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CN-121974894-A - Chromone bisindole derivative and preparation method and application thereof

CN121974894ACN 121974894 ACN121974894 ACN 121974894ACN-121974894-A

Abstract

The invention provides a chromone bisindole derivative, and a preparation method and application thereof. The derivative takes chromone ketone ester compounds with different substituted benzene rings as raw materials, carries out structural modification on the 3 position of the compounds, and successfully synthesizes 21 chromone bisindole derivatives through addition reaction with indole. The derivative contains chromone and indole dominant skeletons, has various biological activities, and especially has outstanding anti-tumor effect. The method has the advantages of simple operation, short reaction time, high yield, readily available raw materials, good air stability and wide applicability, can provide a compound source for bioactive screening, and has important application value for the pharmaceutical screening and pharmacy industries.

Inventors

  • PAN BOWEN
  • SHI YANG
  • XIAO ZHANGPING
  • LIU PEI
  • ZHOU YING
  • SONG SHANSHAN
  • ZENG LINGRONG

Assignees

  • 贵州中医药大学

Dates

Publication Date
20260505
Application Date
20260330

Claims (7)

  1. 1. The chromone bisindole derivative is characterized by having a structure shown in a general formula (I): (I), wherein, R substituent is selected from phenyl, 8-methylphenyl, 7-methylphenyl, 6-methylphenyl, 7-methoxyphenyl, 5-methoxyphenyl, 8-fluorophenyl, 7-fluorophenyl, 6-fluorophenyl, 5-fluorophenyl, 8-chlorophenyl, 7-chlorophenyl, 6-chlorophenyl, 5-chlorophenyl, 8-bromophenyl, 7-bromophenyl, 6-nitrophenyl, 6, 8-dimethylphenyl, 6, 7-dimethylphenyl and naphthyl, and the specific structure is in one-to-one correspondence with the following structural formulas 3a-3 u: 。
  2. 2. The preparation method of the chromone bisindole derivative according to claim 1, which is characterized in that chromone ketone ester with different substituted benzene rings is used as a raw material, the 3-position of the chromone bisindole derivative is subjected to structural modification, DCM is used as a solvent, tsOH is used as a catalyst, and the chromone bisindole derivative is obtained through an addition reaction with indole, and the specific steps are as follows: sequentially adding 0.3 mmol benzene rings of differently substituted chromone ketone ester, 0.9 mmol indole and 0.03 mmol TsOH into a 10mL reaction bottle, adding DCM 3 mL, stirring at room temperature for reacting for 16 hours, monitoring the reaction by adopting thin layer chromatography, and purifying by silica gel column chromatography after the reaction is finished to finally obtain chromone bisindole derivatives 3a-3u; The synthetic route is as follows: 。
  3. 3. The preparation method according to claim 2, wherein the molar ratio of the chromone ketone ester, the indole and the TsOH which are substituted differently by benzene rings is that the chromone ketone ester, the indole, the TsOH=1:3:0.1 which are substituted differently by benzene rings.
  4. 4. The method of claim 2, wherein the monitored solvent system is a 2:1 by volume mixture of PE and EA.
  5. 5. The method according to claim 2, wherein the eluent for silica gel column chromatography purification is a mixed solution of PE and ea=4:1 by volume ratio.
  6. 6. Use of a chromone bisindole derivative according to claim 1 or prepared by a preparation method according to any one of claims 2 to 5 in the preparation of an antitumor drug.
  7. 7. The use according to claim 6, wherein the antineoplastic agent is a medicament for the treatment of leukemia, cervical cancer or gastric cancer.

Description

Chromone bisindole derivative and preparation method and application thereof Technical Field The invention relates to the technical fields of pharmaceutical chemistry and tumor pharmacy, in particular to a chromone bisindole derivative, a preparation method and application thereof. Background Cancer is the second greatest health threat in the world public health area, with disease burden inferior to cardiovascular disease. According to the latest statistics of the world health organization International cancer research organization (IARC), about 2000 thousands of new cancer cases are shown in 2022 worldwide, and 3500 thousands of cases are expected to be broken through by 2050, with an increase of 77%. Current clinical tumor therapies still use surgical resection, radiation therapy and chemotherapy as the primary intervention. Under the background, the research of drug treatment is continuously advanced to a deep degree, and plays an increasingly important role in a comprehensive tumor treatment system. Chromone (Chromone) is used as a benzo-gamma-pyrone oxygen-containing heterocyclic compound, and derivatives thereof are widely distributed in traditional medicinal plant resources, especially the content of plants of Fangfeng genus (Saposhnikovia) of Umbelliferae and eaglewood genus (Aquilaria) of daphne is most remarkable. Such compounds are important active ingredients because of their unique benzo-gamma-pyrone backbone. Of note, chromones are not only widely found in medicinal plants, but are also a common component of the human daily diet, and this natural property imparts unique drug development advantages. Modern pharmacological studies show that the compounds have various biological activities, wherein the antitumor effect is particularly remarkable, and the compounds have proved to play an anticancer role by regulating and controlling cell cycle, inducing apoptosis of tumor cells, inhibiting angiogenesis and other multiple mechanisms. Based on the characteristics, innovative structural modification is carried out on the chromone parent nucleus, the directional synthesis and antitumor activity evaluation of the novel derivative are developed systematically, the inherent rule of the structure-activity relationship is clarified, the lead compound can be provided for the research and development of the antitumor novel medicine based on the natural product, and the method has important scientific value for promoting the modern research of traditional Chinese medicine and the innovation of the tumor targeted treatment strategy. Disclosure of Invention The invention aims to provide a chromone bisindole derivative, a simple and efficient preparation method thereof and application thereof in anti-tumor drugs. In order to achieve the purpose of the invention, the invention adopts the following technical proposal and steps: the invention provides a chromone bisindole derivative, which has a structure shown in a general formula (I): (I), wherein, R substituent is selected from phenyl, 8-methylphenyl, 7-methylphenyl, 6-methylphenyl, 7-methoxyphenyl, 5-methoxyphenyl, 8-fluorophenyl, 7-fluorophenyl, 6-fluorophenyl, 5-fluorophenyl, 8-chlorophenyl, 7-chlorophenyl, 6-chlorophenyl, 5-chlorophenyl, 8-bromophenyl, 7-bromophenyl, 6-nitrophenyl, 6, 8-dimethylphenyl, 6, 7-dimethylphenyl and naphthyl, and the specific structure is in one-to-one correspondence with the following structural formulas 3a-3 u: The invention provides a preparation method of a chromone bisindole derivative, which takes chromone ketone ester with different substituted benzene rings as a raw material, carries out structural modification on the 3 position of the chromone bisindole derivative, takes Dichloromethane (DCM) as a solvent and p-toluenesulfonic acid (TsOH) as a catalyst, and carries out addition reaction with indole to obtain the chromone bisindole derivative, and the preparation method comprises the following specific steps: Sequentially adding 0.3mmol of chromone ester with different benzene rings substituted, 0.9mmol of indole and 0.03mmolTsOH into a 10mL reaction bottle, adding 3mL of DCM, stirring at room temperature for reaction for 16 hours, monitoring the reaction by adopting thin layer chromatography, and purifying by silica gel column chromatography after the reaction is finished to finally obtain chromone bisindole derivatives; The chromone ketone ester with different substituted benzene rings refers to a compound 1a-1u which is formed by substituting phenyl, 8-methylphenyl, 7-methylphenyl, 6-methylphenyl, 7-methoxyphenyl, 5-methoxyphenyl, 8-fluorophenyl, 7-fluorophenyl, 6-fluorophenyl, 5-fluorophenyl, 8-chlorophenyl, 7-chlorophenyl, 6-chlorophenyl, 5-chlorophenyl, 8-bromophenyl, 7-bromophenyl, 6-nitrophenyl, 6, 8-dimethylphenyl, 6, 7-dimethylphenyl and naphthyl; The synthetic route is as follows: 。 the molar ratio of the chromone ketone ester, the indole and the TsOH with different substituted benzene rings is that the chromone