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A class of C19 diterpene alkaloids with novel structure, and uses thereof

A technology of uses and drugs, applied in the field of medicine, can solve the problems of fluctuating symptoms, restoring degenerated neurons, and limited treatment methods

Active Publication Date: 2018-08-28
SOUTHWEST JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the complex pathological mechanism of neurodegenerative diseases, the existing treatment methods are very limited
At present, PD is treated clinically symptomatically, and there is no effective method to restore degenerated neurons; for the treatment of AD, the FDA has so far only approved 5 symptomatic drugs, and drugs that affect the course of the disease are still in the preliminary research stage
Not only that, most drugs for the treatment of neurodegenerative diseases have obvious side effects. For example, levodopa, which is the basic drug for PD treatment, may have adverse reactions such as symptom fluctuations, on-off phenomena, and movement disorders, which limit its wide use

Method used

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  • A class of C19 diterpene alkaloids with novel structure, and uses thereof
  • A class of C19 diterpene alkaloids with novel structure, and uses thereof
  • A class of C19 diterpene alkaloids with novel structure, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] The preparation of embodiment 1 compound of the present invention

[0086] Take 4.3 kg of Aconitum apetalum tuber tuber of Aconitum apetalum. of Ranunculaceae, extract the dry root of Aconitum apetalum four times with 95% ethanol at room temperature, soak for 4 days each time, and concentrate under reduced pressure to obtain Extract (360g).

[0087] The extract is dissolved in water at 50°C, the pH value is adjusted to 3.0 with 10% w / w hydrochloric acid solution, and then extracted with petroleum ether and ethyl acetate successively. The aqueous solution was then adjusted to pH 9.4 with 24% w / w concentrated ammonia water, extracted with dichloromethane, and the dichloromethane fraction was concentrated under reduced pressure to obtain the total alkaloid (40 g).

[0088] Using normal phase silica gel column chromatography, CH 2 Cl 2 :CH 3 OH (1:0-0:1) for gradient elution, detected by thin-layer chromatography, combined fractions in sequence, and obtained eight parts...

experiment example 1

[0106] Experimental example 1 Inhibitory effect of compounds of the present invention on oxidative damage of SH-SY5Y cells

[0107] Take out the SH-SY5Y cell line frozen in liquid nitrogen, and quickly place it in a 37°C water bath and shake it to melt it. Take it out, move it to the ultra-clean workbench, scrub and disinfect it with 75% alcohol, take out the cell suspension under aseptic conditions, pour it into a sterile centrifuge tube, and add an appropriate amount of DMEM complete culture solution containing 10% fetal bovine serum, 1000r / min, Centrifuge for 5 minutes, suck off the supernatant, and then centrifuge once more with the above culture medium. SH-SY5Y cells were diluted with DMEM complete culture medium containing 10% fetal bovine serum to contain 1×10 per 1 mL 5 A cell suspension of 1 cell was seeded in a cell culture flask. After inoculation, place the culture flask at 37°C, 5% CO 2 Conditional CO 2 cultured in an incubator. The culture medium was replace...

experiment example 2

[0113] Experimental example 2 compounds of the present invention to MPP + Protective Effect of Induced Apoptotic SH-SY5Y Cells

[0114] SH-SY5Y cells were cultured in Basic DMEM medium containing 10% fetal bovine serum and incubated at 37°C, 5% CO 2 , in an incubator with saturated humidity, after the cells grow to a suitable density, trypsinize and passage. SH-SY5Y cells were digested and seeded in 96-well cell culture plates. After the cells adhered to the wall, MPP with a concentration of 1.8mM was added. + And the test samples Apetaldine A, Apetaldine B, Apetaldine C, Apetaldine D, and Apetaldine E dissolved by DMSO (administration concentrations are shown in Table 4), and the blank control group only added PBS as a control. Set up three parallel wells for each sample, use an automatic calibration spectrophotometer to measure the inhibitory activity of each sample by the Ehrman method, calculate the protection rate, and detect different concentrations of Apetaldine A, Ap...

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Abstract

The present invention discloses a compound represented by a formula I, or an optical isomer, a pharmaceutically acceptable salt, a crystal form, or a solvate thereof. According to the present invention, the pharmacodynamic experiment results show that the compound has good protection effect on nerve cells, can effectively inhibit oxidative stress induced nerve cell damage and inhibit the apoptosisof nerve cells, has characteristics of remarkable effect, no obvious cytotoxicity and high safety, and is the potential drug for the prevention and treatment of Parkinson's disease and other neurodegenerative diseases; and the compound can be extracted and isolated from the Aconitum plant, and has characteristics of wide drug source, broad clinical application prospect and broad market prospect.The formula I is defined in the specification.

Description

technical field [0001] The present invention relates to a class of structurally novel C 19 A diterpene alkaloid and its use belong to the field of medicine. Background technique [0002] Neurodegenerative diseases are caused by the loss of neurons and / or their myelin sheath, which worsens over time to the point of dysfunction. Clinically common Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and so on. The brain pathological changes of such diseases are mainly the loss of a large number of neurons caused by apoptosis, or there is no obvious reduction in the number of cell bodies in the nervous system, but the structure and function of nerve cells are progressive and degeneration. With the continuous increase of the elderly population in our country, the incidence of neurodegenerative diseases is also increasing year by year. However, only a few drugs are currently available for the treatment of neurodegene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/22A61K31/439A61P25/00A61P25/28A61P25/14A61P25/16
CPCA61K36/714C07D221/22
Inventor 周先礼张吉发高峰黄帅单连海
Owner SOUTHWEST JIAOTONG UNIV
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