Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof

A technology for benzofuranquinoline and derivatives, which is applied in the field of peptidyl-substituted double-chain benzofuranquinoline derivatives and their preparation, can solve problems such as application limitations and need to be improved, and achieves high safety and normal cytotoxicity. Small, good inhibitory effect

Active Publication Date: 2014-09-03
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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. 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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  • Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof
  • Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof
  • Peptidyl-substituted double-chain benzofuran quinoline derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment one: the synthesis of compound D

[0041]Dissolve 0.3mol of chloroacetic acid in 60ml of water, adjust the pH to 9 with sodium hydroxide, then add 0.2mol of p-hydroxyanisole, and reflux at 100°C to obtain T1, then add thionyl chloride for chlorination reaction to obtain T2 , distill off the thionyl chloride solvent to obtain a brown liquid, and then conduct condensation reaction with anthranilic acid to obtain T3, then preheat PPA to 130°C and add T3 for compound reaction to obtain compound T4, and combine T4 with thionyl chloride The chlorination reaction was carried out under reflux at 80°C to obtain compound T5, and then the 7-position methyl group was removed by using boron tribromide in dichloromethane to obtain compound T6. Then under the condition of chloroform (300mL) as solvent, add 6.0g triphenylphosphine, 2.0g T6, 6mL N-methyl-4-piperidinemethanol, 6mL diisopropyl azodicarboxylate, N 2 Under protection, diisopropyl azodicarboxylate was added dropw...

Embodiment 2

[0045] Embodiment two: the synthesis of compound DGG

[0046] Dissolve Fmoc-Gly-OH amino acid in DMF (dimethylformamide) solvent, add HOBT (1-hydroxybenzotriazole) and DIC (N,N-diisopropylcarbodiimide) for condensation Reagent (1:1), react with the deprotected Rink Amide AM resin in a solid-phase reactor for 3h, and then use 5% piperidine, 2% DBU (1,8-diazabicyclo[5.4.0]deca The mixed solution of one carbon-7-ene) and 93% DMF removes the Fmoc group to obtain the amino acid side chain, and then uses the above method to connect the Fmoc-Gly-OH amino acid to the amino acid that has been inserted into the resin.

[0047] Finally, it was condensed with D in the DMF solution of HOBT and DIC. After 72 hours, the resin was removed with trifluoroacetic acid, collected, and purified by preparative high-performance liquid chromatography to finally obtain white solid DGG.

[0048] Pale yellow solid; Yield: 43%. Melting point: 171-173°C; 1 H NMR (400MHz, DMSO-d 6 )δ9.48(s, 1H), 8.64(t,...

Embodiment 3

[0050] Embodiment three: the synthesis of compound DGR

[0051] The method is the same as in Example 2, except that the Fmoc-Arg(Pbf)-OH and Fmoc-Gly-OH amino acids are connected to the Rink Amide AM resin in sequence. Finally, after purification by preparative high performance chromatography, DGR was finally obtained as a light yellow solid.

[0052] Pale yellow solid; Yield: 31%. Melting point: 182-183°C; 1 H NMR (400MHz, DMSO-d 6 )δ9.63(s,1H),8.60(s,2H),8.16(d,J=8.0Hz,1H),8.07(d,J=5.5Hz,1H),8.00(s,1H),7.94( s,1H),7.81-7.65(m,3H),7.69(s,1H),7.44(d,J=8.8Hz,1H),7.37(s,1H),7.08(s,1H),4.73(d ,J=3.4Hz,2H),4.19(s,1H),3.99(d,J=3.9Hz,2H),3.84(s,2H),3.05(s,6H),2.79(s,3H),2.05 (d, J=14.1Hz, 3H), 1.67(s, 2H), 1.57(d, J=12.2Hz, 2H), 1.45(d, J=4.4Hz, 4H).; HRMS(ESI): m / z calcd for C 32 h 41 N 9 o 5 ([M+2H] 2+ );316.6688found316.6175.

[0053]

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Abstract

The invention provides a peptidyl-substituted double-chain benzofuran quinoline derivative. The structural formula of the peptidyl-substituted double-chain benzofuran quinoline derivative is shown in formula (I). In the formula (I), R1 is dipeptide, tripeptide, tetrapeptide and pentapeptide. Experiments prove that the peptidyl-substituted double-chain benzofuran quinoline derivative provided by the invention has very strong inhibition effects on expression of proto-oncogene DNA (deoxyribonucleic acid) such as telomere DNA, c-myc and the like, has significant inhibition effects on various cancer cell lines, has low toxicity to normal cells, is a peptide chain substituted benzofuran quinoline compound with low toxicity and good anti-cancer effects, and has wide application spaces in preparation of anti-cancer medicaments.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, more specifically, to a peptidyl-substituted double-chain benzofuran quinoline derivative and its preparation method and application. 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 significance, is an important aspect f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K5/068C07K5/078C07K5/09C07K5/11C07K1/04C07K1/06A61K38/05A61K38/06A61K38/07A61P35/00
Inventor 黄志纾古练权杜刚谭嘉恒黄世亮欧田苗
Owner SUN YAT SEN UNIV
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