ArticleBioorganic & medicinal chemistry letters2014
Discovery of substituted 4-aminoquinazolines as selective Toll-like receptor 4 ligands.
Article in Bioorganic & medicinal chemistry letters, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 24 citations in OpenAlex.
- Small molecule modulators of immune pattern recognition receptors.RSC chemical biology · 2023Review
- Toll-like Receptor Agonist Conjugation: A Chemical Perspective.Bioconjugate chemistry · 2018Review
- Structure-Activity Relationship Studies of Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands.Journal of medicinal chemistry · 2017Article
- The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling.International journal of molecular sciences · 2017Review
- Identification of Biologically Active Pyrimido[5,4-b]indoles That Prolong NF-κB Activation without Intrinsic Activity.ACS combinatorial science · 2017Article
- Strategies for designing synthetic immune agonists.Immunology · 2016Review
- Computational Approaches to Toll-Like Receptor 4 Modulation.Molecules (Basel, Switzerland) · 2016Review
- A Novel Class of Small Molecule Agonists with Preference for Human over Mouse TLR4 Activation.PloS one · 2016Article
- Identification of Adjuvantic Activity of Amphotericin B in a Novel, Multiplexed, Poly-TLR/NLR High-Throughput Screen.PloS one · 2016Article
- A Light-Controlled TLR4 Agonist and Selectable Activation of Cell Subpopulations.Chembiochem : a European journal of chemical biology · 2015Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
The Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-κB activation. A human cell-based high throughput screen (HTS) revealed substituted 4-aminoquinazolines to be small molecular weight activators of NF-κB. 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-κB 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.