Synthesis of Non-lipid Novel Chalcone Analogs for Inhibitory Activity of NF-κB-Regulated Inflammatory Gene Expression via Targeting LPS-Binding Site of MD2-TLR4 Complex

다국어 초록 (Multilingual Abstract)

To define the role of substituents of chalcones as potent MD-2 inhibitors, we designed and synthesized analogs of 1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (1) for their in vitro activities against RAW 264.7 cell using the SEAP assay as well as for LPS displacement assay. Among all the derivatives, compound 5 (IC50=27.3 μM), showed good inhibition of NF-κB activation by blocking the TLR4-mediated NF-κB activation signalling in RAW 264.7 as well as the rhMD-2 binding to immobilized LPS with 53% inhibition at 30 μM. The SAR studies indicated that small alkyl group like 3-methylbutoxy at 6-position of ring A and substituent with hydrogen bonding capability at 4-position of ring B of chalcone should be very important for inhibition of LPS induced NF-κB activation and LPS displacement of MD-2.