Ferroptosis inhibitor alpha-lipoic acid derivatives and preparation methods and applications thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to an α-lipoic acid derivative, a ferroptosis inhibitor, and a preparation method and application thereof. The preparation method of the α-lipoic acid derivative comprises the following steps: 2-cyano phenothiazine and lithium aluminum hydride undergo a reduction reaction to generate an intermediate product shown in formula II; the intermediate product and α-lipoic acid are mixed, and a condensation reaction occurs under the action of a condensing agent to obtain the α-lipoic acid derivative; the α-lipoic acid derivative of the present invention has both antioxidant and anti-inflammatory activities, improves the pharmacological effect of α-lipoic acid as a ferroptosis inhibitor, and can be further developed into a therapeutic drug for ferroptosis-related diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to an alpha-lipoic acid derivative which is a ferroptosis inhibitor, and a preparation method and application thereof. Background Art

[0002] Ferroptosis is a new type of programmed cell death that depends on intracellular iron but not other metals, and is morphologically, biochemically, immunologically, genetically, and hereditarily different from traditional regulated cell death pathways (including necrosis, apoptosis, and autophagy). Ferroptosis depends on iron and reactive oxygen species (ROS) and is caused by an imbalance in the generation and degradation of intracellular lipid reactive oxygen species. The accumulation of lipid peroxidation and the consumption of membrane polyunsaturated fatty acids are the characteristics of ferroptosis. In recent years, ferroptosis has been widely studied in diseases including cardiovascular disease, kidney disease, and neurological diseases. Most ferroptosis inhibitors have been synthesized, but they cannot be used clinically due to their high toxicity and poor activity.

[0003] α-lipoic acid is a natural antioxidant that can function in aqueous or lipophilic environments. α-lipoic acid also has anti-inflammatory effects, which are unrelated to its antioxidant activity. Studies have also found that supplementation with α-lipoic acid in animal models can prolong life, has neuroprotective effects, and has chelation of toxic metals, anti-cancer effects, and liver protection effects. Therefore, α-lipoic acid deserves further study. Recent studies have found that α-lipoic acid can alleviate fluoride-induced hepatocyte damage by inhibiting ferroptosis. Ferroptosis is closely related to cardiovascular disease, liver disease, and neurodegenerative diseases, and the pathological mechanisms of these diseases include not only ferroptosis but also other mechanisms such as inflammation. Therefore, it is necessary to prepare a ferroptosis inhibitor that has both antioxidant and anti-inflammatory properties. Summary of the invention

[0004] Based on this, the present invention designed and synthesized a ferroptosis inhibitor with both antioxidant and anti-inflammatory activities.

[0005] The specific technical solutions are as follows:

[0006] In a first aspect, the present invention provides an α-lipoic acid derivative, the structural formula of which is shown in Formula I below:

[0007]

[0008] In a second aspect, the present invention provides a method for preparing the α-lipoic acid derivative, comprising the following steps:

[0009] 2-Cyanophenothiazine and lithium aluminum hydride undergo a reduction reaction to generate an intermediate product shown in formula II;

[0010] The intermediate product and α-lipoic acid are mixed, and a condensation reaction is carried out under the action of a condensing agent to obtain the α-lipoic acid derivative;

[0011]

[0012] As a preferred embodiment of the preparation method of the present invention, the condensing agent is a tetrahydrofuran solution of N,N'-dicyclohexylcarbocyanine and N-hydroxysuccinimide.

[0013] In a third aspect, the present invention provides the use of the α-lipoic acid derivative in the preparation of a ferroptosis inhibitor.

[0014] In a specific embodiment of the present invention, 1 μM Erastin was used to induce ferroptosis of PC12 cells, and the EC50 of the α-lipoic acid derivative was measured to be 94.28 nM, and the EC50 of α-lipoic acid was 38.38 μM. After the modification, the pharmacological effect of α-lipoic acid in inhibiting ferroptosis was significantly enhanced.

[0015] In a fourth aspect, the present invention provides use of the α-lipoic acid derivative in the preparation of anti-inflammatory and / or antioxidant preparations.

[0016] In a specific embodiment of the present invention, the free radical DPPH and α-lipoic acid or the α-lipoic acid derivative are mixed in an equal molar ratio and incubated at room temperature for 10 minutes. The results show that there is no significant difference in antioxidant capacity between the α-lipoic acid treatment and the blank control, and excellent antioxidant activity is obtained after the modification.

[0017] In a specific embodiment of the present invention, PC12 cells were treated with 700 ng / ml LPS to construct an inflammation model. After co-treatment with 1 μM α-lipoic acid or the α-lipoic acid derivative, the reduction in cell viability caused by inflammation was inhibited, and the effect of the α-lipoic acid derivative was stronger than that of α-lipoic acid.

[0018] In a fifth aspect, the present invention provides the use of the α-lipoic acid derivative in the preparation of therapeutic drugs for ferroptosis-related diseases.

[0019] Furthermore, the ferroptosis-related disease is a neurological disease, kidney damage, liver damage, tissue ischemia-reperfusion injury or stroke; the neurological disease is Alzheimer's disease, spinal cord injury or Parkinson's disease.

[0020] In a specific embodiment of the present invention, 5 mg / kg of the solution of the α-lipoic acid derivative was injected into the tail vein of SD rats after spinal cord injury, and the recovery of hind limb motor function was evaluated according to the Basso-Beattie-Bresnahan (BBB) ​​motor rating scale score. Except for the BBB score on the first day, which was not significantly different from the spinal cord injury group, the scores on the 2nd to 28th days were significantly increased, indicating that the α-lipoic acid derivative can promote the recovery of motor ability of rats with spinal cord injury and can be used to prepare therapeutic drugs for spinal cord injury.

[0021] In a sixth aspect, the present invention provides a drug for preventing and treating ferroptosis-related diseases, comprising the α-lipoic acid derivative and a pharmaceutically acceptable excipient, wherein the drug contains the α-lipoic acid derivative as the only active ingredient.

[0022] As a preferred embodiment of the drug of the present invention, the auxiliary materials include excipients, fillers, extenders, adhesives, humectants, disintegrants, solubilizers, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, wetting agents, suspending agents, flavoring agents or fragrances.

[0023] As a preferred embodiment of the drug of the present invention, the drug is in the form of capsules, granules, injections, pills, syrups, powders, ointments, emulsions, solutions, suspensions or tinctures.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The results of the present invention show that the α-lipoic acid derivative YADX-2 has both antioxidant and anti-inflammatory activities, and can improve the cell activity in the Erastin-induced PC12 cell ferroptosis model. The activity is 400 times higher than that of α-lipoic acid, and the Fe 2+ content and MDA content, and reduce Fe 2+ The effect of the content is better than that of α-lipoic acid; it can also improve the functional recovery of SD rats with spinal cord injury and reduce the Fe 2+ The content is comparable to the MDA content in serum, and the effect is better than that of α-lipoic acid. The results show that the α-lipoic acid derivatives of the present invention increase the antioxidant activity of the α-lipoic acid derivative compounds by introducing a phenothiazine group into the α-lipoic acid fragment, enhance the pharmacological effect of anti-ferroptosis, and retain anti-inflammatory activity, and can be further developed into therapeutic drugs for ferroptosis-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The synthetic route of α-lipoic acid derivative (YADX-2) is shown in FIG.

[0027] Figure 2 The inhibitory activity of YADX-1, YADX-2, and α-lipoic acid on ferroptosis of PC12 cells;

[0028] Figure A: Dose-response curve of YADX-1 inhibiting ferroptosis induced by Erastin (1 μM);

[0029] Figure B: Dose-response curve of YADX-2 inhibiting ferroptosis induced by Erastin (1 μM);

[0030] Panel C: Dose-response curve of α-lipoic acid inhibiting erastin (1 μM)-induced ferroptosis.

[0031] Figure 3 Comparison of the antioxidant capacity of DMSO, YADX-1, YADX-2, and α-lipoic acid; standard deviation: n=3, ***P<0.001, comparison between DMSO group and YADX-1 group; ***P<0.001, comparison between DMSO group and YADX-2 group; ns, no significant difference, comparison between DMSO group and α-lipoic acid group.

[0032] Figure 4 Comparison of the anti-inflammatory activities of YADX-1, YADX-2, and α-lipoic acid; standard deviation: n=3, ###P<0.001, comparison between blank control group and LPS group; ns, no significant difference, comparison between LPS group and YADX-1 group; ***P<0.001, LPS group vs α-lipoic acid; ***P<0.001, comparison between LPS group and YADX-2 group.

[0033] Figure 5 Effects of DMSO, α-lipoic acid, Fer-1, and YADX-2 on Fe in the ferroptosis model of PC12 cells induced by Erastin (1 μM) 2+ content (A) and MDA content (B); standard deviation: n=3, ###P<0.001, comparison between normal control group and Erastin group; ns, no significant difference, comparison between Erastin group and DMSO group; **P<0.01, comparison between Erastin group and α-lipoic acid group; ***P<0.001, comparison between Erastin group and α-lipoic acid group; ***P<0.001, comparison between Erastin group and Fer-1 group; ***P<0.001, comparison between Erastin group and YADX-2 group.

[0034] Figure 6The BBB score results of SD rats injected with YADX-2 (5 mg / kg) through the tail vein for 28 days after spinal cord injury; standard deviation: n=6, ns, no significant difference, *P<0.05, ***P<0.001, compared between SCI group and YADX-2 group.

[0035] Figure 7 The Fe expression in rat tissues was regulated 3 days after YADX-2 was injected into the tail vein of SD rats with spinal cord injury. 2+ Level (A) and serum MDA level (B); standard deviation: n=3, ###P<0.001, Sham group compared with SCI group; **P<0.01, SCI group compared with α-lipoic acid group; **P<0.01, SCI group compared with Fer-1 group; ***P<0.001, SCI group compared with YADX-2 group; ***P<0.001, SCI group compared with α-lipoic acid group; ***P<0.001, SCI group compared with Fer-1 group. DETAILED DESCRIPTION

[0036] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0037] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0038] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0039] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0040] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0041] The compounds included in the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining other chemical synthesis methods, and equivalent replacement methods known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0042] In the following examples of the present invention, the solvents and their synthetic drugs used can be obtained from the market. The abbreviations used have the following respective definitions: DMF, N, N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPH, 1.1-diphenyl-2-picrylhydrazyl; MDA, malondialdehyde; PC12 cells, rat adrenal medullary pheochromocytoma differentiation cell line; CCK-8, Cell Counting Kit-8; EC50, half maximum effect concentration (concentration for 50% of maximal effect); Fer-1, Ferrostatin-1, CAS No.: 347174-05-4; SCL, spinal cord injury; Sham, control group; BBB, Basso-Beattie-Bresnahan.

[0043] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0044] Example 1: Preparation of α-lipoic acid derivative (YADX-2)

[0045] Synthesis route: Figure 1 shown.

[0046] Synthesis method: 2-cyano phenothiazine (224.28 mg, 1 mmol) and lithium aluminum hydride (265.65 mg, 7 mmol) were dissolved in tetrahydrofuran, and then 2-cyano phenothiazine was slowly dripped into lithium aluminum hydride, reacted at room temperature for 4 hours, and the reaction progress was detected. After the reaction was completed, distilled water was added to quench the reaction, and dichloromethane and saturated brine were used for extraction and chromatography to obtain the intermediate product YADX-1; α-lipoic acid (220.35 mg, 1 mmol) was added to the mixture, and the reaction mixture was stirred for 2 hours. ), N,N'-dicyclohexylcarboximide (206.33 mg, 1 mmol) and N-hydroxysuccinimide (115.09 mg, 1 mmol) were dissolved in tetrahydrofuran, reacted at room temperature for 24 h, and YADX-1 (182.65 mg, 0.8 mmol) dissolved in tetrahydrofuran was added dropwise thereto. After reacting at room temperature for 12 h, the reaction progress was detected. After the reaction was completed, dichloromethane and saturated brine were used for extraction and chromatography to obtain the product YADX-2.

[0047] NMR data:

[0048] YADX-1. 1 H NMR (400MHz, DMSO) δ8.58 (s, 1H), 7.05-6.61 (m, 7H), 3.57 (s, 2H), 1.97 (d, J = 161.5Hz, 2H). 13 C NMR (101MHz, DMSO) δ144.31,142.72,142.43,127.86,126.65,126.32,122.05,120.99,117.08,114.88,114.21,113.72,45.63.HRMS m / z(ESI)calcd forC13H12N2S[M+H]229.0800found:229.0802.

[0049] YADX-2. 1 H NMR(400MHz,DMSO)δ8.60(s,1H),8.27(s,1H),7.01-6.55(m,7H),4.09(s,2H),3.59(s ,1H),3.12(d,J=24.9Hz,2H),2.44(d,J=51.1Hz,2H),1.58(dd,J=117.9,76.9Hz,8H). 13C NMR(101MHz,DMSO)δ172.38,142.53,139.87,127.93,126.55,122.17,121.25,116 .92,114.98,113.91,56.60,42.13,40.36,38.59,35.69,34.61,28.82,25.55.HRMS m / z(ESI)calcd forC 21 H 24 N2OS3[M+H]417.1130found:417.1128.

[0050] Example 2: Biological Activity Test

[0051] 1 Experimental methods

[0052] 1.1 Cell culture: PC12 cells were cultured in DMEM containing 10% fetal bovine serum, 50 U / mL penicillin and 50 μg / mL gentamicin, and then placed in an incubator containing 5% CO2 at 37°C.

[0053] 1.2 DPPH assay: The stable free radical DPPH was dissolved in methanol to a final concentration of 0.05 mM, and 1 mL of DPPH solution was added to each test compound dissolved in DMSO. The final concentration of each test compound (YADX-1, α-lipoic acid or YADX-2) was 0.05 mM. The samples were inverted several times and incubated at room temperature for 10 minutes. Finally, the absorbance at 517 nm was recorded using a microplate reader. All values ​​were normalized to the background value (methanol only).

[0054] 1.3 Cell viability assay: Cell counting kit-8 (CCK-8) was used to assess cell viability. PC12 cells were plated at 5×10 3 The cells were seeded in 96-well plates at a density of 100 μl per well and cultured overnight in culture medium (100 μl per well), and then treated with LPS, Fer-1, YADX-1, α-lipoic acid or YADX-2 alone or in combination at a given concentration for 24 h. Then, the culture medium was replaced with 100 μl of fresh culture medium containing 10 μl of CCK-8 solution and incubated at 37 °C for 1 h. Finally, the OD value was measured at a wavelength of 450 nm using a microplate reader, and the relative cell viability was expressed as a percentage of the control group.

[0055] Experimental groups: blank control group; LPS group, added with 700 ng / ml LPS; YADX-1 group, added with 700 ng / ml LPS and 1 μM YADX-1; α-lipoic acid group, added with 700 ng / ml LPS and 1 μM α-lipoic acid; YADX-2 group, added with 700 ng / ml LPS and 1 μM YADX-2.

[0056] 1.4 Fe in PC12 cell ferroptosis model 2+ Determination of content and MDA content

[0057] PC12 cells were plated at 5 × 10 3 The cells were seeded at a density of 100 cells / well in a 96-well plate and cultured overnight in culture medium (100 μl per well). They were then treated with Erastin, DMSO, Fer-1, YADX-1, α-lipoic acid, or YADX-2 alone or in combination at a given concentration for 24 h. 2+ content and MDA content.

[0058] Experimental groups: blank control (Control) group; Erastin group, added with 1μM Erastin; DMSO group, added with 1μM Erastin + 1μM DMSO solution; α-lipoic acid group: added with 1μM Erastin and 1μM α-lipoic acid; Fer-1 group: added with 1μM Erastin and 1μM Fer-1; YADX-2 group: added with 1μM Erastin and 1μM YADX-2.

[0059] (1) MDA experiment: The malondialdehyde (MDA) detection kit was used to determine the MDA content based on the reactivity of thiobarbituric acid (TBA). Five million cells were collected and added to 1 mL of extract solution. The cells were disrupted by ultrasonic wave (power 200 W, ultrasonic wave 3 s, interval 10 s, repeated 30 times); centrifuged at 8000g for 10 min at 4°C, the supernatant was taken, the working solution was added, and the absorbance of each sample at 532nm and 600nm was finally measured. Rat serum was taken, the working solution was added, and the absorbance of each sample at 532nm and 600nm was finally measured. The concentration of MDA was expressed as a relative percentage of the normal group.

[0060] (2)Fe 2+Experiment: A ferrous iron content detection kit was used. Ferrous iron, i.e., divalent iron, can react with ferrozine to generate a purple-red compound. This colored substance has a characteristic absorption peak at 562nm, and the ferrous iron content was then calculated. After treatment, approximately 5 million cells were added to 1mL of extract solution, and the cells were ultrasonically disrupted (ice bath, power 200W, ultrasound 3s, interval 10s, repeated 30 times); centrifuged at 12000rpm and 4℃ for 10min, the supernatant was taken, the working solution was added, and finally the absorbance of the sample at 562nm was measured. Take approximately 0.1g of tissue, add 1mL of extract solution, and homogenize in an ice bath. Centrifuge at 4℃×12000rpm for 5min, take the supernatant, add the working solution, and finally the absorbance of the sample at 562nm was measured. Fe 2+ The concentrations were expressed as relative percentages of the normal group.

[0061] 1.5 Motor recovery assessment (BBB score)

[0062] The recovery of hindlimb motor function was assessed according to the Basso-Beattie-Bresnahan motor rating scale score. This scale is based on allowing the rats to walk freely in a 90-cm arena for 5 min while the movement and coordination of the hindlimbs are closely observed.

[0063] After anesthetization, SD rats were fixed on the table in prone position. The skin was prepared with T10 spinous process as the center of the circle and disinfected with iodine cotton balls. A 1.5 cm straight incision was made on the back of T9-T10 spinous process, and the subcutaneous fascia was bluntly separated with forceps and hemostats. The erector spinae muscles and ligaments were separated from them with ophthalmic scissors close to the edges of the spinous process. The skin and muscles on both sides were pulled apart with auxiliary fixation hooks to fully expose the spinous process, intervertebral foramen and articular processes of T9-T11. After determining the position of T10 according to the direction of the spinous process, the spinous process of T10 was lifted with hemostats, the ligament between T10 and T11 lamina was slowly cut, the T10 lamina was bitten off, and the dura mater was exposed. Then, the HI-0400 (PSI) spinal cord impactor was used. The rats were prone on the impactor table, and the impact force was set to 200 kdyn / cm2. The rat spinal cord injury model was centered on T10 (recorded as SCI group). After spinal cord injury, SD rats were injected with YADX-2 via tail vein at a dose of 5 mg / kg, which was recorded as the YADX-2 group. A control (Sham) group, i.e. normal SD rats, was also set up.

[0064] The sham, SCI, and YADX-2 groups were evaluated on days 1, 3, 7, 14, 21, and 28 after surgery. The assessors were unaware of the experimental conditions of the rats, and the assessments were repeated three times and recorded immediately. The scores ranged from 0 to 21, with 0 indicating no motor function and 21 indicating normal.

[0065] 1.6 Fe in rat spinal cord injury model tissue 2+ Determination of content and MDA content

[0066] The rat spinal cord injury model was established according to the method in 1.5. After spinal cord injury, SD rats were injected with Fer-1, α-lipoic acid or YADX-2 through the tail vein at a dose of 5 mg / kg. Three days after injection, Fe 2+ content and MDA content.

[0067] (1) MDA experiment: The malondialdehyde (MDA) detection kit was used to determine the MDA content based on the reactivity of thiobarbituric acid (TBA). Rat serum was taken, the working solution was added, and the absorbance of each sample at 532nm and 600nm was finally measured. The concentration of MDA was expressed as a relative percentage of the normal group.

[0068] (2)Fe 2+ Experiment: Use a ferrous iron content detection kit. Ferrous iron, i.e., divalent iron, can react with ferroxine to generate a purple-red compound. This colored substance has a characteristic absorption peak at 562nm, and the ferrous iron content can be calculated. Take about 0.1g of tissue, add 1mL of extract, and homogenize in an ice bath. Centrifuge at 4℃×12000rpm for 5min, take the supernatant, add the working solution, and finally measure the absorbance of the sample at 562nm. 2+ The concentrations were expressed as relative percentages of the normal group.

[0069] 2 Experimental results

[0070] 2.1 Ferroptosis inhibitory activity of YADX-1, YADX-2, and α-lipoic acid

[0071] like Figure 2 As shown, YADX-1, YADX-2 and α-lipoic acid can inhibit Erastin-induced ferroptosis, the EC50 of YADX-1 is 442nM, the EC50 of YADX-2 is 94.28nM, and the EC50 of α-lipoic acid is 38.38μM. The results show that after modification, the inhibitory activity of α-lipoic acid as a ferroptosis inhibitor is significantly improved.

[0072] 2.2 Antioxidant activity of YADX-1, YADX-2 and α-lipoic acid

[0073] like Figure 3 As shown, the cell-free antioxidant potential was monitored by the relative DPPH absorption value. There was no significant difference between α-lipoic acid and the DMSO control group, indicating that α-lipoic acid had no antioxidant activity. The relative DPPH absorption values ​​of YADX-1 and YADX-2 were significantly reduced. The results showed that YADX-1 and YADX-2 had antioxidant activity, and the antioxidant activity of YADX-2 was significantly better than that of YADX-1.

[0074] 2.3 Anti-inflammatory activity of YADX-1, YADX-2 and α-lipoic acid

[0075] like Figure 4 As shown, the cell viability of the PC12 cell inflammation model induced by LPS was significantly decreased, and the decrease in cell viability of PC12 cells treated with LPS+YADX-2 or α-lipoic acid was significantly alleviated. The results showed that both YADX-2 and α-lipoic acid have excellent anti-inflammatory activity, and the anti-inflammatory activity of YADX-2 is better than that of α-lipoic acid.

[0076] 2.4 Effects of YADX-1, α-lipoic acid and YADX-2 on Fe in erastin (1 μM)-induced ferroptosis in PC12 cells 2+ and MDA levels

[0077] like Figure 5 As shown in Figure 2, Fer-1, α-lipoic acid and YADX-2 can significantly inhibit the Fe2+-mediated ferroptosis in PC12 cells induced by Erastin (1 μM). 2+ and MDA levels were increased, and the effect of YADX-2 was superior to that of α-lipoic acid and Fer-1.

[0078] 2.5BBB score results of YADX-2 in SD rats at different time points after spinal cord injury

[0079] like Figure 6 As shown in the figure, the BBB score of SD rats injected with YADX-2 by tail vein after spinal cord injury on the first day was not significantly different from that of the spinal cord injury group. From the 2nd to the 28th day, the score of the YADX-2 group was significantly higher than that of the SCI group. The results showed that YADX-2 can promote the recovery of motor ability of rats with spinal cord injury.

[0080] Effect of 2.6YADX-2 on Fe in SD rats with spinal cord injury 2+ Content, MDA content

[0081] like Figure 7 As shown in the results, YADX-2, Fer-1 and α-lipoic acid can reduce the Fe 2+ content and MDA content, and YADX-2 for Fe 2+ The effect of YADX-2 on reducing MDA content was significantly better than that of Fer-1 and α-lipoic acid. There was no significant difference between YADX-2 and Fer-1 in reducing MDA content, but it was better than α-lipoic acid.

[0082] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0083] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An α-lipoic acid derivative, characterized in that The structural formula is shown in Formula I below: Formula I.

2. The method for preparing the α-lipoic acid derivative according to claim 1, characterized in that: The following steps are involved: 2-Cyanophenothiazine and lithium aluminum hydride undergo a reduction reaction to generate an intermediate product shown in formula II; The intermediate product and α-lipoic acid are mixed, and a condensation reaction is carried out under the action of a condensing agent to obtain the α-lipoic acid derivative; Formula II.

3. The preparation method according to claim 2, characterized in that: The condensing agent is a tetrahydrofuran solution of N,N'-dicyclohexylcarbocyanine and N-hydroxysuccinimide.

4. Use of the α-lipoic acid derivative according to claim 1 in the preparation of a therapeutic drug for ferroptosis-related diseases, characterized in that: The ferroptosis-related disease is spinal cord injury.

5. A drug for preventing and treating ferroptosis-related diseases, characterized in that: The invention comprises the α-lipoic acid derivative according to claim 1 and pharmaceutically acceptable excipients.

6. The drug according to claim 5, characterized in that The auxiliary materials include fillers, extenders, binders, humectants, disintegrants, dissolution regulators, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, wetting agents, suspending agents or flavoring agents.

7. The drug according to claim 6, characterized in that The dosage form of the medicine is capsule, granule, injection, pill, syrup, powder, ointment, emulsion, suspension or tincture.

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