Novel compounds as potential therapeutic agents against various neurodegenerative diseases

A technology of neurodegenerative and chemical compounds, applied in the direction of nervous system diseases, neuromuscular system diseases, muscular system diseases, etc., can solve problems such as elusive molecular mechanisms

Pending Publication Date: 2022-03-15
THE HONG KONG UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Although some progress has been made in developing therapies for these neurodegenerative diseases, the molecular mechanisms remain elusive

Method used

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  • Novel compounds as potential therapeutic agents against various neurodegenerative diseases
  • Novel compounds as potential therapeutic agents against various neurodegenerative diseases
  • Novel compounds as potential therapeutic agents against various neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0181] All data were obtained from at least three independent preparations. Quantification was performed in a blinded manner. Statistical analysis was performed with GraphPad Prism 6. Differences between groups were analyzed by unpaired t-test. A p value < 0.05 was considered significant.

[0182] All patents, patent applications, provisional applications and publications referenced or cited herein are hereby incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the express teachings of this specification.

Embodiment 1

[0184] Example 1 - Initial Screening and Modeling of Neuroprotective Cells

[0185] From bacterial strain Streptomyces coronatum BCC 24770 ( Figure 1A ) to separate the F8, F9, F10, F11 and F13 components from the crude extract extracted with ethyl acetate. These components are based on their UV absorbance patterns and retention times on HPLC ( Figure 1B ), combined with LCMS data, it is predicted that these components are all new compounds.

[0186] Preliminary cytotoxicity tests of F8, F9, F10, F11 and F13 were performed on the neuronal cell line Neuro2a cells and HEK293T. Except F10, all other fractions showed cytotoxicity in Neuro2A cells at 1 μg / ml, and F13 showed cytotoxicity even at 0.1 μg / ml. In contrast, F10 was not cytotoxic even at a high concentration of 10 μg / ml ( Figure 1C to Figure 1H ). Similarly, F8, F9, F11, and F13 showed significant cytotoxicity in HEK293T cells at 10 μg / ml, with cell viability below 50%, whereas when treated with F10, cell viabilit...

Embodiment 2

[0188] Example 2 - Purification of Compound chrexanthomycin A (cA) and Its Analogs

[0189] By semi-preparative HPLC (flow rate: 3mL min -1 , solution A: acetonitrile containing 0.5‰ trifluoroacetic acid (TFA); solution B: Milli-Q water containing 0.5‰ TFA. The acetonitrile concentration was increased from 25% to 45% within 70 minutes. retention time: 38.5 minutes) enriched the pure fraction of F10, and we named this compound chrexanthomycin A (cA). After lyophilization of the product from semi-preparative HPLC, cA was obtained as a yellow powder, the molecular weight of cA was determined to be 621.1235 [M+H] by high resolution mass spectrometry + , the molecular formula is calculated as C 31 h 25 o 14 . Using methanol as a solvent at room temperature, the specific rotation of cA was -49.8. UV(MeOH)λ max 224nm, 243nm, 271nm, 401nm. Similarly, cB and cC were also obtained as yellow powders after lyophilization of the product from semi-preparative HPLC. The molecular ...

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Abstract

The present application relates to compositions and methods for treating neurodegenerative diseases, neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis, epilepsy, stroke, alcohol withdrawal, progressive suprakaryotic paralysis (PSP), PiD, corticobasal degeneration (CBD), chromosome 17 linked frontotemporal dementia with Parkinson's disease (FTDP-17). The methods of the present application also relate to methods of fermentation of bacterial cells and methods of tautomerization of the compounds of the present application.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 078,697, filed September 15, 2020, the entire contents of which, including any tables, figures, or drawings, are incorporated herein by reference. technical field [0003] The present application relates to compositions and methods for treating neurodegenerative diseases. The method of the present application also relates to the fermentation method of bacterial cells and the tautomerization method of the compounds of the present application. Background technique [0004] Neurodegenerative diseases are disorders of the nervous system characterized by progressive loss of neurons and degeneration of neuronal architecture in the central or peripheral nervous system, which have a variety of phenotypes. The most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) (Ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12C07D493/04C07H15/26A61P21/00A61P25/00A61P25/08A61P25/16A61P25/28A61P25/32C12P17/16C12P17/18C12P19/60C12R1/465
CPCC07D407/12C07D493/04C07H15/26A61P25/28A61P25/16A61P21/00A61P25/08A61P25/00A61P25/32C12P17/162C12P17/181C12P19/60
Inventor 钱培元程爱芳刘长东叶文康朱广
Owner THE HONG KONG UNIV OF SCI & TECH
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