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Polyaryl substituted imidazole derivative as well as preparation method and application thereof

A technology of imidazole derivatives and derivatives, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of complex transcription regulation of c-MYC gene

Active Publication Date: 2021-09-14
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]The transcriptional regulation of the c-MYC gene is complex and involves multiple promoter elements
Although researchers at home and abroad have discovered some small molecule ligands targeting c-MYC G-quadruplex, and some small molecule compounds designed to target c-MYC G-quadruplex have entered the second phase. In the clinical stage, however, due to toxicity, selectivity and other reasons, there is still a certain distance from these small molecule ligands to the clinical stage, and new small molecule ligand structure designs are still required

Method used

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  • Polyaryl substituted imidazole derivative as well as preparation method and application thereof
  • Polyaryl substituted imidazole derivative as well as preparation method and application thereof
  • Polyaryl substituted imidazole derivative as well as preparation method and application thereof

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preparation example Construction

[0063] The preparation of embodiment intermediate:

[0064] (1) Preparation of Compound C1-1

[0065] Difluorobenzil (490mg, 2mmol) and potassium carbonate (829mg, 6mmol) were dissolved in 6mL DMF, and N-methylpiperazine (1g, 10mmol) was added dropwise. The mixture was reacted overnight at 80°C. After the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, concentrated and dried, separated and purified by column chromatography to obtain compound C1-1 (818 mg, 99%) as a yellow solid, 1 H NMR (400MHz, CDCl 3 )δ7.85(d, J=9.0Hz, 4H), 6.85(d, J=9.1Hz, 4H), 3.41(t, J=5.2Hz, 8H), 2.54(t, J=5.1Hz, 8H) ,2.34(s,6H).

[0066] (2) Preparation of Compound D1-1

[0067] Difluorobenzil (490mg, 2mmol) and potassium carbonate (829mg, 6mmol) were dissolved in 6mL DMF, and N-methylpiperazine (300mg, 3mmol) was added dropwise. The mixture was reacted overnight at 80°C. After the reaction, the reaction solution was poured int...

Embodiment 1

[0081] Preparation of compound 1a

[0082] Compound 1a was synthesized by general method C. Pale yellow solid (98% yield). 1 H NMR (400MHz, CDCl 3 )δ8.21(s, 1H), 7.93(d, J=7.7Hz, 1H), 7.56(d, J=8.4Hz, 2H), 7.44(dd, J=12.8, 8.1Hz, 2H), 7.37( d,J=8.1Hz,1H),7.23(d,J=8.7Hz,1H),7.18(t,J=7.4Hz,1H),7.00(dd,J=14.1,8.5Hz,4H),6.84( d, J=8.4Hz, 2H), 6.75(t, J=8.9Hz, 4H), 4.31(q, J=7.2Hz, 2H), 4.05(t, J=5.9Hz, 2H), 3.83(t, J=5.9Hz, 2H), 3.25(q, J=5.0Hz, 8H), 2.66(dt, J=13.2, 4.9Hz, 8H), 2.41(s, 3H), 2.39(s, 3H), 2.00( p,J=5.9Hz,2H),1.40(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ158.2,150.1,149.4,140.4,139.7,137.6,132.1,130.8,129.9,129.8,128.3,127.0,125.9,123.2,122.8,122.2,121.7,121.7,120.7,119.1,116.0,115.5,114.8,108.7,108.1 ,65.7,60.2,55.0,54.9,48.8,48.3,45.9,45.8,37.7,32.1,14.0.HRMS(ESI)m / z: calcd for C 48 h 53 N 7 o 2 :380.7203[M+2H] 2+ .Found 380.7203[M+2H] 2+ .

Embodiment 2

[0084] Preparation of compound 2a

[0085] Compound 2a was synthesized by general method A. Pale yellow solid (72% yield). 1 H NMR (500MHz, CDCl 3 )δ8.21(s,1H),7.93(d,J=7.8Hz,1H),7.57(d,J=8.3Hz,2H),7.50–7.40(m,2H),7.36(d,J=8.1 Hz, 1H), 7.22(d, J=8.6Hz, 1H), 7.18(t, J=7.4Hz, 1H), 7.01(dd, J=16.4, 8.3Hz, 4H), 6.84(d, J=8.4 Hz, 2H), 6.75(dd, J=18.0, 8.4Hz, 4H), 4.30(q, J=7.2Hz, 2H), 4.23(t, J=6.2Hz, 2H), 3.96(t, J=6.2 Hz, 2H), 3.21(t, J=5.0Hz, 8H), 2.56(q, J=4.9Hz, 8H), 2.34(s, 6H), 2.08(p, J=6.2Hz, 2H), 2.03( s,3H),1.39(t,J=7.2Hz,3H). 13 C NMR (125MHz, CDCl 3 )δ171.1,158.1,150.2,149.6,147.7,140.3,139.6,137.7,132.1,130.8,129.8,129.7,128.2,126.9,126.7,125.8,123.2,122.7,122.0,121.7,121.6,120.6,119.1,115.8,115.3 ,114.7,108.6,108.0,64.6,61.4,55.3,55.2,49.1,48.5,46.3,37.7,28.6,21.0,13.9.HRMS(ESI)m / z: calcd for C 50 h 55 N 7 o 3 :401.7256[M+2H] 2+ .Found 401.7253[M+2H] 2+ .

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Abstract

The invention discloses a polyaryl substituted imidazole derivative as well as a preparation method and application thereof. The structural formulas of the polyaryl substituted imidazole derivative are shown as formulas (I), (II), (III) and (IV) defined in the description. The polyaryl substituted imidazole derivative is used as a specific ligand of a c-MYC G-quadruplex, a central imidazole structure in the structure of the polyaryl substituted imidazole derivative is favorable for being combined with a negative electricity center of the G-quadruplex, a plane structure of the whole molecule is stacked on a G-quadruplex plane through pi-pi, and a methyl piperazine part can be combined with a phosphoric acid framework in a groove of the G-quadruplex, the carbazole part is beneficial to binding c-MYC G-quadruplex according to research reports, and the sugar part can be used as a targeting scaffold and a cosolvent of cancer cells. The polyaryl substituted imidazole derivative provided by the invention can increase the selectivity to tumor cells, can down-regulate the proto-oncogene c-MYC and inhibit the transcription of c-MYC, and has a wide application prospect in preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a polyaryl-substituted imidazole derivative and its preparation method and application. Background technique [0002] Cancer has now become one of the high incidence diseases in China. With the continuous development of our country's scientific research level and medical level, major breakthroughs have been made in the research and development of anti-tumor drugs, and some tumor diseases can be completely recovered through drug and surgical treatment. However, there are still many scientific challenges. Drug side effects, solubility, bioavailability, drug resistance and other issues are still a major obstacle to the development of new clinical drugs. [0003] G-quadruplex is a special secondary structure of DNA, which is widely distributed in genome and transcriptome and participates in important regulatory processes. The folding and unfolding of the G-quadruplex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04C07D403/14C07H15/26C07H13/04C07H9/04C07H19/056C07H1/00A61K31/496A61K31/706A61P35/00
CPCC07D403/04C07D403/14C07H15/26C07H13/04C07H9/04C07H19/056C07H1/00A61P35/00Y02P20/55
Inventor 黄志纾李茂林谭嘉恒陈硕斌
Owner SUN YAT SEN UNIV
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