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CN-121974912-A - Nitro-substituted dihydro acridine spiro isoquinoline ketone compound, synthesis method thereof and anticancer activity

CN121974912ACN 121974912 ACN121974912 ACN 121974912ACN-121974912-A

Abstract

The invention discloses a nitro-substituted dihydroacridine spiro-isoquinoline ketone compound and a synthesis method and anticancer activity thereof, belonging to the technical fields of organic synthesis and drug discovery. Mixing an N-nitrosodiphenylamine compound 1, a diazoisoquinoline diketone compound 2, a catalyst, an additive and hexafluoroisopropanol, heating, and performing one-pot tandem reaction to obtain a nitro-substituted dihydroacridine spiro-isoquinolone compound 3. The invention is verified by optimizing screening and anticancer cell activity tests, and the provided compound can obviously inhibit the proliferation of two cancer cells of Hela and HCT-116, so that the compound has obvious anticancer activity on cervical cancer and colon cancer and has potential medicinal value.

Inventors

  • ZHANG XINYING
  • SUN YUQIAN
  • ZOU JIAYI
  • FAN XUESEN
  • MA CHUNHUA

Assignees

  • 河南师范大学

Dates

Publication Date
20260505
Application Date
20260401

Claims (9)

  1. 1. The structural general formula of the nitro-substituted dihydroacridine spiro isoquinolone compound is as follows: , Wherein R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen, R 1 is mono-or poly-substituted, or R 1 and a benzene ring connected form phenyl piperate or ibuprofen phenyl ester, R 2 is selected from hydrogen, C 1-4 alkyl, phenyl or halogen, R 3 is selected from hydrogen, C 1-4 chain alkyl, C 3-6 cycloalkyl, phenethyl, benzyl, substituted benzyl, phenyl or substituted phenyl, the substituent on the substituted benzyl benzene ring is mono-or poly-substituted C 1-4 alkyl, C 1-4 alkoxy or halogen, the substituent on the substituted phenyl benzene ring is mono-or poly-substituted C 1-4 alkyl, C 1-4 alkoxy or halogen, and R 4 is selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy.
  2. 2. The use of a nitro-substituted dihydroacridine spiroisoquinolinones according to claim 1 in the preparation of anticancer drugs.
  3. 3. The use of a nitro-substituted dihydroacridine spiroisoquinolinones according to claim 2 in the preparation of anti-cancer drugs, said anti-cancer being anti-cervical cancer and colon cancer.
  4. 4. The pharmaceutical composition for treating cervical cancer and colon cancer comprises the nitro-substituted dihydroacridine spiroisoquinolinone compound as an active ingredient.
  5. 5. The method for synthesizing the nitro-substituted dihydroacridine spiro-isoquinolone compound, as set forth in claim 1, is characterized by comprising the steps of mixing N-nitrosodiphenylamine compound 1, diazo isoquinoline dione compound 2, a catalyst, an additive and hexafluoroisopropanol, and heating to react to obtain nitro-substituted dihydroacridine spiro-isoquinolone compound 3, wherein the reaction equation is as follows: , wherein R 1 -R 4 is as defined in claim 1.
  6. 6. A process for the synthesis of nitro-substituted dihydroacridine spiroisoquinolinones according to claim 5, characterized in that said catalyst is selected from the group consisting of Or (b) 。
  7. 7. The method for synthesizing nitro-substituted dihydroacridine spiroisoquinolone compound according to claim 5, wherein said additive is selected from the group consisting of copper acetate, a mixture of copper acetate and one or more of 2, 6-tetramethylpiperidine oxide, silver acetate, silver oxide, silver carbonate and silver fluoride.
  8. 8. The method for synthesizing nitro-substituted dihydroacridine spiroisoquinoline ketone compounds according to claim 5, wherein the molar ratio of the N-nitrosodiphenylamine compound 1 to the diazoisoquinoline dione compound 2 to the catalyst to the additive is 1:1-1.5:0.04-0.06:2-4.
  9. 9. The method for synthesizing nitro-substituted dihydroacridine spiroisoquinolone compounds according to claim 5, wherein said reaction is carried out in air or oxygen atmosphere at a temperature of 60-100 ℃.

Description

Nitro-substituted dihydro acridine spiro isoquinoline ketone compound, synthesis method thereof and anticancer activity Technical Field The invention belongs to the technical field of organic synthesis and drug discovery, and in particular relates to a nitro-substituted dihydroacridine spiro isoquinolone compound, a synthesis method thereof and anticancer activity. Background Nitrogen-containing heterocycles play an important role in many fields such as synthetic chemistry, pharmaceutical chemistry, and materials science. The 9, 10-dihydro acridine compound has unique and easily-controlled electron and fluorescence characteristics, and is widely applied to development of organic light-emitting diodes, hole-transport materials and heat-activation delay fluorescent materials. In addition, many 9, 10-dihydroacridine compounds also show remarkable biological activities such as antiviral activity, antitumor activity, antimalarial activity and the like, and are important sources for the discovery of new drugs. On the other hand, spiro compounds generally have high rigidity and unique three-dimensional geometry that can effectively identify or bind to protein targets of drugs, while spiro structures are also important building blocks for a variety of catalysts, core structures for chiral ligands, and functional polymers. However, synthesis of the dihydroacridine spiro isoquinolinones is limited at present, and corresponding biological activity research is not reported. Meanwhile, due to the diversity of the reaction performance of the nitro, the nitro heterocycle is a common organic synthesis intermediate, and various target molecules can be conveniently synthesized through diversity guidance. Currently, nitroheterocyclic compounds are generally obtained by nitration of the corresponding heterocyclic compound with a corrosive nitration reagent under harsh reaction conditions. Based on the background, the nitro-substituted dihydroacridine spiro-isoquinolone compounds are researched and developed by a simple, efficient, green and sustainable method, the biological activity of the compounds and the application of the compounds in the aspects of medicinal chemistry, synthetic chemistry, material chemistry and the like are researched, and the method has important theoretical significance and potential application value. Disclosure of Invention In order to solve the problems in the prior art, one of the purposes of the invention is to provide a new nitro-substituted dihydroacridine spiro isoquinolone compound, and researches show that the compound has remarkable anticancer activity. The structural general formula of the nitro-substituted dihydroacridine spiro-isoquinolone compound is as follows: , Wherein R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen, R 1 is mono-or poly-substituted, or R 1 and a benzene ring connected form phenyl piperate or ibuprofen phenyl ester, R 2 is selected from hydrogen, C 1-4 alkyl, phenyl or halogen, R 3 is selected from hydrogen, C 1-4 chain alkyl, C 3-6 cycloalkyl, phenethyl, benzyl, substituted benzyl, phenyl or substituted phenyl, the substituent on the substituted benzyl benzene ring is mono-or poly-substituted C 1-4 alkyl, C 1-4 alkoxy or halogen, the substituent on the substituted phenyl benzene ring is mono-or poly-substituted C 1-4 alkyl, C 1-4 alkoxy or halogen, and R 4 is selected from hydrogen, C 1-4 alkyl or C 1-4 alkoxy. The second purpose of the invention is to provide the application of nitro substituted dihydroacridine spiro isoquinolone compounds in preparing anticancer drugs. Further, in the above technical scheme, the anticancer is cervical cancer and colon cancer resistance. Wherein cervical cancer is aimed at Hela cells, and colon cancer is aimed at HCT-116 cells. The invention further aims to provide a pharmaceutical composition for treating cervical cancer and colon cancer, wherein the active ingredient of the pharmaceutical composition is the nitro-substituted dihydroacridine spiro-isoquinolone compounds. The design experiment of the invention verifies that the compound has the activity of obviously inhibiting the proliferation of two cancer cells, namely Hela and HCT-116, and the compound can be used as an active ingredient of a medicament for resisting cancers such as cervical cancer, colon cancer and the like. Especially, the preferable compounds can obviously inhibit the growth and proliferation of Hela and HCT-116, and the compounds are suggested to have the effects of preventing, treating and inhibiting the progress deterioration of cervical cancer and colon cancer as active ingredients of anticancer drugs. The invention aims at providing a synthesis method of nitro-substituted dihydroacridine spiro-isoquinolone compounds, which comprises the steps of taking N-nitrosodiphenylamine compounds and diazo isoquinoline dione compounds as raw materials. The synthesis method specifically comprises the steps of mixing an N-nitrosodiphenylami