CN-121974826-A - Iron death/HDAC 6 dual-function inhibitor and preparation method and application thereof

Abstract

The invention relates to an iron death/HDAC 6 difunctional inhibitor, a preparation method and application thereof, wherein the structure of the difunctional inhibitor is shown in a formula I, and the difunctional inhibitor has strong ROS scavenging ability and lipid peroxidation inhibiting effect, can inhibit iron death caused by an iron death inducer, and can relieve cerebral ischemia and nerve injury caused by cerebral ischemia, and relieve neurological diseases symptoms such as Alzheimer disease, parkinsonism and the like. Therefore, the iron death/HDAC 6 difunctional iron death inhibitor provided by the invention can play a synergistic effect through multiple actions to treat iron death-related diseases, especially nervous system degenerative diseases, and provides candidate compounds for subsequent drug development. 。

Inventors

• WANG YONG
• Yan Jiangkun
• FAN XUEJING
• Lv ruicheng

Assignees

• 中国海洋大学

Dates

Publication Date

20260505

Application Date

20251222

Priority Date

20250728

Claims (8)

1. 1. An iron death/HDAC 6 bifunctional inhibitor having the structural formula shown in formula I below: ; Wherein R 1 、R 2 is independently selected from hydrogen, C 1-8 alkyl or an isomer thereof, cycloalkyl of C 3-8 , R 1 and R 2 are connected to form cycloalkyl, alicyclic hydrocarbon, heterocyclic group, phenyl, heterocyclic aromatic group, substituted phenyl and substituted heterocyclic aromatic group with 3-7 chain lengths; R 3 is selected from hydrogen, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 alkoxy, C 1-20 alkanoyl, C 1-20 alkoxycarbonyl, C 1-20 alkanoyloxy, C 1-20 alkoxycarbonyloxy, C 3 ~C 12 cycloalkyl, adamantyl or polyalkynyl, aryl or substituents thereof; A. B is independently selected from CH or nitrogen; c is selected from amide or sulfonamide; D and A, B can form an aliphatic ring or an aromatic ring; linker is selected from the group consisting of C 1-20 alkylene, C 6-14 aryl, heteroaryl having 5 to 14 ring atoms, heterocyclyl having 5 to 14 ring atoms, C 3-14 carbocyclyl, or-X-C 2-20 alkenylene; In linker, X is selected from C 6-14 aryl, heteroaryl having 5 to 14 ring atoms, C 3-14 carbocyclyl or heterocyclyl having 5 to 14 ring atoms, C 6-14 aryl, heteroaryl having 5 to 14 ring atoms, heterocyclyl having 5 to 14 ring atoms or C 3-14 carbocyclyl is optionally substituted with one or more groups selected from halogen, oxo, C 1-20 alkyl, C 1-20 haloalkyl, C 1-20 alkoxy, C 1-20 alkanoyl, C 1-20 alkoxycarbonyl, C 1-20 alkanoyloxy, C 1-20 alkoxycarbonyloxy.
2. 2. The iron death/HDAC 6 bi-functional inhibitor according to claim 1, wherein the iron death/HDAC 6 bi-functional inhibitor according to formula I is selected from any one of I-1~I-32, the specific structure of I-1~I-32 is as follows: 。
3. 3. a method of preparing the iron death/HDAC 6 bi-functional inhibitor according to claim 1, comprising the steps of: 1) 4-chloro-3-nitrobenzoyl chloride or 4-chloro-3-nitrobenzenesulfonyl chloride (compound 1) is used as a starting material, and is subjected to amide/sulfonamide amidation reaction with corresponding amine respectively to generate a series of amide/sulfonamide intermediate compounds 2; 2) Respectively carrying out substitution reaction on the compound 2 and different amino fragments under alkaline conditions to generate a compound 3, and then reducing nitro on a benzene ring into amino by catalytic hydrogenation reaction to obtain a compound 4; 3) The compound 4 and the corresponding aldehyde group-containing compound are subjected to reductive amination reaction to form a key intermediate 5; 4) The intermediate 5 reacts with hydroxylamine (NH 2 OH) in methanol solution to generate ester group conversion reaction, and the ester group is converted into hydroxamic acid group, so that the target compound I-1~I-32 is finally obtained; the synthetic route is as follows: ; Reagents and reaction conditions (a) methylamine hydrochloride, triethylamine, dichloromethane, 4 hours at room temperature, (b) cyclohexylamine, potassium carbonate, DMSO,80 ℃ overnight, (C) Pd/C, hydrogen, methanol, room temperature, overnight, (d) methyl 4-formylbenzoate, sodium triacetoxyborohydride, dichloromethane, room temperature, 4 hours, (e) NH 2 OH/CHOH,0 ℃ to room temperature, 6 hours.
4. 4. Use of the iron death/HDAC 6 dual function inhibitor according to claim 1 for the manufacture of a medicament for iron death inhibitor, HDAC6 inhibitor, iron death/HDAC 6 dual function inhibitor, amyloid (aβ) inhibitor, tau protein preparation, prevention and/or treatment of aβ protein or Tau protein mediated diseases.
5. 5. The use according to claim 4, wherein the HDAC6 inhibitor comprises a Histone Deacetylase (HDACs) inhibitor, a formulation that promotes deacetylation of cytohistones H3 and H4 and α -Tubulin, a medicament for preventing and/or treating thioredoxin mediated diseases.
6. 6. The use according to claim 4, wherein the iron death/HDAC 6 bi-functional inhibitor treats iron death as a free radical scavenger to reduce intracellular reactive oxygen species, lipid peroxides, thereby rescuing iron death due to reactive oxygen species.
7. 7. The use according to claim 4, wherein the iron death/HDAC 6 bi-functional inhibitor acts as a free radical scavenger to rescue iron death due to the iron death inducer.
8. 8. An iron death and HDAC6 pharmaceutical composition comprising a compound of the iron death/HDAC 6 bifunctional inhibitor of claim 1, or a stereoisomer, tautomer, solvate, prodrug, isotopic label, or a pharmaceutically acceptable salt, carrier, or adjuvant thereof.

Description

Iron death/HDAC 6 dual-function inhibitor and preparation method and application thereof Technical Field The invention relates to an iron death/HDAC 6 difunctional inhibitor and a preparation method and application thereof, belonging to the technical field of medicines. Background Iron death (ferroptosis) is a novel form of iron-dependent cell death discovered in recent years, which is essentially programmed death caused by oxidative stress-mediated imbalance in lipid peroxidation metabolism. The core mechanism of this process is the disruption of cellular redox homeostasis, manifested by abnormal accumulation of lipid reactive oxygen species (reactive oxygen species, ROS). As a unique pathway distinct from other modes of cell death, such as apoptosis, necrosis, etc., the regulatory network of iron death involves multiple interactions of the iron metabolism, lipid peroxidation, and the cysteine-glutathione antioxidant system. Early studies have elucidated two key regulatory axes of this death pathway, the cysteine uptake and glutathione biosynthesis pathway, and the glutathione peroxidase 4 (GPX 4) -mediated lipid peroxide clearance mechanism. Iron death inducers significantly impair the antioxidant defenses of cells by targeting these pathway nodes (e.g., inhibiting cystine transporter, depleting glutathione reserves or directly inactivating GPX4, etc.), resulting in irreversible accumulation of lipid peroxides, ultimately leading to cell death. Notably, recent studies revealed a more complex metabolic regulation network in which iron homeostasis catalyzes the lipid peroxidation process by Fenton reaction, polyunsaturated fatty acid metabolism provides a substrate for lipid peroxidation, and cysteine metabolism maintains GPX4 activity by glutathione synthesis, and the metabolic triangle network formed by the three has become a key target for iron death regulation. Based on the metabolic interaction mechanism, researchers have developed an intervention strategy for different nodes, namely, an iron chelator inhibits oxidative damage by isolating free iron, while a lipophilic antioxidant such as ferrostatin-1 (Fer-1) can selectively remove lipid free radicals and block peroxidation chain reaction. Currently, iron death control shows wide prospects in the field of disease treatment, namely, drug-resistant tumor cells can be specifically cleared by inducing iron death, and inhibition of iron death has a protective effect on neurodegenerative diseases and ischemia reperfusion injury. Wherein, the Fer-1 and the derivatives thereof are used as free radical capturing agents and have excellent iron death inhibition effect, and the structural formula of the Fer-1 and the derivatives thereof is as follows: The aryl alkylamine structure endows unique free radical capturing capability, and has become an important lead compound for drug development in the field. Intensive research into the structure-activity relationship of these compounds will drive the development of new generation inhibitors with more targeting and bioavailability. Histone deacetylase 6 (HDAC 6) acts as a key effector in epigenetic regulatory networks, playing a dual regulatory role in physiological function and pathological processes of the central nervous system. Under physiological conditions, HDAC6 regulates microtubule network homeostasis by maintaining the deacetylation state of α -tubulin, thereby promoting neuronal synaptic plasticity and axon transport. Its unique cytoplasmic localization properties distinguish it from other nuclear HDAC family members, forming a unique non-histone modification regulatory pattern. In neurodegenerative diseases, HDAC6 exhibits disease-specific alterations in subcellular localization (e.g., nuclear accumulation or aggregation-body enrichment), the expression and activity of which vary depending on the type of disease. Typical pathological stimuli such as apolipoprotein E/Abeta oligomer can trigger abnormal nuclear translocation of HDAC6, and the transcriptional activity of brain-derived neurotrophic factor (BDNF) is obviously reduced by inhibiting acetylation modification of histone H3K9/K14 sites, so that the epigenetic cascade reaction finally leads to synaptic function injury and cognitive dysfunction, and forms the molecular basis of neurodegenerative diseases such as Alzheimer disease. Notably, HDAC6 occupies a pivotal role in protein quality control systems, in that it promotes misfolded protein degradation by modulating the ubiquitin-proteinase system (UPS) on the one hand, and enhances lysosomal clearance by activating chaperone-mediated autophagy (CMA) on the other hand, forming a two-way synergistic protein homeostasis maintenance mechanism. This property makes it a common therapeutic target for a variety of neurodegenerative diseases, including Alzheimer's disease, huntington's disease, parkinson's disease and amyotrophic lateral sclerosis, all of which are characterized by pathological protein accum