Search

EP-4741427-A1 - GLYCAN, PREPARATION METHOD THEREFOR AND USE THEREOF, AND ANTI-TUMOR DRUG

EP4741427A1EP 4741427 A1EP4741427 A1EP 4741427A1EP-4741427-A1

Abstract

A glycan, a preparation method therefor and a use thereof, and an anti-tumor drug, relating to the technical field of medicines. The glycan having a structure as shown in formula I has good anti-tumor activity and good safety. The results of the test example show that the glycan has a good proliferation inhibition effect on pancreatic cancer cells, has no cytotoxicity to the growth of hepatocytes, and shows better safety characteristics compared with a positive drug gemcitabine; in addition, the pancreatic cancer cells are sensitive to the glycan, thereby overcoming the problem that the pancreatic cancer cells have certain drug resistance to gemcitabine.

Inventors

  • YE, XINSHAN
  • QIN, Xianjin
  • XU, CHENGHAO
  • MO, Juan

Assignees

  • Peking University

Dates

Publication Date
20260513
Application Date
20240905

Claims (20)

  1. A glycan having a structure shown in Formula I: wherein in the Formula I, n 1 is 0 to 6, n 2 is 0 to 2, n 3 is 0 to 3, and R is C1-C10 alkoxy.
  2. The glycan of claim 1, wherein n 1 is 1 to 5.
  3. The glycan of claim 2, wherein n 1 is 2 to 4.
  4. The glycan of claim 1, wherein n 2 is 0 to 1.
  5. The glycan of claim 1, wherein n 3 is 1 to 3.
  6. The glycan of claim 5, wherein n 3 is 2 to 3.
  7. The glycan of claim 1, wherein R is selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.
  8. The glycan of claim 7, wherein R is C5-C10 alkoxy.
  9. The glycan of claim 8, wherein R is linear alkoxy.
  10. The glycan of any one of claims 1 to 9, wherein n 1 is 3, n 2 is 0, n 3 is 3, and R is n-octoxy.
  11. A method for preparing the glycan of any one of claims 1 to 10, comprising the following steps: mixing a compound 1-3, silver trifluoromethanesulfonate, p -toluenesulfenyl chloride, and an organic solvent, and conducting a first activation to obtain a first activation product system; mixing the first activation product system and a compound 1-4, and conducting a first glycosylation coupling to obtain a first coupling product system; mixing the first coupling product system, the silver trifluoromethanesulfonate, and the p -toluenesulfenyl chloride, and conducting a second activation to obtain a second activation product system; mixing the second activation product system and a compound 1-5, and conducting a second glycosylation coupling to obtain a compound 1-2; and subjecting the compound 1-2 to debenzoylation and debenzylation-debenzalization in sequence to obtain the glycan having the structure shown in the Formula I, wherein the compound 1-3, the compound 1-4, the compound 1-5, and the compound 1-2 have the following structural formulas, respectively: wherein n 1 , n 2 , n 3 , and R are as defined in the Formula I.
  12. The method of claim 11, wherein in raw materials for the first activation, a molar ratio of the compound 1-3, the silver trifluoromethanesulfonate, and the p -toluenesulfenyl chloride is in a range of 1 : 1.2-5 : 1.
  13. The method of claim 11 or 12, wherein the first activation is conducted at a temperature of -60°C to -78°C for 2 minutes to 10 minutes.
  14. The method of claim 11, wherein in raw materials for the first glycosylation coupling, a molar ratio of the compound 1-3 to the compound 1-4 is in a range of 1 : 0.85-0.92.
  15. The method of claim 11 or 14, wherein the first glycosylation coupling comprises conducting a first stage reaction and a second stage reaction in sequence; wherein the first stage reaction is conducted at a temperature of -60°C to -78°C for 5 minutes to 15 minutes; and after completion of the first stage reaction, an obtained reaction product is subjected to natural heating from the temperature for the first stage reaction to conduct the second stage reaction, and the second stage reaction is conducted for 1.5 hours to 2.5 hours.
  16. The method of claim 11, wherein in raw materials for the second activation, a molar ratio of the compound 1-4, the silver trifluoromethanesulfonate, and the p -toluenesulfenyl chloride is in a range of 1 : 1.2-5 : 1.
  17. The method of claim 11 or 16, wherein the second activation is conducted at a temperature of -60°C to -78°C for 2 minutes to 10 minutes.
  18. The method of claim 11, wherein in raw materials for the second glycosylation coupling, a molar ratio of the compound 1-4 to the compound 1-5 is in a range of 0.8-0.85 : 1-2.
  19. The method of claim 11 or 18, wherein the second glycosylation coupling comprises conducting a first stage reaction and a second stage reaction in sequence; wherein the first stage reaction is conducted at a temperature of -60°C to -78°C for 5 minutes to 15 minutes; and after completion of the first stage reaction, an obtained reaction product is subjected to natural heating from the temperature for the first stage reaction to conduct the second stage reaction, and the second stage reaction is conducted for 1.5 hours to 2.5 hours.
  20. The method of claim 11, wherein subjecting the compound 1-2 to the debenzoylation and the debenzylation-debenzalization in sequence comprises: mixing the compound 1-2 and an organic solvent, and conducting the debenzoylation in a basic environment to obtain a debenzoylated compound; and mixing the debenzoylated compound, a palladium-on-carbon catalyst, an organic solvent, and water, and conducting the debenzylation-debenzalization in a hydrogen atmosphere.

Description

The present application claims priority to Chinese Patent Application No. CN202311139456.1 filed with the China National Intellectual Property Administration (CNIPA) on September 05, 2023 and entitled "GLYCAN AND PREPARATION METHOD AND USE THEREOF, AND ANTITUMOR DRUG", which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to the technical field of pharmaceuticals, and in particular relates to a glycan and a preparation method and use thereof, and an antitumor drug. BACKGROUND Pancreatic cancer, a clinically common digestive system tumor with extremely high malignancy, exhibits a five-year survival rate of not greater than 10%, making it the second leading cause of cancer-related deaths. The lack of sensitive and specific markers for the occurrence and development of pancreatic cancer results in difficulty in early diagnosis, rapid disease progression, and poor prognosis. Since pancreatic cancer develops aggressively, which is characterized by local growth into surrounding nerves and blood vessels and early distant metastasis, most patients are unable to receive complete resection surgery. Current clinical treatment primarily employs comprehensive approaches including radiotherapy, interventional therapy, supportive care, and immunotherapy to alleviate patient symptoms and prolong survival. The first-line drug currently used clinically for treating pancreatic cancer is gemcitabine. While gemcitabine demonstrates significant anti-pancreatic cancer efficacy, gemcitabine generally induces adverse effects such as bone marrow suppression, skin rash, gastrointestinal side effects, and drug resistance while inhibiting tumor growth and alleviating the condition. Furthermore, the side effects inflict systemic damage on the human body. Therefore, there is an urgent clinical need to develop anti-pancreatic cancer drugs that are highly effective and have minimal side effects. SUMMARY An object of the present disclosure is to provide a glycan and a preparation method and use thereof, and an antitumor drug. In the present disclosure, the glycan exhibits a desirable antitumor activity, especially an anti-pancreatic cancer activity, as well as satisfactory safety. To achieve the above object, the present disclosure provides the following technical solutions: The present disclosure provides a glycan having a structure shown in Formula I: where in the Formula I, n1 is 0 to 6, n2 is 0 to 2, n3 is 0 to 3, and R is C1-C10 alkoxy. In some embodiments, n1 is 1 to 5. In some embodiments, n1 is 2 to 4. In some embodiments, n2 is 0 to 1. In some embodiments, n3 is 1 to 3. In some embodiments, n3 is 2 to 3. In some embodiments, R is selected from the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy. In some embodiments, R is C5-C10 alkoxy. In some embodiments, R is linear alkoxy. In some embodiments, n1 is 3, n2 is 0, n3 is 3, and R is n-octoxy. The present disclosure further provides a method for preparing the glycan as described above, including the following steps: mixing a compound 1-3, silver trifluoromethanesulfonate, p-toluenesulfenyl chloride, and an organic solvent, and conducting a first activation to obtain a first activation product system;mixing the first activation product system and a compound 1-4, and conducting a first glycosylation coupling to obtain a first coupling product system;mixing the first coupling product system, the silver trifluoromethanesulfonate, and the p-toluenesulfenyl chloride, and conducting a second activation to obtain a second activation product system;mixing the second activation product system and a compound 1-5, and conducting a second glycosylation coupling to obtain a compound 1-2; andsubjecting the compound 1-2 to debenzoylation and debenzylation-debenzalization in sequence to obtain the glycan having the structure shown in the Formula I,where the compound 1-3, the compound 1-4, the compound 1-5, and the compound 1-2 have the following structural formulas, respectively: where n1, n2, n3, and R are as defined in the Formula I. In some embodiments, a molar ratio of the compound 1-3, the silver trifluoromethanesulfonate, and the p-toluenesulfenyl chloride is in a range of 1 : 1.2-5 : 1. In some embodiments, the first activation is conducted at a temperature of -60°C to -78°C for 2 min to 10 min. In some embodiments, a molar ratio of the compound 1-3 to the compound 1-4 is in a range of 1 : 0.85 to 1 : 0.92. In some embodiments, the first glycosylation coupling includes conducting a first stage reaction and a second stage reaction in sequence; where the first stage reaction is conducted at a temperature of -60°C to -78°C for 5 min to 15 min; and after completion of the first stage reaction, an obtained reaction product is subjected to natural heating from the temperature for the first stage reaction to conduct the second stage reaction, and the second stage reaction is conducted for