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Naphthalimide derivatives, preparation method and applications thereof

A technology of naphthalimide and derivatives, applied in the field of anti-tumor naphthalimide derivatives, can solve the problems of limited clinical activity and unsatisfactory performance.

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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  • Naphthalimide derivatives, preparation method and applications thereof
  • Naphthalimide derivatives, preparation method and applications thereof
  • Naphthalimide derivatives, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0029] (1) Synthesis of 4-piperidinyl-1.8-naphthalene anhydride (compound 2)

[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 carbazate (compound 3)

[0033]

[0034] In a 25mL two-necked bottle, add 3mL (35.6mmol) of dimethyl carbonate and 0.85mL (17.5mmol) of hydrazine hydrate (80%), add 0.2g of zinc powder as a catalyst, heat up and reflux for 5 ...

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 37...

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Abstract

The invention discloses naphthalimide derivatives, a preparation method and applications thereof. The structure of the derivatives is represented by the formula (Y). In the formula (Y), the R represents a six-membered ring containing hetero-atoms, -NHCH2CH2OH, -NHCH2CH2N(CH3)2, or -NHCH2CH2CH2CH3, wherein the hetero-atoms are nitrogen atoms, oxygen atoms, or sulfur atoms, the six-membered ring containing hetero-atoms comprises at least one nitrogen atom, and the R is connected to the mother nucleus of a compound represented by the formula (T) through a nitrogen atom. The provided derivatives are prepared by grafting methyl carbazate to the active sites of naphthalimide. The derivatives can inhibit the growth of tumor cells from different tissues such as mammary glands, cervix, and the like, while normal human cells are barely influenced by the derivatives, and thus the derivatives have a wide prospect in preparation of drugs for inhibiting the growth of tumor cells.

Description

technical field [0001] The invention relates to a class of antitumor naphthalimide derivatives and belongs 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 proliferation. However, in th...

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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