Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands

被引:70
作者
Chan, Michael [1 ]
Hayashi, Tomoko [1 ]
Mathewson, Richard D. [1 ]
Nour, Afshin [1 ]
Hayashi, Yuki [1 ]
Yao, Shiyin [1 ]
Tawatao, Rommel I. [1 ]
Crain, Brian [1 ]
Tsigelny, Igor F. [2 ,3 ]
Kouznetsoya, Valentina L. [1 ,2 ,3 ]
Messer, Karen [1 ]
Pu, Minya [1 ]
Corr, Maripat [4 ]
Carson, Dennis A. [1 ]
Cottamt, Howard B. [1 ]
机构
[1] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, San Diego Supercomp Ctr, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; STRUCTURAL BASIS; INNATE IMMUNITY; LIPID-A; LIPOPOLYSACCHARIDE; MD-2; ACTIVATION; TLR4; LPS; RESPONSIVENESS;
D O I
10.1021/jm301694x
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
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 kappa beta 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 kappa beta and type I interferon associated cytokines, IL-6 and interferon gamma-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.
引用
收藏
页码:4206 / 4223
页数:18
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