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Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug

A technology of furaquinoline and derivatives, which can be used in antitumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as limited resources, and achieve the effects of increasing steric hindrance, increasing groove binding ability, and good inhibitory activity.

Active Publication Date: 2013-11-06
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the anticancer effect of methyl indoquinoline compounds has been confirmed, the selection ability of the existing multiple methyl indoquinoline compounds to G-quadruplex DNA still needs to be improved, and at the same time due to the natural The resources of indoquinoline compounds in China are limited. At present, structural modification based on the mother nucleus of methyl indoquinoline is an important way to discover lead compounds with better anticancer activity.

Method used

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  • Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug
  • Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug
  • Methylbenzofuran quinoline derivative, preparation method thereof, and application of derivative as antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment one: the synthesis of compound 8M7

[0044] 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 M1, and then add thionyl chloride for chlorination reaction to obtain M2 , evaporated the thionyl chloride solvent to obtain a brown liquid, and then carried out condensation reaction with anthranilic acid to obtain M3, then preheated PPA to 130°C and added M3 for a compound reaction to obtain compound M4, and mixed M4 with thionyl chloride The chlorination reaction was carried out under reflux at 80°C to obtain compound M5, and then the 7-position methyl group was removed by using boron tribromide in dichloromethane to obtain compound M6.

[0045] Then, under the condition of chloroform (300mL) as solvent, add 6.0g triphenylphosphine, 2.0g M6, 6mL 4-hydroxyethylmorpholine, 6mL diisopropyl azodicarboxylate, N 2 Under protection, diisopropyl azodicarboxyl...

Embodiment 2

[0049] Embodiment two: the synthesis of compound 9M7

[0050] The method is the same as in Example 1, except that N-hydroxyethylpiperidine is used instead of 4-hydroxyethylmorpholine to obtain compound 9M7.

[0051] Yield: 84%; Melting point: 178.4-180.1°C; 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 8.4, 0.8 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.81 ( d, J = 2.6 Hz, 1H), 7.78 (dd, J = 8.4, 1.4 Hz, 1H), 7.70 (dd, J = 11.1, 4.1 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.28 (dd, J = 8.8, 2.5 Hz, 1H), 4.27 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.59 (m, 4H), 1.71 – 1.59 (m , 4H), 1.51 – 1.44 (m, 2H); C 22 h 21 ClN 2 o 2 ,LC-MS m / z: 381[M+H] + .

[0052]

[0053] Compound 9M7

Embodiment 3

[0054] Embodiment three: the synthesis of compound 6M8

[0055] The method is the same as in Example 1, except that N,N-dimethylethanolamine is used instead of 4-hydroxyethylmorpholine. After the reaction product is separated by a column, the product is added to a 100mL single-necked bottle, and then 15mL of sulfolane is added. React with 10 mL of iodomethane at 68°C for three days, add a large amount of ether, filter, and dry to obtain compound 6M8 as an orange-red solid.

[0056] Yield: 92%; Melting point: 297.2-298.4°C; 1H NMR (400 MHz, DMSO) δ 8.83 (d, J = 9.0 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.32 (t, J = 8.0 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.12 (t, J = 7.8 Hz, 1H), 7.81 (dd, J = 9.2, 2.3 Hz, 1H), 4.93 (s, 3H), 4.75 (t, J=3.6 Hz, 2H), 3.92 (t, J=3.6 Hz, 2H), 3.27 (s, 9H); 21 h 23 ClI 2 N 2 o 2 , ESI-MS m / z: 185 [M-2I] 2+ / 2.

[0057]

[0058] Compound 6M8

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Abstract

The invention discloses a methylbenzofuran quinoline derivative, a preparation method thereof and application of the derivative as an antitumor drug, which belongs to the fields of medicine and chemical engineering. The invention also discloses the preparation method for the methylbenzofuran quinoline derivative and application of the derivative as the antitumor drug. According to results of experiments, the methylbenzofuran quinoline derivative in the invention has a powerful inhibitory effect on the expression of protooncogenes of DNA like telomeric DNA and c-myc, a substantial inhibitory effect on a variety of cancer cell lines, small toxicity to normal cells and wide application prospects in preparation of antitumor drugs.

Description

technical field [0001] The invention relates to the field of methylbenzofuran quinoline derivatives, more specifically, relates to a methylbenzofuran quinoline derivative, a preparation method thereof and an application as an antitumor drug. 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...

Claims

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Application Information

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IPC IPC(8): C07D491/048A61K31/5377A61K31/4741A61P35/00
Inventor 黄志纾古练权杜刚花闻钊
Owner SUN YAT SEN UNIV
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