10.1016/S0008-6215(02)00357-9
The research aimed to synthesize lipid A type carboxymethyl derivatives with ether chains instead of ester chains and evaluate their LPS-antagonistic activities. The purpose was to investigate the potential of these compounds as immunosuppressants and in the treatment of autoimmune diseases and septicemia by deactivating LPS-induced aggressive macrophages. The study focused on the synthesis and biological activities of compounds 18, 19, and 20, which were designed to have ether chains at the C-3 and C-3' positions. The synthesis involved a series of chemical reactions using reagents such as NaH, DMF, NaOH, DCC, DMAP, OsO4, NMO, Pb(OAc)4, NaClO2, Ph2CN2, and PtO2, among others. The compounds were tested for their ability to inhibit LPS-induced TNFα production in human U937 cells, showing IC50 values of 6.5, 6.1, and 12.4 nM, respectively. The results indicated that the presence of an ester bond in the side chain at the 3-position might play a significant role in the LPS-antagonistic activity, as the ether chain compounds showed less activity compared to a related compound with an ester side chain (IC50=0.6 nM). The study concluded that the synthesized compounds exhibited LPS-antagonistic activity, albeit with varying potencies, and could serve as potential candidates for further development in immunomodulation therapies.