CN104844581A - Carbon-carbon oxygen-oxygen four-membered ring compound and application in mass spectrum detection - Google Patents

Carbon-carbon oxygen-oxygen four-membered ring compound and application in mass spectrum detection Download PDF

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Publication number
CN104844581A
CN104844581A CN201510190315.1A CN201510190315A CN104844581A CN 104844581 A CN104844581 A CN 104844581A CN 201510190315 A CN201510190315 A CN 201510190315A CN 104844581 A CN104844581 A CN 104844581A
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oxygen
carbon
compound
membered ring
enzyme
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CN104844581B (en
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马毅
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Guangdong Gaohang Intellectual Property Operation Co ltd
Pizhou Runhong Industry Co ltd
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode

Abstract

The invention discloses a carbon-carbon oxygen-oxygen four-membered ring compound and its application in mass spectrum detection. The compound has the following characteristics: 1, the compound must contain a carbon-carbon oxygen-oxygen four-membered ring structure; 2, the compound must contain an anion group which can be detected by a mass spectrometer; and 3, the compound must contain a functional group which can be connected with macromolecules. In order to stabilizing the carbon-carbon oxygen-oxygen four-membered ring, a group for stabilizing molecules , usually a polysubstituted alkyl group, needs to be introduced into molecules. When the compound is combined with macromolecules and a mass spectrometer is used for detection, the carbon-carbon oxygen-oxygen four-membered ring is specifically fractured. By detecting content of quenched pieces with the anion group after molecular fracture, content of labeled macromolecules can be calculated. The macromolecules are protein, polypeptide, enzyme and antibody. In clinic, content of some macromolecules has a certain relation with diseases. The compound provided by the invention is widely applied in clinic to rapid and accurate detection of macromolecule content.

Description

A kind of carbon carbon oxygen oxygen tetra-atomic ring compound and the application in mass spectrometric detection thereof
Technical field
The invention belongs to mass spectrometric detection field, particularly relate to a kind of compound containing carbon carbon oxygen oxygen tetra-atomic ring structure and when mass spectrometric detection for marker detection thing.
Background technology
At present, the content of the various bioprotein of the most frequently used detection or enzyme is the method by enzyme immunodetection clinically.It is that time of development is longer that ImBaunofenzymatic technique has larger advantage, and Measures compare is ripe.But its limitation is that the result sometimes detected is inaccurate, at present good enzyme immunity detection method is not also had to the detection of some enzyme or albumen.
In the past because the general technology of matter is not mature enough, the exact level of detected material in detection sample that cannot be quantitative.So the application in clinical detection is not extensive.In recent years, due to the develop rapidly of the general detection technique of matter, the advanced general instrument of matter can detect the level of a hundreds of molecule, and the lowest limit that is can detect can to 10 -21mol/L.Such limit of detection is considerably beyond the testing requirement of reality.
But the molecule that the detection molecules amount that the common normal energy of matter is sensitive is relatively little.Detection macromole that cannot be effective and sensitive, as enzyme and albumen.Therefore, conventional method right small molecule tags is on albumen or enzyme.Macromolecular content is indirectly measured by the micromolecular content of certification mark.But to this micromolecular, there is special requirement.Such for the small molecules marked to have when by matter is general detect time can the single-minded same key of fracture, thus with the general instrument of matter sensitive this fragment that ruptures detected.The content of albumen or the enzyme be labeled can be calculated from the content of fragment.But at present, the small molecules with this mark function is also few.
Summary of the invention
In order to solve the problem, the invention provides a kind of carbon carbon oxygen oxygen tetra-atomic ring compound for mass spectrometry tags, fracture that can be single-minded, in carbon carbon oxygen oxygen tetra-atomic ring place, is appointed by the fragment ruptured and is still connected on macromole, and another fragment of fracture can be detected by the general instrument of matter.
Adopt following technical scheme: a kind of carbon carbon oxygen oxygen tetra-atomic ring compound for mass spectrometry tags, has the general formula as shown in (I) or (II) for this reason:
In formula, X is O or S; R 5, R 6, R 7for the alkyl of different chain lengths or stable isotope or halogen or hydrogen, and its end is with an anion-containing functional group; R 1, R 2, R 3, R 4, R 8any four is the alkyl of different chain length, containing the functional group that can be connected with protein or enzyme or polypeptide, is specifically selected from following functional group (III), (IV), (V), (VI), (VII):
。
Further, R 5, R 6, R 7the functional group of end is selected from SO 3 -, OSO 3 -, COO -, P (O) O 3 -.
Further, described carbon carbon oxygen oxygen tetra-atomic ring compound is applied to labelled protein or antibody or polypeptide or enzyme.As follows:
Above formula, Y is albumen or polypeptide or enzyme in compound (VIII).
Further, after described carbon carbon oxygen oxygen tetra-atomic ring compound label albumen or antibody or polypeptide or enzyme, the application in the general detection of matter.
Key of the present invention is that this compound contains a unique structure: oxygen oxygen tetra-atomic ring.Under normal circumstances, this compounds containing aerobic oxygen tetra-atomic ring is unstable, and just decomposed in the mistake of synthesis becomes, as follows, compound (IX) is easily decomposed into two kinds of chain rupture sections of general formula (X) and general formula (XI) in synthesis.
But when while when introducing polysubstituted alkyl, this compounds (XII) or (XIII) are stable, usually at room temperature can preserve 1-2,
But when the general analysis of matter, this oxygen oxygen tetra-atomic ring is the most weak key, always override ruptures this tetra-atomic ring.With the general method for breaking of softer matter, can control this tetra-atomic ring that only ruptures, other key is not interrupted.Complete sliver (XVI) like this containing negatively charged ion just can be detected by the general instrument of matter is complete, and is do not have rule or have similar key to be broken by many places unlike the general fracture of common chemical combination material, does not have the using value in analysis
Due to this compounds (XIV) regular fracture in the general analysis of matter, the compound of different concns can obtain the general figure of matter of different peak value size, and they are proportional.Therefore utilize this compound to come labelled protein or enzyme, when detection general by matter, indicate different tagged compound protein or enzyme just can be measured separately, their relative concentration size also can be found out from peak value size.If have a standard working curve, just can calculate the actual concentration of labelled protein or enzyme.The general instrument of now sensitive matter can detect the level of a hundreds of molecule, that is can detect 10 -21the level of mol/L.
Simple and the sensitive detection of protein or enzyme has important application on clinical diagnose.The content of such as certain enzyme is correlated with in certain cancer, but does not also well detect the method for this enzyme now.The general tagged compound of this matter disclosed in this invention is combined with this enzyme, but goes out its content by matter general instrument energy rapid detection.The general tagged compound of matter disclosed in this invention can mark above all albumen or enzyme, with a wide range of applications.
Embodiment
The preparation of embodiment 1 oxygen oxygen tetra-atomic ring compound:
A) synthesis of compound (XIX):
In the dry three-necked bottle of 250 milliliters, add 200 milliliters of anhydrous tetrahydro furans (THF), 30 mmole aluminium lithiums hydrogen (LAH), slowly add the titanium tetrachloride (TiCl of 30 mmoles in funnel 4) solution in 30 milliliters of toluene.After adding, continue to stir half hour.In the single port bottle of another one 50 milliliters, add the ketone (XVII) of 10 mmoles and the ester (XVIII) of 4 mmoles, then the anhydrous tetrahydro furan (THF) adding 20 milliliters dissolves all compounds.This mixed solution is slowly joining in reaction flask, continues stirring again 3 hours after adding.20 milliliters of triethylamines (TEA) join in reaction, continue stirring 5 minutes.Then all reaction solutions are poured in the frozen water of 500 grams, stir cancellation in 5 minutes reaction with glass stick.Then use 100 milliliters of extraction into ethyl acetate five times, merge all organic phases, with salt washing, anhydrous sodium sulfate drying.Rotary evaporation removing organic solution, residue over silica gel post is separated, and obtains the compound (XIX) of alkene ehter bond.
B) synthesis of compound (XX):
In the single port bottle of 50 milliliters, add the compound (XIX) of 1 mmole, the tetrabutyl ammonium fluoride (t-Bu of 25 milliliters of tetrahydrofuran (THF)s (THF) and 3 mmoles 4nF), room temperature reaction 3 to 5 hours.Rotary evaporation removing tetrahydrofuran (THF), residue with ethyl acetate dilutes, then washes with salt.Anhydrous sodium sulfate drying.Rotary evaporation removing organic solution, residue over silica gel post is separated, and obtains alkenyl ether compound (XX).
C) synthesis of compound (XXII)
In the single port bottle of 25 milliliters, 50 milligrams of compounds (XX) are with activating terephthalamide amine (XXI) to react in the methylene dichloride (DCM) of 15 milliliters with 30 milligrams.Alkali is made with triethylamine (TEA).Room temperature reaction is after one hour, concentrated, and the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 10% at the mixed solvent of methylene dichloride as developping agent.Be separated the alkenyl ether compound (XXII) obtaining required band functional group.
D) synthesis of compound (XXIII)
In the reaction tubes of 15 milliliters, connect oxygen turnover and remove pipe.The compound (XXII) of 30 milligrams and the light-sensitive catalyst (rose bengal) of 1 milligram join in methyl alcohol (Methanol) mixing solutions of the methylene dichloride (DCM) of 5 milliliters and 1 milliliter, pass into oxygen (O 2), reaction tubes is cooled in frozen water, opens the sodium vapor lamp of 1000 watts.Continue reaction 30 to 40 minutes.Turn off sodium vapor lamp and oxygen, reaction solution is poured in the single port bottle of 50 milliliters, rotary evaporation removing organic solvent, the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 10% at the mixed solvent of methylene dichloride as developping agent.Separation obtains carbon carbon oxygen oxygen tetra-atomic ring compound (XXIII).
E) synthesis of compound (XXV)
In the single port bottle of 25 milliliters, 30 milligrams of compounds (XX) are with activating terephthalamide amine (XXIV) to react in the methylene dichloride (DCM) of 10 milliliters with 40 milligrams.Alkali is made with triethylamine (TEA).Room temperature reaction is after one hour, concentrated, and the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 10% at the mixed solvent of methylene dichloride as developping agent.Be separated the alkenyl ether compound (XXV) obtaining required band functional group.
F) synthesis of compound (XXVI)
In the reaction tubes of 15 milliliters, connect oxygen turnover and remove pipe.The compound (XXV) of 30 milligrams and the light-sensitive catalyst (rose bengal) of 1 milligram join in methyl alcohol (Methanol) mixing solutions of the methylene dichloride (DCM) of 10 milliliters and 1 milliliter, pass into oxygen (O 2), reaction tubes is cooled in frozen water, opens the sodium vapor lamp of 1000 watts.Continue reaction 30 to 40 minutes.Turn off sodium vapor lamp and oxygen, reaction solution is poured in the single port bottle of 50 milliliters, rotary evaporation removing organic solvent, the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 10% at the mixed solvent of methylene dichloride as developping agent.Separation obtains carbon carbon oxygen oxygen tetra-atomic ring compound (XXVI).
The preparation of embodiment 2 another kind of oxygen oxygen tetra-atomic ring compound:
A) synthesis of compound (XXVIII):
In the dry three-necked bottle of 250 milliliters, add 200 milliliters of anhydrous tetrahydro furans (THF), 10 mmole aluminium lithiums hydrogen (LAH), slowly add the titanium tetrachloride (TiCl of 10 mmoles in funnel 4) solution in 10 milliliters of toluene.After adding, continue to stir half hour.In the single port bottle of another one 50 milliliters, add the ketone (XVII) of 10 mmoles and the ester (XXVII) of 3.5 mmoles, then the anhydrous tetrahydro furan (THF) adding 20 milliliters dissolves all compounds.This mixed solution is slowly joining in reaction flask, continues stirring again 3 hours after adding.15 milliliters of triethylamines (TEA) join in reaction, continue stirring 5 minutes.Then all reaction solutions are poured in the frozen water of 500 grams, stir cancellation in 5 minutes reaction with glass stick.Then use 200 milliliters of extraction into ethyl acetate five times, merge all organic phases, with salt washing, anhydrous sodium sulfate drying.Rotary evaporation removing organic solution, residue over silica gel post is separated, and obtains the compound (XXVIII) of alkene ehter bond.
B) synthesis of compound (XXX):
In the single port bottle of 50 milliliters, add the compound (XXVIII) of 1 mmole, the anhydrous tetrahydro furan (THF) of 15 milliliters, under nitrogen atmosphere, add the sodium hydride (NaH) of 1 mmole.Room temperature reaction is after 1 hour, and compound (XXIX) joins in reaction solution.Continue stirring reaction to spend the night.Rotary evaporation removing organic solution, the resistates silica gel thin sheet of 20x20 centimetre is separated, and obtains required alkenyl ether compound (XXX).
C) synthesis of compound (XXXI):
In the single port bottle of 50 milliliters, add the compound (XXX) of 1 mmole, the tetrabutyl ammonium fluoride (t-Bu of 25 milliliters of tetrahydrofuran (THF)s (THF) and 3 mmoles 4nF), room temperature reaction 3 to 5 hours.Rotary evaporation removing tetrahydrofuran (THF), residue with ethyl acetate dilutes, then washes with salt.Anhydrous sodium sulfate drying.Rotary evaporation removing organic solution, residue over silica gel post is separated, and obtains alkenyl ether compound (XXXI).
D) synthesis of compound (XXXIII)
In the single port bottle of 25 milliliters, 50 milligrams of compounds (XXXI) are with activating terephthalamide amine (XXXII) to react in the methylene dichloride (DCM) of 15 milliliters with 30 milligrams.Alkali is made with triethylamine (TEA).Room temperature reaction is after one hour, concentrated, and the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 10% at the mixed solvent of methylene dichloride as developping agent.Be separated the alkenyl ether compound (XXXIII) obtaining required band functional group.
E) synthesis of compound (XXXIV)
In the reaction tubes of 15 milliliters, connect oxygen turnover and remove pipe.The light-sensitive catalyst (rose bengal) of the compound (XXXIII) of 30 milligrams and 5 milligrams polystyrene-supported joins in methyl alcohol (Methanol) mixing solutions of the methylene dichloride (DCM) of 5 milliliters and 1 milliliter, passes into oxygen (O 2), reaction tubes is cooled in the dry ice acetone of subzero 78 degree, open the sodium vapor lamp of 1000 watts.Continue reaction 30 to 40 minutes.Turn off sodium vapor lamp and oxygen, reaction solution is poured in the single port bottle of 50 milliliters, rotary evaporation removing organic solvent, the silica-gel plate of preparing of resistates 20X20 centimetre is separated.Methyl alcohol with 15% at the mixed solvent of methylene dichloride as developping agent.Separation obtains carbon carbon oxygen oxygen tetra-atomic ring compound (XXXIV).
The combination of embodiment 3 mouse monoclonal antibody (mlgG) and compound (XXXIII):
The damping fluid of mouse monoclonal antibody (mlgG) converts 50 mmoles to and often rises phosphoric acid buffer (PBS), 0.15 mole of often liter of NaCl, the damping fluid of pH=7.2, and the solution being made into 5 milligrams every milliliter.Compound (XXXIII) is made into dimethyl formamide (DMF) solution of 10 milligrams every milliliter.Get the compound (XXXIII) that 10 milligrams of mouse monoclonal antibody (mlgG) join 10 milligrams every milliliter.Slowly shake reaction in room temperature to spend the night, then reaction solution sephadex G-25(sephadax G-25) pillar separation, often rise phosphoric acid buffer (PBS) with 50 mmoles, 0.15 mole of often liter of NaCl, pH=7.2 does dissociating buffer.With the absorption of ultraviolet 280 nanometer, and correction factor 1.40, calculate the concentration of antibody (mlgG) and compound (XXIII) binding substances (XXXV).
The combination of embodiment 4 bovine serum albumin (BSA) and compound (XXVI):
Bovine serum albumin (BSA) is made into 5 milligrams every milliliter and often rises phosphoric acid buffer (PBS) at 50 mmoles, 0.15 mole of often liter of NaCl, the damping fluid of pH=7.2.Compound (XXVI) is made into dimethyl formamide (DMF) solution of 10 milligrams every milliliter.Get 20 milligrams of bovine serum albumins (BSA), add the compound (XXVI) of 10 milligrams every milliliter.Slowly shake reaction in room temperature to spend the night, then reaction solution sephadex G-25(sephadax G-25) pillar separation, often rise phosphoric acid buffer (PBS) with 50 mmoles, 0.15 mmole often rises NaCl, and pH=7.2 does dissociating buffer.The concentration of binding substances (XXXVI) is measured with bicinchoninic acid procedure.
The combination of embodiment 5 anti-fluorescein antibody and compound (XXXIV):
Anti-fluorescein antibody (anti-FTIC) is made into 5 milligrams every milliliter and often rises phosphoric acid buffer (PBS) at 50 mmoles, 0.15 mole of often liter of NaCl, the damping fluid of pH=7.2.Compound (XXXIV) is made into dimethyl formamide (DMF) solution of 15 milligrams every milliliter.Get 10 milligrams of anti-fluorescein antibody (anti-FTIC), add the compound (XXXIV) of 10 milligrams every milliliter.Reaction is slowly shaken 3 hours, then reaction solution sephadex G-25(sephadax G-25 in room temperature) pillar separation, often rise phosphoric acid buffer (PBS) with 50 mmoles, 0.15 mmole often rises NaCl, and pH=7.0 does dissociating buffer.With the absorption of ultraviolet 280 nanometer, and correction factor 1.36, calculate the concentration of antibody and combinations of compounds (XXXVII).

Claims (4)

1., for a carbon carbon oxygen oxygen tetra-atomic ring compound for mass spectrometry tags, there is the general formula as shown in (I) or (II):
In formula, X is O or S; R 5, R 6, R 7for the alkyl of different chain lengths or stable isotope or halogen or hydrogen, and its end is with an anion-containing functional group; R 1, R 2, R 3, R 4, R 8any four is the alkyl of different chain length, containing the functional group that can be connected with protein or enzyme or polypeptide, is specifically selected from following functional group (III), (IV), (V), (VI), (VII):
。
2., according to the carbon carbon oxygen oxygen tetra-atomic ring compound for mass spectrometry tags a kind of described in claim 1, it is characterized in that: R 5, R 6, R 7the functional group of end is selected from SO 3 -, OSO 3 -, COO -, P (O) O 3 -.
3. be applied to labelled protein or antibody or polypeptide or enzyme according to the carbon carbon oxygen oxygen tetra-atomic ring compound described in claim 1 or 2.
4. according to after the carbon carbon oxygen oxygen tetra-atomic ring compound label albumen described in claim 1 or 2 or antibody or polypeptide or enzyme, the application in the general detection of matter.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1059523A (en) * 1990-09-07 1992-03-18 韦恩州立大学校董会 As 1 of organic and biological molecular chemistry luminous marker, 2-dioxetanes alkyl compound
US5998175A (en) * 1998-07-24 1999-12-07 Lumigen, Inc. Methods of synthesizing and amplifying polynucleotides by ligation of multiple oligomers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1059523A (en) * 1990-09-07 1992-03-18 韦恩州立大学校董会 As 1 of organic and biological molecular chemistry luminous marker, 2-dioxetanes alkyl compound
US5998175A (en) * 1998-07-24 1999-12-07 Lumigen, Inc. Methods of synthesizing and amplifying polynucleotides by ligation of multiple oligomers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAMORU OHASHI ET AL.: "Intramolecular electron-transfer-induced cleavage of dioxetanes observed in fast-atom bombardment tandem mass spectrometry", 《EUROPEAN JOURNAL OF MASS SPECTROMETRY》 *

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