CN-121991139-A - Ferrocenyl hydrophobic tag degradation agent targeting GPX4 as well as preparation method and application thereof

Abstract

The invention relates to a novel ferrocenyl hydrophobic tag degradation agent targeting GPX4, and a preparation method and application thereof. The GPX4 protein degradation agent has a chemical structure shown in a formula (I). Pharmacological experiments show that the derivative or salt disclosed by the invention can obviously degrade GPX4 protein in iron death sensitive cells (such as HT1080, OS-RC-2, 4T1 and 786-O), and has strong antiproliferative activity on four cell lines. The invention also provides a preparation method of the derivative and pharmaceutically acceptable salts thereof, and application of the derivative as a GPX4 degradation agent. Formula (I).

Inventors

• WANG YONG
• ZHU ZEQI
• NING YAO
• WANG YICHENG

Assignees

• 中国海洋大学

Dates

Publication Date

20260508

Application Date

20251219

Claims (8)

1. 1. A ferrocenyl hydrophobic tag degrading agent targeting GPX4 and pharmaceutically acceptable salt thereof, wherein the degrading agent has the following structural general formula: I is a kind of R 1 is selected from one of the following groups: Wherein q is 1-3; x is selected from one of the following linking groups: Wherein n is 1-15, m is 1-6; R 2 is selected from one of the following groups: wherein p is 1 to 5.
2. 2. The GPX 4-targeted ferrocenyl hydrophobic tag degradation agent and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutically acceptable salts are inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, sulfuric acid or phosphate, and the organic acid salts are selected from methanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate, citrate, tartrate, lactate, pyruvate, acetate, maleic acid or succinate, fumarate, salicylate, phenylacetate or mandelate.
3. 3. The GPX 4-targeted ferrocenyl hydrophobic tag degradation agent and pharmaceutically acceptable salts thereof according to claim 1, wherein the GPX 4-targeted ferrocenyl hydrophobic tag degradation agent and pharmaceutically acceptable salts thereof are selected from any one of the following structures: 。
4. 4. The preparation method of the ferrocenyl hydrophobic tag degradation agent targeting GPX4 and the pharmaceutically acceptable salt thereof according to claim 1, comprising the following steps: 1) The synthesis of a key intermediate Z1 comprises the steps of reacting beta-phenethylamine 1 with methyl formate to generate corresponding aldehyde 2, generating an intermediate 3 by the intermediate 2 under the action of DIPEA and POCl 3 , generating an intermediate 7 by the intermediate 3 and raw materials of thiophene-2-formaldehyde 4, 2-chloro-4-aminophenol 5 and propiolic acid 6 through Ugi four-component reaction, and generating the key intermediate Z1 by the intermediate 7 and bromo-tert-butyl ester through substitution reaction and Boc protecting group removal; The synthetic route of the key intermediate Z1 is shown in the following formula: Reagents and reaction conditions (a) methyl formate, N 2 ,,50℃,12 h,(b) POCl 3 , DIPEA, DCM, 40 ℃ C., 1h, (C) MeOH,40 ℃ C., 12h, (d) t-butyl bromoacetate, meCN, K 2 CO 3 , room temperature, 2h; 2) TFA, DCM, room temperature, 1h; 2) The synthesis of the target compound comprises the steps of carrying out condensation reaction on a key intermediate Z1 and tert-butyl (10-aminodecyl) carbamate and 11-aminoundecanoate respectively to generate intermediate 8 and 9, carrying out condensation reaction on the intermediate 8 and R 3 -COOH respectively to generate target compounds HFc-1 and HFc-2 after Boc protection is removed from the intermediate 8, carrying out reductive amination reaction on the intermediate and ferrocene formaldehyde to generate target compounds HFc-3, and carrying out condensation reaction on the intermediate 9 and R 4 -NH 2 and R 5 -H respectively to generate target compounds HFc-4-HFc-9 and HFc-10-HFc-12 after protective groups are removed from the intermediate 9; the synthetic route of the target compound is shown as the following formula: Reagents and reaction conditions (a) t-butyl (10-aminodecyl) carbamate, HATU, DIPEA, DMF, room temperature, 4H,66-78%; (b) t-butyl 11-aminoundecanoate, HATU, DIPEA, DMF, room temperature, 4H, 56-75%; (c) TFA, DCM, room temperature, 1H, 100%; 2) R 3 -COOH/R 4 -NH 2 /R 5 -H, HATU, DIPEA, DMF, room temperature, 4H, 55-65%; (d) NaBH (OAc) 3 ,Mg 2 SO 4 , DCM, room temperature, 12H.
5. 5. The application of the ferrocenyl hydrophobic tag degrading agent targeting GPX4 and pharmaceutically acceptable salt thereof as GPX4 degrading agent in claim 1.
6. 6. The application of ferrocenyl hydrophobic tag degrading agents targeting GPX4 and pharmaceutically acceptable salts thereof as GPX4 protein inhibitors according to claim 1.
7. 7. The application of the ferrocenyl hydrophobic tag degrading agent targeting GPX4 and pharmaceutically acceptable salt thereof as GPX4 degrading agent in preparing antitumor drugs in claim 1.
8. 8. The use according to claim 7, wherein the tumour is an iron death sensitive tumour selected from human breast cancer, human fibrosarcoma and renal cancer.

Description

Ferrocenyl hydrophobic tag degradation agent targeting GPX4 as well as preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a novel ferrocenyl hydrophobic tag degradation agent targeting GPX4, and a preparation method and application thereof. Background Iron death (Ferroptosis) is an iron-dependent, novel apoptosis pattern that is distinguished from apoptosis, cell necrosis, and autophagy. The essence of iron death is the depletion of glutathione, the decrease in glutathione peroxidase (GPX 4) activity, the inability of lipid oxide to metabolize by GPX4 catalyzed glutathione reductase reactions, after which divalent iron ions oxidize lipids to produce reactive oxygen species, thereby contributing to the occurrence of iron death. GPX4 is a key protein mediating iron death, while the GSH-GPX4 antioxidant system plays a central role in the iron death pathway. GPX4 can convert cytotoxic lipid hydroperoxide (LOOHs) into nontoxic lipid alcohol (LOH) in the presence of reduced Glutathione (GSH), and can repair lipid oxidative damage, thereby relieving lipid oxidative stress of cells, and finally avoiding iron death. In addition, studies have reported that GPX4 is also closely related to tumor resistance. Therefore, the expression level of GPX4 is reduced or the activity of GPX4 is inhibited, so that the drug-resistant tumor cells can be effectively induced to die. However, since GPX4 lacks traditional drug binding sites, only a few GPX4 inhibitors (such as RSL3, ML162 and ML 210) are currently found, which are mainly covalent inhibitors that bind to the selenocysteine residue (Sec 46) of GPX 4. Unfortunately, the clinical progress of these GPX4 inhibitors is limited, one of the core reasons being that they have an unresolved problem of poor pharmacokinetic properties. Therefore, the design of the degradation agent targeting GPX4 provides a new direction for the research and development of anti-tumor drugs. In recent years, targeted protein degradation technology (Targeted protein degradation, TPD) has been developed rapidly, and compared with the traditional small molecule inhibitor, TPD drugs have the advantages of being capable of degrading target proteins rapidly, allowing protein site mutation, breaking through non-patent drug targets, reducing drug resistance and the like. Hydrophobic tag (HyT) is another common white matter degradation strategy in TPD technology in addition to proteolytically targeted chimeras (PROTAC). HyT is a bifunctional molecule, one end of which is a ligand that binds to a target protein, unlike PROTAC, and the other end of which is a hydrophobic and bulky group (e.g., adamantane). When HyT binds to a target protein, the hydrophobic moiety is exposed at its surface, resulting in the target protein being in a misfolded state, which is subsequently degraded by cellular Protein Quality Control (PQC) mechanisms. Compared with PROTAC, the HyT molecule has smaller molecular weight, can avoid the related toxicity of the CRBN ligand, and has better bioavailability and pharmacokinetics. HyT do not require the formation of ternary complexes and eliminate the concern of "hook effect" due to high drug concentrations. In addition, a reasonable design is more likely to be achieved than molecular sieves. Therefore, hyT also becomes a promising alternative degradation strategy to PROTAC based on these advantages. Ferrocene is an organic transition metal compound with aromatic properties, having a unique "sandwich structure, which exhibits good lipophilicity, high stability, low toxicity, and reversible redox properties, and is also susceptible to functionalization. With these good properties, ferrocene structures have been widely introduced into drug molecules. After searching, ferrocene is used as a hydrophobic label for degrading GPX4 protein and other proteins, and no document is reported. Disclosure of Invention Aiming at the defects of the prior art, the first object of the invention is to provide a ferrocenyl hydrophobic tag degradation agent targeting GPX 4. The second object of the invention is to provide a preparation method of the ferrocenyl hydrophobic tag degradation agent targeting GPX 4. A third object of the present invention is to provide the use of the above-described GPX 4-targeting ferrocenyl hydrophobic tag degrading agent. The invention designs and successfully synthesizes a series of hydrophobic tag GPX4 degrading agents (HFc) based on ferrocene by taking a GPX4 inhibitor ML162 derivative as a target protein ligand. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a ferrocenyl hydrophobic tag degrading agent targeting GPX4 and pharmaceutically acceptable salt thereof, wherein the degrading agent has the following structural general formula: I is a kind of R 1 is selected from one of the following groups: Wherein q is 1-3; x is selected fr