CN103319567A - Tripeptide compound and preparation method and applications thereof - Google Patents
Tripeptide compound and preparation method and applications thereof Download PDFInfo
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- CN103319567A CN103319567A CN 201210075146 CN201210075146A CN103319567A CN 103319567 A CN103319567 A CN 103319567A CN 201210075146 CN201210075146 CN 201210075146 CN 201210075146 A CN201210075146 A CN 201210075146A CN 103319567 A CN103319567 A CN 103319567A
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Abstract
The invention discloses a novel tripeptide compound which has the following structural formula. The invention further discloses a preparation method of the tripeptide compound. The tripeptide compound provided by the invention has significant APN-inhibiting activity and thus can be used to prepare aminopeptidase N inhibitors.
Description
Technical field
The invention belongs to the compound field, be specifically related to a kind of tripeptide compound and its preparation method and application.
Background technology
Aminopeptidase N (APN/CD13; EC 3.4.11.2), be a class zine ion dependency metalloprotease, it extensively is present in the multiple tissue of humans and animals, on different cells (epithelial cell, endotheliocyte, inoblast and white corpuscle etc.) surface expression is arranged all.Than normal cell, this enzyme is at the tumor cell surface high level expression, and it is played an important role in the forming process of malignant growth, invasion and attack, transfer and neovascularity, becomes an important target spot of research cancer therapy drug.At present, the natural inhibitor of existing report is as Bestatin, Probestatin, and Amastatin, Curcumin etc. are obtaining certain positively effect aspect prevention and the treatment tumour.Bestatin has been used for the treatment of the acute non-lymphoid leukemia of grownup clinically as the APN inhibitor of first listing.In addition, people have also synthesized many small molecules APN inhibitor, as alpha-amino group phosphoric acid class inhibitor, beta-amino thio-alcohol inhibitor etc.
Summary of the invention
First purpose of the present invention is to provide a kind of tripeptide compound that Aminopeptidase N (APN) suppresses activity that has.
Second purpose of the present invention is to provide the preparation method of described tripeptide compound.
The 3rd purpose of the present invention is to provide the application of described tripeptide compound.
Tripeptide compound of the present invention has following structural formula:
The preparation method of tripeptide compound of the present invention may further comprise the steps:
The first step:
Second step:
The 3rd step:
The 4th step:
Tripeptide compound of the present invention has tangible APN and suppresses active, thereby can have the prospect of further Application and Development for the preparation of the APN inhibitor.
Description of drawings
Fig. 1, Fig. 2 are the LC-MS figure of tripeptide compound of the present invention.
Fig. 3 is H-NMR (D6-DMSO) figure of tripeptide compound of the present invention.
Fig. 4 is H-NMR (D6-DMSO+D2O) figure of tripeptide compound of the present invention.
Fig. 5 is the APN inhibition figure of tripeptide compound of the present invention.
Embodiment
Below by specific embodiment, the present invention is described in further detail.Should be understood that following examples are only for explanation the present invention but not for limiting scope of the present invention.
Preparation embodiment
The preparation of embodiment 1, compound
The 250mL there-necked flask add compound 1 (be ubenimex, commercially available, east, Taizhou fine chemistry company limited of nation) (10g, 32.43mmol) and the BOC acid anhydrides (7.8g 35.78mmol), adds 50mLH
2O and 25mL THF (tetrahydrofuran (THF)).(65mL 1mol/L), rises to room temperature, and stirring is spent the night slowly to drip the NaOH aqueous solution down at 0 ℃.Add ethyl acetate and water, separatory gets organic phase.Wash 2 times, saturated common salt washing 1 time adds anhydrous sodium sulphate, standing and drying a moment, suction filtration, vacuum rotary steam to do compound 2 (13.1g, yield 99.0%); Concrete reaction formula is as follows:
Add compound 2 (13.1g at the 500mL there-necked flask, 32.07mmol), compound a (Isoleucine benzyl ester tosilate, commercially available, Shanghai gill biochemistry) 7.8g (32.07mmol) and TBTU (O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid, commercially available, Shanghai gill biochemistry) 10.3g (32.07mmol), add 200mL DCM (methylene dichloride) dissolving.Under 0 ℃, DIEA (diisopropylethylamine, commercially available, the splendid chemistry far away in Shanghai) 11.2mL (64.14mmol) slowly is added dropwise to reaction solution, rises to room temperature, stirred 2 hours.Add ethyl acetate and water, separatory gets organic phase.1% phosphoric acid solution washing 1 time, 2% solution of potassium carbonate washing 1 time wash 1 time, and saturated common salt washing 1 time adds anhydrous sodium sulphate, standing and drying a moment, suction filtration, vacuum rotary steam is to dried crude product.Silica gel column chromatography separate pure product compound 2 (13.5g, yield 70.4%), concrete reaction formula is as follows:
(13.5g 22.07mmol), adds the 200mL acetic acid ethyl dissolution to add compound 3 in the 500mL there-necked flask.Led to the HCl gases 1 hour down at-20 ℃.Rise to room temperature, stir after 1 hour, add ammoniacal liquor and regulate pH=8, wash 2 times, saturated common salt washing 1 time adds anhydrous sodium sulphate, standing and drying a moment, and suction filtration, vacuum rotary steam is to dried compound 4 (10.8g, yield 95.6%);
Concrete reaction formula is as follows:
(10.8g 21.11mmol) with 10% palladium carbon (1.08g), adds the 200mL dissolve with methanol to add compound 4 in the 500mL there-necked flask.Atmospheric pressure at room hydrogenation, stirring is spent the night, suction filtration, vacuum rotary steam to do compound 5 (8.7g, yield 97.8%); Concrete reaction formula is as follows:
The compound 5 that obtains is carried out structure identify, the result is as described in Fig. 1-4, and wherein: Fig. 1, Fig. 2 be that the LC-MS of compound 5 schemes; Fig. 3 is H-NMR (D6-DMSO) figure of compound 5; Fig. 4 is H-NMR (D6-DMSO+D2O) figure of compound 5.
The mass-spectrometric data of compound 5 is as follows:
ESI-MS：422.3[M+1]
+。
1H?NMR(DMSO-d
6，D
2O-d2，500MHz)δ＝7.31-7.23(m，5H)，4.29-4.26(m，1H)，3.99(d，J＝5.5Hz，1H)，3.91(d，J＝3.0Hz，1H)，3.41(td，J
1＝7.0Hz，J
2＝4.0Hz，1H)，2.87-2.90(m，1H)，2.71-2.74(m，1H)，1.99(m，1H)，1.50-1.63(m，3H)，1.40-1.44(m，1H)，1.09-1.13(m，1H)，0.80-0.88(m，14H)。
Identify through said structure, determine that the structural formula of compound 5 is for correct.
Application Example
The inhibition determination of activity reference literature J.Microbiol.Biotechnol. of Aminopeptidase N (APN), 1995,5 (1): the 36-40 reported method, concrete experimental procedure is as follows:
In 96 orifice plates, add substrate (L-leucyl p-Nitroaniline) 100 μ l (1mg/ml, among the 0.1MTris-HCl, pH 7.0), the testing compound 20 μ l of different concns gradient (0.1M Tris-HCl, pH7.0), 37 ℃, the 3min reaction, add Aminopeptidase N (L5006-25UN, Sigma) solution 20 μ l (2mU, 0.1M Tris-HCl again, pH 7.0), 37 ℃, the 30min reaction, absorption value is measured in the back in 405nm wavelength place.
Calculate inhibiting rate according to following formula:
Inhibiting rate=(A-B)/A
Wherein:
The optical density that A records for the reaction system that does not contain inhibitor;
The optical density that B records for the testing compound reaction system is with the damping fluid zeroing of 0.1M Tris-HCl, pH 7.0.
Get tripeptide compound of the present invention (compound 5), measure it as stated above for the inhibition activity of APN, test-results as shown in Figure 5.
As seen from Figure 5, compound of the present invention has tangible APN and suppresses active, obviously has the prospect of further Application and Development.
Claims (3)
1. a tripeptide compound is characterized in that, described tripeptide compound has following structural formula:
2. the preparation method of the described tripeptide compound of claim 1 is characterized in that may further comprise the steps:
The first step:
Second step:
The 3rd step:
The 4th step:
3. the described tripeptide compound of claim 1 is for the preparation of the application of aminopeptidase N inhibitor.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210075146 CN103319567A (en) | 2012-03-20 | 2012-03-20 | Tripeptide compound and preparation method and applications thereof |
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| CN 201210075146 CN103319567A (en) | 2012-03-20 | 2012-03-20 | Tripeptide compound and preparation method and applications thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001301A (en) * | 2014-04-16 | 2015-10-28 | 上海来益生物药物研究开发中心有限责任公司 | 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine synthesis method |
| CN110372775A (en) * | 2019-07-02 | 2019-10-25 | 渤海大学 | Biologically active peptide with APN inhibiting effect |
| CN113845522A (en) * | 2021-10-14 | 2021-12-28 | 山东省药学科学院 | Aminopeptidase N inhibitor and preparation method and application thereof |
| CN114349816A (en) * | 2021-11-30 | 2022-04-15 | 青岛博创生物科学研究院 | Small molecule coupling molecule based on aminopeptidase N/CD13 and preparation method and application thereof |
-
2012
- 2012-03-20 CN CN 201210075146 patent/CN103319567A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001301A (en) * | 2014-04-16 | 2015-10-28 | 上海来益生物药物研究开发中心有限责任公司 | 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine synthesis method |
| CN110372775A (en) * | 2019-07-02 | 2019-10-25 | 渤海大学 | Biologically active peptide with APN inhibiting effect |
| CN110372775B (en) * | 2019-07-02 | 2021-03-26 | 渤海大学 | Bioactive peptides with APN inhibitory effect |
| CN113845522A (en) * | 2021-10-14 | 2021-12-28 | 山东省药学科学院 | Aminopeptidase N inhibitor and preparation method and application thereof |
| CN113845522B (en) * | 2021-10-14 | 2024-05-14 | 山东省药学科学院 | Aminopeptidase N inhibitor and preparation method and application thereof |
| CN114349816A (en) * | 2021-11-30 | 2022-04-15 | 青岛博创生物科学研究院 | Small molecule coupling molecule based on aminopeptidase N/CD13 and preparation method and application thereof |
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Application publication date: 20130925 |