β-carboline-cycloenone derivatives based on dual response of ph and gsh and uses thereof

A technology of cycloalkenone and derivatives, applied in the preparation of anti-tumor diagnosis and treatment agents, β-carboline-cycloalkenone derivatives and the field of preparation, can solve the problems of instability in the body, easy metabolism, slow color development and the like , to achieve the effect of enhancing anti-tumor proliferation and metastatic activity

Active Publication Date: 2020-11-24
NANTONG UNIVERSITY
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

However, traditional pH-sensitive fluorescent probes are mainly activated by acid-sensitive hydrazone bonds or acetal fragments, but these groups themselves have problems such as instability in vivo, slow color development, and easy metabolism.

Method used

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  • β-carboline-cycloenone derivatives based on dual response of ph and gsh and uses thereof
  • β-carboline-cycloenone derivatives based on dual response of ph and gsh and uses thereof
  • β-carboline-cycloenone derivatives based on dual response of ph and gsh and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 (6-oxocyclohex-1-en-1-yl)methyl (1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]ind Indol-3-yl) carbamate (I 1 ) or bis(6-oxocyclohex-1-en-1-yl)methyl(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]ind Indol-3-yl) carbamate (II 1 ) preparation

[0075]

[0076] (1) Preparation of 1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2a)

[0077] Compound 1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (1a) (19.6g, 50mmol) was dissolved in 80mL After methanol, 176.4 mL of 85% hydrazine hydrate (75 g, 1.50 mol) was added and refluxed for 4-5 h. The reaction was monitored by TLC. After the reaction liquid was cooled to 0° C., it was vacuum pumped to obtain a light brown solid. A large amount of cold water was added to the filtrate, and the solid continued to precipitate. After suction filtration and vacuum drying, 16.5 g of a light brown solid was obtained, with a yield of 84.2%.

[0078] (2) Preparation of 1-(3,4,5...

Embodiment 2

[0086] Example 2 (6-oxocyclohex-1-en-1-yl)methyl (1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-yl)aminomethyl Ester (Ⅰ 2 ) or bis(6-oxocyclohex-1-en-1-yl)methyl(1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-yl)aminomethyl Ester (II 2 ) preparation

[0087] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2b)

[0088] Referring to the synthesis method of (2a) in Example 1, (1a) in the method was replaced by (1b), and finally a light yellow solid (2b) was obtained with a yield of 80.9%.

[0089] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-yl azide (3b)

[0090] Referring to the synthesis method of (3a) in Example 1, (2a) in the method was replaced by (2b), and finally a light yellow solid (3b) was obtained with a yield of 87.5%.

[0091] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-amine (4b)

[0092] Referring to the synthesis method of (4a) in Example 1, (3a) in the method was replaced by (3b), and finally a pale yellow solid (4b) was obtained with a yie...

Embodiment 3

[0095]Example 3 (6-oxocyclohex-1-en-1-yl)methyl (1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3- base) carbamate (Ⅰ 3 ) or bis(6-oxocyclohex-1-en-1-yl)methyl(1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3- base) carbamate (II 3 ) preparation

[0096] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2c)

[0097] Referring to the synthesis method of (2a) in Example 1, (1a) in the method was replaced by (1c), and finally a light yellow solid (2c) was obtained with a yield of 81.3%.

[0098] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-ylazide (3c)

[0099] Referring to the synthesis method of (3a) in Example 1, (2a) in the method was replaced by (2c), and finally a light yellow solid (3c) was obtained with a yield of 88.4%.

[0100] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3-amine (4c)

[0101] Referring to the synthesis method of (4a) in Example 1, (3a) in the method was replaced by (3c), and finally a pale yellow so...

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Abstract

The invention discloses β-carboline-cycloenone derivatives, which have the structure shown in the following general formula: the present invention introduces an electron-donating group at a suitable position of β-carboline, and through the 3-position amino group of β-carboline, Using carbamate linkages to link cycloenones with anti-tumor activity, design and synthesize novel β-carboline-cycloenone derivatives. The compound of the present invention can not only realize pH and GSH dual response fluorescence imaging and diagnosis in tumor microenvironment , and can selectively target GSTπ highly expressed in tumor tissue, and play a significant role in inhibiting tumor cell proliferation. The pH / GSH dual response fluorescent and cancer-targeting therapy, diagnosis and treatment drug of the present invention provides a new option for precise tumor diagnosis and targeted therapy, and broadens the application of multifunctional molecules in precision medicine.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to β-carboline-cycloenone derivatives based on pH and GSH dual responses and their preparation methods, as well as their medicinal uses targeting GSH / GSTπ to inhibit tumor growth, especially in the preparation of anti-tumor application in diagnostics. Background technique [0002] Malignant tumors are a serious threat to human health and life, and the number of deaths from cancer has risen rapidly. The research and development of diagnostic and therapeutic agents has become one of the research hotspots in the field of medicine. It combines diagnosis and treatment, and immediately gives effective treatment (surgery and / or drugs) while making a diagnosis, improving treatment efficiency. and specificity of drug release. Among them, there are mainly two types of small molecule therapeutic agents and macromolecular nano therapeutic agents. The preparation of the former is relatively...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C09K11/06A61K49/00A61P35/00G01N21/64
CPCA61K49/0021A61P35/00C07D471/04C09K11/06C09K2211/1044G01N21/6428G01N21/6456
Inventor 凌勇刘季刘昕凌长春张延安钱建强孟迟杭佳颖陈苏蒙
Owner NANTONG UNIVERSITY
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