CN1760172A - Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity - Google Patents
Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity Download PDFInfo
- Publication number
- CN1760172A CN1760172A CN 200410086340 CN200410086340A CN1760172A CN 1760172 A CN1760172 A CN 1760172A CN 200410086340 CN200410086340 CN 200410086340 CN 200410086340 A CN200410086340 A CN 200410086340A CN 1760172 A CN1760172 A CN 1760172A
- Authority
- CN
- China
- Prior art keywords
- copper
- title complex
- sod
- amino acid
- dipeptides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
A tetra-(alpha-amino acid or dipeptide) bicopper match is prepared from copper acetate and alpha-amino acid or dipeptide through reflux-type liquid-solid phase transfer reaction in organic solvent (absolute alcohol, etc). Its chemical structure is also disclosed. Said match has the activity similar to that of SOD, so it can be used to treat the injury and diseases caused by excessive superoxygen anionic free radicals, such as diabetes.
Description
This invention of technical field is a kind of four-(a-amino acid or dipeptides) two copper complexes and synthetic method and SOD (superoxide-dismutase) sample activity, belongs in the chemistry SOD stand-in technical field in a metal-organic complex and pharmacy.
Background technology SOD is a kind of metalloenzyme that exists in the organism, and it can remove excessive active oxygen, thereby keeps the health of body.But old and feeble or when being in morbid state, the amount of active oxygen often increases as the people, therefore give with the ectogenic SOD of body be that treatment is because active oxygen produces a kind of means of the disease that too much causes.But because the natural SOD transformation period in vivo is shorter, the SOD stand-in have therefore arisen at the historic moment.The SOD stand-in are gained the name by the active centre of Simulating SOD, have simple monokaryon amino acid (small peptide) copper complex [1] now, contain the amino acid copper complex [2] of tensio-active agent, two copper complexs [3] of imidazoles bridging and hydroxyl bridging copper complex [4] etc.
We have obtained a kind of four-(a-amino acid or dipeptides) new two copper complexes with new synthetic method, it has the similar dimeric structure with natural SOD, and part is alpha amino acid or polypeptide, the double-core copper complex [3 of original bibliographical information, 4], structurally more approach natural SOD.By literature search, do not find similarly report.Discover that through pulse radiolysis method this novel pair of copper complex has the ability of the removing ultra-oxygen anion free radical suitable with natural SOD.Pharmacodynamic study found that; the administration of diabetic mice oral administration, obviously lowering blood glucose improves the regulating blood fat disorder; heart nephridial tissue to diabetic mice has significant protective effect, so the novel title complex of this kind is the stand-in of a kind of natural SOD of replacement of potentialization.
Summary of the invention
1. one of innovative point of this invention is the two copper complexes that propose a kind of novel texture, and the composition formula of this title complex is:
[R-CH(NH
2)-COO
-；R-CH(NH
2)-CONH-CH(COO-)-R′]
4Cu
2·XH
2O
X=0 in the formula, title complex does not have crystal water; R is C
0～C
14Straight-chain paraffin, also can be C
2～C
14Carbonic acyl radical and the alkyl that contains hydroxyl, sulphur, phenyl ring and nitrogen heterocyclic.R and R ' group can be with can be different.
The crystal structure characteristic of the no crystal water title complex of this kind is:
Cu (II) ion is positioned at the symmetry centre position of molecule, part R-CH (NH
2)-COO
-Or R-CH (NH
2)-CONH-CH (COO
-)-R ' is respectively with two tooth pattern and Cu (II) ion coordination; Two Cu (II) ion mainly by carboxyl-O=C-O-bridging, is aided with the hydrogen bond that exists between contiguous part again, connects into dimer; Dimeric two " monomers " that form are enantiomer each other, is centrosymmetric.
By literature search, find no the report of this kind title complex.The report that two copper imidazolate-bridge contact compounds were once arranged
[3], copper-threonine title complex C
8H
16CuN
2O
6H
2O
[5](C
8H
16CuN
2O
6)
nNH
2The report of O
[6], more than all be not two copper complexes of amino acid or dipeptides, and all contain crystal water.If by our synthetic method, do raw material with Threonine, institute's synthetic title complex consists of (C
8H
16CuN
2O
6)
2, see exemplifying embodiment 1 for details.
2. two of the innovative point of this invention be to propose a kind of no crystal water four-(a-amino acid or dipeptides) two copper complex synthetic methods.
This method is to be raw material with venus crystals or ventilation breather and a-amino acid or dipeptides, and in dehydrated alcohol or ether or acetone and other organic solvent, 35～80 ℃ were refluxed 1～14 hour down, carry out the liquid-solid phase shift reaction.Reaction product is with organic solvent washings such as dehydrated alcohols, and water not.Temperature of reaction and time are different because of raw materials used and selected solvent.The preferred venus crystals of Cu (II) ion raw material; The anhydrous solvent preferred alcohol, this is that boiling point is suitable, and venus crystals has bigger solubleness therein because ethanol is nontoxic.
Reactant venus crystals or ventilation breather: a-amino acid or dipeptides ≈ 1.1: 2.0 (mol ratio).The selection principle of two kinds of raw material consumptions is 1) raw material sources and cost, 2) remove excessive reactant easily, therefore select venus crystals excessive slightly.
The product that adopts this synthetic method to obtain does not have four of aforementioned structure feature-(a-amino acid or dipeptides) two copper complexes for not containing crystal water.Need to prove, though reaction system be anhydrous solid-the liquid phase shift reaction, if there is less water (1～5%) to exist, do not influence the quality of product.
Above-mentioned synthetic method sporadically appears in transition metal organometallic compound synthetic, but used coordination compound difference, therefore central ion difference, and selected solvent difference have obtained a kind of novel title complex.
3. three of the innovative point of this invention be that the two copper complexes of this kind have higher SOD sample activity.
It is characterized in that this kind title complex is the same with superoxide-dismutase (SOD), have Cu (II) ionic activity center, and all be dimer, and can both remove ultra-oxygen anion free radical (O
2 .-).Studies show that through pulse radiolysis method it has the SOD sample activity suitable with natural SOD, some has also surpassed natural SOD.Double-core copper (II) title complex [3] of Ceng Youguan synthetic imidazoles bridging and contain the report of amino acid copper complex [2] activity research of tensio-active agent, their SOD sample activity is all lower.
This pair copper complex is as the stand-in of SOD, structurally more approach natural SOD, and overcome the many restriction of the medicinal enzyme of natural SOD in clinical application, as more natural SOD there is the transformation period in the longer body, relative molecular weight is less, long-term down non-inactivation, the relatively suitable for oral administration of placing of normal temperature, vulnerable to pollution not, price is more cheap.Therefore it is anti-oxidant, and anti-ageing, the preventing disease aspect has bigger potentiality.Also can in food, be used as preservation agent in addition, in makeup, be used as antioxidant, on agricultural, be used to strengthen crop drought resistance, the ability of premature senescence resistance and anti-chemical poisoning.
4. four of the innovative point of this invention be that the two copper complexes of this kind can reduce diabetes blood sugar, blood fat and heart kidney blood vessel is had provide protection.
Adopt basic, normal, high by (0.002%, 0.02%, 0.1%) diabetic mice is fed in four of three kinds of dosage-(a-amino acid or dipeptides) two copper complex groupings, and the heart, the ephrosis reason of measuring its fasting plasma glucose, glycolated hemoglobin, blood fat and diabetic mice change.Found that middle dosage group is lowering blood glucose obviously, reducing cholesterol (TC) reduces low-density lipoprotein (LDL) level and makes high-density lipoprotein (HDL) (HDL) level obviously raise.Middle dosage gastric infusion group diabetic mice cardiac muscle fibre marshalling, nucleus and cytoplasm are evenly distributed; The renal glomerulus structure is normal, and the cell size distribution is even, and dyeing is normal.Therefore the two copper complexs of this kind have effect hypoglycemic significantly, that regulating blood fat is disorderly as can be seen, and the heart nephridial tissue of diabetic mice is played significant protective effect, wherein with middle dosage group (0.02%) best results.This SOD stand-in have bigger application prospect to anti-oxidant, the hypoglycemic treatment of diabetic, control great vessels, microangiopathies clinically.
Embodiment
Synthesizing of embodiment 1 no crystal water four-(a-amino acid or dipeptides) two copper complexes
1. there be not the synthetic of the two copper complexes of crystal water Threonine
Take by weighing the 5.5mmol venus crystals, be dissolved in the 50ml dehydrated alcohol, stir and slowly to add the 10mmolL-Threonine down, 79 ℃ of following back flow reaction 12 hours.Suction filtration, till the redgreen washings, product vacuum-drying obtains blue look solid with the absolute ethanol washing product.
2. there be not the synthetic of crystal water four-(glycylglycine) two copper complexes
Take by weighing the 5.5mmol venus crystals, be dissolved in 50ml 95% ethanol, solution is green transparent.In solution, add the 10mmol glycylglycine, 79 ℃ of following back flow reaction 1～2 hour.Suction filtration, till the redgreen washings, product vacuum-drying obtains blue look solid with the absolute ethanol washing product.
3. there be not the synthetic of crystal water four-(N one positive 12 phosphinylidyne glycylglycines) two copper complexes
At first press the synthetic positive 12 phosphinylidyne glycylglycines of document [7].
Take by weighing the 5.5mmol venus crystals, be dissolved in the 50ml dehydrated alcohol.In solution, add the positive 12 phosphinylidyne glycylglycines of 10mmol, 78 ℃ of following back flow reaction 1～2 hour.Suction filtration, till the redgreen washings, product vacuum-drying obtains blue green solid with the absolute ethanol washing product.
The structural characterization of the two copper complexes of embodiment 2 no crystal water Threonines
One, results of elemental analyses
With U.S. P-E company 2400 type elemental analysers synthetic product has been carried out ultimate analysis, the result is as follows
Table 1 Cu
2(Thr)
4The title complex results of elemental analyses
| Elemental analysis results(％) | ||||
| complex | C | H | N | Infer Mr |
| The theoretical value experimental value | 32.05 32.14 | 5.38 5.30 | 9.34 9.28 | 599.55 |
Two, X-diffraction analysis result
Experiment is being carried out under the room temperature on the Bruker Smart CCD diffractometer, and crystal is the water white transparency bulk of 0.51mm * 0.49mm * 0.38mm, and (λ=0.071073nm) collects the diffracted intensity data to use the Mo K α X ray of monochromatization.In the scope of 2.05 °≤θ≤28.33 °, collect 7627 point diffractions altogether, wherein 1430 independent point diffraction (R
Int=0.03870).
Crystal is resolved and is carried out with SHELXS 97 programs.The non-hydrogen atom coordinate and the isotropy thermal parameter of double-core copper-threonine are listed in table 2, mainly become bond distance and bond angle between the key atom to list in table 3, and molecular structure and atom mark are as shown in Figure 1.
Table 2. non-hydrogen atom coordinate (* 10
4) and isotropy thermal parameter (nm
2* 10
5)
| Atom | x | y | z | U(eq) | Atom | x | Y | z | U(eq) |
| Cu O(11) O(12) O(13) N(11) | 5000 4693(2) 3036(2) 2663(2) 3477(2) | 10000 8059(2) 6691(2) 10684(3) 10929(3) | 0 1521(3) 2687(3) 4808(3) 1208(3) | 24(1) 30(1) 32(1) 34(1) 22(1) | C(11) C(12) C(13) C(14) | 3512(3) 2623(2) 1806(3) 688(3) | 7972(3) 9535(3) 9948(3) 11177(5) | 2037(3) 1713(3) 3342(4) 2773(5) | 23(1) 20(1) 28(1) 46(1) |
*U
eq is defined as one third of the trace of the orthogonalized U
ij tensor.
Bond distance (nm) between the main one-tenth of the table 3. key atom and bond angle (°)
| Cu-O(11) Cu-O(21) Cu-N(11) Cu-N(21) | 0.1942(2) 0.1942(2) 0.1972(2) 0.1972(2) | O(11)-C(11) O(12)-C(11) O(13)-C(13) N(11)-C(12) | 0.1274(3) 0.1240(3) 0.1423(3) 0.1472(3) | C(11)-C(12) C(12)-C(13) C(13)-C(14) | 0.1537(3) 0.1532(3) 0.1513(4) |
| O(11)-Cu-O(21) O(11)-Cu-N(11) O(21)-Cu-N(11) O(11)-Cu-N(21) O(21)-Cu-N(21) N(11)-Cu-N(21) | 180.0 83.01(8) 96.99(8) 96.99(8) 83.01(8) 180.0 | O(12)-C(11)-O(11) O(12)-C(11)-C(12) O(11)-C(11)-C(12) N(11)-C(12)-C(13) N(11)-C(12)-C(11) C(12)-N(11)-Cu | 123.8(2) 119.4(2) 116.7(2) 113.2(2) 108.16(19) 108.47(15) | C(11)-O(11)-Cu O(13)-C(13)-C(14) O(13)-C(13)-C(12) C(14)-C(13)-C(12) C(13)-C(12)-C(11) | 114.31(16) 107.9(2) 109.5(2) 111.5(2) 113.7(2) |
Crystal structure determination shows, Cu (II) ion is arranged in the octahedral coordination environment that the symmetry centre position of molecule and have been elongated.Two L-Threonine roots of being got in touch by symmetry centre are respectively with two tooth pattern and Cu (II) ion coordination, and the parallelogram that O (11), N (11), O (21) and N (21) form is an equatorial plane.Cu and this planar distance are 0.000nm.The bond angle of O (11)-Cu-O (21), N (11)-Cu-N (21) and O (11)-Cu-N (11) is respectively 180.00 °, 180.00 ° and 83.00 °.Fine by bidentate schiff base ligand [O (11), C (11), C (12), N (11)] and the formed five yuan of chelate ring coplanarities of Cu atom, the mean value that each atom departs from their least square plane only is 0.01403nm.
Cu-N bond distance and Cu-O bond distance are respectively 0.1972 (2) nm and 0.1942 (2) nm, with the monohydrate of the mononuclear coordination compound of having studied
[5][Cu (Thr)
2H
2O] average Cu-N bond distance equal substantially with Cu-O bond distance [0.198 (1) nm, 0.195 (1) nm].C (2)-N (1) bond distance (0.14702 (3) nm) is shorter than common C-N singly-bound bond distance, and the value of the Schiff's base type I that this also describes with Ueki etc. is consistent
[8]
The axial coordination atom is carboxylic acid group's Sauerstoffatom O (22A), and Cu-O bond distance is 0.2797nm, and the bond angle of O (22A)-Cu-O (21), O (22A)-Cu-N (21) is respectively 100.90 ° and 94.60 °.Cu (II) ion is positioned at the symmetry centre position of molecule
[9], in the crystal of anhydrous double-core copper-threonine, also have the Sauerstoffatom O (23A) of hydroxyl and the hydrogen bond (bond distance is 0.2814nm) of carboxylic acid group's Sauerstoffatom O (12).
Fig. 1 has represented that the structure of double-core Threonine: Cu (II) ion is positioned at the symmetry centre position of molecule, the copper-threonine molecule of 2 vicinities is connected to form dimer by this hydrogen bond and Cu-O=C=O-Cu, form dimeric 2 molecules enantiomer each other, being centrosymmetric property.
Three, hot analytical results
Adopt Switzerland Mettler TA3000 Thermo System to measure the monokaryon after infrared drying and the pyrolytic process of double-core copper-threonine.Temperature rise rate is 20K/min, and nitrogen (high-purity) flow velocity is 10ml/min, and the experimental temperature sweep interval is 30～400 ℃.
Fig. 2,3 TG, DTG collection of illustrative plates for experiment gained monokaryon and double-core copper-threonine.
Handle the DTG spectrum with this Switzerland Mettler TA3000 Thermo System automatic integrator and obtained pyrolysis Kinetics Parameter, it the results are shown in Table 4.
Table 4 pyrolysis Kinetics Parameter
| step analysis | kinetic analysis | |||||
| complex | step | peak temp.(℃) | Δm(％) | n | Ea(KJ/mol) | lnA |
| Cu(Thr) 2 Cu 2(Thr) 4 | step 1 step 1 step 2 | 224.0 216.0 237.0 | -72.35 -31.79 -43.82 | 3.0 1.5 1.0 | 623.73 702.18 201.35 | 48.52 70.30 44.10 |
1. the pyrolytic process of monokaryon copper-threonine is analyzed monokaryon copper-threonine [Cu (Thr)
2] the pyrolysis kinetics process be one the step finish.Cu (Thr)
2, the relative molecular weight of CuO is respectively 299.78g/mol and 79.55g/mol.Cu (Thr)
2Pyrolysis loses the CO of 1 molecule
2, the CO of 1 molecule, the H of 2 molecules
2O, the CH of 2 molecules
2=CH
2And the C of 1 molecule
2H
2, 1 molecule N
2Theoretical rate of weight loss is 73.46%, and is close with experimental value 72.35%.Cooperate gas phase, solid product The qualitative analysis, can infer Cu (Thr)
2The pyrolytic process reaction equation is:
2. the pyrolytic process of double-core copper-threonine is analyzed double-core copper-threonine [Cu
2(Thr)
4] pyrolytic process be divided into two the step finish.Cu
2(Thr)
4, Cu
2The relative molecular weight of O is 599.55g/mol and 143.09g/mol.The first step pyrolytic process loses 4 H
2O, 4 C
2H
4, its relative molecular weight is respectively 18.02g/mol, 28.05g/mol, and theoretical rate of weight loss is 30.74%, conforms to substantially with experimental value 31.79%.The second step pyrolytic process is for losing 3 CO
2, 1 CO, and 2 C
2H
2, 2 N
2Theoretical rate of weight loss is 45.4%, with experimental value be 43.82% close.Infer that reaction is as follows:
Conclusion: this paper institute synthetic double-core copper-threonine is through ultimate analysis, can not have dual-core architecture by very definite its, but through its thermogravimetric analysis, find that its pyrolytic process with the monokaryon copper-threonine is different, the percentage loss of weight difference, the pyrolysis product of finding them by analysis is also inequality, and monokaryon copper-threonine pyrolysis product is that CuO double-core copper-threonine then is Cu
2O.Through cultivating the monocrystalline of double-core copper Threonine complex compound, carry out the X-diffraction analysis simultaneously, the result shows that this compound has the Cu-O=C=O-Cu dual-core architecture.The copper-threonine molecule of 2 vicinities is connected to form dimer by Cu-O-C-O-Cu, forms dimeric 2 molecules enantiomer each other, is centrosymmetric.
The SOD sample activity of the two copper complexes of embodiment 3 no crystal water glycine
Adopt pulse radiolysis method [1] to measure the SOD sample activity of this title complex, the result shows, under 25 ℃, the condition of pH7.8, and natural SOD catalysis O
2 .-The rate constant of disproportionation reaction is 1.85 * 10
9Mol
-1L
-1S
-1The two copper complex catalysis O of the glycine of surveying
2 .-The rate constant of disproportionation reaction is 3.45 * 10
9Mol
-1L
-1S
-1The result shows that the two copper complexes of glycine have SOD sample activity, and higher than natural SOD activity.
The two copper complexes of embodiment 4 no crystal water Threonines are to the influence of tissue of experimental diabetic mice blood sugar, blood fat and to the renovascular provide protection of the heart
Many studies have shown that, free radical participant's pathophysiological process, and superoxide dismutase (SOD) is a main free-radical scavengers in the body plays crucial effects to the oxidation and the anti-oxidant balance of body.Because the SOD level obviously reduces in the diabetes human body, so the relation of diabetes and SOD is more and more paid attention to by people.After the diabetic subject that experiment confirm reduces to SOD replenishes natural SOD, improve the SOD level of body, remove too much free radical, improve hyperglycemia state and correct disorders of lipid metabolism.Because natural SOD transformation period is short, extract the factor such as high of difficulty and price, be subjected to more restriction to the widespread use of aspects such as medical research.The two copper complexes of Threonine are a kind of long half time, low price, easily extract and the very capable antioxidant of Mulberry Extract; blood sugar, blood fat to tissue of experimental diabetic mice have regulating effect and to the renovascular provide protection of the heart, can intervene the generation and the development of diabetes.
One, materials and methods
1. the foundation of animal model and grouping: 60 of ICR female mices, body weight 26 ~ 30 grams.The foundation of diabetes model: animal fasting 12h all overnight, abdominal injection tetraoxypyrimidine (Alloxan, Sigma company provides) 120mg/kg.Get mouse tail blood micrometer amount blood sugar after one week, blood sugar＞10mmol/L is decided to be diabetic mice.
Diabetic mice evenly divides into groups by blood glucose value, 12 every group, feeds by the component cage.Irritate stomach respectively and give distilled water, the two copper complex low dosages (0.002%) of Threonine, middle dosage (0.02%), high dosage (0.1%) is irritated stomach 0.5ml/20g every day, amounts to administration 45 days.
2. irritate stomach 0,30 and getting tail blood measuring blood in 45 days, getting a hematometry glycolated hemoglobin, blood fat in 45 days, and put to death animal, dissecting dirty, the kidney of coring, making pathological section after 20% formalin fixed.
3. statistical procedures: data are represented with X ± S.Adopt paired t-test to carry out statistical procedures, P＜0.05, difference significance.
Two, experimental result
1. the two copper complexes of various dose Threonine are to the influence of blood sugar, glycolated hemoglobin:
The two copper complexes of table 5 various dose Threonine are to the influence of blood sugar, glycolated hemoglobin
| Group | Example number (only) | 0 day blood sugar (mol/L) | 30 days blood sugar (mmol/L) | 45 days blood sugar (mmol/L) | HbA1c (％) |
| Dosage group high dose group in the distilled water low dose group | 8 8 8 8 | 20.72±6.70 22.3±5.67 23.40±4.67 22.96±6.17 | 22.91±9.20 25.35±6.91 21.50±7.23 22.16±7.62 | 27.06±4.77 19.44±8.80 ** 11.81±4.50 ** 21.16±9.48 * | 8.93±1.87 7.22±1.65 * 5.83±1.11 ** 7.30±2.49 * |
*P＜0.05，**P＜0.01，
Data as can be seen from table 1: give about 30 greatly, each is organized blood sugar and is not changed with there being significance in 0 day, and administration is after 45 days, and low, the middle dosage group of SOD stand-in blood sugar descends obvious, relatively has significant difference (p＜0.01) with the diabetes control group; High dose group blood sugar descends, but not obvious.The glycolated hemoglobin that recorded in 45 days, compare mutually with the distilled water control group as can be seen: the two basic, normal, high dosage group of the copper complex glycolated hemoglobins of Threonine all obviously reduce, and significant difference is arranged.
2. the two copper complexes of various dose Threonine are to the influence of blood fat
The two copper complexes of table 6 various dose Threonine are to the influence of blood fat (X ± S)
| Group | Example number (only) | TC mmol/L | TG mmol/L | HDL mmol/L | LDL mmol/L | Atherogenic index |
| Dosage group high dose group in the distilled water low dose group | 8 8 8 8 | 2.80±0.36 2.76±0.54 2.65±0.22 * 2.74±0.42 | 1.34±0.20 1.16±0.37 * 1.10±0.15 * 1.28±0.19 | 1.24±0.19 1.32±0.22 1.52±0.21 * 1.33±0.17 | 0.24±0.05 0.21±0.04 0.17±0.0 * 0.22±0.06 | 1.317±0.521 1.194±0.357 0.707±0.332 * 1.022±0.354 |
Annotate * P＜0.05 atherogenic index (AI)=(TC-HDL)/HDL
(1) TC: compare with the distilled water group, dosage group TC level obviously reduces in the two copper complexes of Threonine, and significant difference (P＜0.05) is arranged.
(2) TG: compare with the distilled water group, low, middle dosage group TG level all has reduction, has statistical significance (P＜0.05).
(3) HDL: compare with the distilled water group, low dose group HDL level obviously raises, and significant difference (P＜0.05) is arranged.
(4) LDL: compare with the distilled water group, middle dosage group LDL obviously reduces, and significant difference (P＜0.05) is arranged.
5) the basic, normal, high dosage group of atherogenic index (AI) AI all decreases, with middle dosage group effect best (P＜0.05).
3. the two copper complexes of various dose Threonine are to the pathological change (seeing accompanying drawing 4-7) of diabetic mice heart
After to mouse heart section HE dyeing, observations is as follows: Fig. 4 is the distilled water control group, shows the disorder of cardiac muscle fibre structural arrangement among the figure, sex change, myofiber fracture, dissolving; Fig. 5 is a low dosage administration group, show among the figure cardiac muscle fibre arrange normal, edema, sex change, the top be between matter hyperemia.Fig. 6 is middle dosed administration group, has shown among the figure that the cardiac muscle fibre arrangement architecture is normal, and nucleus and cytoplasm are evenly distributed; Fig. 7 is a high dosage administration group, and visible cardiac muscle fibre structure exists among the figure, visible focal cardiac muscle fibre swelling and sex change, and nucleus tails off, and cytoplasm dyeing is thin out.
This shows that dosage group in the two copper complexes of Threonine is higher than low, high dose group to myocardial cell's provide protection.
4. the two copper complexes of various dose Threonine are to the pathological change (seeing accompanying drawing 8-11) of diabetic mice kidney:
After to mouse kidney section HE dyeing, observations is as follows: Fig. 8 is the distilled water control group, shows messangial cell swelling, cellular atrophy, sex change among the figure, and the renal capsule gap broadens.Fig. 9 is a low dosage administration group, show among the figure messangial cell nuclear phase to more, nuclear is little, matter is fine and close between cellular atrophy, mild fibrosis.Figure 10 is middle dosed administration group, has shown the normal configuration renal glomerulus among the figure, and nucleus is evenly distributed, and dyeing is normal.Figure 11 is a high dosage administration group, and visible renal glomerulus size is normal among the figure, and cell count is more relatively, and the nuclear color is darker, cellular atrophy, and a matter has fibrosis.
In sum: the two copper complexes of the Threonine of suitable concn can match in excellence or beauty with natural SOD fully, it is lowering blood glucose effectively, and can also the regulating blood fat metabolism disorder, rising HDL, reduce LDL, sugar, lipid metabolism by the regulation and control diabetic mice alleviate atherosclerotic Hazard Factor, suppress the heart of diabetes, the pathological change of kidney, thus the generation of control of diabetes and development.Therefore the widespread use of the two copper complexes of Threonine provides a kind of new treatment means for preventing and treating diabetes and complication thereof.
Reference:
1. thank to English, Deng Xixian, golden legendary small dragon with horns, Li Dazhen, Li Fengmei " pulse radiolysis method research Cu (Ser)
2And the kinetics of Cu (Gly-Gly) 2 catalysis O2.-disproportionation reactions " Beijing Normal University's journal (natural science edition) 1997,33 (2): 226-230
2.Li Fengmei，Xie Ying，Deng Xixian，Zhou Xuan，Chen Dianhua“Kinetics study on dismutationof superoxide anion catalyzed by Cu(Gly-Gly)by using pulse radiolysis”，Radiation Physics andChemistry，63(2002)：675-679.
3.LUO Qin-Hui (Luo Qinhui) .Chem.J.Chinese Universities (SCI) [J], 1997,18 (7): 1012.1018
4.G.Brookes and L.D.Pettit，“Thermodynamics of complex formation between hydrogen，copper(II)andnickel(II)ions and dipeptides containing non-co-ordinating sustituent groups”，J.C.S.Dalton，1975，2106-2112.
5.V.Amirthlingam，K.V.Muralidharam，Pramana，1975，4，83.
6.A.C.Rizzi，O.E.Piro，E.E.Castellano，O.R.Nascimento，C.D.Brondino，Inorg.Chim.Acta.，2000，305，19-2
7. thank to English, Zhou Xuan, Wang Junbo, Deng Xixian " research of copper-(the positive 12 phosphinylidyne glycylglycines of N-) complex compound Simulating SOD " SCI, 2001,22 (1): 67-69.
8.T.Ueki，T.Ashida，V.Sasada，et al.，Acta Crystallogr.，B，1969，25，328
9.T.G.Fawcett，M.Ushay，J.P.Rose，et al.，Inorg.Chem.，1979，18，327.
Claims (8)
1. one kind four-(a-amino acid or dipeptides) two copper complexes, its composition formula is:
[R-CH(NH
2)-COO
-；R-CH(NH
2)-CONH-CH(COO
-)-R′]
4Cu
2·XH
2O
X=0 in the formula, title complex does not have crystal water; R and R ' can be selected from C respectively
0～C
14Straight-chain paraffin, C
2～C
14Carbonic acyl radical or contain the alkyl of hydroxyl, sulphur, phenyl ring and nitrogen heterocyclic.R and R ' can be identical or different.
2. title complex as claimed in claim 1, its crystalline structure is:
Cu (II) ion is positioned at the symmetry centre position of molecule, part R-CH (NH
2)-COO
-Or R-CH (NH
2)-CONH-CH (COO
-)-R ' is respectively with two tooth pattern and Cu (II) ion coordination; Two Cu (II) ion is aided with the hydrogen bond that exists between contiguous part again by carboxyl-O=C-O-bridging, connects into dimer; Dimeric two " monomers " that form are enantiomer each other, is centrosymmetric.
3. no crystal water four as claimed in claim 1 or 2-(a-amino acid or dipeptides) two copper complexes have purposes in the active medicine of SOD sample in preparation, it is characterized in that this title complex has the activity of removing ultra-oxygen anion free radical.
4. purposes as claimed in claim 3 is characterized in that this title complex can be anti-oxidant, and is anti-ageing.
5. purposes as claimed in claim 3 is characterized in that this title complex can improve diabetic symptom.
6. purposes as claimed in claim 5 is characterized in that this title complex can reduce the diabetes glucose level, and the regulating blood fat disorder has provide protection to the heart nephridial tissue of diabetic.
7. method for preparing title complex as claimed in claim 1 or 2, its step is as follows:
At dehydrated alcohol or ether or acetone solution, 35～80 ℃ were refluxed 1～14 hour down, carry out the liquid-solid phase shift reaction with venus crystals or ventilation breather, a-amino acid or dipeptides.
8. method as claimed in claim 7, the mol ratio of venus crystals wherein or ventilation breather and a-amino acid or dipeptides are 1.1: 2.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100863407A CN100368381C (en) | 2004-10-26 | 2004-10-26 | Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100863407A CN100368381C (en) | 2004-10-26 | 2004-10-26 | Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1760172A true CN1760172A (en) | 2006-04-19 |
| CN100368381C CN100368381C (en) | 2008-02-13 |
Family
ID=36706418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100863407A Expired - Fee Related CN100368381C (en) | 2004-10-26 | 2004-10-26 | Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100368381C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284010B (en) * | 2008-04-25 | 2010-12-15 | 中山大学 | Application of di-(2,2'-dipyridine) copper complex with double-cation side arm in eliminating the superoxide ion free radical |
| CN105949793A (en) * | 2016-05-31 | 2016-09-21 | 西北师范大学 | Preparation of compound obtained through combining soybean protein chitosan microspheres with amino acid metal complex and application as antioxidant |
| CN106188103A (en) * | 2016-07-14 | 2016-12-07 | 河南中医学院 | A kind of azacyclo-transition metal copper complex containing multiple coordination sites, preparation method and application |
| CN109879931A (en) * | 2018-05-23 | 2019-06-14 | 西北工业大学 | A method of utilizing crystallisation separating-purifying superoxide dismutase |
| CN111592660A (en) * | 2020-06-15 | 2020-08-28 | 平顶山学院 | One-dimensional coordination polymer of nickel, preparation method thereof and application thereof in proton conducting membrane of fuel cell |
-
2004
- 2004-10-26 CN CNB2004100863407A patent/CN100368381C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284010B (en) * | 2008-04-25 | 2010-12-15 | 中山大学 | Application of di-(2,2'-dipyridine) copper complex with double-cation side arm in eliminating the superoxide ion free radical |
| CN105949793A (en) * | 2016-05-31 | 2016-09-21 | 西北师范大学 | Preparation of compound obtained through combining soybean protein chitosan microspheres with amino acid metal complex and application as antioxidant |
| CN106188103A (en) * | 2016-07-14 | 2016-12-07 | 河南中医学院 | A kind of azacyclo-transition metal copper complex containing multiple coordination sites, preparation method and application |
| CN109879931A (en) * | 2018-05-23 | 2019-06-14 | 西北工业大学 | A method of utilizing crystallisation separating-purifying superoxide dismutase |
| CN111592660A (en) * | 2020-06-15 | 2020-08-28 | 平顶山学院 | One-dimensional coordination polymer of nickel, preparation method thereof and application thereof in proton conducting membrane of fuel cell |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100368381C (en) | 2008-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1899361A (en) | Zhenqi medicinal composition and its preparation | |
| CN1857642A (en) | Quality control method for depression relieving and tranquilizing preparation | |
| CN1760172A (en) | Tetra-(alpha-amino-acid or dipeptide) complexes of di-copper and synthetic method, and SOD loke activity | |
| CN101032504A (en) | Application of liquiritin in medicines | |
| CN1712056A (en) | Medicinal composition, preparation and quality control thereof | |
| CN103405522B (en) | Hematopoietic Chinese medicinal composition | |
| CN1775247A (en) | Fleece-flower root and rhizoma rehmanniae preparation and new preparing method | |
| CN1733109A (en) | Soft capsule for treating coronary disease and process for preparing the same | |
| CN1899569A (en) | Preparing process for Chinese medicine for treating vocal nodules and polyp of vocal cord and its use | |
| CN100350940C (en) | Medicine for treating diabetes and its complications and its preparing process | |
| CN1258372C (en) | Chinese medicinal composition for treating intestine irritable syndrome and its preparing method | |
| CN102319268B (en) | Preparation method of injection used for treating chronic congestive cardiac failure | |
| CN1264506C (en) | Pharmaceutical combination containing red sage root element and preparation method thereof | |
| CN101020026B (en) | Honeyed Guiqi ointment for enhancing body's resistance and its preparation | |
| CN1887859A (en) | Tiopronin amidate and its prepn | |
| CN1840075A (en) | Diabetes-treating capsule and preparation method thereof | |
| CN1899369A (en) | Heart resurrecting injection preparation and its preparing method | |
| CN1965954A (en) | Tablet having kudzuvine root and astragalus root and method for preparing same | |
| CN1310639C (en) | Effervescence tablet for treating gynecopathy and preparation method thereof | |
| CN1957944A (en) | Application of yew amylose in pharmacy | |
| CN1686388A (en) | Kangai drip pill for treating tumour, hepatitis B and its preparation method | |
| CN101134026B (en) | Vinorelbine soft capsule and method for preparation and application thereof | |
| CN1278705C (en) | Orally disintegrating tablet of 'Tongxinluo' and its preparation | |
| CN101032505A (en) | Treatment medicine and healthy product including liquiritin | |
| CN1836655A (en) | Electrolyte replenisher for treating hypopotassaemia hypomagnesemia and its uses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080213 Termination date: 20151026 |
|
| EXPY | Termination of patent right or utility model |