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CN-122011037-A - Platinum (IV) prodrug taking small-molecule TrxR inhibitor as ligand and preparation method and application thereof

CN122011037ACN 122011037 ACN122011037 ACN 122011037ACN-122011037-A

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly discloses a platinum (IV) prodrug taking a small-molecule TrxR inhibitor as a ligand, a preparation method and application thereof, wherein the synthesized platinum (IV) prodrug has good antiproliferative activity on cancer cells such as MDA-MB-231, MCF-7, 4T1, MDA-MB-231/CDDP and the like, and the anticancer activity of a compound 6b is optimal. In an in vivo anti-tumor activity test, the compound 6b can effectively inhibit proliferation of cis-platinum sensitive and cis-platinum drug-resistant triple negative breast cancer xenograft tumors, has tumor inhibition rate of 73.8% and 66.3%, and has better curative effect than that of a positive drug cis-platinum. In addition, the compound 6b can effectively inhibit proliferation of the mouse breast cancer cell 4T1 allograft tumor, and the tumor inhibition rate is 76.8 percent, which is obviously stronger than that of a cisplatin treatment group. And the compound 6b shows a powerful immunoregulation effect in vivo, which shows that the design of the invention successfully realizes the effective combination of chemotherapy and immunotherapy, and the compound disclosed by the invention has potential application prospect for treating triple negative breast cancer.

Inventors

  • HUANG XIAOCHAO
  • WANG LANG
  • WANG MENG
  • LI GUIMEI
  • TANG JUPING
  • LIU ZHIKUN
  • YANG YONG
  • WANG HENGSHAN

Assignees

  • 淮阴工学院

Dates

Publication Date
20260512
Application Date
20251225

Claims (8)

  1. 1. A platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand, characterized by the chemical structure shown in the formula: ; wherein n=1 or 2; R 1 =-CF 3 、-OCF 3 or-OCH 3 .
  2. 2. The platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand according to claim 1, wherein the chemical structure is as shown in formulas (6 a) - (6 f): 。
  3. 3. A method of preparing a platinum (IV) prodrug having a small molecule TrxR inhibitor as a ligand according to claim 1, comprising the steps of: (1) Reacting the compound 1 with the compound 2 under the condition of concentrated hydrochloric acid and glacial acetic acid to synthesize a compound 3; (2) Reacting the compound 3 with succinic anhydride or glutaric anhydride under the condition of organic base to synthesize a compound 4; (3) Reacting the compound 4 with a platinum (IV) complex 5 under condensing agent and organic base conditions to synthesize a compound 6; The synthetic route is as follows: ; wherein n=1 or 2; R 1 =-CF 3 、-OCF 3 or-OCH 3 .
  4. 4. The method for preparing a platinum (IV) prodrug using a small-molecule TrxR inhibitor as a ligand according to claim 3, wherein in the step (1), the molar ratio of the compound 1 to the compound 2 is 2-3:1, and the volume ratio of the concentrated hydrochloric acid to the glacial acetic acid is 1:8-12; and/or the reaction is carried out at room temperature, and the reaction time is 40-50 h.
  5. 5. The preparation method of the platinum (IV) prodrug taking a small-molecule TrxR inhibitor as a ligand is characterized in that in the step (2), the organic base is triethylamine, DMF is taken as a solvent, and the molar ratio of the compound 3 to succinic anhydride or glutaric anhydride to the organic base is 1:2-4:1-2; and/or the reaction temperature is 40-60 ℃ and the reaction time is 8-12 h.
  6. 6. The preparation method of the platinum (IV) prodrug taking a small-molecule TrxR inhibitor as a ligand is characterized in that in the step (3), the condensing agent is TBTU, the organic base is triethylamine and DMF is taken as a solvent, and the molar ratio of the compound 4 to the platinum (IV) complex 5 to the condensing agent to the organic base is 1:0.8-1.2:1-2:1-2; and/or the reaction temperature is 20-40 ℃ and the reaction time is 8-12 h.
  7. 7. The method of claim 3, wherein the steps (1) - (3) further comprise a separation and purification process.
  8. 8. The use of a platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand according to claim 1 for the preparation of an anti-breast cancer medicament.

Description

Platinum (IV) prodrug taking small-molecule TrxR inhibitor as ligand and preparation method and application thereof Technical Field The invention belongs to the technical field of pharmaceutical chemistry, relates to design and synthesis of a platinum (IV) prodrug, and in particular relates to a synthesis method of a platinum (IV) prodrug taking a small-molecule TrxR inhibitor as a ligand and application of the platinum (IV) prodrug in the field of anti-tumor. Background Breast cancer is the most common type of cancer in women and has become one of the leading causes of cancer death in women. Of these, triple Negative Breast Cancers (TNBC) account for about 15% to 20% of all breast cancer cases. It is characterized by a high degree of malignancy, susceptibility to metastasis, and lack of expression of Estrogen Receptor (ER), progestogen Receptor (PR) and human epidermal growth factor receptor 2 (HER 2). In addition, poor prognosis, limited tumor metastasis and treatment options are also major causes of mortality in TNBC patients. Currently, platinum-based antitumor drugs, such as Cisplatin (CDDP), are widely used in clinical chemotherapy of various solid tumors including lung cancer, ovarian cancer and triple negative breast cancer by virtue of their broad-spectrum anticancer activity and high therapeutic effect. However, such anticancer drugs have various drawbacks in clinical applications, such as poor selectivity, serious side effects, and drug resistance, which limit their clinical applications. Therefore, the development of a novel platinum anti-cancer drug with strong targeting, high curative effect and low toxicity for being applied to TNBC chemotherapy has become urgent. The research proves that the platinum (IV) complex is more chemically inert than the platinum (II) drug in dynamics, can effectively reduce off-target reaction with biological substances, further achieves the purpose of reducing toxicity, and can be used as a prodrug of the platinum (II) drug. It has been found that thioredoxin reductase (TrxR) acts as a key reductase and plays a critical role in maintaining redox balance in cells within an organism. Given that the expression level of TrxR in malignant cancer cells is higher than that of non-cancerous tissues, trxR is considered a promising cancer therapeutic target. Thus, the construction of a novel platinum (IV) prodrug targeting TrxR is expected to provide a new strategy for TNBC treatment. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide a platinum (IV) prodrug taking a small-molecule TrxR inhibitor as a ligand, and the compound can overcome the defects of large toxic and side effects, poor oral availability and the like of the traditional antitumor drug while treating TNBC. The invention is realized by the following technical scheme: A platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand, the chemical structure of which is shown as the following formula: wherein n=1 or 2; R 1=-CF3、-OCF3 or-OCH 3. Further, the chemical structures are shown in the formulas (6 a) - (6 f): 。 The invention further improves the scheme as follows: A method for preparing a platinum (IV) prodrug with a small molecule TrxR inhibitor as a ligand, comprising the steps of: (1) Reacting the compound 1 with the compound 2 under the condition of concentrated hydrochloric acid and glacial acetic acid to synthesize a compound 3; (2) Reacting the compound 3 with succinic anhydride or glutaric anhydride under the condition of organic base to synthesize a compound 4; (3) Reacting the compound 4 with a platinum (IV) complex 5 under condensing agent and organic base conditions to synthesize a compound 6; The synthetic route is as follows: wherein n=1 or 2; R 1=-CF3、-OCF3 or-OCH 3. Further, in the step (1), the molar ratio of the compound 1 to the compound 2 is 2-3:1, and the volume ratio of the concentrated hydrochloric acid to the glacial acetic acid is 1:8-12; Further, the reaction is carried out at room temperature, and the reaction time is 40-50 h. Further, in the step (2), the organic base is triethylamine, DMF is used as a solvent, and the molar ratio of the compound 3 to succinic anhydride or glutaric anhydride to the organic base is 1:2-4:1-2; Further, the reaction temperature is 40-60 ℃ and the reaction time is 8-12 hours. Further, in the step (3), the condensing agent is TBTU, the organic base is triethylamine, DMF is taken as a solvent, and the molar ratio of the compound 4 to the platinum (IV) complex 5 to the condensing agent to the organic base is 1:0.8-1.2:1-2:1-2; Further, the reaction temperature is 20-40 ℃ and the reaction time is 8-12 hours. Further, the steps (1) - (3) also comprise a separation and purification process. The invention further improves the scheme as follows: the application of the platinum (IV) prodrug taking the small-molecule TrxR inhibitor as a ligand in preparing the anti-breast cancer drug. The invention introduces