Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Gliotoxin 6-aromatic ring carboxylic ester series derivatives and preparation method thereof

A technology for aromatic ring carboxylic acid and gliotoxin, which is applied to the derivatives of epipolythiodiketopiperazine natural products gliotoxin, gliotoxin 6-aromatic carboxylic acid ester compounds and the field of preparation thereof , which can solve the problems of poor stability, large toxic and side effects, weak research on synthesis and structure-activity relationship, etc., and achieve the effect of expanding the structure type and good application prospect.

Active Publication Date: 2021-07-13
ZHENGZHOU UNIV
View PDF1 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] ETP compounds have superior pharmacological activity, disulfide bonds and polysulfide bond structures have been confirmed as the anti-tumor activity centers of these compounds, but their poor stability and large toxic and side effects restrict their clinical application And development
In addition, the research on the synthesis and structure-activity relationship of derivatives of such compounds is relatively weak.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Gliotoxin 6-aromatic ring carboxylic ester series derivatives and preparation method thereof
  • Gliotoxin 6-aromatic ring carboxylic ester series derivatives and preparation method thereof
  • Gliotoxin 6-aromatic ring carboxylic ester series derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023]

[0024] 150 mg of gliotoxin was weighed and dissolved in 3 mL of dichloromethane, stirred and dissolved at room temperature, and 1.1 eq of 3-furancarboxylic acid, 1 eq of DCC and 0.1 eq of DMAP were added. During the reaction, TLC monitoring was performed every 30 min, and the reaction was completed in 1-2 h. 30 mL of dichloromethane was added to the reaction system to dilute, and the reaction system was diluted with saturated NH 4 The Cl solution was washed three times, and the aqueous layer was back-extracted once with dichloromethane. All organic phases were combined and washed three times with saturated NaCl solution, and the organic phases were combined. Dry with anhydrous magnesium sulfate for 12h, concentrate the organic phase and add 2 times silica gel, and use column chromatography to separate and purify light yellow compound 2a, yield 58%, m.p.: 105.2-106.1°C; IR (KBr)ν max :3425,2921,1735,1685,1378,1302,1160,1077,873cm -1 . 1 H NMR (400MHz, DMSO-d 6 )...

Embodiment 2

[0026]

[0027] Substitute 3-picolinic acid for 3-furancarboxylic acid, and other operations are the same as in Example 1, to obtain light yellow solid 2b with a yield of 57%. m.p.: 102.0-103.1°C; IR(KBr)ν max :3726,3703,3420,2920,1734,1685,1590,1429,1380,1274,1192,1111,1024,720,668cm -1 . 1 H NMR (400MHz, DMSO-d 6 )δ(ppm): 9.17(d, J=2.2Hz, 1H), 8.92(dd, J=4.8, 1.7Hz, 1H), 8.38(dt, J=8.0, 2.0Hz, 1H), 7.67(dd, J=8.0, 4.8Hz, 1H), 6.09 (dt, J=5.7, 3.0Hz, 1H), 6.01 (ddd, J=9.8, 5.0, 2.8Hz, 1H), 5.69 (d, J=9.7Hz, 1H) ),5.54(s,1H),5.38(d,J=12.8Hz,1H),5.22(d,J=12.8Hz,1H),4.93(d,J=13.1Hz,1H),4.61(d,J =13.3Hz,1H),3.72(ddq,J=17.6,3.4,1.8Hz,1H),3.24(d,J=4.4Hz,3H),2.55(p,J=1.9Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ(ppm): 165.08, 163.55, 163.17, 154.19, 150.12, 137.13, 132.40, 129.55, 124.71, 124.10, 123.59, 118.97, 75.88, 75.74, 72.64, 69.46, 60.65, 35.78 ESI-HRMS:m z cacld.For C 19 H 17 N 3 O 5 S 2 [M+H] + :432.0682,found432.0689.

Embodiment 3

[0029]

[0030]Substitute 4-picolinic acid for 3-furancarboxylic acid, and other operations are the same as in Example 1, to obtain pale yellow solid 2c, yield 62%, m.p.: 168.1-169.2°C; IR(KBr)ν max :3726,3417,2927,2850,1735,1704,1685,1672,1626,1574,1405,1379,1354,1324,1271,1190,1121,1094,1061,708cm -1 . 1 H NMR (400MHz, DMSO-d 6 )δ(ppm): 8.93–8.86 (m, 2H), 7.94–7.88 (m, 2H), 6.08 (dt, J=5.8, 3.0Hz, 1H), 6.00 (ddd, J=8.1, 4.9, 2.8Hz ,1H),5.68(d,J=9.7Hz,1H),5.38(d,J=12.8Hz,1H),5.21(d,J=12.8Hz,1H),4.92(d,J=13.2Hz,1H) ), 4.60(d, J=13.2Hz, 1H), 3.77-3.68(m, 1H), 3.38(s, 2H), 3.23(s, 3H). 13 CNMR (101MHz, DMSO-d 6 )δ(ppm): 163.15, 150.94, 132.38, 129.55, 123.59, 122.58, 118.98, 75.87, 75.65, 72.64, 69.48, 61.00, 35.78, 28.16.ESI-HRMS: m / zcacld.For C 19 H 17 N 3 O 5 S 2 [M+H] + : 432.0682, found 432.0687.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to the fields of medicinal chemistry and microbial pharmacy, and discloses a gliotoxin 6-aromatic ring carboxylic ester compound (general formula I) which is designed and synthesized by taking a secondary metabolite gliotoxin of aspergillus fumigatus as a mother nucleus, and a preparation method thereof. The preparation method of the gliotoxin 6-aromatic ring carboxylate compound comprises the following steps: taking gliotoxin as an initial raw material, and carrying out esterification reaction on 6-site hydroxyl of the gliotoxin and aromatic ring or aromatic heterocyclic carboxylic acid on the premise of not damaging an active center disulfide bond of the gliotoxin, so as to obtain the gliotoxin 6-aromatic ring carboxylate compound. The inhibition activity of the series of compounds on histone lysine demethylase (LSD1) is obviously superior to that of maternal gliotoxin, and the series of compounds can be used for preparing anti-tumor drugs and can be applied to clinical treatment of diseases such as esophageal cancer, gastric cancer, lung cancer, colorectal cancer and breast cancer. The compound has a general formula I shown in the specification.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and microbial pharmacy, in particular to a derivative of the epipolythiodiketopiperazine natural product gliotoxin: a gliotoxin 6-aromatic ring carboxylate compound and a preparation method and application thereof. Background technique [0002] Epipolythiodioxopiperazines (ETPs), which have only been found in fungal metabolites so far, are a large class of biologically active secondary metabolites with diverse structures. It is characterized by having a diketopiperazine skeleton, a six-membered ring with a disulfide or polysulfide bond, and the disulfide or polysulfide functional group is the key part of its biological activity. Gliotoxin (GT), as the first reported ETP compound, was first isolated from fungal metabolites in 1932. Due to its various biological activities such as antiviral, antibacterial, immunosuppressive, enzyme inhibition, platelet aggregation inhibition and antitumor, it ha...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D513/18A61P35/00
CPCC07D513/18A61P35/00
Inventor 单丽红刘宏民安雪李召翔孙莹莹赵瑞云
Owner ZHENGZHOU UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com