Application and preparation of diketopiperazine natural product and derivative and obtained derivative

A technology of diketopiperazines and natural products, applied in the fields of drug combination, organic chemistry, antitumor drugs, etc., can solve the problems of low natural content, restricted application and development, lack of derivative development and application, etc. Good effect on tumor activity and anti-tumor effect

Active Publication Date: 2022-05-06
OCEAN UNIV OF CHINA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]The natural content of Pretrichodermamide B is low, and the milligram-level product obtained by separation and extraction can only be used for preliminary screening of activity, which cannot meet the follow-up mechanism and in vivo drug effect research, which restricts its application and development of
In addition to being unable to increase the yield to obtain sufficient natural products for follow-up research, there is also a lack of in-depth in vivo activity evaluation and mechanism of action research methods for it in the prior art. Therefore, the development of the same series of derivatives of this natural product and Applications are also scarce

Method used

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  • Application and preparation of diketopiperazine natural product and derivative and obtained derivative
  • Application and preparation of diketopiperazine natural product and derivative and obtained derivative
  • Application and preparation of diketopiperazine natural product and derivative and obtained derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Synthesis of 6-((3R,8R,11R,11aR,12aR)-11-chloro-8,11a-dihydroxy-5,13-dioxy-4,5,7a,8,11a,12 having the following structural formula -Hexahydro-3H, 11H-4,12a-(epiaminomethyl)benzo[5,6][1,2]oxazine[3,2-c][1,2,4]dithia 3- base)-2,3-dimethoxyphenyl 4-methoxybenzoate:

[0059]

[0060] Its preparation process is:

[0061] Under cooling in an ice bath, 27 μL of 4-methoxybenzoyl chloride (0.2 mmol) and 28 μL of triethylamine (0.2 mmol) were sequentially added to the acetone solution of 20 mg (0.04 mmol) Pretrichodermamide B, and the reaction was stirred at room temperature for 4 h. The liquid was concentrated under reduced pressure to obtain a crude yellow oily product, which was separated by VLC method (gradient elution with ethyl acetate and petroleum ether) to obtain 24 mg of a white solid product with a yield of 92.3%.

[0062] The reaction formula to obtain the product is as follows:

[0063]

[0064] The product was characterized by proton nuclear magnetic spectr...

Embodiment 2

[0071] Synthesis of 6-((3R,8R,11R,11aR,12aR)-11-chloro-8,11a-dihydroxy-5,13-dioxy-4,5,7a,8,11a,12 having the following structural formula -Hexahydro-3H, 11H-4,12a-(epiaminomethyl)benzo[5,6][1,2]oxazine[3,2-c][1,2,4]dithia 3- base)-2,3-dimethoxyphenyl 4-(trifluoromethyl)benzenesulfonate:

[0072]

[0073] Its preparation process is:

[0074] Use 4-trifluoromethylbenzenesulfonyl chloride to replace the 4-methoxybenzoyl chloride in Example 1, and the rest of the preparation process is the same as in Example 1, separated by VLC (elution with ethyl acetate and petroleum ether gradient), In the elution gradient of petroleum ether: ethyl acetate = 1:1, 0.9 mg of white solid product was obtained (yield 3.2%).

[0075] The reaction formula to obtain the product is as follows:

[0076]

[0077] The product was characterized by proton nuclear magnetic spectrum, carbon spectrum, electrospray ion mass spectrometry and electrospray high-resolution mass spectrometry. The results are...

Embodiment 3

[0083] During the preparation of Example 2, 6-((3R, 8R, 11R, 11aR, 12aR)-11-chloro-8,11a-dihydroxy-5,13- Dioxy-14-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5,7a,8,11a,12-hexahydro-3H,11H-4,12a-(epiaminomethane ) benzo[5,6][1,2]oxazine[3,2-c][1,2,4]dithian 3-yl)-2,3-dimethoxyphenyl 4-(three Fluoromethyl)benzenesulfonate:

[0084]

[0085] Separation by VLC method (gradient elution with ethyl acetate and petroleum ether), 14.5 mg of the white solid product can be obtained at the elution gradient of petroleum ether: ethyl acetate = 2:1, with a yield of 40.1%.

[0086] The product was characterized by proton nuclear magnetic spectrum, carbon spectrum, electrospray ion mass spectrometry and electrospray high-resolution mass spectrometry. The results are as follows:

[0087] 1 HNMR (400MHz, CDCl 3 )δ8.38(d, J=8.1Hz, 2H), 8.23(d, J=8.3Hz, 2H), 7.89(t, J=8.3Hz, 4H), 7.69(d, J=8.9Hz, 1H) ,6.94(d,J=9.0Hz,1H),5.74(dt,J=10.5,2.5Hz,1H),5.66(dt,J=10.5,2.1Hz,2H),4.83–4.80(m,1H), 4.78(...

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Abstract

The invention relates to application and preparation of a diketopiperazine natural product and a derivative thereof, and the obtained derivative. The invention discloses application of a diketopiperazine marine natural product Pretrichodermamide B and a derivative thereof in obtaining in-vivo and in-vitro antitumor drugs and drugs for blocking a JAK/STAT3 signal channel by combining STAT3, and provides a preparation method of the derivative of the Pretrichodermamide B, and the derivative has a structural formula as shown in a formula (I). According to the present invention, the chemical space and the use of the natural product Pretrichodermamide B are developed, and the new choice is provided for the antitumor drug primer;

Description

technical field [0001] The present invention relates to the technical field of derivatives of marine natural products. Background technique [0002] The natural product Pretrichodermamide B (DC1149B) was first isolated and discovered from Trichoderma by Japanese scientists in 1990. It has antibacterial and antitumor activities and can inhibit the proliferation of colon cancer cells. [0003] [0004] The natural content of Pretrichodermamide B is low, and the milligram-level product obtained by separation and extraction can only be used for preliminary activity screening, which cannot meet the follow-up mechanism and in vivo pharmacodynamic studies, which restricts its application and development. In addition to being unable to increase the yield to obtain sufficient natural products for follow-up research, there is also a lack of in-depth in vivo activity evaluation and mechanism of action research methods for it in the prior art. Therefore, the development of the same s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/18C07D513/22A61P35/00
CPCC07D513/18C07D513/22A61P35/00Y02P20/55
Inventor 王长云刘志清杨金波赵晨阳王平原周月李锐张心心杨路佳
Owner OCEAN UNIV OF CHINA
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