Carboline carboxylic acid-tetrapeptide conjugate and synthesis method as well as medical application thereof

A carboline carboxylic acid and peptide coupling technology, applied in the field of biomedicine, can solve the problems of low solubility and bioavailability, and achieve excellent antithrombotic activity

Inactive Publication Date: 2010-12-08
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For 3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in polar solvents and non-polar solvents poor solubility of the problem of low bioavailability brought, the inventors This has been improved

Method used

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  • Carboline carboxylic acid-tetrapeptide conjugate and synthesis method as well as medical application thereof
  • Carboline carboxylic acid-tetrapeptide conjugate and synthesis method as well as medical application thereof
  • Carboline carboxylic acid-tetrapeptide conjugate and synthesis method as well as medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Preparation of 3S-1,2,3,4-tetrahydro-β-carboline-3-acyl-Val-Tyr-Ser-Val (4a) 1) 3S-1,2,3,4-tetra Preparation of Hydrogen-β-carboline-3-carboxylic Acid

[0017] Put 400ml of water in a 500ml round bottom flask, slowly add 0.2ml of concentrated sulfuric acid and shake well. Then add 5.0g (24.5mmol) L-tryptophan, ultrasonically shake until the L-tryptophan is completely dissolved, add 10ml of formaldehyde with a concentration of 35% to the above mixture, stir the reaction, and the TLC plate shows L-tryptophan The raw material point disappeared, and slowly added ammonia water to the reaction solution to pH = 6.0, let it stand for 0.5 hours, filtered under reduced pressure to obtain a white solid, dried and weighed 5.01g, yield: 95.0%, m.p: 228-230°C, ESI -MS(m / z): 217[M+H] +

[0018] 2) Preparation of N-tert-butyryl-3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

[0019] Under ice bath conditions, 1.0g (4.63mmol) 3S-1,2,3,4-tetrahydro-β-carboline-3-carbox...

Embodiment 2

[0038] Example 2 Preparation of 3S-1,2,3,4-tetrahydro-β-carboline-3-acyl-Tyr-Tyr-Ser-Val (4b)

[0039] 1) Preparation of Boc-Tyr-Tyr-Ser(Bzl)-Val-OBzl(1b)

[0040] Using the method for preparing Boc-Tyr-Ser(Bzl)-Val-OBzl, with 1.238g (2.26mmol) Tyr-Ser(Bzl)-Val-OBzl and 0.762g (2.71mmol) Boc-Tyr, the title compound 1.166 was obtained g, colorless solid, yield 63.63%, TLC (chloroform:methanol=20:1, Rf=0.26) m.p: 86.9~88.5°C, ESI-MS(m / z): 812[M+H] + .

[0041] 2) Preparation of Tyr-Tyr-Ser(Bzl)-Val-OBzl(2b)

[0042] Using the method for preparing Ser(Bzl)-Val-OBzl, with 1.098g (1.35mmol) Boc-Tyr-Tyr-Ser(Bzl)-Val-OBzl and 5.5ml hydrogen chloride-ethyl acetate (4N), the title compound was obtained 0.960g, yellow oil, yield 99.79%. ESI-MS(m / z): 712[M+H] +

[0043] 3) Preparation of Boc-3S-1,2,3,4-tetrahydro-β-carboline-3-acyl-Tyr-Tyr-Ser(Bzl)-Val-OBzl (3b)

[0044] Using the method for preparing Boc-Tyr-Ser(Bzl)-Val-OBzl, with 0.960g (1.35mmol) Tyr-Tyr-Ser(Bzl)-Val-OBzl an...

Embodiment 3

[0047] Example 3 Preparation of 3S-1,2,3,4-tetrahydro-β-carboline-3-acyl-Ala-Tyr-Ser-Val (4c)

[0048] 1) Preparation of Boc-Ala-Tyr-Ser(Bzl)-Val-OBzl(1c)

[0049] Using the method for preparing Boc-Tyr-Ser(Bzl)-Val-OBzl, with 1.260g (2.30mmol) Tyr-Ser(Bzl)-Val-OBzl and 0.522g (2.76mmol) Boc-Ala, the title compound 1.169 was obtained g, colorless solid, yield 70.69%, TLC (chloroform:methanol=30:1, Rf=0.27) m.p: 78.9~80.9°C, ESI-MS(m / z): 720[M+H] + .

[0050] 2) Preparation of Ala-Tyr-Ser(Bzl)-Val-OBzl(2c)

[0051] The title compound was obtained by preparing Ser(Bzl)-Val-OBzl with 0.929g (1.29mmol) Boc-Ala-Tyr-Ser(Bzl)-Val-OBzl and 3.7ml hydrogen chloride-ethyl acetate (4N) 0.7988g, yellow oil, yield 99.75%. ESI-MS(m / z): 620[M+H] +

[0052] 3) Preparation of Boc-3S-1,2,3,4-tetrahydro-β-carboline-3-acyl-Ala-Tyr-Ser(Bzl)-Val-OBzl(3c)

[0053] Using the method for preparing Boc-Tyr-Ser(Bzl)-Val-OBzl, with 0.798g (1.29mmol) Ala-Tyr-Ser(Bzl)-Val-OBzl and 0.493g (1.55mmol) ...

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Abstract

The invention discloses a carboline carboxylic acid-tetrapeptide conjugate and a synthesis method as well as application thereof used as an antithrombotic agent. In the invention, tri-carboxyl of 3S-1,2,3,4-tetrahydro-Beta-carboline-3-carboxylic acid with antithrombotic activity is conjugated with the ammonia end of AA-Tyr-Ser-Val tetrapeptide to obtain a finished product after deprotection, wherein AA is selected from alanine, glycine, proline, glutamine, leucine, phenylalanine, isoleucine, valine, tyrosine, tryptophane, histidine, asparaginate, aspartate, glutamate, serine, threonine, methionine, lysine or arginine residue. The evaluation experiment on a thrombotic model of a rat shows that the compound of the invention has excellent antithrombotic activity and can be applied as the antithrombotic agent. In addition, the invention can overcome the defect of low bioavailability caused by low solubility of the 3S-1,2,3,4-tetrahydro-Beta-carboline-3-carboxylic acid in polar solvents and non-polar solvents.

Description

technical field [0001] The conjugates of carboline carboxylic acid and peptide of the present invention especially relate to the conjugates of 3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid and tetrapeptide, and the present invention also relates to this The synthesis method of the conjugates and their application as an antithrombotic agent belong to the field of biomedicine. Background technique [0002] Thrombosis is very common in our country, and occurs in various fields of clinical treatment. Arterial thrombosis in various organs is one of the most dangerous diseases, and it is fatal. Finding antithrombotic drugs is one of the hot spots in new drug research. The inventors have noticed that 3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid is a component in the traditional Chinese medicine Allium, which has anti-platelet aggregation activity (Yao Xinsheng et al., Chinese Journal of Medicinal Chemistry, 1995, 5, 134). For 3S-1,2,3,4-tetrahydro-β-carboline-3-carb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06A61K38/08A61P7/02
Inventor 赵明彭师奇赵晔
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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