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Triphenylphosphine modification-based mitochondrion targeted melatonin as well as preparation method and application thereof

A technology of triphenylphosphine and mitochondria, which is applied in the field of mitochondria-targeted melatonin modified by triphenylphosphine and its preparation, can solve the problems that melatonin does not have mitochondrial targeting, and achieve the prevention and treatment of mitochondria-related diseases Effect

Active Publication Date: 2021-02-09
重庆医药高等专科学校附属第一医院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Melatonin itself does not have mitochondrial targeting, and the double-membrane structure of mitochondria also prevents most drugs from fully passing through the double-membrane to reach the interior of the mitochondria.

Method used

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  • Triphenylphosphine modification-based mitochondrion targeted melatonin as well as preparation method and application thereof
  • Triphenylphosphine modification-based mitochondrion targeted melatonin as well as preparation method and application thereof
  • Triphenylphosphine modification-based mitochondrion targeted melatonin as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of the compound represented by formula (IV)

[0052] In this example, the compound represented by formula (IV) is specifically brominated (4-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-4-oxo Butyl)triphenylphosphine, see formula (VII) for the specific compound structure.

[0053] The synthetic process of formula (VII) is roughly as follows: bromide (3-carboxypropyl) triphenylphosphine is obtained by reacting tetrabromobutyric acid and triphenylphosphine in an aprotic solvent, after removing the solvent, in an aprotic solvent After reacting with carbon-based diimidazole, then reacting with 5-methoxytryptamine to obtain the product, distilling off the solvent and recrystallizing with distilled water to obtain brominated (4-((2-(5-methoxy-1H-indole- 3-yl)ethyl)amino)-4-oxobutyl)triphenylphosphine.

[0054] The synthesis process of formula (VII) is specifically: 16.7 grams of 4-bromobutyric acid, 26.3 grams of triphenylphosphine, and 50 millili...

experiment example 1

[0070] Experimental Example 1: Toxicity Study of Compounds

[0071] After treated with different concentrations of Mito-Mel (10uM-10mM) for 24 hours, the cell viability of Neuro-2a cells (neuroma blastocytes derived from mice) was not changed compared with the control group. Experimental results such as image 3 As shown, the data format in the figure is: Mean±SEM, N=5. The specific detection method of this experimental example is as follows: the cell viability was detected with a CCK-8 kit. CCK-8 is a rapid and high-sensitivity detection reagent widely used in cell proliferation and cytotoxicity based on WST-8. In the experiment, the 5×10 4 Cells were seeded in a 96-well plate with a total volume of 100 μl per well. When detecting cell activity, aspirate the medium in each well, and add 100ul of fresh medium containing CCK-8 (the volume ratio of CCK-8 to medium is 1:10), and incubate at 37°C for 2h. Then use a microplate reader to measure the OD value of each well, selec...

experiment example 2

[0072] Experimental Example 2: The protective effect of the compound on the cytotoxicity of heavy metal cadmium

[0073] Experimental results such as Figure 4 As shown, Mito-Mel (1mM) can effectively improve heavy metal cadmium exposure (CdCl 2) caused cell damage. Moreover, under the same conditions, the protective effect of Mito-Mel on cell viability after 24h exposure to cadmium was better than that of non-targeted melatonin itself. For the specific detection method, see Experimental Example 1 (CCK-8 method), in Figure 4 Among them, the data form is Mean±SEM, N=5; * indicates that compared with the control group, p2 p<0.05 compared to treatment group.

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Abstract

The invention belongs to the field of biological medicines, and relates to mitochondrial targeting melatonin as well as a preparation method and application thereof, in particular to triphenylphosphine modification-based mitochondrial targeting melatonin as well as a preparation method and application thereof. The triphenylphosphine-melatonin synthesized by the preparation method provided by the technical schemes of the invention is a drug which takes mitochondria as a target and has an antioxidant effect, and can relieve and treat mitochondrial dysfunction, so as to regulate mitochondria-mediated cell damage. The compound in the technical schemes can be used as a mitochondrial targeted antioxidant drug, can be used for preventing and treating mitochondrial toxicity caused by environmentalor occupational harmful factors such as heavy metals, and can also be used for treating and relieving cell damage caused by mitochondrial oxidative stress.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a mitochondria-targeted melatonin and a preparation method and application thereof, in particular to a mitochondria-targeted melatonin modified based on triphenylphosphine, a preparation method and an application thereof. Background technique [0002] Mitochondria are the main site of oxidative stress and the sensitive target of oxidative stress. Studies have shown that excessive oxidative stress can oxidize structural and functional proteins, unsaturated fatty acids and mitochondrial DNA and other biomacromolecules in mitochondria, resulting in mitochondrial dysfunction and oxidative damage to cells. Mitochondrial dysfunction caused by oxidative stress is not only an important toxic mechanism of body damage caused by environmental pollutants such as heavy metals and occupational hazards, but also a common pathway for the development of neurodegenerative diseases, metabolic diseases, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/572A61K31/675A61P39/02A61P39/06
CPCC07F9/5728A61P39/02A61P39/06Y02P20/55
Inventor 许商成刘永生段郁段维霞刘聪付冠艳杨梅蓉周取
Owner 重庆医药高等专科学校附属第一医院
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