CN104744505A - Vanadyl complex and application thereof - Google Patents
Vanadyl complex and application thereof Download PDFInfo
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- CN104744505A CN104744505A CN201510078860.1A CN201510078860A CN104744505A CN 104744505 A CN104744505 A CN 104744505A CN 201510078860 A CN201510078860 A CN 201510078860A CN 104744505 A CN104744505 A CN 104744505A
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- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 229940123940 PTEN inhibitor Drugs 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
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- -1 oxo vanadic acid Chemical compound 0.000 claims description 10
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Landscapes
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Abstract
The invention discloses a vanadyl complex and application thereof. The vanadyl complex has the structure of formula (I) or formula (II) shown in the specification, wherein L-L' is defined in the specification, and L' is COO or O. The vanadyl complex is applied to preparing a PTEN inhibitor used as medicine for nervous diseases, and the medicine has the effect characteristics of high efficiency, low toxicity and strong specificity.
Description
Technical field
The invention belongs to field of medicaments, more specifically, relate to a kind of vanadyl class title complex and application thereof.
Background technology
PTEN gene (gene of phosphate and tension homology deleted onchromsome ten) is a kind of cancer suppressor gene, it is positioned karyomit(e) 10q23.3, be made up of 9 exons, to be encoded the pten protein matter formed by 403 amino acid, there is two acid phosphatase active, by protein and lipid substrates dephosphorylation.But with most of Protein Tyrosine Phosphatases unlike, the phosphoric acid on this albumen preference dephosphorylate inositol substrate.The level of phosphatidylinositols-3,4,5-triphosphoric acid in this albumen negative regulate born of the same parents, and play cytostatic effect by negative regulate Akt/PKB signalling channel, therefore, suppress PTEN Promote cell's growth.
Two vanadyl class title complex of crossing is found the earliest and is used as being the phosphate group hydrolase inhibitor of phosphorylated protein.The vanadyl class title complex be in the news has bpv (pic), bpv (HOpic), bpv (phen) and bpv (bipy), they to PTEN and Protein-tyrosine-phosphatase (PTPs) all inhibited.Based on vanadyl class title complex to the restraining effect of PTEN, current cell and experimentation on animals find that it has certain therapeutic action to nervous system injury disease (as: cerebral ischemia, hematencephalon, traumatic brain injury and spinal neuronal damage), nerve degenerative diseases (as: Parkinson and alzheimer's disease etc.) and Other diseases, but the specificity for the treatment of and validity need to verify further and improve.Therefore, novel, special, effective, hypotoxic vanadyl title complex is researched and developed significant to Treatment of Central Nervous System Diseases.
Summary of the invention
For above defect or the Improvement requirement of prior art, the invention provides a kind of vanadyl class title complex and application thereof, its object is to there is inhibiting compound by the exploitation of design aglucon is new to PTEN, be used for the treatment of the diseases such as nervous system injury disease, nerve degenerative diseases, solve current medicine for central nervous system poor specificity, technical problem that toxicity is large thus.
For achieving the above object, according to one aspect of the present invention, provide a kind of vanadyl class title complex, there is the structure of formula (I) or formula (II):
or
Wherein L-L ' is:
or
L ' is COO or O.
Preferably, described vanadyl class title complex, its L-L ' is:
Preferably, described vanadyl class title complex, vanadyl class title complex is peroxide (pyridine-2-squaric amide) oxo vanadic acid or two peroxide (pyridine-2-squaric amide) oxovanadate.
According to another aspect of the present invention, provide the application of described vanadyl class title complex, it is applied to preparation PTEN inhibitor.
Preferably, described vanadyl class title complex, it is applied to the medicine of preparation treatment nervous system injury disease.
Preferably, described vanadyl class title complex, it is applied to the medicine of preparation treatment cerebral ischemia, hematencephalon, traumatic brain injury or spinal neuronal damage.
Preferably, described vanadyl class title complex, it is applied to the medicine of preparation treatment nerve degenerative diseases.
Preferably, described vanadyl class title complex, it is applied to the medicine of preparation treatment Parkinson or alzheimer's disease.
According to another aspect of the present invention, provide a kind of PTEN inhibitor medicaments composition, containing described vanadyl class title complex.
In general, the above technical scheme conceived by the present invention compared with prior art, as drugs for nervous, has efficient, low toxicity, high specificity action character.Meanwhile, its preparation is simple, and cost is lower, is applicable to scale operation.
Accompanying drawing explanation
Fig. 1 is vanadyl class title complex infrared detection collection of illustrative plates prepared by embodiment 1;
Fig. 2 is vanadyl class title complex infrared detection collection of illustrative plates prepared by embodiment 2;
Fig. 3 is vanadyl class title complex infrared detection collection of illustrative plates prepared by embodiment 3;
Fig. 4 is vanadyl class title complex infrared detection collection of illustrative plates prepared by embodiment 4;
Fig. 5 is embodiment 5 human neuroblastoma cells experimental result picture;
Fig. 6 is embodiment 5 glioma cell experimental result picture;
Fig. 7 is embodiment 5 measuring content of lactic dehydrogenase experimental result picture, and wherein Fig. 7 a is the treatment effect being used alone vanadyl class title complex, and Fig. 7 b is the treatment effect of conbined usage Paraquat and vanadyl class title complex;
Fig. 8 is middle cerebral artery occlusion model in rats experimental result picture.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.In addition, if below in described each embodiment of the present invention involved technical characteristic do not form conflict each other and just can mutually combine.
Vanadyl class title complex provided by the invention, has the structure of formula (I) or formula (II):
or
Wherein L-L ' is:
or
be preferably
L ' is COO or O.
, by imidazoles-4-formic acid or pyridine-2-squaric amide and vanadylic sulfate or Vanadium Pentoxide in FLAKES, there is complex reaction and obtain in vanadyl class title complex provided by the invention.
Experiment confirms, vanadyl class title complex provided by the invention has the effect suppressing PTEN, can be used for preparation PTEN inhibitor.PTEN is active by its two acid phosphatases, by protein and lipid substrates dephosphorylation, negative regulate Akt/PKB signal path cell growth inhibiting, therefore, suppress PTEN Promote cell's growth, thus in cerebral ischemia, hematencephalon, traumatic brain injury, spinal neuronal damage, Parkinson's disease, the experimental model of the Other diseases such as alzheimer's disease produces result for the treatment of, the medicine for the treatment of nervous system injury disease can be prepared thus further with PTEN inhibitor, as: cerebral ischemia, hematencephalon, traumatic brain injury and spinal neuronal damage, nerve degenerative diseases, as: Parkinson and alzheimer's disease etc.
Compound described herein is most preferably with the form administration of appropriately combined thing.As suitable composition, all compositions being usually used in whole body or topical can be suitable for.Pharmaceutically acceptable carrier should be inertia substantially, not have an effect with active ingredient.The inert support be applicable to comprises water, alcohol, polyoxyethylene glycol, mineral oil or mineral jelly, propylene glycol etc.Described pharmaceutical preparations can be formulated into the administration of any suitable mode, is used in the mankind or veterinary science.
As mentioned below, pharmaceutical composition of the present invention can be specifically mixed with solid or liquid form administration, comprise those that take following manner: (1) oral administration, such as Haust, tablet, bolus, pulvis, granule, be applied to the paste of tongue; (2) administered parenterally, such as subcutaneous, intramuscular or intravenous injection, such as sterile solution or suspension; (3) local application; (4) intravaginal or internal rectum; But in some embodiments, can simply bulk composition be dissolved or suspended in sterilized water.In some embodiments, pharmaceutical preparations is non-heating, and does not namely raise the body temperature of patient.Wording used herein " significant quantity " means one or more promoting agents, material or comprises one or more compositions comprising promoting agent of the present invention effective amount with regard to effect needed for aprowl producing necessarily.Be recognized that when a kind of promoting agent is used to reach result for the treatment of, the actual dose forming " significant quantity " will be different because of a large amount of condition, comprise treated particular condition, the seriousness of disease, the size of patient and approach etc. that is healthy, administration.The method that medical technician utilizes field of medicaments to know can easily determine suitable dosage.Wording " pharmaceutically acceptable " is in this article for representing such compound, material, composition and/or formulation, they are suitable for and human and animal's contact tissue within the scope of rational medical judgment, there is no excessive toxicity, hormesis, transformation reactions or other problem or complication, match with rational interests/Hazard ratio.
Wording used herein " pharmaceutically acceptable carrier " represents pharmaceutically acceptable material, component or vehicle, such as liquid or solid weighting agent, thinner, vehicle, solvent or encapsulating material, participate in delivery or transport main body promoting agent from an organ of body or part to another organ of body or part.Each carrier must be " acceptable " in the meaning compatible with other composition of preparation.Some examples of materials can serving as pharmaceutically acceptable carrier comprise: (1) carbohydrate; (2) starch; (3) cellulose and its derivates; (4) powdery twelve month yam glue; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) vehicle; (9) oils; (10) glycol; (11) polyvalent alcohol; (12) lipid; (13) agar; (14) buffer reagent; (15) algae; (16) apirogen water; (17) isotonic saline solution; (18) Green's formula solution; (19) ethanol; (20) phosphate buffer soln; (21) other is used in the non-toxic compatible material in pharmaceutical preparation.In some embodiments, one or more promoting agents can contain basic functionality, such as amino or alkylamino, thus can generate pharmaceutically acceptable salt with pharmaceutically acceptable acid.Term " pharmacy acceptable salt " represent in this respect relative nontoxic, the inorganic and organic acid addition salt of the compounds of this invention.These salt can be prepared on the spot during final the compounds of this invention isolation and purification, or make separately the free alkali form of purified the compounds of this invention and the organic or inorganic acid-respons be applicable to, then are separated the salt generated.Representative basic metal or alkaline earth salt comprise lithium, sodium, potassium, calcium, magnesium, aluminium salt etc.The example of pharmaceutically acceptable antioxidant comprises (1) water soluble antioxidant; (2) oil-soluble inhibitor; (3) metal chelator; Preparation is prepared as follows: the solid carrier of promoting agent of the present invention and liquid vehicle or fine pulverizing or the two all evenly to be associated closely, then if necessary make product be shaped.
The compounds of this invention as medicine to humans and animals administration time, they can using former state or as pharmaceutical composition administration, and described composition is such as containing the combination of 0.1-99.5% activeconstituents with pharmaceutically acceptable carrier.Except aforesaid combination beyond the region of objective existence, the coverture wherein containing appropriate therapeutical agent can be utilized, such as plaster, bandage, dressing, Sticky pad etc.As mentioned previously, therapeutic composition can administration on support, device, Prostheses and implants again.
Be below embodiment:
Embodiment 1
A kind of vanadyl class title complex, its chemical name is peroxide (imidazoles-4-formic acid) oxo vanadic acid, and be abbreviated as pV (imc), structure is as follows:
Synthetic method is as follows:
Concrete operations are: under argon shield, get VOSO
4 .3H
2o (1.00g, 4.6mmol) be dissolved in the degassed distilled water of 5mL, add again and be dissolved with imidazoles-4-formic acid (1.03g, 5mL aqueous solution 9.2mmol), by slowly adding the NaOH (0.90g of 11mL 2M, 23.0mmol) solution adjust ph is to 12, stir after adding NaOH solution and spend the night, produce a large amount of precipitation, fast filtering, with cold water and washed with ether filter cake, be drying to obtain target compound peroxide (imidazoles-4-formic acid) oxo vanadic acid (pV (imc)), yield is 78%.Product structure is determined by infrared, mass spectrum.IR v (KBr): 3439,1635 (CN), 960 (VO) cm
-1, infared spectrum as shown in Figure 1.
Embodiment 2
A kind of vanadyl class title complex, its chemical name is two peroxide (imidazoles-4-formic acid) oxovanadate, and be abbreviated as bpV (imc), structure is as follows:
Synthetic method is as follows:
Concrete operations are: get V
2o
5(1.43g, 7.84mmol), KOH (1.04g, 18.53mmol) joins in the degassed distilled water of 15mL and stirs 5 minutes, and solution can become green gradually, toward turing the H adding 2mL 30% in green solution
2o
2, stir 25 minutes, after solid dissolves gradually, add the H of 12mL30%
2o
2stir 15 minutes, now add again and be dissolved with imidazoles-4-formic acid (1.76g, 20mL water 15.68mmol) and the mixing solutions of 5mL ethanol, react 30 minutes under room temperature, produce solid, filter, be drying to obtain two peroxide (imidazoles-4-formic acid) oxovanadate (bpV (imc)) of target product, yield is 84%.Product structure is determined by infrared, mass spectrum.IR v (KBr): 3456,1621 (CO), 947 (VO), 842 (OO) cm
-1, infared spectrum as shown in Figure 2.
Embodiment 3
A kind of vanadyl class title complex, its chemical name is peroxide (pyridine-2-squaric amide) oxo vanadic acid, and be abbreviated as pV (pis), structure is as follows:
Synthetic method is as follows:
Concrete operations are: under argon shield, get VOSO
4 .3H
2o (1.00g, 4.6mmol) be dissolved in the degassed distilled water of 5mL, add again and be dissolved with pyridine-2-squaric amide (1.75g, 5mL aqueous solution 9.2mmol), by slowly adding the NaOH (0.90g of 11mL 2M, 23.0mmol) solution adjust ph is to 12, stir after adding NaOH solution and spend the night, produce a large amount of precipitation, fast filtering, with cold water and washed with ether filter cake, be drying to obtain target compound peroxide (pyridine-2-squaric amide) oxo vanadic acid (pV (pis)), yield is 68%.Product structure is determined by infrared, mass spectrum.IR v (KBr): 3452,1683 (CO), 1013 (VO) cm
-1, infared spectrum as shown in Figure 3.
Embodiment 4
A kind of vanadyl class title complex, its chemical name is two peroxide (pyridine-2-squaric amide) oxovanadate, and be abbreviated as bpV (pis), structure is as follows:
Synthetic method is as follows:
Concrete operations are: get V
2o
5(1.43g, 7.84mmol), KOH (1.04g, 18.53mmol) joins in the degassed distilled water of 15mL and stirs 5 minutes, and solution can become green gradually, toward turing the H adding 2mL 30% in green solution
2o
2, stir 25 minutes, after solid dissolves gradually, add the H of 12mL30%
2o
2stir 15 minutes, now add again and be dissolved with pyridine-2-squaric amide (2.98g, 20mL water 15.68mmol) and the mixing solutions of 5mL ethanol, react 30 minutes under room temperature, produce solid, filter, be drying to obtain two peroxide (pyridine-2-squaric amide) oxovanadate (bpV (pis)) of target product, yield is 76%.Product structure is determined by infrared, mass spectrum.IR v (KBr): 3194,1617 (CO), 960 (VO), 816 (OO) cm
-1, infared spectrum as shown in Figure 4.
Embodiment 5
Be below the effect of vanadyl class title complex in SH-SY5Y, U251 cell strain and SD rat of synthesis in embodiment 1 to 4.
(1) human neuroblastoma cells's experiment
By containing PTEN, brain source, human neuroblastoma cells's strain SH-SY5Y is after ECS (extracellular fluid) processes 1 hour, process 1 hour respectively with the vanadyl class title complex (200nM) of synthesis in embodiment 1 to 4 again, then use western blot technology for detection Akt active.Akt is a kind of Protein Serine/threonine kinase, and P-Akt is the manifestation of Akt protein activation, and Akt can Promote cell's growth after activating, inhibited apoptosis.As shown in Figure 5: the process of four kinds of vanadyl title complexs (200nM) causes p-Akt in cell to express apparently higher than control group CON (n=6, ANOVA test, * P<0.05vs.CON respectively; T-Akt is Akt total protein content), prompting has provide protection.
(2) glioma cell experiment
By the glioma cell line U251 of PTEN genetically deficient through ECS process after 1 hour, then process 1 hour respectively with the vanadyl class title complex (200nM) of synthesis in embodiment 1 to 4, then use westernblot technology for detection Akt activity.As shown in Figure 6: vanadyl title complex (200nM) process does not cause the expression of p-Akt in cell to change (n=6, ANOVA test; T-Akt is Akt total protein content).Because known PTEN can suppress p-Akt active, this experimental result shows, the effect of this kind of vanadyl title complex enhancing Akt activity is the mediation by PTEN.
(3) LDH (serum lactic dehydrogenase) assay experiment
LDH (serum lactic dehydrogenase) is very important a kind of glycolytic ferment in viable cell, and when cell sustains damage or cytolemma is damaged, LDH can discharge, so the burst size of LDH can embody cell survival conditions or degree of injury.As shown in Figure 7a, as the vanadyl class title complex (200nM with synthesis in embodiment 1 to 4,2 μMs) distinguish treatment S H-SY5Y cell after 12 hours, the process of this kind of vanadyl title complex does not only increase LDH burst size but also (n=6 fewer than ECS treatment group, ANOVA test), show that such title complex does not have cytotoxic effect in 200nM-2 μM of concentration range.In addition, when cell is through PQ (Paraquat) damage process, this group obviously increases (Fig. 7 b n=6, ANOVA test than the LDH burst size of PQ+ vanadyl title complex group; * P<0.05vs.control; #P<0.05vs.PQ), show that such title complex has cytoprotection.
(4) rat MCAO (middle cerebral artery occlusion) model experiment
Carry out MCAO operation to SD rat, ischemic is revascularization after 1.5 hours, causes ischemical reperfusion injury, set up cerebral apoplexy model with this.Blood vessel Reperfu-sion, after 3 hours, injects the vanadyl class title complex (2 μMs) of synthesis in embodiment 1 to 4 respectively through lateral ventricle of rat brain.After 24 hours, brain is got in perfusion, carries out TTC dyeing.TTC (2,3,5-triphenyltetrazolium chloride) is fat-soluble photaesthesia mixture, and its dyeing can be used to the ischemic infarct size detecting mammalian tissues.Experimental result is as shown in Figure 8: cerebral ischemia area obviously (n=9, the ANOVA test less of the ischemic areas of injecting normal saline control group of injection vanadyl class title complex animal; * P<0.05vs.CON).Show that such Novel oxygen vanadium complex has provide protection to cerebral apoplexy ischemic injuries.
Those skilled in the art will readily understand; the foregoing is only preferred embodiment of the present invention; not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1. a vanadyl class title complex, is characterized in that, has the structure of formula (I) or formula (II):
Wherein L-L ' is:
L ' is COO or O.
2. vanadyl class title complex as claimed in claim 1, it is characterized in that, described L-L ' is:
3. vanadyl class title complex as claimed in claim 2, it is characterized in that, described vanadyl class title complex is peroxide (pyridine-2-squaric amide) oxo vanadic acid or two peroxide (pyridine-2-squaric amide) oxovanadate.
4. an application for the vanadyl class title complex as described in claims 1 to 3 any one, is characterized in that, is applied to preparation PTEN inhibitor.
5. the application of vanadyl class title complex as claimed in claim 4, is characterized in that, is applied to the medicine of preparation treatment nervous system injury disease.
6. the application of vanadyl class title complex as claimed in claim 5, is characterized in that, is applied to the medicine of preparation treatment cerebral ischemia, hematencephalon, traumatic brain injury or spinal neuronal damage.
7. the application of vanadyl class title complex as claimed in claim 4, is characterized in that, is applied to the medicine of preparation treatment nerve degenerative diseases.
8. the application of vanadyl class title complex as claimed in claim 7, is characterized in that, is applied to the medicine of preparation treatment Parkinson or alzheimer's disease.
9. a PTEN inhibitor medicaments composition, is characterized in that, containing, for example the vanadyl class title complex described in claims 1 to 3 any one.
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Citations (3)
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| JPH10158533A (en) * | 1996-12-02 | 1998-06-16 | Yamamoto Chem Inc | Production of vanadyl naphthalocyanine compound |
| WO2005097119A2 (en) * | 2004-04-06 | 2005-10-20 | Semafore Pharmaceuticals, Inc. | Pten inhibitors |
| CN101932331A (en) * | 2008-01-17 | 2010-12-29 | 刘奎 | Methods for in vitro maturation of ovarian follicles |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10158533A (en) * | 1996-12-02 | 1998-06-16 | Yamamoto Chem Inc | Production of vanadyl naphthalocyanine compound |
| WO2005097119A2 (en) * | 2004-04-06 | 2005-10-20 | Semafore Pharmaceuticals, Inc. | Pten inhibitors |
| CN101932331A (en) * | 2008-01-17 | 2010-12-29 | 刘奎 | Methods for in vitro maturation of ovarian follicles |
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| CRAIG C. MCLAUCHLAN ET AL.: "Inhibition of acid, alkaline, and tyrosine (PTP1B) phosphatases by novel vanadium complexes", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 * |
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