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Fluorine-containing gossypol derivatives with antitumor activity, preparation method and application thereof

A technology of fluorine-containing gossypol and anti-tumor drugs, which is applied in the fields of anti-tumor drugs, imino compound preparation, organic chemistry, etc., and can solve the problems of weakening the therapeutic effect of drugs, limiting the maximum tolerated dose of gossypol, and increasing toxicity , to achieve significant in vitro inhibitory effect, low toxicity, and simple preparation

Inactive Publication Date: 2020-12-04
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After research, it was found that the aldehyde groups at both ends of the molecular structure of L-gossypol are considered to be related to toxicity. Although the effect is weak, it largely limits the maximum tolerance of the human body to L-gossypol. In addition, this mixture enters the human body Afterwards, it is easy to combine with other proteins, which weakens the therapeutic effect of the drug and increases the toxic effect

Method used

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  • Fluorine-containing gossypol derivatives with antitumor activity, preparation method and application thereof
  • Fluorine-containing gossypol derivatives with antitumor activity, preparation method and application thereof
  • Fluorine-containing gossypol derivatives with antitumor activity, preparation method and application thereof

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preparation example Construction

[0025] The preparation method of above-mentioned fluorine-containing gossypol derivative comprises the following steps:

[0026] (1) get gossypol and dissolve in methanol;

[0027] (2) Add one of 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline or 4-trifluoromethylaniline, heat and stir at constant temperature , Refluxed, a yellow solid was precipitated and filtered. Preferably, the stirring is magnetic stirring. Preferably, the temperature is 60-70° C. during stirring, and the mixture is heated, stirred and refluxed for 3-5 hours.

[0028] (3) Wash with petroleum ether-ethyl acetate solution, and recrystallize with petroleum ether-ethyl acetate. Preferably, the volume ratio of petroleum ether-ethyl acetate used for washing is 14-18:1. Preferably, the recrystallization method is as follows: dissolve the fluorine-containing gossypol derivative with ethyl acetate in a water bath at 50-70°C, then drop petroleum ether to sat...

Embodiment 1

[0030] Embodiment 1 (gossypol derivative 3a)

[0031] 8,8'-bis((E)-(2-fluorophenylimino)methyl)-5,5'-diisopropyl-3,3'-dimethyl-2,2'-binaphthyl-1,1',6,6', 7,7'-h exaol

[0032]

[0033] Steps: Take 0.5789g (1mmol) of gossypol, add 40ml of methanol to dissolve, add 0.45ml (4mmol) of 2-fluoroaniline, add a stirrer, place the reaction device in a collector type constant temperature heating magnetic stirrer, and adjust the temperature to Heat, stir and reflux at 65°C for 4 hours, a yellow solid precipitates, filters, washes with petroleum ether-ethyl acetate (16:1), and recrystallizes with petroleum ether-ethyl acetate.

[0034] The specific method of recrystallization: dissolve the fluorine-containing gossypol derivative 3a with ethyl acetate in a 60°C water bath, then slowly drop petroleum ether to saturate the solution, and let it cool to room temperature. After 3 days, yellow crystals precipitate out.

[0035] Get 0.61g of fluorine-containing gossypol derivative 3a product...

Embodiment 2

[0036] Embodiment 2 (gossypol derivative 3b)

[0037] 8,8'-bis((E)-(3-fluorophenylimino)methyl)-5,5'-diisopropyl-3,3'-dimethyl-2,2'-binaphthyl-1,1',6,6', 7,7'-h exaol

[0038]

[0039] Steps: Take 0.5789g (1mmol) of gossypol, add 40ml of methanol to dissolve, add 0.45ml (4mmol) of 3-fluoroaniline, add a stirrer, place the reaction device in a collector type constant temperature heating magnetic stirrer, and adjust the temperature to Heat, stir and reflux at 65°C for 4 hours, a yellow solid precipitates, filters, washes with petroleum ether-ethyl acetate (16:1), and recrystallizes with petroleum ether-ethyl acetate.

[0040] The specific method of recrystallization: dissolve the fluorine-containing gossypol derivative 3b with ethyl acetate in a 60°C water bath, then slowly drop petroleum ether to saturate the solution, and let it cool to room temperature. After 3 days, yellow crystals precipitate out.

[0041] Obtain 0.58g of fluorine-containing gossypol derivative 3b prod...

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Abstract

The invention discloses a fluorine-containing gossypol derivative with antitumor activity and a preparation method and application of the fluorine-containing gossypol derivative with the antitumor activity. Gossypol reacts with 2-fluoroaniline, 3-fluoroaniline, 4-fluoroaniline, 2-trifluoromethylaniline, 3-trifluoromethylaniline or 4-trifluoromethylaniline to obtain the fluorine-containing gossypol derivative. The fluorine-containing gossypol derivative disclosed by the invention is simple in preparation, and research finds that compared with a gossypol compound, the fluorine-containing gossypol derivative has lower toxicity for human normal VEC, and more obvious in-vitro inhibiting effects for HeLa cells, human non-small cell lung cancer A-549 cells and gastric cancer BGC-823 cells, therefore, the fluorine-containing gossypol derivative can be applied to preparation of anti-tumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a gossypol derivative with antitumor activity, a preparation method and application thereof. Background technique [0002] Gossypol is a natural yellow polyphenol hydroxyl bis-naphthaldehyde compound extracted from the roots, stems and seeds of the cotton sunflower plant upland cotton. The purified gossypol should be a bright yellow crystal, which contains six Hydroxyl polycyclic aldehydes with the formula C 30 h 30 0 8 , the relative molecular mass is 518.562, and the chemical name is 2,2'-bis-8-formyl 1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene. In recent years, the anticancer effect of gossypol has received more and more attention. Its significant killing effect on tumor cells has been shown in head and neck cancer cell lines, prostate cancer cell lines, human pancreatic cancer cell lines, human chronic myelogenous leukemia cell lines, multiple Tumor cell culture an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C249/02C07C251/24A61P35/00
CPCC07C249/02C07C251/24
Inventor 陈活记刘强曾丽莹朱红霞翁立冬安佰超乡世健洪军辉曹思玮阮世发
Owner SOUTHERN MEDICAL UNIVERSITY
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