536703-77-2Relevant academic research and scientific papers
Identification of substituted pyrimido[5,4-b]indoles as selective toll-like receptor 4 ligands
Chan, Michael,Hayashi, Tomoko,Mathewson, Richard D.,Nour, Afshin,Hayashi, Yuki,Yao, Shiyin,Tawatao, Rommel I.,Crain, Brian,Tsigelny, Igor F.,Kouznetsova, Valentina L.,Messer, Karen,Pu, Minya,Corr, Maripat,Carson, Dennis A.,Cottam, Howard B.
, p. 4206 - 4223 (2013/07/19)
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
