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Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof

A technology of naphthalene imide and compound, applied in the field of organic synthesis, can solve the problems of limited clinical activity and unsatisfactory performance, etc.

Inactive Publication Date: 2015-12-09
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the clinical trials of Mitonafide, it was found to have very severe central nervous system (CNS) toxicity, and its clinical activity was limited; the performance of Amonafide in clinical trials was also unsatisfactory, causing myelosuppression, vomiting, rash And side effects such as moderate phlebitis

Method used

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  • Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof
  • Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof
  • Nitrogen-containing sulfur substituent naphthalimide compound, preparation method and applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Synthesis of N-(N'-methyl dithioformate amino)-6-piperidinyl-1,8-naphthalimide (compound Y1):

[0029] (1) Synthesis of 4-piperidinyl-1.8-naphthalene anhydride

[0030]

[0031] Add 5g (18.1mmol) of 4-bromo-1,8 naphthalene anhydride to a 100mL two-necked flask, add 40mL ethylene glycol monomethyl ether and stir to dissolve, add 2mL (20.2mmol) piperidine to the reaction system, heat to reflux, and magnetically After stirring for 4h, the reaction was stopped, cooled at room temperature, cold water was added to the reaction solution, a yellow precipitate was precipitated, filtered and dried, purified by silica gel column chromatography (eluent was CH 2 Cl 2 ) to obtain 4.77 g of yellow solid, yield: 93.6%.

[0032] (2) Synthesis of methyl dithiocarbazinate (compound 4)

[0033]

[0034] Add 6.6g (0.12mol) of potassium hydroxide, 8.0mL of water and 6.7mL of isopropanol into a 50mL three-neck flask, stir to dissolve, and slowly add 5.7mL (0.12mol) of hydrazine hydra...

Embodiment 2

[0042] Determination of growth inhibition activity of tumor cells and normal cells in vitro:

[0043] The in vitro cell growth inhibitory activity of Hela cervical cancer cells, MCF-7 breast cancer cells and HL7702 human normal liver cells was determined by tetrazolium salt (microculturetetrozolium, MTT) reduction method.

[0044] The concrete operation of tetrazolium salt (MTT) reduction method is:

[0045] (1) Inoculating cells and culturing cells: When the cells are in the logarithmic growth phase, digest the adherent cells with trypsin, collect them in serum-containing medium, and dilute the cell suspension to a concentration of about 4×10 5 ~6×10 5 individual / mL. Inoculate the above culture medium into a sterile 96-well plate, add 100 μL of cell suspension to each well (about 5000 cells per well), and add 200 μL of PBS buffer to each well at the outermost periphery to provide sufficient water environment for the cell growth ring. Place the inoculated culture plate at 3...

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Abstract

The present invention discloses a class of nitrogen-containing sulfur substituent naphthalimide compound, a preparation method and applications thereof, wherein the compound has a structure represented by a general formula Y, R is one selected from a six-membered ring containing hetero atom, the following structures defined in the specification, -NHCH2CH2OH, -NHCH2CH2N(CH3) and -NHCH2CH2CH2CH3, the hetero atom is at least one selected from N, O and S, the six-membered ring containing the hetero atom at least has a N atom, and R is bound with the mother nucleus in the general formula T through the N atom. According to the present invention, the methyldithiocarbazate is bounded into the active site of the naphthalimide to prepare the compound of the present invention, and the class of the compounds provide growth inhibition activities on breast cancer cells, cervical cancer cells and a variety of tumor cells with different tissue origins while provide low inhibition activities on human body normal cells, and have wide prospects in the tumor cell growth inhibition drug preparation. The general formula Y is defined in the specification.

Description

technical field [0001] The invention relates to a class of anti-tumor nitrogen-sulfur substituent naphthalimide compounds, belonging to the technical field of organic synthesis. Background technique [0002] Studies have found that naphthalimide derivatives have good anticancer activity, among which Amonafide (N-(β-dimethylaminoethyl)-3-amino-1,8-naphthalimide) (MalviyaVK, LiuPY, AlbertsDS, etal.Am.J.Clin.Oncol.,1992,15:41-44.) and Mitonafide (N-(β-dimethylaminoethyl)-3-nitro-1,8-naphthalene Amine) (BranaM.F, SantosA., RoldanC.M., etal.Eur.J.Med.Chem.Chim.Ther., 1981,16,207-212) are two very well-known compounds that have entered Phase II clinical trials . This type of compound can effectively inhibit the growth of tumor cells, and its mechanism of action is to intercalate between the base pairs of DNA, induce DNA strand breaks under the intervention of topoisomerase II, and affect the normal physiological functions of DNA, thereby achieving Inhibition of cancer cell prol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/14A61P35/00
CPCC07D221/14
Inventor 李晓莲徐强范丽丽
Owner DALIAN UNIV OF TECH
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