CN102603695A - Amino acid-fluorophore compound and application thereof - Google Patents
Amino acid-fluorophore compound and application thereof Download PDFInfo
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Abstract
The invention relates to an amino acid-fluorophore compound and application of the compound, wherein the general structural formula of the amino acid-fluorophore compound is (I), (II), (III), and (IV) or a free form thereof, wherein R1 is selected from various amino acid side chains, preferably methyl, propyl, 2-methylthio ethyl, benzyl, phenylethyl, 2-cyclohexyl ethyl, 4-isopropyl phenyl and 4-dimethyl amino phenyl; R2 is selected from various fluorophores, preferably 7-hydroxyl coumarin, naphthalimide fluorophores, Nile red series and Cy fluorophores; and X is C or N. Fluorescent probe molecules can be used for detecting the activity (enzyme level and cell level) of aminopeptidase N, can be used as a probe tool for detecting the tissue distribution of aminopeptidase N and tumor tissue imaging, and can be used as a diagnosis tool for various diseases due to abnormal expression of aminopeptidase N. In addition, the preparation method of the compound has the advantages of mild reaction conditions, easily-accessible and cheap raw materials and simplicity in operation and after-treatment.
Description
Technical field
The present invention relates to amino acid-linker-fluorophore compounds and, belong to technical field of pharmaceuticals as the small molecules fluorescent probe of Aminopeptidase N and the application in the screening aminopeptidase N inhibitor.
Background technology
Aminopeptidase N (A PN; CD 13) wide expression is in kidney and IBB cell, marrow progenitor cell film, monocyte film, cns cynapse cytolemma, inoblast, endothelial cell membrane, placenta cells film surface, can discharge amino acid from proteinic N-terminal degraded.With the moving phase ratio of normal cell, this enzyme is in the tumor cell surface over-expresses, and invasion and attack, the vasculogenesis of tumour had vital role.In addition, this proteolytic enzyme is participated in corresponding physiological response as the acceptor of many viruses (as cause the dissemination marcy agent of neonatal pig acute gastroenteritis and cause people's upper respiratory tract infection coronavirus HCV 229E).It can also be expressed in the antigen presenting cell surface, and degraded panimmunity active substance descends immunity of organisms, weakens scavenger cell and N K cell identification and kill capability [Zhang, the X.P. to tumour cell; Xu, W.F.Aminopeptidase N (APN/CD13) as a target for anti-cancer agent design.Curr Med Chem 2008,15,2850-2865].
Though human function to APN has had a lot of understandings, detection method active for APN and tissue distribution does not have too many research.Existing method comprises immune labeled method, isotope-labelling method and fluorescent method.Immune labeled method can not realize intravital detection, though isotope-labelling method can be realized in vivo detecting, has radiotoxicity.Comparatively speaking fluorescent method have sensitivity, toxicity little, can realize the advantage that in vivo detects.Fluorophore is connected with APN target property part NGR, and the target property mensuration of the utilizing NGR in vivo tissue distribution situation of APN is research method [(a) vonWallbrunn, the A. of recent years; Waldeck, J.; Holtke, C.; Zuehlsdorf, M.; Mesters, R.; Heindel, W.; Schafers, M.; Bremer, C.In vivo optical imaging of CD 13/APN-expression in tumor xenografts.J Biomed opt2008,13,011007-1--011007-9. (b) Smith, R.A.; Giorgio; T.D.Quantitative measurement ofmultifunctional quantum dot binding to cellular targets using flow cytometry.Cytometry Part A2009; 75A; 465-474] yet., the use of these molecular probes is owing to stronger background signal is restricted.Therefore, the design APN fluorescent probe that synthesis of selective is good, highly sensitive, SNR is big, toxicity is little has great importance.
Research shows, do not have fluorescence based on the activated probe self of enzymic activity, after itself and enzyme effect, discharges fluorophore and produces fluorescence [Chen, X. Q.; Sun, M.; Ma, H.M.Progress in spectroscopic probes with cleavable activebonds.Curr org chem 2006,10,477-489].Because APN can be from the aminoterminal of the peptide chain peptide chain of progressively degrading; Syntheticly have APN and optionally can activate the small molecules fluorescent probe if APN specific amino acid residue and fluorophore be connected through peptide bond; And then measure intravital APN activity of various APN high expression level animal models and tissue distribution; Study itself and tumour, vasculogenesis and immune relation, certainly will be able to foundation be provided for the getting up early diagnosis and the prevention of tumour and disease of immune system.In addition, be main to the screening of aminopeptidase N inhibitor or with ultraviolet absorption method, this method has shortcomings such as sensitivity is low, cost is high, the test duration is long.The experiment if the enzyme that we can find an ideal fluorescent probe to carry out Aminopeptidase N is lived, the screening that also can be aminopeptidase N inhibitor provides a platform.
Summary of the invention
The present invention is directed to the deficiency of prior art, one seed amino acid-fluoresceins compound and preparation method thereof is provided and in the application of pharmacy field.
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
One seed amino acid-fluorophore compounds and application thereof.Its general structure is (I), (II), (III) or (IV), or their free form,
In the formula: R1 is various amino acid side chains, preferable methyl, propyl group, 2-methylmercaptoethyl, phenmethyl, styroyl, 2-cyclohexyl ethyl, 4-isopropyl phenyl, 4-dimethylamino phenyl; R2 is various fluorophores, preferred umbelliferone, benzene-naphthalene diimide class fluorophore, Nile red series and Cy series fluorophore; X is C or N.
Preferably, above-claimed cpd has one of following structure:
Compound of the present invention is as the application of the small molecules fluorescent probe of Aminopeptidase N.
Compound of the present invention detects the tissue distribution of Aminopeptidase N and the application of tumour cell and imaging of tissue at screening aminopeptidase N inhibitor (comprising enzyme level and cell levels).
Compound of the present invention is as the application of reference fluorescent probe in screening aminopeptidase N inhibitor (comprising enzyme level and cell levels).
The application of compound of the present invention in the medical diagnosis on disease of all kinds of Aminopeptidase N unconventionality expression.
Description of drawings
Fig. 1 has the probe L1 of reference wavelength character and the transmitted wave spectrogram of APN effect.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
The preparation of instance one: 2-amino-4 methylthio groups-N-(4-(2-oxo-2 hydrogen-chromene-7-base oxygen base) phenyl) butanamide hydrochloride [L3]
Synthetic route 1
The preparation of midbody 1:
The 14.9g methionine(Met) is dissolved in the 110mL1M sodium hydroxide solution; Ice bath, slowly Dropwise 5 0mL contains the anhydrous THF solution of 2118g dimethyl dicarbonate butyl ester, controls reaction solution pH about 9 with the sodium hydroxide solution of 1M simultaneously; About 1h dropwises; Stir 1h under the condition of ice bath, remove ice bath, stirring at room 15h.Whole process keeps system pH about 9, and reaction finishes the back steaming except that THF, with petroleum ether (100mL * 3); Water is regulated pH2～3 with saturated citric acid solution, and with ethyl acetate extraction (100mL * 3), anhydrous magnesium sulfate drying spends the night; Concentrate faint yellow oily thing 20.5g, yield 87%.
The preparation of midbody 2:
Under the ice bath, in the 100mL anhydrous methanol, drip the 8.73mL Acetyl Chloride 98Min., ice bath stirred 15 minutes, added the 5.4g para-amino benzoic acid, and ice bath stirs after 1 hour and refluxed 2 hours.Concentrate white solid, get white powder 6.55g with methyl alcohol-ether recrystallization, yield 95%.
The preparation of midbody 3:
2.7g midbody 1 is dissolved in the 100mL methylene dichloride, adds 1.5g HOBT, 2.1g EDCI, stirring at room 15min adds 1.9g midbody 2 and 1.4mL triethylamine, stirring at room 6 hours.With reaction solution with saturated Hydrocerol A (50mL * 3) wash, saturated sodium bicarbonate (50mL * 3) washes, saturated aqueous common salt (50mL * 1) is washed.Anhydrous magnesium sulfate drying spends the night.Concentrate, get white solid 3.1g with ETHYLE ACETATE-normal hexane recrystallization, productive rate 80%, fusing point 100-102 ℃.
The preparation of midbody 4:
0.76g midbody 3 is dissolved in the 20mL anhydrous diethyl ether, and cryosel is bathed gradation adding 0.23g Lithium Aluminium Hydride down, room temperature reaction 1 hour.Under the ice bath, in reaction solution, add 3mL ETHYLE ACETATE, regulate PH to 7 with 2M hydrochloric acid.Filter, organic phase is washed with saturated aqueous common salt (20mL * 3), and anhydrous magnesium sulfate drying spends the night.Concentrate, combiflash separate colorless oil 0.34g, yield 48%.
Midbody 5 preparations:
0.26g midbody 4 is dissolved in the anhydrous THF of 40mL, and ice bath adds 0.3mL triethylamine and 0.18mL methylsulfonyl chloride down, stirring reaction below 5 ℃, and afterreaction finished in 4 hours.Reaction solution with 0.5M hydrochloric acid (20mL * 3) wash, saturated common salt washing (20mL * 1), anhydrous magnesium sulfate drying.Concentrate yellow oil 0.28g, thick productive rate 80% need not to purify, and directly is used for next step reaction.
The preparation of midbody 6:
The 0.12g umbelliferone is dissolved in 10mLDMF, adds the 0.2g Anhydrous potassium carbonate, stirring at room added 0.23g midbody 5 after 15 minutes, and reaction is spent the night.Reaction solution is poured in the 100mL ETHYLE ACETATE, washed with unsaturated carbonate potassium solution (50mL * 5), saturated aqueous common salt (50mL * 1) is washed.Concentrate, get white solid 0.12g with ETHYLE ACETATE-normal hexane recrystallization, yield 60%.Fusing point 128-129 ℃.
The preparation of compound L 3
0.06g midbody 6 is dissolved in the saturated hydrogenchloride-ethyl acetate solution of 3mL, and stirring at room had a large amount of white precipitates to produce after 2 hours, filtered, dry white powder 0.06g, the yield 92% of getting.Fusing point 234.2-235.7 ℃.
1HNMR(300MHz，D
2O)δppm：7.75(d，1H，J＝9.3Hz)，7.37-7.45(m，5H)，6.85(d，1H，J＝9.3Hz)，6.75(d，1H，J＝14.1Hz)，6.17(d，1H，J＝0.9Hz)，5.01(s，2H)，4.19(t，1H，J＝6.6Hz)，2.58(t，2H，J＝7.2Hz)，2.17-2.41(m，2H)，2.01(s，3H)。
Instance two: the preparation of 2-amino-N-(2-((2-oxo-2 hydrogen-chromene-7-base oxygen base)-methyl) phenyl) valeramide hydrochloride [L98]
Synthetic route 2
The preparation of midbody 7:
1.2g Boc-L-norvaline is dissolved in the 50mL methylene dichloride, adds 0.75g HOBT, 1.05g EDCI, stirring at room 15min adds the adjacent aminobenzyl alcohol of 0.62g, stirring at room 10 hours.With reaction solution with saturated Hydrocerol A (50mL * 3) wash, saturated sodium bicarbonate (50mL * 3) washes, saturated aqueous common salt (50mL * 1) is washed.Anhydrous magnesium sulfate drying spends the night.Concentrate, get white solid 0.97g with ETHYLE ACETATE-normal hexane recrystallization, productive rate 60%, fusing point 110.0-122.3 ℃.
The preparation of midbody 8:
With midbody 7 is raw material, gets midbody 8, brown oil, yield 80% according to the preparation method of midbody 5.Midbody 9 preparations:
With midbody 8 is raw material, gets midbody 9, white solid, yield 21% according to the preparation method of midbody 6.Fusing point: 158.0-160.1 ℃.
The preparation of compound L 98
With midbody 8 is raw material, gets L98, white solid, yield 95% according to the preparation method of L3.Fusing point: 230.7-232.2 ℃.
1HNMR(300MHz，D
2O)δppm：7.91(d，1H，J＝9.6Hz)，7.56(d，2H，J＝3.0Hz)，7.31-7.50(m，3H)，6.96(dd，2H，J＝9.3Hz，3.0Hz)，6.28(d，1H，J＝9.6Hz)，5.13(d，1H，J＝11.1Hz)，5.03(d，1H，J＝11.1Hz)，4.07(t，1H，J＝6.3Hz)，1.61-1.74(m，2H)，1.18-1.31(m，2H)，0.57(t，3H，J＝7.2Hz)。
Instance three: the preparation of 2-amino-N-(2-((2-oxo-2 hydrogen-chromene-7-base oxygen base)-methyl) pyridin-3-yl) propionamide hydrochloride [L337]
Midbody 10 and 11 synthetic reference literature [(a) Beyermann, M.; Bienert, M.; Niedrich, H; Carpino, L.A.; Sadat-Aalaee; D.Rapid continuous peptide synthesis via FMOC amino acid chloridecoupling and 4-(aminomethyl) piperidine deblocking.J Org Chem, 1990,55; 721-728. (b) Carpino, L A.; Xia, J.S.; El-Faham, A.3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene.J Org Chem, 2004,69,54-61.].
The preparation of midbody 12:
2.67g midbody 11 and 3mL pyridine are dissolved in the 50mL dioxane, add 0.63g midbody 10, the 1 hour postcooling that refluxes is to room temperature.Concentrate, use the 200mL acetic acid ethyl dissolution, wash with saturated sodium bicarbonate (50mL * 3), saturated aqueous common salt (50mL * 1) is washed.Anhydrous magnesium sulfate drying spends the night.Concentrate, get white solid 0.44g with re-crystallizing in ethyl acetate, productive rate 25.0%, fusing point: 136.6-138.6 ℃.
The preparation of midbody 13:
With midbody 12 is raw material, gets midbody 13, white solid, yield 17.9%, fusing point: 166.8-168.7 ℃ according to the preparation method of midbody 4.
The preparation of midbody 14:
With midbody 13 is raw material, gets midbody 14, white solid, yield 66.6%, fusing point: 139.3-141.7 ℃ according to the preparation method of midbody 5.
The preparation of midbody 15:
The 0.02g umbelliferone is dissolved in 10mL acetone, adds the 0.02g Anhydrous potassium carbonate, stirring at room added 0.04g midbody 14 after 30 minutes, reacted 30 minutes.Reaction solution is poured in the 100mL ETHYLE ACETATE, washed with unsaturated carbonate potassium solution (50mL * 5), saturated aqueous common salt (50mL * 1) is washed.Anhydrous magnesium sulfate drying spends the night.Concentrate, the silicagel column purifying gets white solid 0.03g, yield 66%.Fusing point 150.1-151.9 ℃.
The preparation of compound L 337
0.03g midbody 15 is dissolved in 8mL20% piperidines-DMF solution, and stirring at room one hour removes piperidines and DMF under reduced pressure.Residue is used the 100mL acetic acid ethyl dissolution, washes with water (50mL * 3), and saturated aqueous common salt (50mL * 1) is washed.Anhydrous magnesium sulfate drying spends the night.Concentrate, the silicagel column purifying gets white solid 0.015g, yield 83%.Fusing point 59.0-61.3 ℃.
1H-NMR(DMSO，600MHz)：δ8.39(d，1H，J＝6Hz)，8.34(d，1H，J＝6Hz)，7.99(d，1H，J＝12Hz)，7.64(d，1H，J＝12Hz)，7.44(dd，1H，J＝12Hz，6Hz)，7.13(d，1H，J＝6Hz)，7.07(dd，1H，J＝12Hz，6Hz)，6.31(d，1H，J＝12Hz)，5.38(s，2H)，3.45(q，1H，J＝6Hz)，1.24(d，3H，J＝6Hz).
Instance four: KINETIC METHOD detection probes compound is to the avidity of APN.
Reference literature [Huang, H.Z.; Tanaka, H.; Hammock, B.D.; Morisseau, c.Novel and highlysensitive fluorescent assay for leucine aminopeptidases.Anal biochem 2009,391,11-16], measure L1, L2, L3 be to the kinetic parameter of APN, result such as following table.
Annotate: reference substrate leucyl p-Nitroaniline is to the K of APN
mBe respectively 423 μ M, 0.125U/mL, K with LOD
mBe worth that the bright compound of novel is strong more to the avidity of APN more.The consumption of the APN of the detection signal strength that LOD refers to produce during more than or equal to three times of background signal.
The result shows that test-compound has kinetic property and avidity preferably to APN.
Instance five: the reference wavelength character of detection probes compound
Add APN (0.01U) to probe compound (200 μ M), excite with λ=330nm excitation wavelength, PM once.Judge whether to have reference wavelength character according to its collection of illustrative plates, Fig. 1 has the probe L1 of reference wavelength character and the transmitted wave spectrogram of APN effect.
The result shows that test-compound is the fluorescent probe that one type of ability is discerned and had reference wavelength character by APN.
Instance six: the application (enzyme level) of target compound in the APN inhibitor screening
Reference literature [Chen, L.Z.; Mou, J.J.; Xun, Y.Y.; Fan, H.; Xu; W.F.Design, synthesis andactivity study of aminopeptidase N targeted 3-amino-2-hydroxy-4-phenyl-butanoic acidderivatives.Drug Discov Ther.2011,5; 61-65]; Compound L 1 as the APN substrate, as the APN suppressor factor, is measured the IC of bestatin with marketed drug bestatin
50, the application of examination target compound in the APN inhibitor screening.Result such as following table.
| Compound | [S]/μM | [E]/mIU | IC 50/μM |
| L1 | 22.5 | 1 | 0.35±0.05 |
| Leu-p- |
400 | 10 | 2.3±0.07 |
The result shows the IC that uses the test-compound test to obtain
50Close with traditional Leu-p-nitroanilide, explain that it can use in the APN inhibitor screening.And use the used enzyme amount of this substrate test less, greatly reduce testing cost, for the high flux screening of APN suppressor factor provides an effective means.
Instance seven: the application (cell levels) of target compound in the APN inhibitor screening
The reference fluorescent probe is affected by environment little, can PBS and substratum in to measure the inhibition that listing APN suppressor factor ubenimex lives to ES-2 cell (APN high expression level) surface enzyme active, testing method and instance six are similar, the result is as shown in the table.
| Compound | Test system | [S]/μM | Cell/10 4 | IC 50/μM |
| L1 | Medium | 25 | 5 | 105.4±10.8 |
| L1 | PBS | 25 | 5 | 39.1±1.5 |
| Leu-p-nitroanilide | PBS | 320 | 20 | 20±1.7 |
The result shows, is soundd out pin can be measured the APN suppressor factor exactly in substratum IC
50Because the survival time of cell in substratum is far longer than buffer salt solution, compared with conventional test methods (PBS system), this probe can be more exactly at cell levels screening APN suppressor factor.
Claims (8)
1. one seed amino acid-fluorophore compounds, its general structure are (I), (II), (III) or (IV), or their free form,
In the formula: R1 is various amino acid side chains; R2 is a fluorophore; X is C or N.
2. compound according to claim 1 is characterized in that, said R1 is methyl, propyl group, 2-methylmercaptoethyl, phenmethyl, styroyl, 2-cyclohexyl ethyl, 4-isopropyl phenyl or 4-dimethylamino phenyl.
3. compound according to claim 1 is characterized in that, said R2 is umbelliferone, benzene-naphthalene diimide class fluorophore, Nile red series or Cy series fluorophore.
4. compound according to claim 1 is characterized in that having one of following structure:
5. like of the application of each described compound of claim 1-4 as the small molecules fluorescent probe of Aminopeptidase N.
6. screening aminopeptidase N inhibitor like each described compound of claim 1-4, the tissue distribution of detection Aminopeptidase N and the application of tumour cell and imaging of tissue.
Like each described compound of claim 1-4 as the reference fluorescent probe in the application of screening in the aminopeptidase N inhibitor.
8. like the application of each described compound of claim 1-4 in the medical diagnosis on disease of all kinds of Aminopeptidase N unconventionality expression.
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| CN109438319A (en) * | 2018-09-17 | 2019-03-08 | 湖北大学 | A kind of compound and its preparation method and application detecting leucine amino peptidase |
| CN109438319B (en) * | 2018-09-17 | 2022-05-10 | 湖北大学 | Compound for detecting leucine aminopeptidase and preparation method and application thereof |
| CN110330505B (en) * | 2019-07-30 | 2021-07-09 | 济南大学 | Two-photon ratio type fluorescent probe compound for aminopeptidase N detection and preparation method thereof |
| CN110330505A (en) * | 2019-07-30 | 2019-10-15 | 济南大学 | A kind of two-photon Ratiometric fluorescent probe compound and preparation method thereof for Aminopeptidase N detection |
| CN116462639A (en) * | 2023-04-18 | 2023-07-21 | 吉林大学 | Fluorescent probe for specifically recognizing alanine aminopeptidase as well as preparation method and application thereof |
| CN116535364A (en) * | 2023-04-18 | 2023-08-04 | 吉林大学 | Fluorescent probe for specifically recognizing leucine aminopeptidase and preparation method and application thereof |
| CN116462639B (en) * | 2023-04-18 | 2023-12-08 | 吉林大学 | Fluorescent probe for specifically recognizing alanine aminopeptidase as well as preparation method and application thereof |
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