CN108659044A - A kind of phosphorylation glyoxaline compound and preparation method thereof - Google Patents
A kind of phosphorylation glyoxaline compound and preparation method thereof Download PDFInfo
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- CN108659044A CN108659044A CN201810645693.8A CN201810645693A CN108659044A CN 108659044 A CN108659044 A CN 108659044A CN 201810645693 A CN201810645693 A CN 201810645693A CN 108659044 A CN108659044 A CN 108659044A
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Abstract
The present invention relates to a kind of phosphorylation glyoxaline compounds and preparation method thereof, belong to biomedicine field.Main technical schemes are as follows：A kind of phosphorylation glyoxaline compound, structural formula are：Wherein：R1=H, (CH2)nCH3；R2=H, (CH2)nCH3；A=(CH2)n, (CH2‑O)m, B=COOH, NH2, SH, OH；N is derived from 1 20 arbitrary integer, and m is derived from 1 20 arbitrary integer.Phosphorylation glyoxaline compound structure prepared by the present invention is more nearly natural phosphate histidine, while substituting the N P keys in natural phosphate histidine, molecular chemistry stability higher with C P keys.
Description
Technical field
The invention belongs to biomedicine field, it is specifically related to a kind of phosphorylation glyoxaline compound and preparation method thereof.
Background technology
Protein phosphorylation is a kind of protein post-translational modification form being widely present in organism, this amino acid with
The modification pattern that phosphate group is covalently attached plays important regulative to protein structure and function.For example, microorganism
Two component signal transduction system, the system by cross-film receptor histidine kinase (receptor histidine kinase,
RHK it) is formed with intracytoplasmic reaction regulatory protein (response regulator, RR).When RHK senses that external environment stimulates
Afterwards, autophosphorylation, the conservative asparagicacid residue being then transferred to phosphate group on RR occur for histidine residue.RR
The expression of downstream gene is regulated and controled after phosphorylation occurs.Research shows that Two component signal transduction system is not only to the base of bacterium
This vital movement has an adjustment effect, also participates in the generation of the virulence and resistance mechanism of many pathogens, with it is pathogenic closely
It is related, it is considered to be potential drug whip mark.
So far, it has been found that 9 kinds of natural amino acids (serine, threonine, tyrosine, lysine, arginine, asparagus fern ammonia
Acid, glutamic acid, cysteine and histidine) it can be phosphorylated with hydroxyproline.The mode of phosphorylation includes mainly 4 kinds of patterns,
That is O- phosphorylations, N- phosphorylations, S- phosphorylations and acylphosphate.Currently, for phosphorylation serine, phosphorylation threonine with
The comparison of the preparation research of the synthesis of phosphorylated tyrosine analogue and phospho-AB based on its analogue
It is more.
Phosphorylation histidine is a kind of phosphorylated amino acid being widely present, and modified phoshorylation pattern is N- phosphorylations, but due to
The chemical instability of phosphorylation histidine itself, functional study in vivo are restricted.In phosphorylation histidine
Phosphate group connect to form phosphinylidyne amine key with the N atoms on histidine imidazole ring, and the P-N chemical bonds itself in phosphinylidyne amine structure
It is highly unstable.From thermodynamics, the Gibbs free (about -12~-14kcal/mol) of hydrolytic process is compared with phosphate
The Gibbs free of P-O chemical bond hydrolytic processes in structure (phosphorylation serine, phosphorylation threonine, phosphorylated tyrosine)
(about -6.5~-9.5kcal/mol) is much higher；From aerodynamic point, phosphorylation histidine is more sensitive to acid, in 1mol/L
At 49 DEG C of hydrochloric acid solution, the half-life period of free phosphorus acidification histidine only has tens of seconds.Therefore in traditional research method, phosphoric acid
Change histidine to be easy to that hydrolysis dephosphorylation occurs.
Based on the unstability of phosphorylation histidine itself, people consider that design synthesizes some analogues and carried out to it
Simulation.Designing the main thought of synthesis phosphorylation histidine structure analog is：(1) thiophosphorylation histidine and its more is synthesized
Peptide, the type compound high stability in acid condition；(2) imidazole ring is transform as other heterocycles, such as furan nucleus, triazole
The phosphinylidyne amine key of facile hydrolysis is changed to C-P keys by ring etc..However, there is certain limitations for these analogues：(1) single
One histidine thiophosphorylation cannot achieve in vivo, because the process can make all histidine residues and other
Nucleophilic residues whole thiophosphorylation；In addition, thiophosphorylation can only obtain N3 isomers, it is not institute in biochemical reaction
Some histidine kinases can use γ-35S-ATP and γ-35S-thio-GTP is as substrate.(2) furan nucleus and three are based on
The analogue of azoles ring, though solving the problems, such as that N-P key stability is poor, their ring structure is differed with natural histidine
Larger, when preparing phosphorylation polyhistidine antibody using it as haptens, the specificity of gained antibody is relatively poor.Due to lacking above
Point, existing histidine structure analog the separation of modified body and context of detection can not also obtain after phosphohistidinoprotein matter is translated
With deep application, the function that phosphohistidinoprotein matter translates rear modified body is still unknown.
Invention content
To make up the deficiencies in the prior art, the present invention is substituted using imidazole ring as architecture basics with the C-P keys that property is stablized
N-P keys design and synthesize a series of phosphorylation histidine structure analog that structures are more approximate, chemical property is more stable.
Technical scheme is as follows：A kind of phosphorylation glyoxaline compound, structural formula are：
Wherein：R1=H ,-(CH2)nCH3；R2=H ,-(CH2)nCH3；A=- (CH2)n,-(CH2-O)m, B=-COOH ,-
NH2,-SH ,-OH；N is derived from the arbitrary integer of 1-20, and m is derived from the arbitrary integer of 1-20.
The preparation method of the compound is claimed in the present invention simultaneously, and steps are as follows：Imidazolium compounds containing iodine and phosphorous
For diethyl phthalate under catalyst existence condition, 10~200 DEG C of reactions generate compound 1 in 1~72 hour；Compound 1 and Boc is protected
Bromo compound under catalyst existence condition, 10-200 DEG C reaction 1~72 hour generate compound 2；Compound 2 takes off Boc
Protection generates phosphorylation glyoxaline compound.
In above-mentioned reaction equation (I), digital 1-7 represents catalyst；1 is palladium or palladium carbon；2 be triphenylphosphine；
3 be CH3-(CH2)n-CH2OH (n=1-10), acetone, tetrahydrofuran, acetonitrile, N-Methyl pyrrolidone, dimethyl
Sulfoxide, dioxanes, dimethylformamide or toluene；
4 be potassium hydroxide, potassium carbonate, saleratus, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, phosphoric acid hydrogen two
Potassium, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, cesium carbonate, sodium acetate, potassium acetate or triethylamine；
5 be CH3-(CH2)n-CH2OH (n=1-10), acetone, tetrahydrofuran or acetonitrile；
6 be cesium carbonate, sodium acetate, potassium acetate or triethylamine；
7 be trifluoroacetic acid, hydrobromic acid or hydrochloric acid.
Beneficial effects of the present invention are as follows：
(1) the advantages that present invention has reaction temperature low, and the reaction time is short, and purification process is simple, and yield is high.
(2) the phosphorylation glyoxaline compound structure that designs of the present invention is more nearly natural phosphate histidine, while with
C-P keys substitute the N-P keys in natural phosphate histidine, molecular chemistry stability higher.
Description of the drawings
Fig. 1 compounds 11H nuclear magnetic spectrograms.
Fig. 2 1- (2- t-butoxycarbonyl aminos ethyl) -1- hydrogen-imidazol-4 yl phosphonic acids1H nuclear magnetic spectrograms.
Fig. 3 1- (2- amino-ethyls) -1- hydrogen-imidazol-4 yl phosphonic acids1H nuclear magnetic spectrograms.
Fig. 4 1- (2- amino-ethyls) -1- hydrogen-imidazol-4 yl phosphonic acids13C nuclear magnetic spectrograms.
Fig. 5 1- (2- t-butoxycarbonyl aminos butyl) -1- hydrogen-imidazol-4 yl phosphonic acids1H nuclear magnetic spectrograms.
Fig. 6 1- (2- aminobutyls) -1- hydrogen-imidazol-4 yl phosphonic acids1H nuclear magnetic spectrograms.
Fig. 7 1- (2- aminobutyls) -1- hydrogen-imidazol-4 yl phosphonic acids13C nuclear magnetic spectrograms.
Specific implementation mode
With reference to specific embodiment, the present invention is described further, if without specified otherwise, the raw materials used in the present invention
It is commercially available.
Phosphorylation histidine structure analog provided by the invention is using compound 1 as initial reaction raw material.Compound 1
Specific synthetic method it is as follows：
In the round-bottomed flask equipped with 25mL ethyl alcohol, addition 15mmol 4- iodine imidazoles, 30mmol diethyl phosphites,
6mmol triphenyl phosphorus, 30mmol triethylamines, stirring and dissolving under nitrogen atmosphere.Solution is heated to 80 DEG C, 1.5mmol vinegar is added
Sour palladium.Reaction mixture is vigorously stirred 12 hours in a nitrogen atmosphere, is then saturated NH with 25mL4Cl aqueous solutions (pH=7) are quenched
It goes out and ethyl acetate (4 × 25mL) is used to extract.Merge organic phase and washed with 25ml saturations NaCl, then simultaneously with separatory funnel separation
It is evaporated under reduced pressure (35 DEG C).Gained yellow residue is loaded into silicagel column, and (5cm × 25cm uses ethyl acetate:Petroleum ether=1:1
Filling) on, use ethyl acetate：Petroleum ether=1：1 elution.Eluent is rotated to obtain yellow solid, as compound 1, yield
30%.
Elemental analysis data：Theoretical value：C, 41.18%；H, 6.42%；N, 13.72%；O, 23.51%；P, 15.17%；
Actual value：C, 41.21%；H, 6.40%；N, 13.83%；O, 23.41%；P, 15.15%.
The nuclear magnetic data of compound 1 is as shown in Figure 1：1HNMR (400MHz, CDC13), (s, 1H, the Imidazole C- of δ 7.53
H), 7.46 (s, 1H, Imidazole C-H), 4.22 (s, 1H, pyrazoleN-H), 1.32 (s, 6H, P (OCH2CH3)2), 0.92
(s, 4H, P (OCH2CH3)2)ppm。
The preparation of 1 1- of embodiment (2- amino-ethyls) -1- hydrogen-imidazol-4 yl phosphonic acids
(1) in the round-bottomed flask equipped with 2mL acetonitriles, 3.0mmol compounds 1 and 6.0mmol 2- (Boc- amino) is added
Dissolving is stirred at room temperature under nitrogen atmosphere in bromoethane.12.80mmol cesium carbonates are added in reaction mixture, at room temperature acutely
Stir 12h.Reaction mixture is diluted with 36mL ethyl acetate and is filtered to remove solid.Acquired solution is evaporated under reduced pressure, slightly
Product is purified by silica gel flash column chromatography (100% ethyl acetate), obtains 100mL white refined solutions；Again by acquired solution
Reduction vaporization obtains yellow liquid, becomes white solid powder i.e. 1- (2- t-butoxycarbonyl aminos ethyl) -1- hydrogen-miaow after cooling
Azoles -4- base phosphonic acids, yield 40%.
Elemental analysis data：Theoretical value：C, 41.24%；H, 6.23%；N, 14.43%；O, 27.47%；P, 10.63%；
Actual value：C, 41.22%；H, 6.25%；N, 14.42%；O, 27.48%；P, 10.63%.
Nuclear magnetic data such as Fig. 2 of 1- (2- t-butoxycarbonyl aminos ethyl) -1- hydrogen-imidazol-4 yl phosphonic acids：1HNMR
(400MHz, CDC13), δ 7.54 (s, 1H, Imidazole C-H), 7.02 (s, 1H, Imidazole C-H), 4.84 (s, 1H,
NHBoc), 4.11 (s, 2H, N-CH2), 3.73 (d, 2H, NH-CH2), 1.43 (t, m, 9H, tent-butyl) ppm.
(2) in the round-bottomed flask equipped with magnetic agitation, 0.5mmol1- (2- t-butoxycarbonyl aminos ethyl) -1- is added
HBr (33% acetic acid, 2.4ml, 0.25M) solution is added in hydrogen-imidazol-4 yl phosphonic acids at room temperature.Under nitrogen atmosphere, mixture exists
48h is stirred at room temperature.It is washed (10 × 2.0mL) with acetone, liquid is washed till colourless by yellow.Revolving obtains white solid powder i.e. 1-
(2- amino-ethyls) -1- hydrogen-imidazol-4 yl phosphonic acids, yield 90%.
Elemental analysis data：Theoretical value：C, 31.42%；H, 5.27%；N, 21.99%；O, 25.11%；P, 16.21%.
Actual value：C, 31.41%；H, 5.28%；N, 22.00%；O, 25.10%；P, 16.21%.
Nuclear magnetic data such as Fig. 3, Fig. 4 of 1- (2- amino-ethyls) -1- hydrogen-imidazol-4 yl phosphonic acids：1HNMR (400MHz, D2O)
δ 7.72 (s, 1H, Imidazole CH), 7.58 (s, 1H, Imidazole CH), 4.38 (s, 2H, alkyl CH2), 3.71 (s,
2H, alkyl CH2)ppm。13C NMR (400MHz, D2O) δ 144.29 (- CH=N), 125.91 (=CH-N), 61.14 (P-C),
39.38(N-CH2), 36.00 (CH2-NH2)。
The preparation of 2 1- of embodiment (2- aminobutyls) -1- hydrogen-imidazol-4 yl phosphonic acids
(1) in the round-bottomed flask equipped with 2mL acetonitriles, 3.0mmol compounds 1 and 6.0mmol 2- (Boc- amino) is added
Dissolving is stirred at room temperature under nitrogen atmosphere in bromobutane.12.80mmol cesium carbonates are added in reaction mixture, at room temperature acutely
Stir 12h.Reaction mixture is diluted with 36mL ethyl acetate and is filtered to remove solid.Acquired solution is evaporated under reduced pressure, slightly
Product is purified by silica gel flash column chromatography (100% ethyl acetate), obtains 100mL white refined solutions；Again by acquired solution
Reduction vaporization obtains yellow liquid, becomes white solid powder i.e. 1- (2- t-butoxycarbonyl aminos butyl) -1- hydrogen-miaow after cooling
Azoles -4- base phosphonic acids, yield 50%.
Elemental analysis data：Theoretical value：C, 45.14%；H, 6.95%；N, 13.16%；O, 25.05%；P, 9.70%；
Actual value：C, 45.15%；H, 6.94%；N, 13.14%；O, 25.05%；P, 9.72%.
Nuclear magnetic data such as Fig. 5 of 1- (2- t-butoxycarbonyl aminos butyl) -1- hydrogen-imidazol-4 yl phosphonic acids：1HNMR
(400MHz, CDC13), δ 7.76 (s, 1H, Imidazole C-H), 7.11 (s, 1H, Imidazole C-H), 4.53 (s, 1H,
NHBoc), 3.42 (s, 2H, N-CH2), 3.30 (d, 2H, C-CH2), 3.16 (s, 2H, C-CH2), 2.14 (s, 2H, P-OH),
1.84, (s, 2H, C-CH2) 1.43 (t, m, 9H, tent-butyl) ppm.
(2) in the round-bottomed flask equipped with magnetic stirring bar, 0.50mmol1- (2- t-butoxycarbonyl aminos butyl)-is added
HBr (33% acetic acid, 2.4ml, 0.25M) solution is added in 1- hydrogen-imidazol-4 yl phosphonic acids at room temperature.Under nitrogen atmosphere, mixture
4h is stirred at room temperature.It is washed (10 × 2.0mL) with acetone, liquid is washed till colourless by yellow.Obtain white solid powder i.e. 1- (2-
Aminobutyl) -1- hydrogen-imidazol-4 yl phosphonic acids, yield 90%.
Elemental analysis data：Theoretical value：C, 38.36%；H, 6.44%；N, 19.17%；O, 21.90%；P, 14.13%；
Actual value：C, 38.34%；H, 6.44%；N, 19.20%；O, 21.89%；P, 14.13%.
Nuclear magnetic data such as Fig. 6, Fig. 7 of 1- (2- aminobutyls) -1- hydrogen-imidazol-4 yl phosphonic acids,1HNMR (400MHz, D2O)
δ 7.78 (s, 1H, Imidazole CH), 7.62 (s, 1H, Imidazole CH), 3.63 (s, 2H, alkylCH2), 3.20 (s,
2H, alkyl CH2), 2.82 (s, 2H, alkyl CH2), 1.82 (s, 2H, alkyl CH2)ppm.13CNMR (400MHz, D2O)δ
141.08 (- CH=N), 131.82 (=CH-N), 60.06 (P-C), 45.33 (N-CH2), 40.37 (CH2-NH2), 27.08 (C-
C), 24.06 (C-C).
Above-described embodiment is only intended to the citing to the present invention and explanation, and is not intended to limit the invention to described
In scope of embodiments.In addition it will be appreciated by persons skilled in the art that the present invention is not limited to the above embodiment, according to this hair
Bright introduction can also make more kinds of variants and modifications, these variants and modifications all fall within present invention model claimed
In enclosing.
Claims (2)
1. a kind of phosphorylation glyoxaline compound, which is characterized in that structural formula is：
Wherein：R1=H ,-(CH2)nCH3；R2=H ,-(CH2)nCH3；A=- (CH2)n,-(CH2-O)m, B=-COOH ,-NH2,-
SH ,-OH；N is derived from the arbitrary integer of 1-20, and m is derived from the arbitrary integer of 1-20.
2. the preparation method of phosphorylation glyoxaline compound as described in claim 1, which is characterized in that preparation process is as follows：
For iodine imidazolium compounds with diethyl phosphite under catalyst existence condition, 10~200 DEG C are reacted 1~72 hour generationization
Close object 1；The bromo compound that compound 1 is protected with tertbutyloxycarbonyl is under catalyst existence condition, 10-200 DEG C of reaction 1~72
Hour generates compound 2；Compound 2 takes off tertbutyloxycarbonyl protection and generates phosphorylation glyoxaline compound；
In above-mentioned reaction equation (I), 1 is palladium or palladium carbon；2 be triphenylphosphine；
3 be CH3-(CH2)n-CH2OH (n=1-10), acetone, tetrahydrofuran, acetonitrile, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO),
Dioxanes, dimethylformamide or toluene；
4 be potassium hydroxide, potassium carbonate, saleratus, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, phosphorus
Acid dihydride potassium, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, cesium carbonate, sodium acetate, potassium acetate or triethylamine；
5 be CH3-(CH2)n-CH2OH (n=1-10), acetone, tetrahydrofuran or acetonitrile；
6 be cesium carbonate, sodium acetate, potassium acetate or triethylamine；
7 be trifluoroacetic acid, hydrobromic acid or hydrochloric acid.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160311838A1 (en) * | 2013-10-02 | 2016-10-27 | The Trustees Of Princeton University | Phosphohistidine mimetics and antibodies to same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160311838A1 (en) * | 2013-10-02 | 2016-10-27 | The Trustees Of Princeton University | Phosphohistidine mimetics and antibodies to same |
Non-Patent Citations (1)
| Title |
|---|
| PAVLENKO, N. V. ET AL.: "Novel structural analogs of glyphosate based on azoles. Part 2. N-Substituted imidazoles and pyrazoles obtained by alkylation of heterocycles containing carboxyl or phosphoryl groups in the ring", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
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