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CN-122010949-A - Benzenesulfonamide derivative, preparation method thereof and application thereof in preparing PARP1 inhibitor and antitumor drug

CN122010949ACN 122010949 ACN122010949 ACN 122010949ACN-122010949-A

Abstract

The invention provides a benzenesulfonamide derivative, a preparation method thereof and application thereof in preparing PARP1 inhibitors and antitumor drugs, and belongs to the technical field of medicines. The invention synthesizes a new benzenesulfonamide derivative, namely a compound N, 4-dimethyl-N- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) benzenesulfonamide, and the benzenesulfonamide derivative provided by the invention can inhibit PARP1 enzyme activity in a targeted manner so as to inhibit DNA repair, activate p 53-mediated DDR signal path, induce apoptosis of lung cancer tumor cells and influence lung cancer tumor cell cycle, has obvious antitumor activity, and has the advantages of simple synthesis method, easily obtained raw materials, high synthesis route yield, environmental friendliness and simple operation process. The PARP1 inhibitor has the advantages of simple preparation process, high medicine purity, high yield and stable quality, and is easy to carry out mass production. The compound has wide prospect in development and application of anti-tumor medicaments.

Inventors

  • LIU XIAOCHUN
  • XU XIMING
  • LUO DONGDONG
  • HOU NING
  • ZHAO JUN
  • LIU LI
  • YANG MENGLIN
  • ZHANG PENGYAN
  • ZHANG JUNYI

Assignees

  • 中国海洋大学
  • 青岛海洋生物医药研究院

Dates

Publication Date
20260512
Application Date
20251231

Claims (10)

  1. 1. The benzenesulfonamide derivative is N, 4-dimethyl-N- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) benzenesulfonamide, and the structural formula of the benzenesulfonamide derivative is shown as formula I: , Formula I.
  2. 2. The method for producing a benzenesulfonamide derivative according to claim 1, characterized in that said method comprises the steps of: , (1) Weighing compound 1, dissolving in dichloromethane solution, adding TrtCl, stirring at room temperature, pouring water after the reaction is completed, extracting with dichloromethane for three times, separating organic phase, washing with saturated saline solution, drying, rotary evaporating, concentrating, and purifying by column chromatography to obtain compound 2; (2) Weighing the compound 2, dissolving in dichloromethane solution, adding CH 3 NH 2 , stirring at room temperature, pouring water after the reaction is completed, extracting with dichloromethane for three times, separating an organic phase, washing with saturated saline solution, drying, concentrating by rotary evaporation, and purifying by column chromatography to obtain a compound LD-J-7; (3) Weighing the compound LD-J-7, dissolving in ultra-dry dichloromethane, slowly adding NaH mineral oil mixture, stirring, then adding p-toluenesulfonyl chloride, carrying out reflux reaction, slowly pouring into water for quenching reaction after the reaction is completed, extracting with dichloromethane for three times, separating an organic phase, washing with saturated saline solution, drying, rotary evaporation and concentration, and purifying by column chromatography to obtain the compound LD-J-8; (4) Weighing the compound LD-J-8, dissolving in dichloromethane, adding trifluoroacetic acid, stirring at room temperature, adjusting pH to alkalescence after the reaction is completed, pouring into water, extracting with dichloromethane for three times, concentrating by rotary evaporation, and purifying by column chromatography to obtain the benzenesulfonamide derivative.
  3. 3. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.
  4. 4. Use of a benzenesulfonamide derivative of claim 1 or a pharmaceutical composition of claim 3 in the preparation of a PARP1 inhibitor.
  5. 5. The use according to claim 4, wherein the benzenesulfonamide derivative is capable of inhibiting PARP1 enzyme activity, inducing DNA damage and activating DDR signaling pathways.
  6. 6. Use of the benzenesulfonamide derivative of claim 1 or the pharmaceutical composition of claim 3 in the preparation of an antitumor drug.
  7. 7. The use of claim 6, wherein the tumor comprises squamous cell carcinoma, lung adenocarcinoma, large cell lung carcinoma and non-small cell lung carcinoma.
  8. 8. The use according to claim 7, wherein the benzenesulfonamide derivative is used in an amount of 0.1-50 μm.
  9. 9. The use according to claim 7, wherein the derivative comprising a benzenesulfonamide structure is capable of inducing lung cancer cell cycle arrest and apoptosis.
  10. 10. Use of a benzenesulfonamide derivative as claimed in claim 1 in combination with cisplatin for the preparation of an antitumor drug.

Description

Benzenesulfonamide derivative, preparation method thereof and application thereof in preparing PARP1 inhibitor and antitumor drug Technical Field The invention belongs to the technical field of medicines, and particularly relates to a benzenesulfonamide derivative, a preparation method thereof and application thereof in preparing PARP1 inhibitors and antitumor drugs. Background Lung cancer is one of the most common malignant tumors with highest morbidity and mortality, and constitutes a serious threat to human health. PARP1 (poly ADP-ribose polymerase 1) is a key DNA damage sensing and repair enzyme, mainly involved in the detection and repair of DNA Single Strand Breaks (SSBs). When DNA is damaged, PARP1 is able to rapidly localize to the site of damage and catalyze ADP-ribosylation reactions, recruiting repair-related proteins, thereby maintaining genomic stability. However, PARP1 is abnormally high in tumor cells, promoting tumor survival and growth by a variety of mechanisms (e.g., regulating tumor-associated gene transcription, promoting tumor microenvironment formation, etc.). When PARP1 is inhibited by inhibitor drugs, its repair function is lost, resulting in accumulation of DNA single strand breaks and conversion to more deadly double strand breaks upon DNA replication. This severe DNA damage strongly activates upstream kinases such as ATM/ATR, which lead to significant stabilization and accumulation of p53 protein by phosphorylating p 53. Eventually, the activated p53 pathway triggers a powerful cell cycle arrest or apoptosis program, thereby inhibiting tumor growth. At present, PARP1 inhibitors as drugs targeting DNA damage repair pathways have made remarkable progress in the treatment research and clinical practice of various tumors, particularly in BRCA1/2 mutation or homologous recombination repair defect (HRD) related tumors, and have been approved by FDA in tumor species such as ovarian cancer, breast cancer and the like. PARP1 inhibitors allow lesions to be converted into double strand breaks during replication by blocking PARP 1-mediated single strand DNA break repair, whereas in tumor cells lacking efficient homologous recombination repair, such cumulative lesions lead to cell death, thus implementing a "synthetic lethal" therapeutic strategy. In the field of lung cancer, especially non-small cell lung cancer (NSCLC), studies have shown that some patients have defects in DNA repair or abnormal P53 pathways, and may be sensitive to PARP1 inhibitors. Currently, a number of PARP1 inhibitors (e.g., olapari, tazopari, nilaparib) are being tested clinically in lung cancer patients, focusing on exploring their use in combination with chemotherapy, radiation therapy, and Immune Checkpoint Inhibitors (ICIs) in an effort to improve efficacy and overcome resistance. Therefore, the PARP1 inhibitor has potential accurate medication value in lung cancer treatment, can become an important component of combined treatment, and provides more treatment options for patients with specific molecular characteristics. The benzenesulfonamide moiety is the basic pharmacophore of modern pharmaceutical chemistry. The scaffold is characterized in that the benzene ring is linked to a sulfonamide group (-SO 2NH2), which is the basis for a number of therapeutic agents. Its unique chemical properties, including the ability of the sulfonamide group to act as an effective zinc binding group, makes it possible to develop drugs against a wide range of enzymes and receptors. This versatility has led to the discovery of benzenesulfonamide derivatives for use in anticancer, antibacterial, anti-inflammatory, anticonvulsant and antidiabetic agents. Disclosure of Invention The invention aims to provide a benzenesulfonamide derivative, a preparation method thereof and application thereof in preparing PARP1 inhibitors and antitumor drugs. The invention synthesizes a new benzenesulfonamide derivative, namely a compound N, 4-dimethyl-N- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) benzenesulfonamide (LD-J-9 for short), which belongs to a derivative containing a benzenesulfonamide structure, and the invention proves that the LD-J-9 directly targets PARP1 in NSCLC to cause DNA damage and regulate and control p53 signal channels to inhibit the growth of non-small cell lung cancer tumors. The invention provides candidate lead compounds for the research and development of novel PARP1 inhibitors of anti-lung cancer drugs. In order to achieve the aim of the invention, the invention is realized by adopting the following technical scheme: The invention provides a benzenesulfonamide derivative with PARP1 inhibitory activity, the structural formula of which is shown as formula I; Formula I. The invention provides a preparation method of the benzenesulfonamide derivative, which comprises the following steps: (1) Weighing compound 1, dissolving in dichloromethane solution, adding TrtCl, stirring at room temperature, pouring water after the reaction is co