Use of 2-(ethylaminomethyl)-5-(phenyl)furan in the preparation of medicines for inhibiting tlr7/8
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A technology of ethylaminomethyl and phenyl, applied in the field of TLRs receptor inhibitors, can solve problems such as side effects of TLR agonists
Active Publication Date: 2021-07-27
CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI
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[0007] The object of the present invention is to provide the application of 2-(substituted ethylaminomethyl)-5-(substituted phenyl) furan compound or its medicinal salt in the preparation of medicines for inhibiting TLR7 / 8, which can solve the problem of existing TLR agonists have the problem of side effects
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Embodiment 1
[0039] Effect of compound 1, compound 2 and control compound TLR7 / 8 activator on the inhibitory activity of TLR7 / 8 protein in HEK293 cells and the cell proliferation rate measured by CCK-8
[0040] Solution: HEK-Blue TM -hTLR7 cells (HEK293 cells transfected with humanized TLR7, purchased from InvivoGen) were seeded in 96-well plates at a density of 4×10 4 To each well, agonist CL097 (5 μM) and test compound 1 or compound 2 (40 μM) were added overnight to obtain supernatant. The obtained supernatant was aspirated with a pipette gun, the supernatant (20 μL) was tested by Quanti-blue (OD 630 nm), and the residual liquid was tested for cell proliferation rate by CCK-8. If the cell proliferation rate is high, it means that it is less toxic to cells and the cells can grow normally.
[0041] Index of Quanti-Blue value=(A-B) / (C-B); where A: the average value of the wells to be tested; B: the average value of the matrix containing cells; C: the positive control (CL097).
[0042] St...
Embodiment 2
[0054] NO activity test and cell survival experiment of compound 1 / compound 2
[0055] Protocol: RAW264.7 cells were seeded in 96-well plates at a density of 4×10 4 One per well, compound 1, compound 2 or indomethacin (40 μM) and lipopolysaccharide (LPS) (1 μg / mL, 10 μL / well) were added after 1.5 h. After 24h, the NO concentration was tested by Griess reagent (540nm); the cell growth was tested by MTT (200μL, 0.5mg / mL, 450nm).
[0056] Steps:
[0057] ① Culture RAW264.7 cells in DMEM medium (10% FBS + 1% penicillin / streptomycin), 37°C, 5% CO 2 ; After the cells grew stably, they were seeded in 96-well plates (5×10 4 per well), overnight.
[0058] ②Add compound (40 μM, 100 μL) and then add LPS (1 μg / mL, 10 μL / well).
[0059] ③The next day, take 50 μL of the cell supernatant and use the Griess kit (nitric oxide kit, purchased from Beyond Biotechnology Co., Ltd.) to draw a standard curve at the same time.
[0060] ④ Discard the supernatant, add MTT [3-(4,5-dimethylthiazole-...
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Abstract
The invention discloses the use of 2-(substituted ethylaminomethyl)-5-(substituted phenyl) furan compound or its pharmaceutically acceptable salt in the preparation of medicines for inhibiting TLR7 / 8, characterized in that the 2 ‑(substituted ethylaminomethyl)‑5‑(substituted phenyl) furan compound is shown in the following formula I: the above-mentioned 2‑(substituted ethylaminomethyl)‑5‑(substituted phenyl) furan compound has TLR7 / 8 Inhibitor effect By inhibiting TLR7 / 8, it can block hyperglycemia caused by tumor treatment and its adverse consequences, such as infection and non-malignant tumor-related death, cell proliferation rate > 80%, low cytotoxicity, does not affect Cells grow normally; the anti-inflammatory effect is better than that of indomethacin, which has better anti-inflammatory activity and lower cytotoxicity. It can block NF‑κB by inhibiting TLR7 / 8, thereby inhibiting the expression of pro-inflammatory genes. And then achieve the purpose of treating inflammation.
Description
technical field [0001] The present invention relates to a TLRs receptor inhibitor, in particular to a 2-(substituted ethylaminomethyl)-5-(substituted phenyl) furan compound or a pharmaceutically acceptable salt thereof used in the preparation of TLR7 / 8 inhibitors Uses in medicine. Background technique [0002] TLRs (Toll-like receptors) receptors are members of the interleukin receptor (IL-1R) superfamily and mainly play a role in the innate immune system. They are a single, transmembrane, non-catalytic receptor that recognizes the source of Structurally specific molecules for microorganisms. Among them, TLR7 not only recognizes small molecular compounds with antiviral and antitumor effects such as imidazoquinoline analogues, but also recognizes viral ssRNA, activates MyD88 signaling pathway, activates immune cells, and promotes downstream IFN, TNF-α, IL-12 and other cells The expression of these factors mediates the immune regulation of the body and the regulation of tumo...
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