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2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative

A technology of chalcone derivatives and estrogen, applied in the field of chalcone derivatives and their preparation

Inactive Publication Date: 2015-12-16
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with 2-ME as the mother nucleus, there are few reports on the introduction of chalcone structural fragments at its 2 or 16 positions

Method used

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  • 2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative
  • 2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative
  • 2/16-site-substituted chalcone derivative taking estrogen as mother nucleus and preparation method and application of derivative

Examples

Experimental program
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preparation example Construction

[0087] Preparation of Example 1 Series I Estrogen Nucleus Raw Material

[0088] (1) Preparation of 2-acetylestradiol-17β-ethyl ester (A2)

[0089] References Steroids, 2002, 67:1065–1070 method, weigh 30.0g (111.65mmol) of estradiol and transfer it to a 1000ml round bottom flask, add 300ml of anhydrous pyridine, fully stir and dissolve, then slowly add 75ml (396.7mmol) of acetic anhydride was stirred at room temperature under dark conditions. After 15 hours, the reaction was basically completed. In order to ensure the complete reaction, the stirring was continued for 1 hour to detect no significant change, and it was determined that the reaction was complete. Treatment: Stir and cool the reaction mixture in an ice bath, quickly pour it into a container filled with a large amount of ice water, continue to stir, and a white flocculent precipitate precipitates, let it stand for 30 minutes, vacuum filter, and wash the filter cake with water until there is no pyridine smell , vac...

Embodiment 32

[0106] The preparation of embodiment 32-phenylacryloyl estradiol (I-1)

[0107] Dissolve 2-acetylestradiol-17β-ethyl ester (A2, 200mg, 0.562mmol) in 5ml of 95% ethanol solution, add 5ml of 10% aqueous sodium hydroxide solution, and stir on a stirrer until dissolved; dropwise at room temperature 5ml of 95% ethanol solution of benzaldehyde (69.17mg, 1.2eq) was added dropwise, and the system turned orange red. After the dropwise addition, it was transferred to an oil bath at 45°C, and after four hours of reflux, TLC detection was carried out. The agent is ethyl acetate:petroleum ether=1:2, the reaction is complete. Stop heating, after the temperature drops, add 10% hydrochloric acid under ice bath, adjust the pH to about 5, filter with suction, and pass through the column with ethyl acetate:petroleum ether=1:3 to obtain the compound 2-phenylacryloylestradiol ( Ⅰ-1) Yellow powder 183 mg, yield 83%. 1HNMR (400MHz, CDCl3) δ12.60(s, 1H), 7.90(d, J=15.5HZ, 1H), 7.79(s, 1H), 7.67(dd,...

Embodiment 4

[0108] Preparation of Example 42-(3',4',5'-trimethoxyphenylacryloyl)estradiol (I-2)

[0109]Dissolve 2-acetylestradiol (A1, 177mg, 0.562mmol) in 10ml of 95% ethanol solution, stir on a stirrer, add 5ml of 8% sodium hydroxide aqueous solution and stir until dissolved, then slowly drop into 10ml3,4 , 95% ethanol solution of 5-trimethoxybenzaldehyde (132.3mg, 1.2eq), the system turns orange, after the dropwise addition, it is transferred to an oil bath at 60°C, and after two hours of reflux, TLC detection , The developer is ethyl acetate:petroleum ether=1:2, the reaction is complete. Stop heating, and after the temperature drops, add 10% hydrochloric acid under ice bath, adjust the pH to about 5, filter with suction, and pass through the column with ethyl acetate:petroleum ether=1:3. 235 mg of compound 2-(3',4',5'-trimethoxyphenylacryloyl)estradiol (I-2) yellow powder was obtained with a yield of 85%. 1 HNMR (400MHz, CDCl 3 )δ12.58(s,1H),7.81(d,J=15.4Hz,1H),7.76(s,1H),7.47(d,J...

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Abstract

The invention belongs to the field of medicinal chemicals, and relates to a 2 / 16-site-substituted chalcone derivative taking estrogen as a mother nucleus and a preparation method and application of the derivative. The preparation method comprises the following step: combining chalcone structural fragments on an estrogen body in parallel, thereby keeping or improving the activity of anti-tumor cells and inhibiting activity of tumor cell angiogenesis. The structural formula of the 2 / 16-site-substituted chalcone derivative is as shown in the specification. The in-vitro anti-tumor cell proliferation activity test and the chick embryo allantois test show that the derivative has certain anti-tumor cell proliferation activity and inhibiting activity of tumor cell angiogenesis; and the dose-effect relationship study shows that the tumor cell inhibition function of the derivative is prior to that of 2-methoxy estradiol with broad-spectrum anti-tumor activity, and moreover the half-life period can be prolonged.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and mainly relates to a class of 2- or 16-substituted chalcone derivatives with estrogen as the mother nucleus, a preparation method and application thereof. Background technique [0002] Angiogenesis refers to the formation of new capillaries from pre-existing blood vessels through the proliferation and migration of vascular endothelial cells (VEC) on the basis of the original vascular structure. (capillaries) process, also known as angiogenesis. Angiogenesis is a physiological change necessary for embryonic development, wound healing, tissue regeneration and repair, but it is also the pathological basis of a variety of systemic and local diseases. Angiogenesis involves a complex multi-step process, including proliferation, migration, erosion and lumen formation of vascular endothelial cells. The process of angiogenesis is strictly regulated by angiogenesis-inducing factors and inhibitors. U...

Claims

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Application Information

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IPC IPC(8): C07J1/00C07J31/00C07J41/00A61K31/5685A61K31/568A61P35/00
Inventor 施秀芳王淙张振中高海英孙帅军路翔王志豪杨腾蛟李鹏王铭铭杜昕芮
Owner ZHENGZHOU UNIV
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