CN106928093B - The preparation of cyano unnatural amino acid and its application in bio-orthogonal Raman detection - Google Patents
The preparation of cyano unnatural amino acid and its application in bio-orthogonal Raman detection Download PDFInfo
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Abstract
The present invention relates to the synthetic method of several aliphatic cyanoaminopyrimidine acid and the application in bio-orthogonal Raman, which is methionine derivatives and lysine derivative, which comprises the compound that will be had the following structureWith the POCl being dissolved in pyridine3Reaction obtains cyano compound.The synthetic method of cyanoaminopyrimidine acid provided by the invention is primarily adapted for use in aliphatic cyanoaminopyrimidine acid, such as the cyanoaminopyrimidine of amide bond and carbonic ester acid.The precusor amino acids that reaction is protected using part introduce cyano by being formed on amino acid backbone for dehydration, amido bond or carbonic acid ester bond as skeleton, and when deprotection avoids the hydrolysis of cyano, and synthesis process high temperature or low-temperature operation are few, require the energy low.Final product is purified using hydrophilic interaction chromatography (HILIC), obtains the cyanoaminopyrimidine acid of very high purity.Cyanoaminopyrimidine acid can be inserted into albumen through gene codon amplification technique, be used for bio-orthogonal Raman detection.
Description
Technical field
The present invention relates to the synthetic method of organic synthesis field more particularly to cyano unnatural amino acid and its biology just
Hand over the application in Raman detection.
Background technique
Unnatural amino acid is the native amino acid derivative with functional groups, the non-natural ammonia reported now mostly
Base acid has methionine derivatives, lysine derivative, tyrosine derivative, cysteine derivative etc..Some non-natural ammonia
Base acid can be inserted into protein by metabolic pathway, such as methionine derivatives Aha and Hpg, can be competed with methionine, be led to
It crosses metabolic pathway and replaces the methionine site of albumen, to make albumen with nitrine or alkynyl group.Some non-natural aminos
Acid can use gene codon expansion technique and enter in protein sequence.Lysine derivative, such as Penk, BCN, can use
Aminoacyl-tRNA synthetase PylRS/tRNAPyl CUAIt is specifically inserted into a certain site of albumen.Unnatural amino acid can
It assigns albumen new function, realizes multiple use, such as albumen using the property of themselves and with the interaction of albumen
Site-specific labeling, with biological significance nuclear-magnetism, infrared, FRET, fluorescence probe, be transformed and modulin enzyme
It is living, posttranslational modification, which is introduced, in the specific site of albumen studies its function, etc..
The functional groups modified in unnatural amino acid at present mainly have orthogonal reaction group (alkynyl, nitrine, double
Key, carbonyl etc.), photo-crosslinking group, light removing group, nuclear-magnetism active group, infrared active group etc..Wherein cyano is to utilize pole
Few group.However, all containing cyano group in the drug of many clinical uses, cyano is that have more highly polar carbon nitrogen three
Key has stronger electron withdrawing properties, and volume is only the 1/8 of methyl, and the cyano substitution in drug design has become guideization
Close one of the research strategy of object structure optimization.Meanwhile cyano can be converted into the carboxyl of negative electricity by electroneutral after hydrolysis.Another party
The Raman signal in face, cyano and nitrine, alkynyl, C-D is respectively positioned on the Raman silent region (1800-2800cm of cell-1).Based on cyano
These characteristics, cyanoaminopyrimidine acid is possibly used in the research of relevant albumen.
Mostly cyanoaminopyrimidine acid registered is aromatic nitriles, and relative to Arneel SD, aromatic nitriles volume and rigidity are bigger, may
The structure and function of protein can be produced bigger effect.The report of synthctic fat race cyano unnatural amino acid is few at present,
The application of cyanoaminopyrimidine acid also more lacks.
Summary of the invention
The purpose of the present invention is being directed to problem existing in the prior art, a few class aliphatic cyano unnatural amino acids are provided
Design and synthesis method, they are belonging respectively to methionine derivatives and lysine derivative.With the raw material, simple being easy to get
Operation, less step, suitable purification process obtain the cyanoaminopyrimidine acid of high-purity.And cyanoaminopyrimidine acid is explored in life
Application in the orthogonal Raman of object.
A kind of synthetic method of aliphatic cyanoaminopyrimidine acid provided by the invention, the aliphatic cyanoaminopyrimidine acid are first sulphur ammonia
Acid derivative, this method comprises:
The compound that will be had the following structure
With the POCl being dissolved in pyridine3Reaction obtains cyano compound.
Preferably, the synthetic method of above-mentioned aliphatic cyanoaminopyrimidine acid includes following reaction formula:
A kind of synthetic method of aliphatic cyanoaminopyrimidine acid provided by the invention, the aliphatic cyanoaminopyrimidine acid are lysine
Derivative, this method comprises:
The compound that will be had the following structure
With NC- (CH2)n- O-C (O)-R or NC- (CH2)n- C (O)-R reacts to obtain cyano compound, and wherein R is easily to leave away
Group.
Preferred above-mentioned easy leaving group are as follows:
Preferably this method includes following reaction formula:
Or
The present invention also provides a kind of method that unnatural amino acid is inserted into albumen, this method passes through gene codon
Expansion technique carries out.
Preferably, it is above-mentioned by unnatural amino acid be inserted into albumen in method in unnatural amino acid through PylRS/
tRNAPyl CUASystem is inserted into albumen.
Preferably, unnatural amino acid is aliphatic cyano ammonia in the above-mentioned method by unnatural amino acid insertion albumen
Base acid.
Preferably, it is above-mentioned by unnatural amino acid be inserted into albumen in method in aliphatic cyanoaminopyrimidine acid group according to above-mentioned rouge
The synthetic method of fat race cyanoaminopyrimidine acid (the aliphatic cyanoaminopyrimidine acid is methionine derivatives) is made.
Aliphatic cyanoaminopyrimidine acid (the aliphatic cyanoaminopyrimidine acid synthesized according to the above method present invention provides one kind
For lysine derivative) application in bio-orthogonal Raman detection or in protein conformation Changeement.
Carbonic ester cyano lysine derivative (such as CAOK) can be inserted into albumen through gene codon technology in the present invention.
Carbonic ester cyano lysine derivative can be used for bio-orthogonal Raman.Cyano is sensitive to chemical environment variation, is inserted into the cyanogen of albumen
The Raman signal of base may change with protein conformation generates larger offset, can be used for studying the bio-orthogonal of protein conformation variation
Raman detection.
The synthetic method of above-mentioned cyanoaminopyrimidine acid provided by the invention is primarily adapted for use in aliphatic cyanoaminopyrimidine acid, such as contains acyl
The cyanoaminopyrimidine of amine key and carbonic ester acid.The precusor amino acids that reaction is protected using part is skeletons, by dehydration, amido bond or carbon
Being formed on amino acid backbone for acid esters key introduces cyano, and when deprotection avoids the hydrolysis of cyano, synthesis process high temperature or
Low-temperature operation is few, requires the energy low.Final product is purified using hydrophilic interaction chromatography (HILIC), obtains purity pole
High cyanoaminopyrimidine acid.
The Raman shift of cyano has bio-orthogonal and the characteristic sensitive to chemical environment, by the cyano carbonic ester ammonia of synthesis
Base acid is through PylRS/tRNAPyl CUASystem is inserted into albumen, can develop cyanoaminopyrimidine acid answering in bio-orthogonal Raman detection
With such as conformation change for studying cell protein.
Detailed description of the invention
Fig. 1 is the normal Raman spectroscopy figure of cyano carbonic ester lysine (CAOK)；
Fig. 2 is the result figure with the expression of the method detection GFP of Western-blotting.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right
The present invention is further elaborated.It should be appreciated that described herein, specific examples are only used to explain the present invention, not
For limiting the present invention.
The synthesis of a few class aliphatic cyanoaminopyrimidine acid proposed by the present invention and purification process, and screened PylRS/
tRNAPyl CUABy the specific site of carbonic ester cyanoaminopyrimidine acid insertion albumen.
The synthesis of methionine derivatives Cyanohomoalanie (Cha):
The synthesis of lysine analogues cyano lysine:
Or
Product is all made of HILIC chromatographic process and is further purified.
The synthesis of 1 methionine derivatives Cyanohomoalanie (Cha) of embodiment
20mL methanol is added in 1.2g N-Fmoc-L- glutamine, 0.5mL SOCl is added dropwise under ice bath2, restore to room
Temperature reacts 4h, is spin-dried for solvent, with silica gel column separating purification, obtains yellow product a 1.1g.A is dissolved in 4mL pyridine, 0.2mL
POCl3It is dissolved in 1mL pyridine, under ice bath, by POCl3Solution is added drop-wise in the solution of a, and reaction is overnight；Revolving removes pyridine, uses
Silicagel column is isolated and purified, and 0.4g white product b is obtained.B is dissolved in the solution of 20% (v/v) diethylamine/methylene chloride,
6h is reacted at room temperature, revolving removes solvent, and by silica gel chromatography column purification obtains product c 150mg.It is added 0.8M LiOH's in c
Water/methanol (1: 4) solution reacts 2h, and 6M hydrochloric acid is adjusted to pH 6~7, and revolving removes methanol, and surplus solution crosses ion exchange column,
Crude product about 50mg is afforded, obtains final product about 30mg after purification through HILIC.
The synthesis of 2 Cyanopropionyl lysine of embodiment
By 2.4g NCCH2CH2COOH is dissolved in 30mL tetrahydrofuran, and 1.7g n-hydroxysuccinimide is added in ice bath
With 1.1g dicyclohexylcarbodiimide, reaction overnight, filters to obtain solution a '.2g Boc- lysine is added in 30mL methanol, is added
Enter 6.4mL triethylamine (TEA), solution a ' is added dropwise, reacts at room temperature 8h.Revolving removes solvent, and by silica gel chromatography column purification is produced
Object b ' 0.5g.At -15 DEG C, b ' is dissolved in 2mL trifluoroacetic acid (TFA), and after reacting 1h, revolving removes TFA, and 0.5mL methanol is added
Dissolution adds 10mL ice ether, and solid is precipitated, and ether washs 3 times, obtains crude product c ', obtains whole production after purification through HILIC
Object about 20mg.
The synthesis of 3 cyano carbonic ester lysine CAOK of embodiment
0.7g hydroxypropionitrile and 1.2mL pyridine are added in 10mL methylene chloride, 2.4g is gradually added under ice bath to nitro
Benzene chloro-formate, after being protected from light 3h, revolving removes solvent, and by silica gel chromatography column purification obtains product a " 1.8g.2g Boc- relies
Propylhomoserin is added in DMF, and 1.2mL triethylamine, cooled on ice is added.1.8g product a " is dissolved in 10mL DMF, is added drop-wise to Boc- and is relied
In propylhomoserin system, it is protected from light overnight.50 DEG C of revolvings remove DMF, are isolated and purified with preparative liquid chromatography, obtain product b "
1.4g；4mL TFA is added, reacts at room temperature 1h, revolving removes TFA, and about 1mL methanol is added, is transferred in 50mL centrifuge tube, is added
40mL ice ether, there is Precipitation, centrifugation, ether washing precipitating 3 times, obtains crude product c ", obtains final product after purification through HILIC
Cyano carbonic ester lysine (CAOK) about 100mg.
The orthogonal Raman application of 4 cyano carbonic ester lysine of embodiment
The normal Raman spectroscopy of cyano carbonic ester lysine (CAOK) is as shown in Figure 1, cyano carbonic ester lysine CAOK
Three key of carbon nitrogen is in 2255cm-1There is Raman signal at place, positioned at the Raman silent region (1800-2800cm of cell-1), it can be used for orthogonal
Raman detection.
The strategy of bio-orthogonal Raman tag label, i.e., introduced in biomolecule the orthogonal group of Raman signal (such as alkynyl,
Nitrine, C-D etc.), the silent region (1800-2800cm of their Raman signal in cell Raman signal-1).This strategy solves
The problem of raman spectra overlapping of biomolecule, enormously simplify the analytic process of Raman data.Gene codon amplification technique
Do not encode amino acid using terminator codon TAG in eucaryote and the property low using probability, introduce by screening with
TAG and orthogonal-tRNA pairs of aminoacyl transferases of unnatural amino acid make cell that the TAG of unnatural amino acid insertion albumen to dash forward
Displacement point.CAOK is inserted into target protein using gene amplification technology, carries out bio-orthogonal Raman detection.
Using green fluorescent protein GFP as model protein, it is transferred to N149 in bacterium and has carried out TAG mutation and has contained His6
The plasmid of the GFP of label, while the plasmid for being transferred to the different PylRS of expression respectively uses Anti- in the presence of CAOK
The tag antibody of His carries out the expression of Western-blotting detection GFP-N149-TAG, as a result as shown in Figure 2.Wherein
Penk be the energy that is had verified that in document with PylRS system be efficiently inserted into albumen containing alkynyl amino acids, here as positive control；
Coomassie coomassie brilliant blue staining shows that bacterioprotein applied sample amount is consistent.Thus filter out, No. 9 PylRS can most effectively by
CAOK is inserted into albumen.Thus cyano group can be introduced through the albumen different loci that is inserted in of cyanoaminopyrimidine acid, by detecting cyanogen
The conformation change of albumen on the orthogonal Raman signal research cell of base.
The preferred embodiment of the present invention has been described in detail above, however, the present invention is not limited to these examples, in the present invention
Application range in can carry out various changes.Although only illustrating several preferred embodiments of the invention above,
It is that person of ordinary skill in the field will be apparent that the range for not departing from novel teachings and advantage of the invention substantially
It is interior, illustrative embodiment can be carry out various modifications.
Claims (1)
1. a kind of application of aliphatic cyanoaminopyrimidine acid in bio-orthogonal Raman detection or in protein conformation Changeement,
Wherein, the aliphatic cyanoaminopyrimidine acid is lysine derivative, and the aliphatic cyanoaminopyrimidine acid has the following structure:
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| Application Number | Priority Date | Filing Date | Title |
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| CN201511009813.8A CN106928093B (en) | 2015-12-31 | 2015-12-31 | The preparation of cyano unnatural amino acid and its application in bio-orthogonal Raman detection |
| PCT/CN2016/000007 WO2017113428A1 (en) | 2015-12-31 | 2016-01-06 | Preparation of unnatural cyanoamino acids and application thereof in bioorthogonal raman detection |
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| CN201511009813.8A CN106928093B (en) | 2015-12-31 | 2015-12-31 | The preparation of cyano unnatural amino acid and its application in bio-orthogonal Raman detection |
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Non-Patent Citations (4)
| Title |
|---|
| "Amino Acid Homologation by the Blaise Reaction: A New Entry into Nitrogen Heterocycles";Cam Thuy Hoang，et al.;《J. Org. Chem.》;20090507;第74卷(第11期);4177-4187 |
| "Genetic Encoding and Labeling of Aliphatic Azides and Alkynes in Recombinant Proteins via a Pyrrolysyl-tRNA Synthetase/tRNACUA Pair and Click Chemistry";Duy P. Nguyen，et al.;《J. AM. CHEM. SOC.》;20090610;第131卷(第25期);8720-8721 |
| "Live-cell bioorthogonal Raman imaging";Senlian Hong，et al.;《Current Opinion in Chemical Biology》;20141115;第24卷;91-96 |
| "Total Synthesis of HUN-7293";Dale L. Boger，et al.;《J. AM. CHEM. SOC.》;19990619;第121卷(第26期);6197-6205 |
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