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Uses of cimiracemate and related compounds for treating inflammation and modulating immune responses

A compound, lipoxygenase technology, used in anti-inflammatory agents, drug combinations, plant raw materials, etc.

Active Publication Date: 2013-09-11
BAGI RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, cimiracemate A and its related compounds have not previously been reported to play a role in the inhibition of 5-lipoxygenase (5-LOX) activity or leukotriene biosynthesis

Method used

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  • Uses of cimiracemate and related compounds for treating inflammation and modulating immune responses
  • Uses of cimiracemate and related compounds for treating inflammation and modulating immune responses
  • Uses of cimiracemate and related compounds for treating inflammation and modulating immune responses

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0149] Preparation of cell extracts

[0150] To collect whole-cell lysates, wash PBMac with cold PBS and dissolve in cold lysis buffer (50 mM tris(hydroxymethyl)aminomethane hydrochloride (Tris-C1) (pH 7.4); 150 mM chloride Sodium (NaCl); 50 mM Sodium Fluoride (NaF); 10 mM β-Glycerol Phosphate; 0.1 mM Ethylenediaminetetraacetic Acid (EDTA); 10% Glycerol; 1% Triton X-100; 1 mM Benzyl sulfonyl fluoride (PMSF); 1 mM sodium orthovanadate; 2 μg / ml pepstatin A; 2 μg / ml aprotinin; and 2 μg / ml leupeptin) for 20 min. Then, the lysate was centrifuged at 4°C for 20 minutes. Collect the supernatant and store it at -70 °C until use.

[0151] To collect nuclear protein extracts, treated cells were washed with PBS and resuspended in buffer A (10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (pH 7.9), 10 mM potassium chloride (KCl), 0.1 mM EDTA, 0.1 mM ethylene glycol tetraacetic acid (EGTA). 1 mM dithiothreitol (DTT), 0.5 mM phenylmethylsulfonyl fluoride or phenylmethylsul...

Embodiment 1

[0161] Example 1 - Prediction of Cimiracemate A as a Lipoxygenase Inhibitor

[0162] Similarity Ensemble (SEA), a search tool provided by Shoichet's lab in the Department of Medicinal Chemistry at the University of California, San Francisco (UCSF), quantitatively grouped Target protein pharmacology grouping and correlating target protein pharmacology 1-10 . Similarity values ​​between ligands are expressed as expected values ​​(E-values), which can be used to supplement chemical similarity values ​​generated by BLAST 1,10-11 .

[0163] A SEA search was performed using cimi A as a query compound to generate an E-value between cimi A and the ligand of the target protein. The Tanimoto coefficient (Tc) for chemical similarity was also calculated. E-value less than 1×10 -10 Indicates a significant similarity, while an E-value greater than 1.0 indicates an insignificant similarity. A Tc value between 0 and 0.5 indicates an insignificant similarity, while a Tc greater than 0.5 ...

Embodiment 2

[0166] Example 2—Determination of the inhibitory effect of cimiracemate A on 5-lipoxygenase activity

[0167] This example demonstrates that cimiracemate A strongly inhibits the activity of 5-LOX. Briefly, 5-LOX inhibition assays were performed by using Cayman's Lipoxygenase Inhibitor Screening Assay Kit (Cayman Chemical Company, Ann Arbor, MI) according to the manufacturer's instructions. 5-LOX and linoleic acid (substrate) were simultaneously added to dimethyl sulfoxide (DMSO) (control) or cimiracemate A at concentrations of 12.5, 25 and 50 μg / ml, respectively. After 5 min of incubation, the developer for the 5-LOX inhibition assay was added. Hydroperoxide production was measured with a microplate reader at a wavelength of 490 nm. The enzyme activity of 5-LOX is calculated in nmol / min / ml. The results showed that cimiracemate strongly inhibited 5-LOX activity in a dose-dependent manner (Fig. 1A).

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Abstract

The present invention pertains to Cimiracemate A and related compounds that are useful as inhibitors of 5 -lipoxygenase (5-1. OX) activity and various proinflammatory mediators such as lipoxins, leukotrienes (e.g., LTA4, LTB4, LTC4, LTD4, and LTE4), prostaglandins, and thromboxanes. The present invention also provides therapeutic methods and compositions for treatment of inflammation and inflammatory conditions, including allergenic reactions, diseases associated with cell proliferation, neoangiogenesis, and cardiovascular diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 369,428, filed July 30, 2010, which is incorporated herein by reference in its entirety, including all Figures, Tables, and Sequences. [0003] The sequence listing of this application is marked as "As-filed_ST25.txt", which was created on July 26, 2011 and is 2 KB in size. All content is incorporated herein by reference in its entirety. Background technique [0004] 5-Lipoxygenase (5-LOX), expressed primarily in leukocytes, including monocytes and macrophages, is the rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene lipid mediators. Leukotrienes have been found to be involved in many inflammatory diseases, allergic responses, diseases related to cell proliferation, neovascularization and cardiovascular diseases 2-9 . The biosynthesis of leukotrienes begins with the conversion of arachidonic acid by 5-LOX into leukotriene A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/216A61K36/71A61P29/00A61P37/08A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P11/06A61P17/00A61P19/02A61P35/00
CPCA61K31/216A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P11/06A61P17/00A61P19/02A61P29/00A61P35/00A61P37/08
Inventor A·S·Y·劳C·L·H·杨
Owner BAGI RES
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