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CN-121990968-A - Method for stereoselectively synthesizing chiral triarylmethane thioether compound with anti-tumor bioactivity

CN121990968ACN 121990968 ACN121990968 ACN 121990968ACN-121990968-A

Abstract

The invention discloses a method for stereoselectively synthesizing a chiral triarylmethane thioether compound with anti-tumor biological activity, and relates to the technical field of medicine synthesis. The invention takes a class of seven-membered ring system 3-indolyl [1,4] thiazepine compounds as raw materials, and realizes asymmetric Friedel-crafts alkylation reaction with nucleophilic indole by using a novel strategy of catalyzing carbon-nitrogen bond breaking by using a spiro chiral phosphonic acid catalyst, thereby providing a high-quality path for synthesizing chiral triarylmethane thioether compounds, and simultaneously having the characteristics of easily available raw materials, mild conditions and high technical advantages of high enantioselectivity and atom economy. The chiral triarylmethane thioether compound provided by the invention has obvious inhibition effect on the growth of human cervical cancer cells (HeLa), pancreatic cancer cells (Panc-1) and human marrow neuroblastoma cells (Sy 5Y), shows good anti-tumor biological activity, and has important positive significance for promoting the research and development of anti-tumor drugs.

Inventors

  • LIU TENG
  • GUO YIJIANG
  • LI YONGQIN
  • WU JIANPING
  • YAN XIAO

Assignees

  • 曲靖师范学院

Dates

Publication Date
20260508
Application Date
20260202

Claims (10)

  1. 1. A chiral triarylmethane thioether compound is characterized by having a structural general formula shown in the specification: ; Wherein R 1 is selected from H, alkyl or halogen, R 2 is selected from H, alkyl or halogen, and R 3 is selected from H or alkyl.
  2. 2. The chiral triarylmethane sulfide compound of claim 1, selected from any one of the following structures: 。
  3. 3. The process for preparing a chiral triarylmethane sulfide compound as claimed in any one of claims 1 to 2, comprising the steps of: Taking 3-indolyl [1,4] thiazepan compound and indole compound as raw materials, and obtaining the chiral triarylmethane thioether compound through a first reaction under the catalysis of a spiro chiral phosphonic acid catalyst; The 3-indolyl [1,4] thiazepine compound has the structure: ; The preparation method of the 3-indolyl [1,4] thiazepine compound comprises the following steps: Mixing an azathia heterocyclic compound and indole in a solvent, adding trifluoroacetic acid, and obtaining the 3-indolyl [1,4] thiazepine compound through a second reaction; the structure of the nitrogen-sulfur heterocyclic compound is as follows: ; wherein R 1 is selected from H, alkyl, or halogen; The structure of the indole compound is as follows: ; Wherein R 2 is selected from H or alkyl or halogen, R 3 is selected from H or alkyl; the structure of the spiro chiral phosphonic acid catalyst is as follows: 。
  4. 4. the process of claim 3, wherein the first reaction is carried out at a temperature of-10 ℃ to 0 ℃ for a period of 64 to 72 hours, and the second reaction is carried out at room temperature for a period of 2 to 5 hours.
  5. 5. A process according to claim 3, wherein the spiro chiral phosphonic acid catalyst is added in an amount of 10 to 15 mol% of the molar amount of the 3-indolyl [1,4] thiazepine compound.
  6. 6. The method according to claim 3, further comprising a step of separating by column chromatography after the completion of the first reaction, wherein the eluent used for the column chromatography is a mixture of petroleum ether and ethyl acetate.
  7. 7. A pharmaceutical composition, characterized in that the active ingredient comprises a chiral triarylmethane sulfide compound according to any one of claims 1-2.
  8. 8. The pharmaceutical composition according to claim 7, wherein the concentration of the chiral triarylmethane sulfide compound in the pharmaceutical composition is 1.1 μmol/L to 100 μmol/L.
  9. 9. Use of a chiral triarylmethane sulfide compound according to any one of claims 1-2 or a pharmaceutical composition according to claim 7 in the preparation of a medicament for the treatment of an anti-tumor.
  10. 10. The use according to claim 9, wherein the tumour comprises human cervical cancer, pancreatic cancer and/or neuroblastoma.

Description

Method for stereoselectively synthesizing chiral triarylmethane thioether compound with anti-tumor bioactivity Technical Field The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing chiral triarylmethane thioether compounds with anti-tumor biological activity in a stereoselective manner. Background Chiral triarylmethane compounds are important heterocyclic molecules with various biological activities and medicinal values, are compounds with structural characteristics of anticancer, antibacterial, antituberculosis and the like, and are often developed into organic dyes, novel pH indicators, fluorescent probes and the like, such as vorozole (vorozole) with aromatase inhibition function, sulfatase inhibitor compounds and the like. Meanwhile, the chiral triarylmethane thioether compound contains diaryl thioether structural units in the structure, and the structural units are often present in a plurality of drug molecules and pesticide molecules, so that the chiral triarylmethane thioether compound has good pharmacological effects in the aspects of anti-tumor, antivirus, anti-inflammatory and analgesic effects and the like. At present, many researches on synthesis of chiral triarylmethane have been reported, and the synthesis strategy mainly focuses on asymmetric 1, 4-or 1, 6-conjugated addition reaction catalyzed by small organic molecules of quinone methides and intramolecular or intermolecular serial cyclization reaction of functional reactants mediated by metal-chiral ligand catalytic system. Although these methods have been used to promote the construction of chiral triarylmethane compounds, no study has been made to achieve intramolecular fusion of chiral triarylmethane with diaryl sulfide building blocks, and the study of the biological activity of related compounds is also in a blank state. According to the core principle of combinatorial chemistry and compound structure modification, two types of structural fragments with good biological activity are integrated in the same molecule, so that the pharmacological performance of the compound can be synergistically improved. Therefore, the synthesis of the chiral triarylmethane thioether compound has important potential application value and is a research direction to be explored urgently. However, the prior art lacks a universal and efficient synthesis path, and how to develop an organic asymmetric catalytic system with high atom economy and high stereoselectivity based on easily available raw materials, so as to realize the accurate synthesis of the compounds, which is a key subject to be perfected in the field. Based on the above, the invention aims to provide an efficient synthesis method, which fills the blank of the prior art. Disclosure of Invention The invention aims to provide a method for synthesizing chiral triarylmethane thioether compound with anti-tumor biological activity in a stereoselective manner, so as to solve the problems in the prior art. In order to achieve the above object, the present invention provides the following solutions: The technical scheme of the invention is that a chiral triarylmethane thioether compound is provided, and the structural general formula is shown as follows: ; Wherein R 1 is selected from H, alkyl or halogen, R 2 is selected from H, alkyl or halogen, and R 3 is selected from H or alkyl. Further, the chiral triarylmethane thioether compound is selected from any one of the following structures: 。 the second technical scheme of the invention is to provide a preparation method of the chiral triarylmethane thioether compound, which comprises the following steps: 3-indolyl [1,4] thiazepan compound and indole compound are used as raw materials, and the chiral triarylmethane thioether compound is obtained by reaction under the catalysis of a spiro chiral phosphonic acid catalyst; the chiral triarylmethane thioether compound is obtained by catalyzing carbon-nitrogen bond breaking bond of seven-membered ring system 3-indolyl [1,4] thiazepine compound through a spiro chiral phosphonic acid catalyst to realize asymmetric Friedel-crafts alkylation reaction with nucleophilic indole. The 3-indolyl [1,4] thiazepine compound has the structure: ; The preparation method of the 3-indolyl [1,4] thiazepine compound comprises the following steps: Mixing an azathia heterocyclic compound and indole in a solvent, adding trifluoroacetic acid, and obtaining the 3-indolyl [1,4] thiazepine compound through a second reaction; the structure of the nitrogen-sulfur heterocyclic compound is as follows: ; wherein R 1 is selected from H, alkyl, or halogen; The structure of the indole compound is as follows: ; Wherein R 2 is selected from H or alkyl or halogen, R 3 is selected from H or alkyl; the structure of the spiro chiral phosphonic acid catalyst is as follows: 。 Further, the temperature of the first reaction is-10 ℃ to 0 ℃ and the time is 64 to 72 hours, and the reaction solvent is pre