Structure-activity relationship study and biological evaluation of SAC-Garlic acid conjugates as novel anti-inflammatory agents
| Autor: | Kui Cheng, Kun Chen, Jingjie Bi, Wenqing Wang, Junxi Du |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
THP-1 Cells
medicine.medical_treatment Inflammation Nitric Oxide 01 natural sciences Peripheral blood mononuclear cell Nitric oxide 03 medical and health sciences chemistry.chemical_compound Lipopeptides Mice Structure-Activity Relationship Drug Discovery medicine Hydroxybenzoates Animals Humans Viability assay Cysteine Garlic 030304 developmental biology Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Macrophages Organic Chemistry Anti-Inflammatory Agents Non-Steroidal General Medicine Molecular biology 0104 chemical sciences TLR2 Cytokine RAW 264.7 Cells Alkaline phosphatase Cytokines Tumor necrosis factor alpha medicine.symptom |
| Zdroj: | European journal of medicinal chemistry. 179 |
| ISSN: | 1768-3254 |
| Popis: | A series of S-allyl- l -cysteine (SAC) with garlic acid conjugates as anti-inflammatory agents were designed and synthesized. Among the 40 tested compounds, SMU-8c exhibited the most potent inhibitory activity to Pam 3 CSK 4 -induced nitric oxide (NO) in RAW264.7 macrophages with IC 50 of 22.54 ± 2.60 μM. The structure-activity relationship (SAR) study suggested that the esterified carboxyl group, carbon chain extension and methoxylation phenol hydroxy could improve the anti-inflammatory efficacy. Preliminary anti-inflammatory mechanism studies showed that SMU-8c significantly down-regulated the levels of Pam 3 CSK 4 triggered TNF-α cytokine in human THP-1 cells, mouse RAW 264.7 macrophages, as well as in ex-vivo human peripheral blood mononuclear cells (PBMC) with no influence on cell viability. SMU-8c specifically blocked the Pam 3 CSK 4 ignited secreted embryonic alkaline phosphatase (SEAP) signaling with no influence to Poly I:C or LPS triggered TLR3 or TLR4 signaling. Moreover, SMU-8c suppressed TLR2 in HEK-Blue hTLR2 cells and inhibited the formation of TLR1-TLR2, and TLR2-TLR6 complex in human PBMC. In summary, SMU-8c inhibited the TLR2 signaling pathway to down-regulate the inflammation cytokines, such as NO, SEAP and TNF-α, to realize its anti-inflammatory activity. |
| Databáze: | OpenAIRE |
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