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Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament

A technology of benzofuran quinoline and its derivatives, which is applied to the peptide derivatives of benzofuran quinoline and its preparation, and is used in the application field of anticancer drugs, which can solve the problems of application restrictions and limited resources. Achieve the effects of high safety, broad market prospects and significant inhibition

Inactive Publication Date: 2014-05-07
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the anticancer effect of indoquinoline compounds has been confirmed, the selection ability of the existing indoquinoline compounds to G-quadruplex DNA still needs to be improved, and at the same time due to the indoquinoline compounds in nature The resources of morphine compounds are limited. At present, the application of indoquinoline compounds in anticancer is still relatively limited.

Method used

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  • Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament
  • Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament
  • Peptide derivative of benzfuran quinoline and preparation method thereof and application thereof as antitumor medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Synthesis of compound P7

[0027] Dissolve 0.3 mol chloroacetic acid in 60 ml water, adjust the pH to 9 with sodium hydroxide, add 0.2 mol phenol, reflux at 100°C, and then add thionyl chloride for chlorination to obtain P2, distill off thionyl chloride The solvent obtains a brown liquid, which is then subjected to condensation reaction with anthranilic acid to obtain P3, and then PPA is preheated to 130° C. and added to P3 for compound reaction to obtain compound P4. P4 and thionyl chloride are refluxed for chlorination reaction at 80° C. to obtain compound P5, and then methyl iodide is performed in a system with sulfolane as a solvent to obtain compound P6. Then 0.05 mol of P6 and 0.25 mol of glycine were refluxed at 120° C. for 4 h with ethylene glycol ether as the solvent, and purified by silica gel chromatography with methanol / dichloromethane as the eluent to finally obtain the light green compound P7.

[0028] Yield: 41%; 1 H NMR (400MHz, DMSO) δ 9.75 (t, J...

Embodiment 2

[0031] Example 2: Synthesis of Compound R

[0032] Dissolve 0.2mol Fmoc-Arg(Pbf)-OH amino acid in DMF (dimethylformamide) solvent, add 0.8mol HOBT(1-hydroxybenzotriazole), 0.8molDIC(N,N-diisopropyl) Carbodiimide) two condensation reagents (condensation reagent ratio is 1:1), react with the deprotected Rink Amide AM resin in a solid phase reactor for 3 hours, and then use 25% piperidine to remove the Fmoc group. The amino acid side chain is obtained. Then it was condensed with P7 in HOBT and DIC in DMF solution, 24h, the resin was removed with trifluoroacetic acid, collected, and purified by preparative high performance chromatography, and finally a light yellow solid R was obtained.

[0033] Yield: 32%; 1 H NMR (400MHz, DMSO) δ 9.71 (t, J = 6.4 Hz, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.15-8.07 (m, 1H), 7.87 (ddd, J = 21.5, 15.3, 8.0 Hz, 3H), 7.64 (t, J = 7.4Hz, 2H), 7.49(s, 1H), 7.13(s, 2H), 4.79(d, J=6.4Hz...

Embodiment 3

[0036] Example 3: Synthesis of compound GG

[0037] The method is the same as in Example 2, except that Fmoc-Gly-OH is used, and the amino acid is connected to Rink Amide AM resin twice. Finally, it was purified by preparative high performance chromatography to obtain white solid GG.

[0038] Yield: 29%; 1 H NMR (400MHz, DMSO) δ 9.72 (t, J = 6.5 Hz, 1H), 8.70 (t, J = 8.4 Hz, 2H), 8.64 (d, J = 8.2 Hz, 1H), 8.44 (d, J =8.9Hz, 1H), 8.12(dd, J=9.8, 6.4Hz, 2H), 7.93(t, J=5.9Hz, 2H), 7.87-7.77(m, 1H), 7.65(ddd, J=8.2, 5.8, 2.4 Hz, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 4.78 (d, J = 6.4 Hz, 2H), 4.59 (s, 3H), 3.83 (d, J = 5.7 Hz, 2H), 3.60 (d, J=5.8 Hz, 2H); C 22 H 22 N 5 O 4 + , LC-MS m / z: 420[M+H] + .

[0039]

[0040] Compound GG

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Abstract

The invention belongs to the fields of medicaments and chemical industry, and discloses a peptide derivative of benzfuran quinoline and a preparation method thereof and an application thereof as an antitumor medicament. The structural formula of the peptide derivative of benzfuran quinoline is shown in the specifications, wherein R is a peptide chain, i.e., R, GG, GR, GK, GH, GF, HR, KR, FR, GGR, GFR, GFRK, GFHR or GGGR; R represents arginine; G represents glycine; K represents lysine; H represents histidine; and F represents phenyl alanine. The invention further discloses a preparation method of the peptide derivative of benzfuran quinoline and an application of the peptide derivative as an anticancer medicament. As proved by an experiment, the peptide derivative of benzfuran quinoline related to the invention has a very strong inhibiting effect on the expression of telomere DNAs (Deoxyribose Nucleic Acids) and proto-oncogene DNAs such as c-myc and the like, a remarkable inhibiting effect on various cancer cell lines, low toxicity on normal cells and a wide application space on the preparation of an anticancer medicament.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a benzofuran quinoline peptide derivative and a preparation method thereof, and its application in the preparation of anticancer drugs. Background technique [0002] Cancer is one of the main diseases threatening human health and life safety. According to statistics, there are about 4 million new cancer patients worldwide each year. The research and development of anti-cancer drugs has always been a hot spot for chemists and pharmacologists. One of the important directions of drug research and development is to find anti-cancer drugs with high efficiency, high selectivity and low side effects. Designing and synthesizing anti-cancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors for the special high-level structure of telomere DNA and c-myc and other proto-oncogene DNA with important physiological significance, is important fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/078C07K5/097C07K5/117C07K7/06C07K1/04A61K38/05A61K38/06A61K38/07A61K38/08A61P35/00
Inventor 黄志纾古练权龙易李增谭嘉恒欧田苗
Owner SUN YAT SEN UNIV
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