Gliotoxin 6-aromatic ring carboxylate series derivatives and preparation method thereof

A technology of aromatic ring carboxylic acid and gliotoxin, applied in the field of epipolymerized polythiodiketopiperazine natural product gliotoxin derivatives, gliotoxin 6-aromatic ring carboxylate compounds and their preparation fields , can solve the problems of large toxic side effects, poor stability, restricting application and development, etc., achieve good application prospects, and expand the effect of structure types

Active Publication Date: 2022-07-01
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 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

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  • Gliotoxin 6-aromatic ring carboxylate series derivatives and preparation method thereof
  • Gliotoxin 6-aromatic ring carboxylate series derivatives and preparation method thereof
  • Gliotoxin 6-aromatic ring carboxylate 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 of silica gel, 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 )δ...

Embodiment 2

[0026]

[0027] Substitute 3-picolinic acid for 3-furancarboxylic acid, and other operations are the same as those 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 carboxylate compound (general formula I) designed and synthesized with the secondary metabolite of Aspergillus fumigatus gliotoxin as the parent nucleus. and its preparation method. Its preparation method: using gliotoxin as a starting material, under the premise of not destroying the disulfide bond of its active center, the 6-hydroxyl group undergoes an esterification reaction with an aromatic ring or an aromatic heterocyclic carboxylic acid to obtain the gliotoxin 6- Aromatic ring carboxylates. The inhibitory activity of this series of compounds on histone lysine demethylase (LSD1) is significantly better than that of its parent gliotoxin, and can be used for the preparation of antitumor drugs for clinical treatment of human esophageal cancer, gastric cancer, lung cancer, and colorectal cancer. cancer and breast cancer. It has the following general formula: general formula I.

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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Patent Type & Authority Patents(China)
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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