CN103524368B - A kind of Gd coordination compound and synthetic method strengthening probe as solution paramagnetic relaxation - Google Patents
A kind of Gd coordination compound and synthetic method strengthening probe as solution paramagnetic relaxation Download PDFInfo
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- CN103524368B CN103524368B CN201310503539.4A CN201310503539A CN103524368B CN 103524368 B CN103524368 B CN 103524368B CN 201310503539 A CN201310503539 A CN 201310503539A CN 103524368 B CN103524368 B CN 103524368B
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Abstract
The invention discloses a kind of Gd coordination compound strengthening probe as solution paramagnetic relaxation, the mixture that this Gd coordination compound is made up of 4 kinds of isomerss of triethylenetetramine hexaacetic acid trimethamide, adopt this Gd coordination compound as the enhancing probe of solution paramagnetic relaxation, water molecules is not had to participate in coordination, abnormal signal hydrogen exchange on water molecules and albumen can be eliminated, thus improve the accuracy that protein structure is described.The invention also discloses the synthetic method of above-mentioned Gd coordination compound.The advantages such as it is cheap that the method has raw material, and synthesis condition is gentle, and purification is convenient.
Description
Technical field
The present invention relates to Gd coordination compound, this title complex is mainly as the enhancing probe of solution paramagnetic relaxation.
Background technology
Nuclear magnetic resonance method is a kind of important method of Study on Protein structure in the solution.It is introduce paramagnetic probes at protein surface that paramagnetic relaxation strengthens (PRE) technology, the relaxation rate of core is caused to accelerate by the dipole-dipole interaction between the core on single electron unpaired on probe and protein, i.e. PRE effect is one of important means of a kind of Study on Protein transient buildup.
It is a kind of novel method grown up in recent years that solution paramagnetic relaxation strengthens (sPRE) technology.The feature that the method is different from conventional P RE technology is, it is evenly distributed in solution by paramagnetic probes, by the non-sharing electron of paramagnetic center on probe and the dipole-dipole interaction of protein atomic core, carry out a kind of method of the Structure and dynamics associated viscera of Study on Protein.
Triethylenetetramine hexaacetic acid compounds is the compound of the potential sPRE probe of a class, it is the ammonia carboxylic coordination agent of a quasi-representative, ten ligating atoms can be provided, gadolinium ion as paramagnetic center " is wrapped " participation not having water molecules in coordination agent entirely, and the probe as sPRE can eliminate the abnormal signal that water molecules exchanges.Because simple triethylenetetramine hexaacetic acid-Gd coordination compound is with electrically, can combine with protein belt positive electricity region, thus the accuracy that impact describes protein structure.
Existing technology is used in the middle of the experiment of sPRE by mri contrast agent Omniscan.Omniscan is a kind of Gd coordination compound containing water molecule coordination, find that the amino acid whose abnormal signal some being exposed to solution surface becomes large in for Protein Assav, this is hydrogen exchange caused due in the water of the hydrogen on these amino acid and Omniscan coordination.
Summary of the invention
The object of this invention is to provide a kind of Gd coordination compound strengthening probe as solution paramagnetic relaxation.The mixture that this Gd coordination compound is made up of 4 kinds of isomerss of triethylenetetramine hexaacetic acid trimethamide, adopt this Gd coordination compound as the enhancing probe of solution paramagnetic relaxation, water molecules is not had to participate in coordination, abnormal signal hydrogen exchange on water molecules and albumen can be eliminated, thus improve the accuracy that protein structure is described.
Another object of the present invention is to provide the synthetic method of above-mentioned Gd coordination compound.The advantages such as it is cheap that the method has raw material, and synthesis condition is gentle, and purification is convenient.
In order to achieve the above object, the present invention adopts following technical scheme.
Strengthen the Gd coordination compound of probe as solution paramagnetic relaxation, this Gd coordination compound be by
The mixture of 4 kinds of triethylenetetramine hexaacetic acid trimethamide isomers compositions.
Strengthen a synthetic method for the Gd coordination compound of probe as solution paramagnetic relaxation, the method comprises the following step:
A, triethylenetetramine hexaacetic acid is dissolved in the acetonitrile of 15 ~ 25 times of triethylenetetramine hexaacetic acid weight;
B, add the triethylamine of 0.6 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, be heated to 50 DEG C ~ 60 DEG C, stir 20 ~ 60 minutes;
After c, naturally cooling, under cryosel bath, add the N of 1.2 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, N-dicyclohexylcarbodiimide, stirs 30 minutes;
The triethylamine of d, the methylamine hydrochloride adding 0.4 ~ 0.6 times of triethylenetetramine hexaacetic acid weight again and 0.6 ~ 0.8 times of triethylenetetramine hexaacetic acid weight continues reaction;
E, the bath of 2 hours recession deicings, room temperature reaction spends the night;
F, filtration, remove throw out, crosses anionresin (SourceQ, pH=8.3), collects the trisubstituted product of teiethylene tetramine-hexacetic acid;
G, collection liquid in, add the gadolinium oxide powders of 0.1 ~ 0.2 times of triethylenetetramine hexaacetic acid weight, be heated to 60 DEG C ~ 90 DEG C, stirring is spent the night;
H, mistake filter precipitation, revolve and steam except desolventizing, obtain white powder, and by Mass Spectrometric Identification, products therefrom is a kind of Gd coordination compound strengthening probe as solution paramagnetic relaxation.
Advantage of the present invention is: Gd coordination compound of the present invention is strengthened probe as solution paramagnetic relaxation, owing to not having water molecules to participate in coordination, can eliminate the abnormal signal that water molecules exchanges, improve the accuracy described protein structure.The advantages such as it is cheap that Gd coordination compound synthetic method of the present invention has raw material, and synthesis condition is gentle, and purification is convenient.
Accompanying drawing explanation
Fig. 1 is the figure of Omniscan for the sPRE of GB1 albumen.
Wherein: the solid dot in figure represents that hollow dots represents the calculated value of the crystalline structure (PDB:2GB1) with GB1, and dependency is 0.71 by the value of Omniscan as the sPRE of probe.Wherein, 2,23,43, No. 56 amino acid are obviously bigger than normal owing to there is the problem PRE value exchanged.
Fig. 2 is the figure of TTHTTMA-Gd for the sPRE of GB1 albumen.
Wherein: the solid dot in figure represents that hollow dots represents the calculated value of the crystalline structure (PDB:2GB1) of GB1, and dependency is 0.86 by the value of TTHATMA-Gd title complex as the sPRE of probe, does not occur that PRE value is abnormal and becomes large phenomenon.
From Fig. 1 and Fig. 2, the solution paramagnetic relaxation that a kind of Gd coordination compound as solution paramagnetic relaxation enhancing probe of the present invention applies to GB1 albumen is strengthened and measures, compare with the solution paramagnetic relaxation Enhancement test of traditional Omniscan, adopt probe of the present invention and calculated value more close, the local PRE value that there is water coke slurry at original Omniscan has clear improvement, and the dependency of experimental value and calculated value has brought up to 0.86 from original 0.71.
Embodiment
By the following examples, the present invention is further illustrated.
Strengthen the Gd coordination compound of probe as solution paramagnetic relaxation, this Gd coordination compound be by
The mixture of the isomers composition of 4 kinds of triethylenetetramine hexaacetic acid trimethamides.
Embodiment 1
Strengthen a synthetic method for the Gd coordination compound of probe as solution paramagnetic relaxation, the method comprises the following step:
A, triethylenetetramine hexaacetic acid is dissolved in the acetonitrile of 15 ~ 25 times of triethylenetetramine hexaacetic acid weight;
B, add the triethylamine of 0.6 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, be heated to 50 DEG C ~ 60 DEG C, stir 20 ~ 60 minutes;
After c, naturally cooling, under cryosel bath, add the N of 1.2 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, N-dicyclohexylcarbodiimide, stirs 30 minutes;
The triethylamine of d, the methylamine hydrochloride adding 0.4 ~ 0.6 times of triethylenetetramine hexaacetic acid weight again and 0.6 ~ 0.8 times of triethylenetetramine hexaacetic acid weight continues reaction;
E, the bath of 2 hours recession deicings, room temperature reaction spends the night;
F, filtration, remove throw out, crosses anionresin (Source Q, pH=8.3), collects the trisubstituted product of teiethylene tetramine-hexacetic acid;
G, collection liquid in, add the gadolinium oxide powders of 0.1 ~ 0.2 times of triethylenetetramine hexaacetic acid weight, be heated to 60 DEG C ~ 90 DEG C, stirring is spent the night;
H, mistake filter precipitation, revolve and steam except desolventizing, obtain white powder, and by Mass Spectrometric Identification, products therefrom is a kind of Gd coordination compound strengthening probe as solution paramagnetic relaxation.
Embodiment 2
Strengthen a synthetic method for the Gd coordination compound of probe as solution paramagnetic relaxation, the method comprises the following step:
A, 0.49g triethylenetetramine hexaacetic acid is dissolved in 10ml acetonitrile;
B, add 0.60g triethylamine, be heated to 50 DEG C, stir 1 hour;
After c, naturally cooling, under cryosel bath, add 0.72gN, N-dicyclohexylcarbodiimide, stir 30 minutes;
D, add 0.24g methylamine hydrochloride and 0.35g triethylamine again and continue reaction;
E, the bath of 2 hours recession deicings, room temperature reaction spends the night;
F, filtration, remove throw out, crosses anionresin (SourceQ, pH=8.3), collects the trisubstituted product of teiethylene tetramine-hexacetic acid;
G, collection liquid in, add 0.05g gadolinium oxide powders, be heated to 90 DEG C, stirring is spent the night;
H, mistake filter precipitation, revolve and steam except desolventizing, obtain white powder, and by Mass Spectrometric Identification, products therefrom is a kind of Gd coordination compound strengthening probe as solution paramagnetic relaxation.
Claims (2)
1. Gd coordination compound, is characterized in that, this Gd coordination compound be by
The mixture of the isomers composition of 4 kinds of triethylenetetramine hexaacetic acid trimethamide-Gd coordination compounds.
2. the synthetic method of Gd coordination compound according to claim 1, is characterized in that, the method comprises the following step:
A, triethylenetetramine hexaacetic acid is dissolved in the acetonitrile of 15 ~ 25 times of triethylenetetramine hexaacetic acid weight;
B, add the triethylamine of 0.6 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, be heated to 50 DEG C ~ 60 DEG C, stir 20 ~ 60 minutes;
After c, naturally cooling, under cryosel bath, add the N of 1.2 ~ 1.5 times of triethylenetetramine hexaacetic acid weight, N-dicyclohexylcarbodiimide, stirs 30 minutes;
The triethylamine of d, the methylamine hydrochloride adding 0.4 ~ 0.6 times of triethylenetetramine hexaacetic acid weight again and 0.6 ~ 0.8 times of triethylenetetramine hexaacetic acid weight continues reaction;
E, the bath of 2 hours recession deicings, room temperature reaction spends the night;
F, filtration, remove throw out, crosses anionresin, collects the trisubstituted product of triethylenetetramine hexaacetic acid;
G, collection liquid in, add the gadolinium oxide powders of 0.1 ~ 0.2 times of triethylenetetramine hexaacetic acid weight, be heated to 60 DEG C ~ 90 DEG C, stirring is spent the night;
H, mistake filter precipitation, revolve and steam except desolventizing, obtain white powder, and by Mass Spectrometric Identification, products therefrom is and applies to the Gd coordination compound that solution paramagnetic relaxation strengthens probe.
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Non-Patent Citations (4)
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| Gd(TTHA): An Aqueous Carbon-13 Relaxation Reagent;Jonathan Lettvin et al.;《JOURNAL OF MAGNETIC RESONANCE》;19771231;第28卷;第459页第1段至第461页倒数第1段 * |
| Multinuclear Nuclear Magnetic Resonance Study of Three Aqueous Lanthanide Shift Reagents: Complexes with EDTA and Axially Symmetric Macrocyclic Polyamino Polyacetate Ligands;Charles C. Bryden et al.;《Anal. Chem.》;19811231;第53卷;第1418页第1段至第1425页倒数第1段 * |
| OBSERVATIONS ON THE RARE EARTHS—LXXXIX A SPECTRAL STUDY OF NEODYMIUM(III) COMPLEXES OF AMINECARBOXYLIC ACIDS;ROBERT B. GAYHART et al.;《J. inorg. nucl. Chem.》;19771231;第39卷;第49页第1段至第51页倒数第1段 * |
| 水溶液中Ln(III)-TTHA 络合物的多核NMR研究;华士英等;《高等学校化学学报》;19920131;第13卷(第1期);第81页第1段至第84页倒数第1段 * |
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