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Olefinated estradiol compounds and preparation and application thereof

A technology for olefinizing estradiol and compounds, which is applied in the fields of steroids, organic chemistry, drug combination, etc., can solve the problems of long time, the correlation between occurrence and progress is not well explained, and many factors are involved. Achieve excellent inhibitory activity and good antitumor activity

Active Publication Date: 2019-07-09
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it takes a long time to regulate the occurrence and progression of diseases by blocking signaling pathways and involves many factors, so there is a greater risk
[0005] Several drugs have been developed against breast cancer, but the morbidity and mortality of the disease are so high and the relationship of these steroid sex hormones to the development and progression of the disease is still not well explained

Method used

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  • Olefinated estradiol compounds and preparation and application thereof
  • Olefinated estradiol compounds and preparation and application thereof
  • Olefinated estradiol compounds and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: preparation 2-iodoestradiol intermediate

[0035]

[0036] Add 0.1mmol estradiol to 4ml of acetonitrile solvent, add 0.01mmol indium trifluoromethanesulfonate, 0.11mmol N-iodosuccinimide, and react at 23°C for 6-10h. After the reaction, the reaction solution Add saturated aqueous NaCl solution to the mixture, extract with dichloromethane, take the organic phase, dry it over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain the crude compound of formula (7). The crude product of the EI compound was subjected to silica gel column chromatography, and the solution of ethyl acetate and petroleum ether with a volume ratio of 1:5 was used as the mobile phase, and R f The eluate with a value of 0.3-0.5 was collected, the solvent was removed under reduced pressure, and 25 mg of the compound represented by formula (7) was obtained after drying.

[0037] Pale yellow solid, yield 72%. 1 H NMR (500MHz, CDCl 3 )δ7.52(s,1H...

Embodiment 2

[0038] Embodiment 2: preparation 2,4-diiodoestradiol intermediate

[0039]

[0040] Add 0.1mmol estradiol to 4ml of absolute ethanol solvent, add 0.05mmol iodine element, 0.2mmol hydrogen peroxide (mass concentration 30%), and react at 50°C. After the reaction, add saturated NaCl aqueous solution to the reaction solution , extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude compound of formula (8). The crude compound of formula (8) was subjected to silica gel column chromatography, and the solution with a volume ratio of ethyl acetate and petroleum ether of 1:3 was used as the mobile phase, and R f The eluate with a value of 0.4-0.6 was collected, the solvent was removed under reduced pressure, and the eluate was dried to obtain 39 mg of the pure compound represented by formula (8).

[0041] Yellow solid, 88% yield. 1 H NMR (500MHz, CDCl 3 )δ7.63(s,1...

Embodiment 3

[0042] Example 3: Preparation of estradiol-modified drug EXS (i.e. compound (1))

[0043]

[0044]Add 0.1mmol of compound (7) (prepared in Example 1) into 4ml of N,N-dimethylformamide solvent, add 0.12mmol of methyl vinyl sulfone, 0.01mmol of palladium acetate, 0.2mmol of triethylamine, 90°C After the reaction, a saturated NaCl aqueous solution was added to the reaction solution, extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude EXS compound. The crude EXS compound was subjected to silica gel column chromatography, with a solution of ethyl acetate and petroleum ether at a volume ratio of 1:8 as the mobile phase, and TLC followed and collected R f The eluate with a value of 0.4-0.5 was collected, the solvent was removed under reduced pressure, and the eluate was dried to obtain 9 mg of the pure compound represented by the formula EXS.

[0045] Pale ye...

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Abstract

The invention relates to olefinated estradiol compounds, a preparation thereof and application thereof, and optimal olefination modification sites for estradiol drugs are provided through screening. The structures of estradiol drugs modified at different sites are as shown in formulas (1) to (6). The estradiol drugs have excellent inhibitory activity on prostate cancer cell line PC-3 and breast cancer cell MCF-7, and the anti-tumor activity can be increased by 2-3 times. The present invention provides a basis for modification of estradiol drugs by providing the optimal olefination modificationsites for estradiol drugs (position No. 2 is an optimal modification site) through screening.

Description

[0001] (1) Technical field [0002] The invention relates to olefinated estradiol compounds and their preparation and application. [0003] (2) Background technology [0004] The "2018 Global Cancer Statistics" report shows that the incidence and mortality of cancer in China rank first in the world, among which breast cancer and lung cancer are the cancers with the highest incidence and mortality in women and men in my country, respectively. The occurrence of breast cancer is closely related to the content of estrogen in the body. Estrogen is known to stimulate the development of estrogen-dependent diseases such as endometrial and breast cancers. At present, in addition to surgery, chemotherapy and immunotherapy, the treatment of most estrogen-dependent diseases, the inhibition of estrogen biosynthesis and the blockade of estrogen action are also the standard therapy for these diseases, but the side effects of this treatment are extremely severe and The cycle is long. Curren...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J31/00C07J1/00A61P35/00
CPCA61P35/00C07J1/0066C07J31/006
Inventor 朱勍顾晓旭窦言东瞿姣姣
Owner ZHEJIANG UNIV OF TECH
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