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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 derivatives, which is applied in the preparation of anticancer drugs. The field of peptide derivatives of benzofuran quinoline and its preparation can solve the problems of application restrictions and limited resources. Achieve high safety, broad market prospects, and low toxicity

Inactive Publication Date: 2012-06-27
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

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment one: the synthesis of compound P7

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

[0028] Yield: 41%; 1 H NMR (400MHz, DMSO) δ9....

Embodiment 2

[0031] Embodiment two: the synthesis of compound R

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

[0033] Yield: 32%; 1H NMR (400MHz, DMSO) δ9.71(t, J=6.4Hz, 1H), 8.71(d, J=8.5Hz, 1H), 8.63(d, J=8.2Hz, 1H), 8.56(d, J =8.2Hz, 1H), 8.43(d, J=9.0Hz, 1H), 8.15-8.07(m, 1H), 7.87(ddd, J=21.5, 15.3, 8.0Hz, 3H), 7.64(t, J= 7.4Hz, 2H), 7.49(s, 1H), 7.13(s, 2H), 4.79(d, J=6.4Hz, 2H), 4.58(s, 3H), 4.25(dd, J=14.7, 7.0Hz,...

Embodiment 3

[0036] Embodiment three: the 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 the Rink Amide AM resin twice. Finally, after purification by preparative high performance chromatography, GG was finally obtained as a white solid.

[0038] Yield: 29%; 1 H NMR (400MHz, DMSO) δ9.72(t, J=6.5Hz, 1H), 8.70(t, J=8.4Hz, 2H), 8.64(d, J=8.2Hz, 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, 2.4Hz, 1H), 7.23(s, 1H), 7.02(s, 1H), 4.78(d, J=6.4Hz, 2H), 4.59(s, 3H), 3.83(d, J=5.7Hz, 2H), 3.60(d, J=5.8Hz, 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 peptide derivative of benzofuran quinoline, a preparation method thereof, and an application thereof in preparation of anticancer drugs. Background technique [0002] Cancer is one of the major diseases that threaten human health and life safety. According to statistics, there are about 4 million new cancer patients in the world every year. The research and development of anticancer drugs has always been a hot spot for chemists and pharmacologists. Finding anticancer drugs with high efficiency, high selectivity and less toxic side effects is one of the important directions of drug research and development. Designing and synthesizing anticancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors for the special advanced structure of proto-oncogene DNA such as telomere DNA and c-myc, which have important physiological signifi...

Claims

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Application Information

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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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