Redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate, and preparation method and application thereof

A technology of cyclodextrin and conjugates, which is applied in redox-responsive cyclodextrin-modified 1-methyl-β-carboline-3-carboxylic acid conjugates and its preparation and application fields, which can solve Issues such as responsive response and reduced toxicity of doxorubicin have not been disclosed, and the effects of improving solubility and bioavailability, excellent anti-tumor activity, and reducing toxicity have been achieved

Inactive Publication Date: 2017-12-19
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese invention patent (publication number CN 102952207 A) discloses that the compound obtained by linking β-cyclodextrin as a drug carrier with 1-methyl-β-carboline-3-carboxylic acid through ethylenediamine as a linking arm and Adriamycin The supramolecular inclusion complexes formed by the protein reduce the toxicity of doxorubicin, but it is not disclosed that the compound has a responsive response to the reducing environment of the tumor, and the tumor inhibition rate of the compound at a high dose of 6 μmol / kg is only 31.60 %

Method used

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  • Redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate, and preparation method and application thereof
  • Redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate, and preparation method and application thereof
  • Redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Preparation of (3S)-1,2,3,4-tetrahydromethyl-β-carboline-3-carboxylic acid (1)

[0033] Add 0.2ml of concentrated sulfuric acid dropwise to 80ml of water, add L-tryptophan (2.0g, 9.79mmol) into the aqueous solution, dissolve it by ultrasonic, add 2ml of 40% acetaldehyde solution, and stir at room temperature for 6h. When the reaction was terminated, ammonia water was added to adjust the pH to 6-7, and the mixture was left to stand overnight in a refrigerator at 4°C. Filtration under reduced pressure gave a white solid (1.8 g, 80%). ESI / MS(m / z):231[M+H] + .

Embodiment 2

[0034] Example 2 Preparation of (3S)-1,2,3,4-tetrahydromethyl-β-carboline-3-carboxylic acid methyl ester (2)

[0035] Add 75ml of methanol to a 250ml eggplant bottle, add thionyl chloride (6.6ml, 60.06mmol) dropwise under ice bath, stir for 30min under ice bath, then slowly add (3S)-1,2,3,4-tetrahydro Methyl-β-carboline-3-carboxylic acid (5 g, 21.64 mmol) was reacted for 9-10 h, the reaction solvent was drained, and 20 ml of diethyl ether was added to grind and wash 3 times to obtain a white solid. The obtained white solid was dissolved in 100ml of ethyl acetate, added to saturated sodium bicarbonate solution and stirred at room temperature for 30min and then extracted, the ethyl acetate layer was dried with anhydrous sodium sulfate for 30min, and the ethyl acetate was spun off to obtain a light yellow oil (4.8 g, 90.57%). ESI / MS(m / z):245[M+H] + .

Embodiment 3

[0036] Example 3 Preparation of 1-methyl-β-carboline-3-carboxylic acid methyl ester (3)

[0037] Add (3S)-1,2,3,4-tetrahydromethyl-β-carboline-3-carboxylic acid methyl ester (4.8g, 19.59mmol) into a 250ml eggplant bottle, add acetone under ice-cooling to dissolve it , Potassium permanganate (6.2g, 39.24mmol) was added several times in small amounts, the solvent was removed after reacting at room temperature for 6h, and 50ml of methanol was added to redissolve. Column chromatography separation and purification (dichloromethane:methanol=60:1, R f =0.3) gave a white solid (1.6 g, 34%). ESI / MS(m / z):241[M+H] + .

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Abstract

The invention discloses a redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate, and a preparation method and application thereof, belonging to the field of preparation of 1-methyl-beta-carboline-3-carboxylic acid conjugates. According to the invention, cystamine is used as a connecting arm for coupling of 1-methyl-beta-carboline-3-carboxylic acid with beta-cyclodextrin so as to form the 1-methyl-beta-carboline-3-carboxylic acid conjugate. The novel beta-carboline conjugate in the invention can improve the solubility and bioavailability of 1-methyl-beta-carboline-3-carboxylic acid, and response to redox in a tumor environment via a disulfide bond allows intelligent targeted drug release to be realized, so antineoplastic activity s significantly improved and antineoplastic efficacy is performed at low dosage. The redox-responsive cyclodextrin-modified 1-methyl-beta-carboline-3-carboxylic acid conjugate provided by the invention can be applied to preparation of antineoplastic drugs.

Description

technical field [0001] The present invention relates to 1-methyl-β-carboline-3-carboxylic acid conjugates, in particular to redox-responsive β-cyclodextrin modified 1-methyl-β-carboline-3-carboxylic acid conjugates The present invention also relates to the application of the redox-responsive β-cyclodextrin modified 1-methyl-β-carboline-3-carboxylic acid conjugate in antitumor, which belongs to the 1-methyl The field of preparation of base-β-carboline-3-carboxylic acid conjugates. Background technique [0002] Malignant tumor is a multiple disease, which has caused serious harm to human health. The development of clinical chemotherapy drugs for malignant tumors has always been one of the hot spots in tumor research. Drugs based on natural sources are gaining more and more attention from drug developers. Since Gobel first isolated Harmine from the Zygophyllaceae plant Peganum harmala in 1841, β-carboline alkaloids have become the most deeply studied carboline alkaloids. β-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16A61K47/69
CPCC08B37/0012
Inventor 李莉徐笑松王玉记赵明彭师奇
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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