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Beta-carboline-cycloenone derivative based on dual response to pH value and GSH and application thereof

A technology of cycloalkenone and its derivatives, applied in the preparation of anti-tumor diagnostic and therapeutic agents, β-carboline-cycloalkenone derivatives and its preparation field, can solve problems such as instability in vivo, slow color development, easy metabolism, etc. , to enhance the effect of anti-tumor proliferation and metastasis

Active Publication Date: 2020-04-10
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • 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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  • Beta-carboline-cycloenone derivative based on dual response to pH value and GSH and application thereof
  • Beta-carboline-cycloenone derivative based on dual response to pH value and GSH and application thereof
  • Beta-carboline-cycloenone derivative based on dual response to pH value and GSH and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] 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

[0074]

[0075] (1) Preparation of 1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2a)

[0076] 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 solution was cooled to 0° C., it was filtered by a vacuum pump 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%.

[0077] (2) Preparati...

Embodiment 2

[0085] 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

[0086] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2b)

[0087] 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%.

[0088] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indole-3-yl azide (3b)

[0089] 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%.

[0090] Preparation of 1-(p-tolyl)-9H-pyrido[3,4-b]indol-3-amine (4b)

[0091] 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

[0094]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

[0095] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carbonylhydrazide (2c)

[0096] 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%.

[0097] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-ylazide (3c)

[0098] 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%.

[0099] Preparation of 1-(3-methoxyphenyl)-9H-pyrido[3,4-b]indol-3-amine (4c)

[0100] 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 a beta-carboline-cycloenone derivative with a structure as shown in a general formula which is described in the specification. According to the invention, an electron-donatinggroup is introduced into a proper part of beta-carboline, and the 3-site amino group of beta-carboline is connected with cycloenone having anti-tumor activity by utilizing a carbamate bond, so the novel beta-carboline-cycloenone derivative is designed and synthesized. The derivative realizes pH and GSH dual-response fluorescence imaging and diagnosis in a tumor microenvironment, and can selectively target to GSTpi highly-expressed in tumor tissue, so tumor cell proliferation can be significantly inhibited. Such a pH / GSH dual-response fluorescence and cancer-targeting treatment diagnosis and treatment drug provides a new choice for accurate diagnosis and targeting treatment of tumors, and broadens the application of multifunctional molecules in accurate medical treatment.

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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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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