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L-amino acid-6-gliotoxin ester trifluoroacetate and preparation method thereof

A technology of ester trifluoroacetate and gliotoxin, which is applied in the field of L-amino acid-6-gliotoxin ester trifluoroacetate compounds and their preparation, and can solve the problems of poor stability, severe toxic side effects, and restricted applications and development issues, to achieve the effect of expanding the structure type and good application prospects

Active Publication Date: 2021-07-09
ZHENGZHOU UNIV
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  • 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

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  • L-amino acid-6-gliotoxin ester trifluoroacetate and preparation method thereof
  • L-amino acid-6-gliotoxin ester trifluoroacetate and preparation method thereof
  • L-amino acid-6-gliotoxin ester trifluoroacetate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] Weigh 200mg of gliotoxin and dissolve it in 4mL of dichloromethane, stir at room temperature and add 1.1eq of N-Boc-L-sarcosine, 1eq of DCC and 0.1eq of DMAP, and perform TLC monitoring every 30min during the reaction , After 1.5-2h, the reaction is complete. Add 50mL of dichloromethane to the reaction system for dilution, and dilute the reaction system with saturated NH 4 The Cl solution was washed three times, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, washed three times with saturated NaCl solution, dried over anhydrous magnesium sulfate for 12 h, the organic phase was concentrated to obtain a crude extract, which was separated and purified by column chromatography to obtain a light yellow solid. Dissolve the above product in dichloromethane, add 300 μL trifluoroacetic acid under ice bath and stir, monitor by TLC every 30 minutes during the reaction, after 2-3 hours the reaction is complete, remove th...

Embodiment 2

[0031]

[0032] N-Boc-L-sarcosine was replaced by N-Boc-methyl-L-alanine, and other operations were the same as in Example 1 to obtain light yellow solid 3b with a yield of 65%, m.p.: 125.9-126.8°C; IR (KBr,cm -1 ):3429,1761,1685,1420,1383,1202,1062,798,722,703,672. 1 H NMR (400MHz, DMSO-d 6 )δ9.33(s,2H),6.06(dt,J=5.8,3.1Hz,1H),5.98(ddd,J=8.1,4.8,2.7Hz,1H),5.65(d,J=9.8Hz,1H ),5.18(d,J=12.7Hz,1H),5.08(d,J=12.7Hz,1H),4.86(d,J=13.1Hz,1H),4.56(d,J=13.1Hz,1H), 4.25(q,J=7.1Hz,1H),3.23(s,1H),3.18(s,1H),3.10(s,3H),2.62(s,3H),1.67(ddq,J=39.4,8.2, 3.9Hz, 1H), 1.48(d, J=7.2Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 )δ168.17, 164.92, 163.06, 158.13, 132.21, 129.42, 123.66, 119.08, 118.09, 75.79, 75.32, 72.63, 69.45, 61.04, 54.92, 35.71, 30.43, 28.03, 13.63 17 h 22 N 3 o 5 S 2 [M-CF 3 COO - ] + :412.0995, found 412.1100.

Embodiment 3

[0034]

[0035] N-Boc-L-sarcosine was replaced by N-Boc-L-2-aminobutyric acid, and other operations were the same as in Example 1 to obtain light yellow solid 3c with a yield of 48%, m.p.: 121.6-122.5°C; IR( KBr,cm -1 ):3433,2928,1762,1685,1414,1379,1356,1203,1137,1061,835,799,722. 1 H NMR (400MHz, DMSO-d 6 )δ8.52(s,3H),5.98(dd,J=5.1,2.8Hz,1H),5.90(ddd,J=9.7,5.0,2.8Hz,1H),5.58(d,J=9.8Hz,1H ),5.41(d,J=18.3Hz,1H),5.12(d,J=12.8Hz,1H),4.99(d,J=12.7Hz,1H),4.79(d,J=13.1Hz,1H), 4.49(dd,J=13.0,2.8Hz,1H),3.61-3.54(m,1H),3.16(d,J=1.7Hz,1H),3.11(d,J=1.6Hz,1H),3.03(s ,3H),1.84–1.76(m,2H),0.91(t,J=7.5Hz,3H). 13 C NMR (100MHz, DMSO-d 6 )δ168.32, 164.91, 163.05, 158.12, 132.27, 129.46, 123.63, 119.04, 114.97, 75.81, 75.31, 72.62, 69.48, 61.01, 52.89, 35.73, c28.04, 23.33, 8.9ld.ESI 17 h 22 N 3 o 5 S 2 [M-CF 3 COO - ] + :412.0995, found 412.1001.

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Abstract

The invention relates to the fields of medicinal chemistry and microbial pharmacy, and discloses an L-amino acid-6-gliotoxin ester trifluoroacetate 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 comprises the following steps: (1) taking gliotoxin as an initial raw material, carrying out esterification reaction on 6-site hydroxyl of the gliotoxin and N-Boc-amino acid on the premise that an active center disulfide bond of the gliotoxin is not damaged to obtain a gliotoxin 6-site amino-acid ester derivative, then removing a Boc protecting group in excessive trifluoroacetic acid, and salifying to obtain the L-amino acid-6-gliotoxin ester trifluoroacetate compound. The inhibitory activity of the compound on histone lysine demethylase (LSD1) is obviously superior to that of maternal gliotoxin, and the compound can be used for preparing anti-tumor drugs and is applied to clinical treatment of human esophageal cancer, gastric cancer, lung cancer, colorectal cancer, breast cancer and other diseases. The general formula I is shown in the specification.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and microbial pharmacy, in particular to derivatives of epipolythiodiketopiperazine natural product gliotoxin: L-amino acid-6-gliotoxin ester trifluoroacetate compound and its preparation methods and applications. Background technique [0002] Epipolythiodioxopiperazines (Epipolythiodioxopiperazines, ETPs), which have only been found in the metabolites of fungi so far, are a large class of biologically active secondary metabolites with diverse structures. It is characterized in that it has a diketopiperazine skeleton and 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 diverse biological activities such as antiviral, antibacterial, immunosuppressive, enzyme inhibitory, p...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04A61P35/00Y02P20/55
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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