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Carboline carboxylic-Orn(ClCH2NH)-AA-benzylamine, its synthesis, activity and application thereof

A technology of carboline and tetrahydrocarboline, applied in the application field of β-carboline-3-formyl-Orn-AA-NHCH2C6H5, in the preparation of antitumor drugs

Active Publication Date: 2017-01-11
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Therefore, the inventor returned to the experimental exploration of β-carboline-3-formyl derivatives without substituents at the 1-position. After 3 years of experimental research, the applicant found that Orn-AA-NHCH 2 C 6 h 5 Substitution of AA-OBzl yields β-carboline-3-formyl-Orn-AA-NHCH 2 -C 6 h 5 Not only has a clear anti-tumor effect at a dose of 0.1 μmol / kg, but also has no problems such as gastric irritation, undesired drug metabolism results and poor water solubility

Method used

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  • Carboline carboxylic-Orn(ClCH2NH)-AA-benzylamine, its synthesis, activity and application thereof
  • Carboline carboxylic-Orn(ClCH2NH)-AA-benzylamine, its synthesis, activity and application thereof
  • Carboline carboxylic-Orn(ClCH2NH)-AA-benzylamine, its synthesis, activity and application thereof

Examples

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Effect test

Embodiment 1

[0022] Example 1 Preparation of (3s)-β-tetrahydrocarboline-3-carboxylic acid (1)

[0023]Slowly add 0.1 mL of concentrated sulfuric acid to 200 mL of water, stir for 10 minutes, add 2.5 g (12.2 mmol) of tryptophan to the obtained dilute sulfuric acid, and ultrasonically shake to completely dissolve the tryptophan. Then add 0.3 mL of 40% formaldehyde solution, react at room temperature for 6 hours, slowly add concentrated ammonia water to the reaction solution under ice bath, and adjust the pH to 6. The reaction solution became turbid and was filtered to obtain 2.2 g (85%) of the title compound as a colorless powder, ESI-MS (m / z): 205 [M+H] + .

Embodiment 2

[0024] Example 2 Preparation of (3s)-β-tetrahydrocarboline-3-carboxylic acid methyl ester (2)

[0025] Stir the solution of 18mL methanol and 1.2mL thionyl chloride in an ice bath for 30min, then add 750mg (3.2mmol) (3s)-β-tetrahydrocarboline-3-carboxylic acid, gradually return to room temperature and continue Reaction 24h. TLC (dichloromethane:methanol, 20:1) detected the disappearance of the reaction starting material. The reaction mixture was concentrated to dryness under reduced pressure, methanol was added to the residue, and concentrated to dryness under reduced pressure. This operation was repeated 3 times. The residue was added with diethyl ether and concentrated under reduced pressure to obtain 250 mg (35%) of the title compound as a yellow powder. ESI-MS(m / e): 231[M+H] + .

Embodiment 3

[0026] Embodiment 3 prepares β-carboline-3-carboxylic acid methyl ester (3)

[0027] Dissolve 230 mg (1 mmol) methyl tetrahydrocarboline-3-carboxylate in 50 mL of acetone, slowly add 100 mg (1 mmol) potassium permanganate to the solution under ice-cooling, and react at room temperature for 4 h. TLC (dichloromethane:methanol, 20:1) detected the end of the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and spin-dried, the filter cake was dissolved with acetone, filtered under reduced pressure, the filtrate was concentrated to dryness, this operation was repeated 3 times, and the filtrate was combined to obtain a yellow oil separated and purified by column chromatography (dichloromethane: Methanol, 40:1), afforded 60 mg (20%) of the title product as a yellowish solid, ESI-MS (m / e): 227 [M+H] + .

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Abstract

The invention discloses 13 types of beta-carboline-3-formyl- Orn(ClCH2NH)-AA-NHCH2C6H5 in a following formula (in the formula, AA is selected from L-Arg, L-Asn, L-Asp, L-Glu, L-Gly, L-Ile, L-Leu, L-Met, L-Phe, L-Pro, L-Thr, L-Trp, and L-Val residues), also discloses the preparation methods thereof, discloses the inhibition effect for tumor cells growth, and discloses an application of the substrates as the antitumor drugs.

Description

technical field [0001] The present invention relates to 13 kinds of β-carboline-3-formyl-Orn(ClCH 2 NH)-AA-NHCH 2 C 6 h 5 , relate to their preparation methods, and relate to their inhibitory effect on tumor cell growth, thus the present invention relates to their application in the preparation of antitumor drugs. The invention belongs to the field of biomedicine. Background technique [0002] β-carbolines are important natural products with a wide range of pharmacological effects, such as antithrombotic and antitumor effects. The inventor once disclosed a series of β-carboline-3-formyl-amino acids, β-carboline-3-formyl-amino acid benzyl esters, β-carboline-3-formyl-amino acids with antithrombotic and antitumor activities. Acyl-oligopeptides. Their intraperitoneal doses are 8.9-10 μmol / kg. The inventors were not satisfied with this level of activity. Therefore, the inventors started the experimental exploration of low-dose oral administration of the target. The inve...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04
Inventor 赵明彭师奇吴建辉王玉记刘烁
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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