Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands
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- 作者：Michael Chan ; Tomoko Hayashi ; Richard D. Mathewson ; Afshin Nour ; Yuki Hayashi ; Shiyin Yao ; Rommel I. Tawatao ; Brian Crain ; Igor F. Tsigelny ; Valentina L. Kouznetsova ; Karen Messer ; Minya Pu ; Maripat Corr ; Dennis A. Carson ; Howard B. Cottam
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：56
- 期：11
- 页码：4206-4223
- 全文大小：681K
- 年卷期：v.56,no.11(June 13, 2013)
- ISSN：1520-4804
文摘
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 NF魏B 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 NF魏B and type I interferon associated cytokines, IL-6 and interferon 纬-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.