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Chloroquine cholesterol derivative, and preparation method and application thereof

A technology of cholesterol derivatives, chloroquine cholesterol, which is applied in the field of chemical medicine, can solve problems that need to be studied, and achieve the effect of inhibiting proliferation and treating pulmonary fibrosis

Active Publication Date: 2018-08-21
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Hydroxychloroquine is a commonly used antimalarial drug, and it can also be used in the treatment of systemic lupus erythematosus and rheumatoid arthritis. More and more literature reports that it has a significant preventive effect on cardiovascular diseases. New application directions under study

Method used

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  • Chloroquine cholesterol derivative, and preparation method and application thereof
  • Chloroquine cholesterol derivative, and preparation method and application thereof
  • Chloroquine cholesterol derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Synthesis of 2-(4-(7-chloroquine-4-amino)pentyl-(ethyl)aminoethyl)-cholesterol succinate (compound 1)

[0034]

[0035] Put cholesterol, succinic anhydride, and DMAP in an appropriate amount of dichloromethane in a molar ratio of 1:2.5:2.5, stir at room temperature for 48 hours, extract 5 times with 1mol / L HCl at the end of the reaction, and wash 5 times with 200mL water to remove Concentrate most of dichloromethane, add 100mL glacial acetic acid, remove all solvents to dryness, wash the product with a little glacial acetic acid several times in a Buchner's hole until white, dry at 60°C overnight to obtain cholesterol succinic acid Single fat.

[0036] After hydroxychloroquine sulfate is desalted and dried with NaOH solution, hydroxychloroquine, cholesterol succinic acid monoester, DMAP, EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ) According to the molar ratio of 1:1.2:1.2:1.2 ratio feeding reaction. First, dissolve hydroxychloroqui...

Embodiment 2

[0039] Embodiment 2 Compounds of the present invention inhibit rat fibroblast proliferation

[0040] Fibroblasts were isolated from rat lung tissue, and the 4-8 generation cells were used for experiments, and they were indeed fibroblasts identified by Vimentin (vimentin) immunofluorescent staining. The cells were cultured in DMEM medium containing 10% FBS (fetal bovine serum, purchased from GIBCO).

[0041]Inoculate 4,000 fibroblasts in each well of a 96-well plate, add compound 1 for treatment after adherence, divide into DMSO control group, set the concentration gradient from 1 to 100 μM, treat for 24 hours, add MTT (tetrazolium bromide) for incubation, and crystal violet dissolves The absorbance value was detected in DMSO (dimethyl sulfoxide) at a wavelength of 570 nm.

[0042] See the experimental results figure 1 Shown: Rat fibroblasts treated with different concentrations of compound 1, the absorbance value at 570nm wavelength at 24 hours, as the concentration increase...

Embodiment 3

[0043] Embodiment 3 compound 1 anti-pulmonary fibrosis animal experiment

[0044] SD rats, female, with a body weight of about 250 grams, were given a single large dose of bleomycin (5 mg / kg body weight) in the rat's trachea for the modeling of pulmonary fibrosis, and the administration began the next day, and PBS (phosphate Buffer solution) control group, empty liposome control group, hydroxychloroquine sulfate control group (8mg / kg / day), compound 1 treatment group (20mg / kg / day). 15 rats per group were tested. Rats were sacrificed on the 7th day, 14th day, and 28th day, and the lung tissues were taken out, fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, H&E (hematoxylin-eosin) staining and Masson staining (three color staining) to evaluate the therapeutic effect.

[0045] See the experimental results figure 2 Shown: Compound 1 and hydroxychloroquine sulfate are used as the animal experimental research results of anti-pulmonary fibrosis treatment drug, A is ...

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Abstract

The invention specifically relates to a chloroquine cholesterol derivative, and a preparation method and application thereof, belonging to the field of the chemical pharmaceutical industry. The chloroquine cholesterol derivative provided by invention has a structure as shown in a formula I which is described in the specification. The invention also provides the preparation method and application of the chloroquine cholesterol derivative. The chloroquine cholesterol derivative provided by the invention can effectively inhibit the proliferation of rat fibroblasts and treat pulmonary fibrosis, exerts anti-inflammatory effect, and offers a novel option for preparation of anti-fibrotic, anti-inflammatory and anti-tumor drugs.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a chloroquine cholesterol derivative and a preparation method and use thereof. Background technique [0002] Hydroxychloroquine is a commonly used antimalarial drug, and it can also be used in the treatment of systemic lupus erythematosus and rheumatoid arthritis. More and more literature reports that it has a significant preventive effect on cardiovascular diseases. New application directions is under study. Therefore, it is particularly important to find new compounds that produce similar effects. The structural formula of hydroxychloroquine is as follows: [0003] [0004] Patent CN101428025A protects the sensitization effect of this compound in the treatment of multiple myeloma with chemotherapy drugs, which can significantly increase the effect of chemotherapy drugs such as doxorubicin, epirubicin, cisplatin and mitoxantrone on multiple myeloma cells. letha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P11/00A61P13/12A61P1/16A61P1/18A61P1/00A61P17/00A61P19/02A61P29/00A61P37/02A61P37/08A61P35/00
CPCC07J43/003
Inventor 魏于全刘丽何治尧
Owner SICHUAN UNIV
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