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Applications of bisbenzimidazole bicarbazole compound in specific binding nucleic acid G-quadruplex structure and anti-tumor drug

A technology of dibenzimidazole and bicarbazole, which is applied in the application field of anti-tumor drugs and can solve the problems of no change in optical properties and the like

Active Publication Date: 2014-04-16
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many benzimidazole compounds can bind to nucleic acids, and the V-type bisbenzimidazole derivatives linked by benzene ring and pyridine ring can selectively bind to the G-quadruple chain, but there is no significant change in optical properties [A.K.Jain et al.Biochemistry -Us,2009,48,10693-10704; G.R.Li et al.Chem Commun,2008,4564-4566]

Method used

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  • Applications of bisbenzimidazole bicarbazole compound in specific binding nucleic acid G-quadruplex structure and anti-tumor drug
  • Applications of bisbenzimidazole bicarbazole compound in specific binding nucleic acid G-quadruplex structure and anti-tumor drug
  • Applications of bisbenzimidazole bicarbazole compound in specific binding nucleic acid G-quadruplex structure and anti-tumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: the synthesis of compound E1:

[0061] (1) Dissolve 1-methylpiperazine (690mg, 6.9mmol) with 5-chloro-2-nitroaniline (1g, 5.8mmol) and potassium carbonate (1.25g, 9mmol) in dry DMF (6mL) , react at a temperature of 110°C for 6 hours to obtain a crude product, place the obtained crude product in water, suspend the crude product in water, extract with ethyl acetate, wash the obtained organic phase with water three times, and then use anhydrous MgSO 4 Drying; purification by neutral alumina column chromatography with chloroform as eluent to obtain 1.1 g of a bright yellow solid, which is compound A1, with a yield of 81%. 1 H NMR (500MHz, CDCl 3 )δ8.01(d,J=9.7Hz,1H),6.28(dd,J=9.7,2.7Hz,1H),6.14(s,2H),5.95(d,J=2.6Hz,1H),3.49- 3.25 (m, 4H), 2.61-2.42 (m, 4H), 2.34 (s, 3H). The structure of the compound A1 is:

[0062]

[0063] The obtained compound A1 was dissolved in ethanol, and the Pd / C with a mass content of 10% was added as a catalyst, and H 2 , r...

Embodiment 2

[0071] Embodiment 2: the synthesis of compound E2:

[0072] (1) Step (1) is basically the same as in Example 1, except that the compound 1-(2-hydroxyethyl)piperazine is used instead of 1-methylpiperazine, and reacted at 140°C overnight to obtain a bright yellow solid compound A2. Yield: 90%; 1 H NMR (500MHz, CDCl 3 )δ8.02(d,J=9.3,1H),6.29(dd,J=9.3,J=2.7,1H),6.1(bs,2H,NH2),5.95(d,J=2.7Hz,1H), 3.8(t,4H), 3.7(t,2H), 2.59-2.65(m,6H). The structure of the compound A2 is:

[0073]

[0074] The obtained compound A2 was dissolved in methanol, and the Pd / C with a mass content of 5% was added as a catalyst, and H 2 , reacted overnight to obtain a compound B2 solution, and filtered out impurities with diatomaceous earth. Since the structure of o-phenylenediamine is easily oxidized and unstable, it is directly put into the next step without purification; the structure of the compound B2 is:

[0075]

[0076] (2) Step (2) was basically the same as in Example 1, except that th...

Embodiment 3

[0082] Embodiment 3: the synthesis of compound E3:

[0083] (1) Step (1) was basically the same as in Example 1, except that the compound morpholine was used instead of 1-methylpiperazine, and reacted at 130° C. for 8 hours to obtain compound A3 as a bright yellow solid. Yield: 75%; 1 H NMR (500MHz, CDCl 3 )δ7.93(d,J=8.4Hz,1H),6.83(bs,J=8,2H),6.18(dd,J=8.4,1.9Hz1H),6.10(d,J=8.8Hz,1H), 3.50-4.00 (m, 4H), 2.40-2.50 (m, 4H). The structure of the compound A3 is:

[0084]

[0085] The obtained compound A3 was dissolved in ethanol, and the Pd / C with a mass content of 5% was added as a catalyst, and H 2 , reacted overnight to obtain a compound B3 solution, and filtered out impurities with diatomaceous earth. Since the structure of o-phenylenediamine is easily oxidized and unstable, it is directly put into the next step without purification; the structure of the compound B3 is:

[0086]

[0087] (2) Step (2) was basically the same as in Example 1, except that the compound...

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Abstract

The invention relates to a bisbenzimidazole bicarbazole compound, in particular to applications of the bisbenzimidazole bicarbazole compound in a specific binding nucleic acid G-quadruplex structure and an anti-tumor drug. The bisbenzimidazole bicarbazole compound and a nucleic acid sample to be detected are incubated in a buffer solution with a pH (Potential of Hydrogen) value of 6-8; an absorption peak of an ultraviolet-visible absorption spectrum within the range of 390-440nm is obviously enhance through observation; or whether a fluorescence spectrum has a fluorescence peak between within the range of 430-540 is observed to detect whether the nucleic acid sample to be detected is nucleic acid in the G-quadruplex structure. The bisbenzimidazole bicarbazole compound is added into a culture solution containing tumor cells as a drug, cultured together with the tumor cells, and used for inhibiting tumor cell proliferation, or the bisbenzimidazole bicarbazole compound is used for inhibiting the tumor cell proliferation as a most active ingredient of the drug. A method has the advantages of simplicity, quickness and cheapness.

Description

technical field [0001] The present invention relates to bisbenzimidazole bicarbazole compounds, in particular to the application of bisbenzimidazole bicarbazole compounds in specific binding to nucleic acid G-quadruplex structure and the application in antitumor drugs. Background technique [0002] G-quadruplex (G-quadruplex) is a special kind of nucleic acid secondary structure. It is a special nucleic acid secondary structure formed by the accumulation of four or four G-rich nucleic acid fragments through the formation of Hoogsteen base pairing between the chains or the corresponding G bases in the chain through the G-rich nucleic acid chain[ S. Burge et al. Nucleic Acids Res, 2006, 34, 5402-5415]. It has been reported that the human genome contains approximately 376,000 sequences that are prone to G-quadruplex formation. Sequences of guanine-rich nucleic acids are ubiquitous in some key genomic regions in organisms, such as telomeres, gene promoters, growth control gene...

Claims

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Application Information

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IPC IPC(8): G01N21/78G01N21/33G01N21/31G01N21/64A61K31/496A61K31/5377A61K31/4184A61K31/4545A61P35/00C09K11/06C07D403/14C07D405/14C07D401/14
Inventor 上官棣华金冰刘祥军王林林张楠
Owner INST OF CHEM CHINESE ACAD OF SCI
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