP1B compare curve;
Embodiment
Below in conjunction with accompanying drawing and example, the invention will be further described.
Embodiment 1
The preparation of title complex
(1) 4-amino-5-sulfydryl-1,2,4-triazole is synthesized: get 10mmol(1.06g) two thiosemicarbazide is in round-bottomed flask, add 10mL formic acid solution, stirring and refluxing 4h, be chilled to room temperature, underpressure distillation goes out unreacted formic acid, washes to obtain thick product, obtains white crystalline product with water recrystallization;
(2) 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand is synthesized: get 5mmol(0.58g) 4-amino-5-sulfydryl-1,2,4-triazole, in round-bottomed flask, adds 50ml anhydrous alcohol solution, drips 5mmol(0.78g under stirring) the ethanol solution 40ml of 5-chloro-salicylic aldehyde and the 0.4ml vitriol oil, there is a large amount of pale yellow precipitate, reflux is after 4 hours, and cooling, filters, pressed powder is recrystallization in dehydrated alcohol, separates out faint yellow crystallite;
Determination of elemental analysis: C
9h
7clN
4oS is theoretical value (%): C42.56 (42.44) in bracket; H2.79 (2.77); N22.13 (22.00).
Infrared measurement: IR (KBr), ν: 3110,1613,1541,1474,1453,1283,947,663.
(3) vanadyl title complex of the present invention is synthesized: get 1mmol(0.255g) 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand puts into round-bottomed flask, adds 20ml dehydrated alcohol, drips 1mmol(150 μ l) triethylamine, heated and stirred makes part dissolve, then add and be dissolved with 1mmol(0.364g) the ethanol solution 10ml of vanadyl acetylacetonate, stirring and refluxing is after 4 hours, cooling, filter, in filtrate, separate out yellow bulk crystals;
Determination of elemental analysis: C
9h
6clN
4o
3sVC
6h
15n is theoretical value (%): C 41.28 (41.15) in bracket; H 4.90 (4.83); N 16.13 (16.00).
Complex monocrystal structure
Under powerful microscope, picking rule, transparent yellow bulk-shaped monocrystal particle X-ray crystalline diffraction method test, and parse match crystal body structure with SHELXTL-NT5.10 version routine package.The crystalline structure of title complex, if accompanying drawing 1(is for making clear in structure, deletes solvent molecule), about some other detailed information of crystal lists in table 1 and table 2.In this title complex, central atom vanadium is pentavalent, in complex structure except two VO double bonds, vanadium atom also with 5-chloro-salicylic aldehyde contracting 4-amino-5-sulfydryl-1,2, imine nitrogen atom in 4-triazole schiff base ligand, the sulphur atom coordination of phenolic group Sauerstoffatom and triazolinthione forms the distortion tetragonal pyramid structure (VO of pentacoordinate
3nS).
Table 1 title complex [VO
2(C
9h
6clN
4oS) C
6h
15n] structure cell and measuring parameter
Table 2 title complex [VO
2(C
9h
6clN
4oS) C
6h
15n] the main bond distance of part
with bond angle data (°).
Embodiment 2 vanadyl title complex of the present invention detects PTP1B inhibition.
Vanadyl complex crystal dimethyl sulfoxide (DMSO) (DMSO) is dissolved, is made into 10
-2the mother liquor of M, then the solution (10 being diluted to different concns with DMSO
-4m, 10
-5m, 10
-6m, 10
-7m, 10
-8m, 10
-9m, 10
-10m).The mensuration of inhibition of enzyme activity experiment be with 2mM 4-NPP salt (pNPP) for reaction substrate at pH be 7.20 MOPS buffer system [20mM morpholinepropanesulfonic acid (MOPS), 50mM NaCl] in carry out, experimental technique is: this experiment carries out in 96 orifice plates, add 83 μ l successively containing enzyme buffer solution, the inhibitor of 10 μ l different concns gradients, reaction is started with the pNPP of 2 μ l (0.1M), place after about 15 minutes, add 5 μ l(2M again) NaOH termination reaction, measure the degradation production of substrate at A by microplate reader
405uv-absorbing intensity, determine the amount of p-NP (pNP) generated, each sample is parallel does three times, deducts blank simultaneously, uses Origin to calculate its IC by the suppression curve of title complex to PTP1B
50value, shows the IC5 of title complex inhibition
0value gets the mean value of many experiments.Calculate the IC of vanadium complex of the present invention to PTP1B as shown in Figure 2
50for 78nM.Illustrate that this vanadyl title complex has efficient inhibition to PTP1B enzymic activity.
Embodiment 3 vanadyl title complex of the present invention suppresses the determination of type to PTP1B.
Vanadyl complex crystal dimethyl sulfoxide (DMSO) (DMSO) is dissolved, is made into 10
-2the mother liquor of M, then the solution (200nM, 100nM, 50nM, 25nM) being diluted to different concns with DMSO, the concentration of substrate pNPP is 4mM, 2mM, 1mM, 0.5mM, 0.3mM, 0.2mM respectively.Experiment reaction system is: 88 μ l contain containing enzyme (PTP1B) buffered soln: 20mM morpholinepropanesulfonic acid (MOPS), 50mM NaCl, the inhibitor of 10 μ l different concns gradients, add 2 μ l different concns pNPP in reaction system and start reaction, measure the changing value of photoabsorption at 405nm place.Measure the absorbance of each inhibitor concentration to each concentration of substrate respectively, according to formula A=ε bc(b=1cm, ε=1.78 × 10
4a is 405nm absorbancy, C is reactant concn mol/L) draw speed of reaction ν under each inhibitor concentration, as shown in Figure 3, with concentration of substrate inverse 1/ [S] for X-coordinate, map for ordinate zou with 1/ ν, obtain the straight line that one group of vertical axis intercept is constant, represent that the suppression type of this title complex is competitive type inhibitor.As shown in Figure 4, the slope according to Lineweaver-Burk equation straight line is mapped as straight line to title complex concentration, and the intersection point of this straight line and X-axle is for suppress constant and K
ifor 109nM.
Embodiment 4 vanadyl of the present invention title complex and the interactional binding constants of PTP1B and bonding ratio.
With MOPS buffered soln dilution PTP1B mother liquor to 2ml, concentration is 5.9 × 10
-7m, setting excitation wavelength is 280nm, excites and launch slit width to be 5nm, and experimental temperature is 310K, measures the fluorescence intensity of PTP1B solution, then uses the titration of vanadyl title complex, add 4 μ l(1 × 10 at every turn
-3m) solution, reacted after 5 minutes, measured the fluorescence spectrum of 290 ~ 500nm scope.Accompanying drawing 5 shows adding along with title complex, PTP1B fluorescence intensity constantly reduces, and shows that vanadyl title complex and PTP1B bonding form mixture, according to Sterm mono-Volme fluorescent quenching equation, as shown in Figure 6, the binding constants calculating vanadyl title complex and PTP1B is 1.06 × 10
-6m
-1, bonding ratio is 0.095082, and experimental result illustrates, vanadyl title complex and PTP1B are with the ratio stable bond of 1:1.
Claims (3)
1. a vanadyl title complex, its structural formula is:
2. the preparation method of a kind of vanadyl title complex as claimed in claim 1, is characterized in that, comprise the steps:
(1) 4-amino-5-sulfydryl-1,2,4-triazole is synthesized: get the two thiosemicarbazide of 10mmol in round-bottomed flask, add 10mL formic acid solution, stirring and refluxing 4h, be chilled to room temperature, underpressure distillation goes out unreacted formic acid, washes to obtain thick product, obtains white crystalline product with water recrystallization;
(2) 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand is synthesized: by equimolar amount 4-amino-5-sulfydryl-1,2,4-triazole and 5-chloro-salicylic aldehyde are dissolved in dehydrated alcohol, under stirring respectively, the ethanol solution of 5-chloro-salicylic aldehyde is added drop-wise to 4-amino-5-sulfydryl-1, in the ethanol solution of 2,4-triazole, then drip the vitriol oil of 1-2 times of molar weight, reflux after 4 hours, cooling, filter, solid is recrystallization in dehydrated alcohol;
(3) vanadyl title complex is synthesized: by the vanadyl acetylacetonate of equimolar amount and 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2,4-triazole schiff base ligand is dissolved in dehydrated alcohol respectively, heated and stirred 5-chloro-salicylic aldehyde contracting-4-amino-5-sulfydryl-1,2, the ethanol solution of 4-triazole schiff base ligand, the triethylamine dripping equimolar amount makes part dissolve, then, then add the ethanol solution of vanadyl acetylacetonate, stirring and refluxing is after 4 hours, cooling, filter, collect mother liquor, separate out yellow bulk crystals.
3. the application of vanadyl complex preparation protein-tyrosine phosphatase 1B inhibitor as claimed in claim 1.
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| CN104447852B (en) * | 2014-11-17 | 2017-02-22 | 云南大学 | Schiff base vanadium oxide compound as well as preparation method and application thereof |
| CN104530185A (en) * | 2014-12-13 | 2015-04-22 | 中国海洋大学 | Oxo-vanadium glutathione |
| CN104910212B (en) * | 2015-05-07 | 2017-08-11 | 山西大学 | A kind of schiff bases platinum complex and its preparation method and application |
| CN105037402B (en) * | 2015-06-19 | 2017-05-17 | 山西大学 | Schiff base and zinc coordination compound and preparation method and application thereof |
| CN106749393A (en) * | 2017-01-09 | 2017-05-31 | 山西大学 | Picoline hydrazonic acid derivative dioxygen vanadium（V）Complex and preparation method thereof |
| CN108558935B (en) * | 2018-04-08 | 2019-06-14 | 广西师范大学 | Vanadic anhydride crystalline material and its synthetic method based on the modification of tartaric acid chiral derivatives |
| CN110078639A (en) * | 2019-05-24 | 2019-08-02 | 云南大学 | A kind of schiff bases vanadium complex and the preparation method and application thereof |
| CN113105499A (en) * | 2021-04-16 | 2021-07-13 | 河北民族师范学院 | Schiff base vanadyl complex and preparation method thereof |
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| CN102134738A (en) * | 2010-12-24 | 2011-07-27 | 华东师范大学 | Preparation method of oxalic acid hydroxylamine vanadium coordination compound crystalloid with bioactivity |
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| CN102134738A (en) * | 2010-12-24 | 2011-07-27 | 华东师范大学 | Preparation method of oxalic acid hydroxylamine vanadium coordination compound crystalloid with bioactivity |
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| Synthesis and spectral investigations of vanadium(IV/V) complexes derived from an ONS donor thiosemicarbazone ligand;Neema Ani Mangalam et al;《Spectrochimica Acta Part A》;20080805;第71卷;第2040–2044页 * |
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