Molecular rotor driven by near-infrared light and application of molecular rotor in treatment of Parkinson's disease

Abstract

The invention belongs to the technical field of Parkinson's disease treatment, and particularly relates to a near-infrared light driven molecular rotor and application thereof in Parkinson's disease treatment. The molecular rotor is EDEM, the structural formula of the molecular rotor is as follows: # imgabs0, the molecular rotor is excited by near-infrared light to generate a distorted intramolecular charge transfer (TICT) effect, and alpha-synuclein aggregates are effectively degraded, so that the symptoms of the Parkinson's disease are improved. The method has the characteristics of non-invasiveness, high efficiency and safety, and provides a new strategy for treatment of Parkinson's disease.

Description

Technical Field

[0001] The present invention belongs to the technical field of Parkinson's disease treatment, and particularly relates to a near-infrared light-driven molecular rotor and its application in the treatment of Parkinson's disease. Background Art

[0002] Parkinson's disease (PD) is a common chronic neurodegenerative disease in the elderly. Lewy bodies formed by the abnormal accumulation of α-synuclein aggregates are the core elements of the pathogenesis of this disease. Currently, the treatment of PD mainly relies on drugs that improve dopamine function, but the effectiveness of these drugs weakens as the disease progresses and may cause serious complications. Therefore, new treatment strategies are needed to effectively remove α-synuclein aggregates to prevent or slow down the disease process. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to overcome the above-mentioned deficiencies existing in the prior art, and provide a near-infrared light-driven molecular rotor and its application in the treatment of Parkinson's disease. The Chinese name of the molecular rotor of the present invention is 2-(((E)-2-chloro-3-(2-((E)-1-ethyl-3,3-dimethyl-1,3,3a,7a-tetrahydro-2H-indol-2-ylidene)ethylidene)cyclohex-1-en-1-yl)methylene)malononitrile, and the English name is 2-(((E)-2-chloro-3-(2-((E)-1-ethyl-3,3-dimethyl-1,3,3a,7a-tetrahydro-2H-indol-2-ylidene)ethylidene)cyclohex-1-en-1-yl)methylene)malononitrile, named EDEM. After being excited by near-infrared light, this molecular rotor undergoes a twisted intramolecular charge transfer (TICT) effect, effectively degrading α-synuclein aggregates, thereby improving the symptoms of Parkinson's disease. This method has the characteristics of non-invasiveness, high efficiency, and safety, providing a new strategy for the treatment of Parkinson's disease.

[0004] To achieve the above purpose, the technical solution of the present invention is as follows:

[0005] On the one hand, the present invention provides a near-infrared light-driven molecular rotor, and its structural formula is:

[0006]

[0007] On the other hand, the present invention provides the application of the above-mentioned molecular rotor in the preparation of drugs for the treatment of Parkinson's disease.

[0008] Furthermore, the molecular rotor degrades α-synuclein aggregates, the pathogenic protein of Parkinson's disease, by undergoing molecular rotation under the action of near-infrared light.

[0009] On the other hand, the present invention also provides a pharmaceutical composition, which comprises the molecular rotor as described above and a pharmaceutically acceptable excipient.

[0010] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0011] 1. The EDEM molecular rotor of the present invention has a low cost and simple synthesis steps;

[0012] 2. The EDEM molecular rotor of the present invention can achieve the depolymerization of the Parkinson's disease-causing protein, α-synuclein aggregates, under near-infrared light irradiation;

[0013] 3. The Parkinson's treatment scheme provided by the present invention is simple to operate and has excellent effects on the treatment of Parkinson's disease. Description of the Drawings

[0014] Figure 1 It is the 1H NMR spectrum of the EDEM molecular rotor.

[0015] Figure 2 It is the 13C NMR spectrum of the EDEM molecular rotor.

[0016] Figure 3 It is the mass spectrum of the EDEM molecular rotor.

[0017] Figure 4 It is the fluorescence spectrum of EDEM in different viscosity systems.

[0018] Figure 5 It is the fluorescence spectrum of the binding of the EDEM molecular rotor to α-synuclein aggregates.

[0019] Figure 6 It is the degradation of α-synuclein aggregates by the EDEM molecular rotor under near-infrared laser irradiation.

[0020] Figure 7 It is the behavioral test of mice after near-infrared laser treatment with the EDEM molecular rotor.

[0021] Figure 8 It is the biological transmission electron microscope of the substantia nigra region after near-infrared laser treatment with the EDEM molecular rotor. Detailed Embodiments

[0022] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0023] Unless otherwise defined, all technical terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention.

[0024] Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchase or prepared by existing methods.

[0025] Example 1

[0026] (E)-2-Chloro-3-(hydroxyimino)cyclohex-1-ene-1-carbaldehyde (3 mmol, 0.516 g) and 1-ethyl-2,3,3-trimethyl-3H-indol-1-ium (4 mmol, 1.26 g) were dissolved in a mixed solution of toluene and n-butanol (v / v = 3:2.5), and the mixture was heated at 100 °C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the intermediate (E)-2-chloro-3-(2-((E)-1-ethyl-3,3-dimethylindolin-2-ylidene)ethylidene)cyclohexene-1-carbaldehyde was separated by column chromatography (dichloromethane). The aforementioned intermediate compound (0.343 mmol, 0.1 g) and malononitrile (0.066 g, 1 mmol) were dissolved in a methanol solution, and then a methanol solution of saturated potassium carbonate (40 μL) was added dropwise. The solution was heated overnight under reflux conditions. After the mixture was cooled to room temperature, a blue product was obtained, and EDEM was obtained after filtration.

[0027] 2 mL of buffer solution and 1 μL of DMSO solution of EDEM were added to cuvettes containing different ratios of glycerol (0%, 20%, 40%, 60%, 80%, 100%) and ethanol (100%, 80%, 60%, 40%, 20%, 0%). Detection was carried out on a fluorescence spectrophotometer, and it was found that as the proportion of glycerol increased and the proportion of ethanol decreased, that is, the viscosity of the system increased; this process was accompanied by an increase in the fluorescence intensity of EDEM, and it was also proved that there was excited-state intramolecular planar rotation in EDEM, that is, EDEM was a molecular rotor; the fluorescence spectrum is as Figure 4 shown.

[0028] Example 2

[0029] Take 2 mL of buffer solution and 1 μL of the DMSO solution of EDEM and add them to a cuvette. Then add 12.5 μM of α-synuclein aggregates and detect on a fluorescence spectrophotometer. An emission peak centered at 705 nm appears in the fluorescence spectrum, indicating that EDEM can enter the interior of the aggregated protein. Place the cuvette under the irradiation of a laser with a wavelength of 660 nm (100 mW / cm²). As the irradiation time increases, the intensity of the 705-nm emission peak gradually decreases, indicating that this molecular rotor can effectively degrade the aggregated protein. The fluorescence spectrogram is as Figure 5 , Figure 6 shown.

[0030] Example 3

[0031] Dissolve compound EDEM in DMSO to prepare a 20 mM solution; take EDEM (400 μM) and dissolve it in 50 μL of physiological saline, and inject it into the Parkinson's model mice through the tail vein. After 90 minutes, fix the heads of the mice and irradiate the heads with a laser with a wavelength of 660 nm (100 mW / cm²) for 5 minutes. Perform such operations once every other day, and repeat a total of 3 times; conduct behavioral tests and brain tissue bioelectron microscopy tests on the treated Parkinson's mice, untreated Parkinson's mice, and normal mice. It is found that under the action of near-infrared light, the molecular rotor EDEM can effectively treat Parkinson's disease, and has obvious treatment effects on limb movement and the recovery of neuronal activity, as Figure 7 , Figure 8 shown.

[0032] The above are only examples for better explaining the present invention, and are not intended to limit it. Any modification or equivalent replacement that does not depart from the spirit and scope of the present invention shall fall within the scope covered by the present invention.

Claims

1. A near-infrared light-driven molecular rotor, characterized in that: Its structural formula is:

2. Use of the molecular rotor according to claim 1 in preparing a drug for treating Parkinson's disease.

3. The use according to claim 2, characterized in that: The molecular rotor degrades Parkinson's disease-causing protein α-synuclein aggregates by causing molecular rotation under the action of near-infrared light.

4. A pharmaceutical composition, characterized in that The invention comprises the molecular rotor according to claim 1 and a pharmaceutically acceptable excipient.

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