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A CCL2-CCR2, application technology, applied in the field of CCR2 antagonists, can solve the problem of little curative effect of liver resection
Active Publication Date: 2017-10-03
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI +1
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However, hepatectomy is rarely curative, with recurrence occurring in 60-70% of cases
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Embodiment 1
[0108] Embodiment 1: the preparation of compound 747
[0109]Grind 22kg of the dry aerial part of Abies longbract into coarse powder, and extract it 3 times with 200L of 80% ethanol under reflux for 3 hours each time, combine the extracts, concentrate under reduced pressure to obtain 25L thick extract. The extract was diluted with 10L of water and then extracted sequentially with chloroform, ethyl acetate and n-butanol, and the extracted parts were collected and concentrated into extracts respectively. Wherein the extractum 300g of the ethyl acetate extraction part is dissolved and filtered with methanol and carried out silica gel column chromatography, eluting with chloroform-methanol 2:1, checking the eluted fraction with thin-layer chromatography, and the fractions with the same single spot are merged, Concentration to obtain fractions 1-10, wherein the first fraction was further purified by silica gel chromatography to obtain a yellow amorphous powder, whose structure was ...
Embodiment 2
[0119] Embodiment 2: the activity test of compound 747
[0120] 1. Experimental steps
[0121] 1.1 Cell Migration
[0122] Human mononuclear cell line THP-1 (high expression of CCR2), 96-well transwell (corning 3788), hCCL2 (peprotech), after THP-1 cells were co-incubated with drugs for 30 minutes, take 1x10 5 THP-1 cells / well, adding hCCL2 50ng / ml to the lower medium to induce their migration, after 6 hours The LμMinescent Cell Viability Assay (promega) measures the number of cells crossed by the substratum medium.
[0123] 1.2 Calcium flux experiment
[0124] THP-1 cells were stably transfected with the calcium influx indicator protein GCAMP6 to obtain a stable transfection strain THP-1 GCAMP6. After THP-1 cells were co-incubated with drugs for 30 minutes, 1x10 6 THP-1 cells / well and Mg added 2+ : 2mM, Ca 2+ : 2mM, hCCL2 100ng / ml (peprotech) recorded data (488nm, 520nm).
[0125] 293FT cells were stably transformed with the calcium flux indicator protein GCAMP6 to ...
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Abstract
The invention relates to a novel CCR2 antagonist and an application thereof. Specifically, the invention discloses an application of a compound as shown in formula I (referring to the Description) or pharmaceutically acceptable salt in preparing medicines or reagents for regulating tumor microenvironment, relieving aggregation of macrophage or bone marrow cells towards primary tumors, inhibiting tumor growth, inhibiting angiogenesis and / or increasing CD8T cells in a required object, as well as an application in preparing medicines for preventing or treating CCR2-mediated diseases in the object or an application in preparing medicines or reagents for inhibiting a CCR2 or CCL2-CCR2 pathway, wherein in the formula, a, b, c, d, R1, R2, R3 and R4 are as described in the Description.
Description
technical field [0001] This application relates to a novel CCR2 antagonist and its use. Background technique [0002] As described in CN103328479A, the chemokine receptor CCR2 is found on the surface of monocytes, macrophages, B cells, activated T cells, dendritic cells, endothelial cells and tumor cells. It is a receptor for several chemokine ligands, including MCP-1, MCP-2, MCP-3 and MCP-4. Of these, MCP-1 (monocyte chemoattractant protein-1, also known as CCL2) appears to only interact with CCR2 and not with any other chemokine receptors identified so far. MCP-1 is expressed by cardiomyocytes, vascular endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, mesangial cells, alveolar cells, T lymphocytes, macrophages, etc. After activation by its MCP-1, the CCR2 receptor signaling cascade involves the activation of phospholipases, protein kinases and lipid kinases. [0003] CCR2-mediated monocyte recruitment is one of the earliest steps leading to the develop...
Claims
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Application Information
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