CN106588997A - Bipyridine-methionine trihydrate ruthenium complex and preparation method thereof - Google Patents
Bipyridine-methionine trihydrate ruthenium complex and preparation method thereof Download PDFInfo
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- methionine
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- 239000012327 Ruthenium complex Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- RQPOMTUDFBZCHG-UHFFFAOYSA-N ruthenium;trihydrate Chemical compound O.O.O.[Ru] RQPOMTUDFBZCHG-UHFFFAOYSA-N 0.000 title abstract 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 24
- 229930182817 methionine Natural products 0.000 claims abstract description 24
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 24
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 229920001184 polypeptide Polymers 0.000 claims description 16
- 238000006703 hydration reaction Methods 0.000 claims description 13
- 230000002776 aggregation Effects 0.000 claims description 11
- 238000004220 aggregation Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000005481 NMR spectroscopy Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000012512 characterization method Methods 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000001629 suppression Effects 0.000 claims description 3
- 230000006919 peptide aggregation Effects 0.000 abstract description 10
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 20
- 235000006109 methionine Nutrition 0.000 description 18
- 239000002245 particle Substances 0.000 description 12
- 230000036571 hydration Effects 0.000 description 10
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XPZWWTIIKSODDO-MBNDGZRNSA-N 148439-49-0 Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)CC1=CN=CN1 XPZWWTIIKSODDO-MBNDGZRNSA-N 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000835 fiber Substances 0.000 description 6
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 6
- 230000005540 biological transmission Effects 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 102000003797 Neuropeptides Human genes 0.000 description 4
- 108090000189 Neuropeptides Proteins 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000010413 mother solution Substances 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 150000003303 ruthenium Chemical class 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 239000010931 gold Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 208000014644 Brain disease Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 229940125650 NAMI-A Drugs 0.000 description 2
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000003941 amyloidogenesis Effects 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002508 compound effect Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QWWVBNODQCWBAZ-WHFBIAKZSA-N (2r)-2-amino-3-[(2r)-2-carboxy-2-(methylamino)ethyl]sulfanylpropanoic acid Chemical compound CN[C@H](C(O)=O)CSC[C@H](N)C(O)=O QWWVBNODQCWBAZ-WHFBIAKZSA-N 0.000 description 1
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 0 CC([C@@](*)NCSC)*=O Chemical compound CC([C@@](*)NCSC)*=O 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- -1 NAMI-A Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000002742 methionines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- BIXNGBXQRRXPLM-UHFFFAOYSA-K ruthenium(3+);trichloride;hydrate Chemical compound O.Cl[Ru](Cl)Cl BIXNGBXQRRXPLM-UHFFFAOYSA-K 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 108010064245 urinary gonadotropin fragment Proteins 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention provides a bipyridine-methionine trihydrate ruthenium complex and a preparation method of the bipyridine-methionine trihydrate ruthenium complex. According to the invention, methionine and bipyridine are used as ligands to prepare a new metal ruthenium complex, the synthesis method is simple, and the obtained bipyridine-methionine trihydrate ruthenium complex is higher in biocompatibility and very strong inhibition in amyloid peptide aggregation, thereby being a very good amyloid peptide aggregation inhibitor.
Description
Technical field
The invention belongs to technical field of function materials, especially, is related to the hydration ruthenium complex Ru of bipyridyl-methionine three
(bipy)(met)2·3H2O and preparation method thereof.
Background technology
In recent years, the generation of protein conformation disease and its pathogenesis are widely paid attention to and are studied.Some protein
Or biologically active polypeptide is in the case where keeping primary structure stable, it would still be possible to produce significant secondary structure change, cause egg
White matter assembles to form fiber, and causes a series of generation of diseases.The A- β albumen related to degenerative brain disorder, with parkinson
Sick related alpha-synapse albumen, the PrPC and with type ii diabetes relevant people islet amyloid sample peptide relevant with bovine spongiform encephalopathy belongs to
It is such.They are moved back because false folding causes structural transformation and protein to produce amyloid deposition with some typical nerves
Row disease and type ii diabetes have close relation.
Amyloid and polypeptide are noteworthy characterized by its aggregation fibrosis, therefore the aggregation for amyloid suppresses
Agent research becomes the important means for capturing relevant disease.The people islet amyloid sample inhibitor peptides research table relevant with type ii diabetes
Bright, armaticity organic molecule such as Congo red, caffeic acid etc. can effectively suppress the amyloid deposition；With polypeptide 20-29 sequence phases
Some near small peptides can be combined and be prevented the formation of fiber by hydrophobic interaction with polypeptide；And send out in document report in recent years
It is existing, can effectively suppress the aggregation of people's islet amyloid sample peptide as the vanadium complex of diabetes medicament, this is type ii diabetes
Pathogenesis and medicament research and development provide new thinking.
In the drug research relevant with degenerative brain disorder and bovine spongiform encephalopathy, find for A- β albumen and PrPC nerve
The inhibitor of peptide aggregation in addition to organic synthesis reagent, the metal-chelator of element also including Cu, Zn etc., and gold, platinum, ruthenium class chemical combination
Thing.As gold complex realizes the aggregation inhibitory action to amyloid polypeptide by hydrophobic interaction and coordination combination.
Ruthenium complex has widely been paid close attention to and has been paid attention in biomedicine field.The phase of ruthenium complex and DNA first
The existing a great deal of document of study on interaction, because its cytotoxicity it is little, it is easy to by blood brain barrier, with becoming very much anticarcinogen greatly
The potentiality of thing.Multiple ruthenium complexes such as NAMI-A, KP1019 etc. are had at present has enter into clinical experimental stage.Secondly, ruthenium is matched somebody with somebody
Compound and has also been seen in report using its luminosity as the inhibitor of enzyme as reagent for clinical diagnosis.
Ruthenium complex has shown the inhibitory action to amyloid peptide aggregation, and such as organic ruthenium complex suppresses the poly- of A- β albumen
Collection；Some fragrant ruthenium complexes can be combined with PrPC Neuropeptide P rP106-126 by coordination, suppress the aggregation of polypeptide
And reduce by cytotoxicity caused by polypeptide aggregation；And the combination of NAMI-A classes ruthenium complex and PrP106-126 passes through electrostatic phase
Interaction is realized.Compared to elements such as gold, platinum, ruthenium complex cytotoxicity is little, suppresses in the aggregation of amyloid and polypeptide
Agent application aspect has a high potential.
The certain synthesis document of ruthenium complexes of amino acid reports that the advantage of this kind of compound is it with antitumaous effect
The raising of biocompatibility.
Amyloid or polypeptide contain hydrophobic patches, and it is most important that this core fragment assembles fibrosiss to it.
For these reasons, the aromatic molecules and certain hydrophobic aminoacid of appropriate configuration, the metal for exploring this kind of part are selected to match somebody with somebody
Compound, as the agglutination inhibitor of 4 amyloid, is protein configuration disease study mechanism and the important topic in drug development.
The content of the invention
The present invention seeks to prepare a kind of novel metal ruthenium complex for part using methionine and bipyridyl.
Bipyridyl-methionine three be hydrated ruthenium complex, chemical formula be Ru (bipy) (met)2·3H2O, molecular structural formula
It is as follows：
Bipyridyl-the methionine three is hydrated the Infrared Characterization characteristic peak (cm of ruthenium complex-1) as follows：3455,2069,
1600,1352,1167,1069,951,858,537。
Bipyridyl-the methionine three hydration ruthenium complex nuclear magnetic resonance, NMR characteristic feature peak (1H, ppm) it is as follows：
7.95 (H4/H4 '), 8.48 (H3/H3 ', H5/H5 '), 8.89 (H6/H6 ') are (bipy)；4.06(CαH),2.70(CβHs),2.27
(CγHs),2.16(CεHs)(met)。
Bipyridyl-the methionine three is hydrated into ruthenium complex and is applied to the system that amyloid polypeptide aggregation suppresses medicine
It is standby.
Bipyridyl-the methionine three is hydrated the preparation method of ruthenium complex, and step is as follows：
Step one：Three chloride hydrate rutheniums are dissolved in into ethanol, 3-4h are heated to reflux and are obtained dark green solution, rotate after filtration to
The 20-30% of original volume, adds methionine, water and hydrochloric acid, 70-80 DEG C of reacting by heating 2-3h to revolve except solvent is cooled to room temperature,
Obtain methionine ruthenium complex；
Step 2：2-2 '-bipyridyl, second alcohol and water are added in the product of step one, after stirring 2-3h solvent is spin-dried for, then
Add ethanol to filter, filtrate is spin-dried for be vacuum dried, obtain brown solid bipyridyl-hydration ruthenium of methionine three and coordinate
Thing.
In said method, three chloride hydrate rutheniums, methionine, the quality rate of charge of 2-2 '-bipyridyl are：1：4-4.5：
0.3-0.4。
The present invention obtains a kind of to amyloid by introducing aromatic ligand 2,2 '-bipyridyl in methionine ruthenium complex
The aggregation hydration ruthenium complex of the new bipyridyl-methionine three with significant inhibitory action of polypeptide.Bipyridyl-the first
The hydration ruthenium complex of methyllanthionine three has compared with high-biocompatibility, in amyloids such as PrPC neuropeptide, people's islet amyloid sample peptides
Polypeptide aggregation suppression aspect have obvious action, and the coordination compound specifically preparation is simple.
Description of the drawings
Fig. 1 is the molecular structural formula that bipyridyl-methionine three is hydrated ruthenium complex in embodiment 1.
Fig. 2 is the infrared spectrogram that bipyridyl-methionine three is hydrated ruthenium complex in embodiment 1.
Fig. 3 is the dynamic that the hydration of bipyridyl-methionine three ruthenium complex suppresses PrPC nerve peptide aggregation in embodiment 2
Light-scattering analysises figure, wherein abscissa be grain size, unit：nm；Vertical coordinate is particle diameter distribution relative intensity percent.Solid line
The particle diameter distribution of PrP106-126 is represented, dotted line represents the particle diameter distribution for adding PrP106-126 after 1 part of coordination compound, and dotted line is represented
The particle diameter distribution of PrP106-126 after 3 times of concentration coordination compounds, pecked line is added to represent and add PrP106- after 5 times of concentration coordination compounds
126 particle diameter distribution.
Fig. 4 is the transmission that the hydration of bipyridyl-methionine three ruthenium complex suppresses PrPC nerve peptide aggregation in embodiment 2
Electron microscope, wherein scale bar are 500nm.A is independent PrP106-126 shape appearance figures, and B is to add the PrP106- after equivalent loading thing
126 shape appearance figures, C is to add the PrP106-126 shape appearance figures after 3 times of concentration coordination compounds, and D is to add after 5 times of concentration coordination compounds
PrP106-126 shape appearance figures.
Fig. 5 is that the hydration of bipyridyl-methionine three ruthenium complex suppresses the dynamic of people's islet amyloid sample peptide aggregation in embodiment 3
State light-scattering analysises figure, wherein abscissa be grain size, unit：nm；Vertical coordinate is particle diameter distribution relative intensity percent.It is real
Line represents the particle diameter distribution of hIAPP, and dotted line represents the particle diameter distribution for adding hIAPP after equivalent loading thing, and dotted line is represented and adds 3 times
The particle diameter distribution of hIAPP after concentration coordination compound, pecked line represents the particle diameter distribution for adding hIAPP after 5 times of concentration coordination compounds.
Fig. 6 is that the hydration of bipyridyl-methionine three ruthenium complex suppresses the saturating of people's islet amyloid sample peptide aggregation in embodiment 3
Electron microscope is penetrated, wherein scale bar is 500nm.A is independent hIAPP shape appearance figures, and B is to add the hIAPP patterns after equivalent loading thing
Figure, C is to add the hIAPP shape appearance figures after 3 times of concentration coordination compounds, and D is to add the hIAPP shape appearance figures after 5 times of concentration coordination compounds.
Specific embodiment
Embodiment 1
Three chloride hydrate ruthenium 100mg are dissolved in 10mL ethanol, 3h are heated to reflux and are obtained dark green solution.Rotate after filtration
To the 25% of original volume, the hydrochloric acid of 420mg methionines, 5mL water and 50 μ L 36-38wt%, 80 DEG C of heating 3h are added.Rotation is removed
Solvent is cooled to after room temperature and adds 35mg 2-2 '-bipyridyl, 6mL ethanol and 8mL water, and after stirring 2h solvent is spin-dried for, and adds ethanol
Filter；Filtrate is spin-dried for be vacuum dried, gained brown solid is target bipyridyl-hydration ruthenium complex of methionine three
Ru(bipy)(met)2·3H2O, molecular structural formula is as shown in fig. 1.
Bipyridyl-the methionine three for obtaining is hydrated into ruthenium complex Ru (bipy) (met)2·3H2O carries out elementary analysiss,
Its result is as follows：RuC20H34N4O7S2:Value of calculation (%):C39.53,N9.22,H5.60；Experiment value (%):C39.56,
N8.82,H6.09。
Bipyridyl-the methionine three for obtaining is hydrated into ruthenium complex Ru (bipy) (met)2·3H2O carries out Infrared Characterization
(such as Fig. 2), its characteristic peak (cm-1) as follows：3455,2069,1600,1352,1167,1069,951,858,537.
Bipyridyl-the methionine three for obtaining is hydrated into ruthenium complex Ru (bipy) (met)2·3H2O carries out nuclear magnetic resonance, NMR
Characterize, its characteristic peak (1H, ppm) it is as follows：7.95 (H4/H4 '), 8.48 (H3/H3 ', H5/H5 '), 8.89 (H6/H6 ')
(bipy)；4.06(CαH),2.70(CβHs),2.27(CγHs),2.16(CεHs)(met)。
Embodiment 2
The change of size of 4 amyloid after coordination compound effect is detected by dynamic light scattering experiment：By 50 μM of PrPCs of 1mL
Neuropeptide P rP06-126 solution and variable concentrations ratio (1:1,3:1,5:1) ruthenium complex co-cultivation 24h at 37 DEG C, so
10-15min is centrifuged under 12,000rpm rotating speeds afterwards to remove precipitation, transfer supernatant is measured into sample cell.With cooperation
Thing concentration ratio increases, and 4 amyloid particle diameter is down to nanometer scale by micron, as shown in Figure 3.
Transmission electron microscope morphology characterization：Bipyridyl-the methionine three for obtaining is hydrated into ruthenium complex Ru (bipy)
(met)2·3H2O is dissolved in DMSO as mother solution；Configuration concentration is molten for the PrPC Neuropeptide P rP106-126 of 1mmol/L
Liquid, takes appropriate coordination compound mother solution and adds in polypeptide solution, makes the two concentration ratio be 1:1, cultivate 24h. H at 37 DEG C2O is diluted to
Liquor capacity is 0.5mL, and final peptide concentration is controlled at 10 μM.It is stain from phosphotungstic acid, phosphotungstic acid is dissolved in H2Match somebody with somebody in O
Into the solution that concentration is 2mg/mL.With the syringe pipette samples 10-20 μ L drops of 1mL on copper mesh, it is allowed to form liquid pearl, stands
Treat that sample is closely done, the μ L of drop phosphotungstic acid stain 10 after to be dyed dose of drying, with secondary water copper mesh 2-3 time are rinsed, and sample is in room
Temperature is lower to be spontaneously dried completely.Transmission electron microscope experiment amplification is 10K times, and accelerating potential is 200KV.Coordination compound is different from polypeptide
Concentration ratio (3:1,5:1) experiment condition is the same.Increase with coordination compound concentration ratio, 4 amyloid pattern is changed into by netted fiber
Bulk fine fibre, point-like oligomer, and great majority exist with monomer, as shown in Figure 4.
Embodiment 3
Dynamic light scattering experiment is used to detect the change of size of 4 amyloid after coordination compound effect：By 5 μM of people's islets of langerhans of 1mL
4 amyloid solution and variable concentrations ratio (1:1,3:1,5:1) ruthenium complex co-cultivation 72h at 37 DEG C, then 12,
15min is centrifuged under 000rpm rotating speeds to remove precipitation, transfer supernatant is measured into sample cell.Increase with coordination compound concentration ratio
Plus, 4 amyloid particle diameter is down to nanometer scale by micron, as shown in Figure 5.
Transmission electron microscope morphology characterization：Bipyridyl-the methionine three for obtaining is hydrated into ruthenium complex Ru (bipy)
(met)2·3H2O is dissolved in DMSO as mother solution；Configuration concentration is 50 μM of people's islet amyloid sample peptide hIAPP solution, is taken suitable
Amount coordination compound mother solution is added in polypeptide solution, makes the two concentration ratio be 1:1, cultivate 72h at 37 DEG C.Use H2O is diluted to solution body
Product is 0.5mL, and final peptide concentration is controlled at 5 μM.It is stain from phosphotungstic acid, phosphotungstic acid is dissolved in H2Concentration is made in O
For the solution of 2mg/mL.With the syringe pipette samples 10-20 μ L drops of 1mL on copper mesh, it is allowed to form liquid pearl, standing treats sample
Near dry, the μ L of drop phosphotungstic acid stain 10 after to be dyed dose of drying, with secondary water copper mesh 2-3 time are rinsed, and sample is at room temperature certainly
So it is dried complete.Transmission electron microscope experiment amplification is 10K times, and accelerating potential is 200KV.Coordination compound and polypeptide variable concentrations ratio
(3:1,5:1) experiment condition is the same.Increase with coordination compound concentration ratio, 4 amyloid pattern is changed into bulk thin by netted fiber
Fiber, point-like oligomer, and great majority exist with monomer, as shown in Figure 6.
The present invention prepares the hydration ruthenium complex of bipyridyl-methionine three using methionine and bipyridyl for part, closes
Simple into method, the ability with higher biocompatibility and very strong suppression amyloid peptide aggregation, is a kind of shallow lake well
Powder sample peptide aggregation inhibitor.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention is not limited thereto,
Any those familiar with the art the invention discloses technical scope in, the change or replacement that can be readily occurred in,
All should be included within the scope of the present invention.Therefore, protection scope of the present invention should be described with the protection model of claim
Enclose and be defined.
Claims (6)
1. a kind of bipyridyl-methionine three is hydrated ruthenium complex, it is characterised in that its chemical formula be Ru (bipy) (met)2·
3H2O, molecular structural formula is as follows：
2. bipyridyl-methionine three according to claim 1 is hydrated ruthenium complex, it is characterised in that its Infrared Characterization
Characteristic peak (cm-1) as follows：3455,2069,1600,1352,1167,1069,951,858,537.
3. bipyridyl-methionine three according to claim 1 is hydrated ruthenium complex, it is characterised in that its nuclear magnetic resonance, NMR
Characteristic feature peak (1H, ppm) it is as follows：7.95 (H4/H4 '), 8.48 (H3/H3 ', H5/H5 '), 8.89 (H6/H6 ') are (bipy)；
4.06(CαH),2.70(CβHs),2.27(CγHs),2.16(CεHs)(met)。
4. bipyridyl-the methionine three described in claim 1 is hydrated into ruthenium complex and is applied to amyloid polypeptide aggregation suppression
The preparation of medicine.
5. bipyridyl-the methionine three described in claim 1 is hydrated the preparation method of ruthenium complex, it is characterised in that its step
It is rapid as follows：
Step one：Three chloride hydrate rutheniums are dissolved in into ethanol, 3-4h are heated to reflux and are obtained dark green solution, rotated to substance after filtration
Long-pending 20-30%, adds methionine, water and hydrochloric acid, 70-80 DEG C of reacting by heating 2-3h to revolve except solvent is cooled to room temperature, obtain
Methionine ruthenium complex；
Step 2：2-2 '-bipyridyl, second alcohol and water are added in the product of step one, after stirring 2-3h solvent is spin-dried for, added
Ethanol is filtered, and filtrate is spin-dried for be vacuum dried, and obtains brown solid bipyridyl-hydration ruthenium complex of methionine three.
6. bipyridyl-methionine three according to claim 5 is hydrated the preparation method of ruthenium complex, it is characterised in that
Three chloride hydrate rutheniums, methionine, the quality rate of charge of 2-2 '-bipyridyl are：1：4-4.5：0.3-0.4.
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| CN101747382A (en) * | 2009-12-29 | 2010-06-23 | 广东药学院 | Ruthenium polypyridyl complex using quinolones compound as ligand, preparation method and application thereof |
| WO2012052821A1 (en) * | 2010-10-18 | 2012-04-26 | Universiteit Leiden | Light induced drug release |
| CN103275077A (en) * | 2013-01-29 | 2013-09-04 | 中山大学 | Ruthenium complex and preparation method thereof and purpose of product as histone deacetylase inhibitor |
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| CN101747382A (en) * | 2009-12-29 | 2010-06-23 | 广东药学院 | Ruthenium polypyridyl complex using quinolones compound as ligand, preparation method and application thereof |
| WO2012052821A1 (en) * | 2010-10-18 | 2012-04-26 | Universiteit Leiden | Light induced drug release |
| CN103275077A (en) * | 2013-01-29 | 2013-09-04 | 中山大学 | Ruthenium complex and preparation method thereof and purpose of product as histone deacetylase inhibitor |
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| CN107365331A (en) * | 2017-08-02 | 2017-11-21 | 中国人民大学 | A kind of different dual-nuclei structure model and preparation method and application |
| CN107365331B (en) * | 2017-08-02 | 2019-11-29 | 中国人民大学 | A kind of different dual-nuclei structure model and the preparation method and application thereof |
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