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
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  • 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 ...

Method used

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  • 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
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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.

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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

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Application Information

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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
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