Chrysamide B derivative with anti-tumor activity and preparation and application of Chrysamide B derivative

A technology of anti-tumor activity and derivatives, which can be used in anti-tumor drugs, organic active ingredients, medical preparations containing active ingredients, etc.

Active Publication Date: 2020-07-24
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such drugs have poor selectivity to normal cells and tumor cells, and while killing tumor cells, they also cause damage to normal metabolic cells of the human body, causing relatively large toxic and side effects to the human body, so that the clinical application of cytotoxic drugs is limited

Method used

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  • Chrysamide B derivative with anti-tumor activity and preparation and application of Chrysamide B derivative
  • Chrysamide B derivative with anti-tumor activity and preparation and application of Chrysamide B derivative
  • Chrysamide B derivative with anti-tumor activity and preparation and application of Chrysamide B derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation route of carboxylic acid compound (Ⅲ or Ⅵ):

[0055]

[0056] Preparation of Compound II: Dissolve 3g (19.87mmol) benzaldehyde (I) in 40mL ultra-dry dichloromethane in a 250mL reaction flask under argon atmosphere, and slowly add 8.3g (23.84mmol) Wittg reagent (methyl 2-(triphenylphosphoranylidene) propanoate), stirred at room temperature for 12h. After the reaction was detected by TLC, it was diluted with dichloromethane, extracted with water, and the organic phase was collected, dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (V / V PE:EA=15:1 ) to obtain light yellow solid 4g, yield 92%. The same synthetic process is applicable to benzaldehyde, 3-nitrobenzaldehyde, and 2-nitrobenzaldehyde as the starting material (I), and can prepare intermediates (II) with different nitro position substitutions or no substituents; wittig The reagent can also be methyl 2-(triphenyl-l5-phosphaneylidene) acetate, and ...

Embodiment 2

[0062] 2, the preparation route of 5-dimethylpiperazine compound (X):

[0063]

[0064] Preparation of compound 2: (1), in a 500mL reaction flask, 5g (35.97mmol) D-alanine methyl ester hydrochloride (1) and 6.8g (35.97mmol) Boc protected D-alanine were dissolved in In 90mL DMF, move the reaction bottle to an ice bath, and add 20.52g (53.96mmol) 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid in sequence Salt, 15 mL (107.91 mmol) triethylamine, stirred at room temperature for 16h. It was detected by TLC that the reaction was complete, washed with water, then extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (V / V PE:EA=3:1) to obtain 8.9 g of a white solid. Rate 90%. (2), in a 500mL reaction flask, 5g (35.97mmol) L-alanine methyl ester hydrochloride (VII) and 6.8g (35.97mmol) Boc protected L-alanine were dissolved in 90mL DMF, and The reaction...

Embodiment 3

[0068] Preparation of dimer compounds of formula (two): In a 50mL reaction bottle, mix 100mg (0.45mmol) (2S, 3R)-2-methyl-3-phenyloxirane-2-carboxylic acid (Ⅵ) with 20mg (0.18mmol )(2S,5S)-2,5-dimethylpiperazine (Ⅸ) was dissolved in 2mL of DMF, followed by adding 104mg (0.54mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine hydrochloride, 73mg (0.54mmol) 1-hydroxybenzotriazole, 0.19mL (1.08mmol) triethylamine, stirred at room temperature for 16h. The reaction was complete as detected by TLC, washed with water, and the organic phase was collected, dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (V / V PE:EA=1:1) to obtain 75 mg of white solid Chrysamides B, with a yield of 80% . In a 50mL reaction bottle, mix 100mg (0.48mmol) (Z)-2-methyl-3-(4-nitrophenyl) acrylic acid (Ⅲ) with 20mg (0.18mmol) (2S,5S)-2,5-dimethylpiperazine ( Ⅸ) Dissolve in 2mL DMF, then add 104mg (0.54mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimid...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a marine natural product Chrysamide B and a derivative thereof. The marine natural product Chrysamide B comprisesstereoisomers or pharmaceutically acceptable salts, solvates and prodrugs of the marine natural product Chrysamide B, general formulas are shown in a formula (I), a formula (II) and a formula (III).The invention also provides preparation and application of the compound. The compound has an anti-cancer effect; the compound has good inhibitory activity on digestive system cancers, leukemia, livertumors, non-small cell lung cancers, cervical cancers, breast cancers and the like and has the effects of inducing tumor cell apoptosis, activating apoptosis protein expression, retarding cycle, inhibiting proliferation and the like and is a potential antitumor drug.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a Chrysamide B derivative with antitumor activity and its preparation and application. Background technique [0002] The incidence and mortality of cancer in my country are increasing year by year, and it has become the leading cause of death and a major public health problem in China. With the development of medical technology, the drug treatment of cancer has developed from traditional chemotherapy to today's immunotherapy, monoclonal antibody therapy and gene therapy, but traditional chemotherapy still occupies a dominant position in drug treatment. Traditional chemotherapy drugs are cytotoxic drugs (cisplatin, nitrogen mustard, etc.). Such drugs have poor selectivity to normal cells and tumor cells, and while killing tumor cells, they also cause damage to normal metabolic cells of the human body, causing relatively large toxic and side effects to the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D241/04C07D303/48C07D301/00A61K31/496A61K31/495A61P35/00
CPCC07D405/14C07D241/04C07D303/48C07D301/00
Inventor 王震李俊芳朱龙青范晓红石桃张红花唐爱民
Owner LANZHOU UNIVERSITY
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