Discovery of substituted 4-aminoquinazolines as selective Toll-like receptor 4 ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Nour, Afshin¹  Hayashi, Tomoko¹  Chan, Michael¹  Yao, Shiyin¹  Tawatao, Rommel I.¹  Crain, Brian¹  Tsigelny, Igor F.^1,2,3,4  Kouznetsova, Valentina L.^1,2,3  Ahmadiiveli, Alast¹  Messer, Karen¹  Pu, Minya¹  Corr, Maripat⁵  Carson, Dennis A.¹  Cottam, Howard B.¹ 

[1] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[2] San Diego Supercomp Ctr, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

关键词: Toll-like receptor 4;    MD-2;    4-Aminoquinazolines;    NF-kappa B activation;    Innate immune response;   

DOI  :  10.1016/j.bmcl.2014.09.039

来源: Elsevier

【 摘 要 】

The Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-kappa B activation. A human cell-based high throughput screen (HTS) revealed substituted 4-aminoquinazolines to be small molecular weight activators of NF-kappa B. The most potent hit compound predominantly stimulated through the human TLR4/MD2 complex, and had less activity with the mouse TLR4/MD2. There was no activity with other TLRs and the TLR4 activation was MD-2 dependent and CD14 independent. Synthetic modifications of the quinazoline scaffold at the 2 and 4 positions revealed trends in structure-activity relationships with respect to TLR dependent production of the NF-kappa B associated cytokine IL-8 in human peripheral blood mononuclear cells, as well as IL-6 in mouse antigen presenting cells. Furthermore, the hit compound in this series also activated the interferon signaling pathway resulting in type I interferon production. Substitution at the O-phenyl moiety with groups such as bromine, chlorine and methyl resulted in enhanced immunological activity. Computational studies indicated that the 4-aminoquinazoline compounds bind primarily to human MD-2 in the TLR4/MD-2 complex. These small molecules, which preferentially stimulate human rather than mouse innate immune cells, may be useful as adjuvants or immunotherapeutic agents. (C) 2014 The Authors. Published by Elsevier Ltd.

【 授权许可】

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