CN100368381C - 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
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Abstract
The present invention discloses a tetra-(alpha-amino-acid or dipeptide) double-copper composition, a synthetic method and the SOD (superoxide dismutase) sample activity thereof, which belongs to the technical fields of a metal organic composition in chemistry and an SOD simulacrum in pharmacy. The composition is obtained by using cupric acetate and alpha-amino acid or dipeptides as raw materials to be refluxed to carry out a liquid-solid phase transfer reaction in organic solvents, such as anhydrous alcohol, etc. A composition without crystallization water obtained by the synthetic method has the technical scheme that the alpha-amino acid or the dipeptides are coordinated with Cu (II) ions in a double-tooth form; the Cu (II) ions are mainly in bridge connection with each other by a carboxyl group-O=C-O-and are assisted with a hydrogen bond arranged between adjacent ligands to be connected into a dipolymer, two monomers formed into the dipolymer are enantiomers with each other and are in central symmetry, and a structure is shown in an attached figure 1. The composition has a structure similar to that of natural SOD, has the higher capacity for removing superoxide anion radicals (O2<->) synchronously and can be used for treating damage and diseases resulted from excessive O2<-> in human bodies. The double-copper composition can obviously reduce the blood sugar for dose oral taking administration to a mouse in a diabetes model, the blood-fat disturbance is improved and regulated, and the double-copper composition has the obvious protect action for organizations of the heart and the kidney of the diabetes mouse.
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]All not two copper complexes of amino acid or dipeptides below, 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.
Brief Description Of Drawings:
Fig. 1 is the two copper complex Cu of Threonine
2(Thr)
4Crystalline structure; Fig. 2 is monokaryon copper-threonine Cu (Thr)
2TG and DTG spectrogram; Fig. 3 is the two copper complex Cu of Threonine
2(Thr)
4TG and DTG spectrogram; Fig. 4 is pathological change HE * 400 of distilled water control group to the diabetic mice heart; Fig. 5 is pathological change HE * 400 of the two copper complex groups of low dosage Threonine to the diabetic mice heart; Fig. 6 is pathological change HE * 400 of the two copper complex groups of middle dosage Threonine to the diabetic mice heart; Fig. 7 is pathological change HE * 200 of the two copper complex groups of high dosage Threonine to the diabetic mice heart; Fig. 8 is pathological change HE * 400 of distilled water administration control group to the diabetic mice kidney; Fig. 9 is pathological change HE * 400 of the two copper complex groups of low dosage Threonine to the diabetic mice kidney; Figure 10 is pathological change HE * 200 of the two copper complex groups of middle dosage Threonine to the diabetic mice kidney; Figure 11 is pathological change HE * 400 of the two copper complex groups of high dosage Threonine to the diabetic mice kidney.
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-(the positive 12 phosphinylidyne glycylglycines of N-) 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 1Cu
2(Thr)
4The title complex results of elemental analyses
| complex | Elemental analysis results(％) | |||
| 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 MoK 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.
Two, 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
| complex | step analysis | kinetic analysis | ||||
| 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
2The rate constant of disproportionation reaction is 1.85 * 10
9Mol
-1L
-1S
-1The two copper complex catalysis O of the glycine of surveying
2The 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 (mmol/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 are as can be seen from table 1: administration 30 days, and each is organized blood sugar and was not had significance to change in 0 day, and administration is after 45 days, and low, the middle dosage group of SOD stand-in blood sugar descends obviously, 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 | TG | HDL | LDL | Artery congee sample |
| mmol/L | mmol/L | mmol/L | mmol/L | Hardenability value | ||
| 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 (Al)=(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 " kinetics of pulse radiolysis method research Cu (Ser) 2 and 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 (7)
1. one kind four-(a-amino acid or dipeptides) two copper complexes, its composition formula is: L
4Cu
2XH
2O, wherein L is
R-CH (NH
2)-COO-or R-CH (NH
2)-CONH-CH (COO-)-R '
X=0 in the formula, title complex does not have crystal water; R and R ' can be selected from the alkyl that contains hydroxyl, sulphur, phenyl ring and nitrogen heterocyclic respectively, and R and R ' can be identical or different; 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.
2. no crystal water four as claimed in claim 1-(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.
3. purposes as claimed in claim 2 is characterized in that this title complex can be anti-oxidant, and is anti-ageing.
4. purposes as claimed in claim 2 is characterized in that this title complex can improve diabetic symptom.
5. purposes as claimed in claim 4 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.
6. method for preparing title complex as claimed in claim 1, 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.
7. method as claimed in claim 6, the mol ratio of venus crystals wherein or ventilation breather and a-amino acid or dipeptides are 1.1: 2.0.
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| 脉冲辐解法研究CU SER 2和CU GLY GLY 2催化歧化反应动力学. 谢英等.北京师范大学学报 自然科学版，第33卷第2期. 1997 * |
| 铜一NG一正十二碳酰双士肽配合物模似研究. 谢英等.高等学校化学学报，第22卷第1期. 2001 * |
| 铜锌超氧化歧化酶的模拟化学研究. 罗勤慧.高等学校化学学报，第18卷第7期. 1997 * |
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