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CN-122005582-A - Application of 1,2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs

CN122005582ACN 122005582 ACN122005582 ACN 122005582ACN-122005582-A

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of 1,2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs. The invention discloses AARS1 as lactate modification enzyme for the first time, which can catalyze NMNAT1 to generate lactate modification, further enhance the interaction between the NMNAT1 and PARP1, promote PARP1 activity, and cause the tumor cells with homologous recombination repair defects to generate drug resistance to PARP inhibitors. Based on the new mechanism, the invention screens and verifies that the small molecular compound 1,2,3, 6-tetra-O-galloyl-beta-D-glucose can effectively inhibit the catalytic activity of AARS1, and reduce the lactate modification level of NMNAT1, thereby recovering the sensitivity of drug-resistant tumors to PARP inhibitors.

Inventors

  • JU JUNYI
  • SONG YIRAN
  • Hua Huilian

Assignees

  • 泰州市人民医院

Dates

Publication Date
20260512
Application Date
20260310

Claims (9)

  1. The application of 1.1,2,3,6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs is characterized in that the structural formula of the 1,2,3, 6-tetra-O-galloyl-B-D-glucose is as follows: 。
  2. 2. the use according to claim 1, wherein the anti-tumor or tumor-sensitizing agent is formulated per liter as follows: S1, weighing 1-10 g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose, and dissolving the 1-10 g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose in 100mL of DMSO to obtain a1, 2,3, 6-tetra-O-galloyl-BETA-D-glucose solution; S2, mixing the 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose solution in the S1 with 400mL PEG300, 50mL Tween-80 and 450mL physiological saline to obtain the antitumor drug or tumor sensitization drug.
  3. 3. The use according to claim 2, wherein the anti-tumor or tumor-sensitizing agent is formulated per liter as follows: S1, weighing 2g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose, and dissolving the 2g in 100mL of DMSO to obtain 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose solution; S2, mixing the 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose solution in the S1 with 400mL PEG300, 50mL Tween-80 and 450mL physiological saline to obtain the antitumor drug or tumor sensitization drug.
  4. 4. The use according to claim 2, wherein the antineoplastic or tumor sensitization agent further comprises pharmaceutically acceptable excipients.
  5. 5. The use according to claim 4, wherein the pharmaceutically acceptable auxiliary material is one or more of a filler, a flavoring agent, an adhesive, a disintegrant, a lubricant, an antacid and a nutrition enhancer.
  6. 6. The use according to claim 2, wherein the anti-tumor or tumor-sensitizing pharmaceutically acceptable dosage form is any one of an oral, an injectable, and a nano-targeting formulation.
  7. 7. The use of claim 2, wherein the anti-tumor drug or tumor-sensitizing drug is directed against a tumor type comprising any one of ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer.
  8. 8. The use of claim 1, wherein the anti-tumor drug potentiated by the tumor-sensitizing drug is a PARP inhibitor.
  9. 9. The use of claim 8, wherein the PARP inhibitor comprises at least one of Olaparib, niraparib, rucaparib and Talazoparib.

Description

Application of 1,2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of 1,2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs. Background Synthetic lethal effects refer to the selective killing of cancer cells by utilizing the specific weakness of cancer cell BRCA gene mutations leading to homologous recombination repair defects, using PARP inhibitors to block their backup DNA repair pathways. PARP inhibitors have been widely used clinically to treat tumors such as ovarian cancer, breast cancer, prostate cancer and pancreatic cancer, which are defects in homologous recombination repair, and have remarkable therapeutic effects. However, with the wide clinical application of PARP inhibitors, the problem of drug resistance is increasingly prominent, becoming a major bottleneck limiting their long-term efficacy. Studies have shown that some patients develop acquired resistance after treatment with PARP inhibitors, leading to disease progression. The current research on the drug resistance mechanism of PARP inhibitors mainly focuses on the aspects of BRCA gene back mutation, drug efflux pump up regulation, homologous recombination restoration function recovery and the like, but a considerable proportion of drug resistance cases cannot be explained by the mechanism, so that other unknown drug resistance regulation and control ways are suggested. Tumor cells undergo metabolic remodeling, one of the most important features of which is the metabolism of glucose to lactic acid by aerobic glycolysis. In recent years, lactic acid is found to be not only an intermediate product of energy metabolism, but also can be used as a substrate to mediate protein to undergo lactate modification, and is involved in the regulation and control of various biological processes such as gene transcription, DNA repair and the like. AARS1, alanyl tRNA synthetase 1, is a recently discovered lactate modification enzyme that mediates lactate modification of various proteins, thereby regulating their function. Research shows that AARS1 plays an important role in the occurrence and development of various tumors such as gastric cancer and the like. In the prior art, beta-alanine has been reported to be an inhibitor of AARS1, capable of inhibiting the catalytic activity of AARS1 to some extent. However, the function of the lactate metabolism of tumor cells and related protein lactate modification in PARP inhibitor resistance is not clear, and no research has been made so far to reveal whether the lactate modification is involved in regulating the sensitivity of homologous recombination repair deficient tumors to PARP inhibitors. In particular, although β -alanine is known as an AARS1 inhibitor, no prior art has reported targeting AARS1 or using β -alanine to restore sensitivity to PARP inhibitors in tumors such as ovarian cancer, breast cancer, etc. that are deficient in homologous recombination repair. In addition, the inhibition effect of beta-alanine on AARS1 is limited, clinical application requirements are difficult to meet, and there is a need to develop more efficient AARS1 inhibitors and to reverse the effective strategy of PARP inhibitor resistance by interfering with the lactate modification pathway. Disclosure of Invention The invention aims to provide application of1, 2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs, which solves the problems that the prior art lacks high-efficiency AARS1 inhibitors and does not have the function of inhibiting NMNAT1 lactate modification by targeting AARS1 to restore drug-resistant tumors to PARP inhibitor sensitivity. The technical scheme adopted by the invention is as follows: The invention provides application of 1,2,3, 6-tetra-O-galloyl-B-D-glucose and derivatives thereof as antitumor drugs and/or tumor sensitization drugs, wherein the structural formula of the 1,2,3, 6-tetra-O-galloyl-B-D-glucose is as follows: 。 preferably, the derivative is a compound derived from 1,2,3, 6-tetra-O-galloyl-B-D-glucose as a basic backbone. Preferably, the formulation of the antitumor drug or tumor-sensitized drug per liter is as follows: S1, weighing 1-10 g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose, and dissolving the 1-10 g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose in 100mL of DMSO to obtain a1, 2,3, 6-tetra-O-galloyl-BETA-D-glucose solution; S2, mixing the 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose solution in the S1 with 400mL PEG300, 50mL Tween-80 and 450mL physiological saline to obtain the antitumor drug or tumor sensitization drug. Preferably, the formulation of the antitumor drug or tumor-sensitized drug per liter is as follows: S1, weighing 2g of 1,2,3, 6-tetra-O-galloyl-BETA-D-glucose, and dissolving th