Discovery and Structure–Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists

Morin, Matthew D.; Wang, Ying; Jones, Brian; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, E; Zhang, Hong; Beutler, Bruce; Boger, Dale L.

doi:10.1021/acs.jmedchem.6b00177

Cited by 33 publications

(29 citation statements)

References 65 publications

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“…Because our results are unable to completely explain the usefulness of S100A8 and S100A9, it is imperative to unveil the drug-resistance mechanism for personal therapy and develop novel resistant drugs (including peptides and chemical compounds) based on TLR4 agonists, such as S100A8 and S100A9. Therapeutic drugs that target TLR4 and S100A8 or S100A9 have been examined, and potential candidate agents have been discovered ( 37 – 40 ). New materials based on our research can proceed in the quest for activators that induce TLR4-mediated apoptotic signal transduction and inhibitors of transcription-associated components that control transcription of the FIP1L1-PDGFRα+ gene.…”

Section: Discussionmentioning

confidence: 99%

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

Lee

Kashif

et al. 2020

Front. Immunol.

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S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.

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Section: Discussionmentioning

confidence: 99%

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

Lee

Kashif

et al. 2020

Front. Immunol.

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“…Motivated by the ring structure of the highly unstable triacetone triperoxide, we envisaged the synthesis also of nine‐membered peroxides, so‐called 1,2,4‐trioxononanes. The C 4 ‐linked phenol 10 was converted with caroate into the hydroperoxide 11 in 79 % yield. The ferric chloride catalyzed peroxyacetalization with three ketones delivered the 1,2,4‐trioxocanes 12 a – 12 c in low yields (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Spirofused and Annulated 1,2,4‐Trioxepane‐, 1,2,4‐Trioxocane‐, and 1,2,4‐Trioxonane‐Cyclohexadienones: Cyclic Peroxides with Unusual Ring Conformation Dynamics

et al. 2018

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C3- or C4-hydroxyalkylated phenols are highly reactive towards peroxidation with oxone, which results in the formation of tertiary C3 hydroperoxides. This reaction can also be performed with photochemically generated singlet oxygen. However, other characteristic singlet oxygen reactions do not proceed with caroate. The initially formed hydroperoxides cyclize in the presence of a Lewis acid catalyst based on boron, indium, or iron to give spiroannulated peroxides. These exhibit restricted ring inversion whereas larger nine-membered-ring peroxides are thermally less stable and show higher ring flexibility (according to NMR analysis).

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“…Synthetic compounds with a linear scaffold instead of glucosamine disaccharide such as ER-112022 [ 57 ] are active as TLR4 agonist, thus showing that the disaccharide connecting the two anionic phosphates can be substituted by chemical spacers of different chemical structure and with increased conformational mobility. More recently, new classes of non-LPS-like small molecules, the neoseptins [ 58 , 59 ], Euodenine A and analogues [ 60 ], have been reported to be MD-2-dependent TLR4 agonists [ 5 , 59 , 61 , 62 , 63 ].…”

Section: Structure-activity Relationship In Natural and Synthetic mentioning

confidence: 99%

The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling

Cochet

Peri

2017

IJMS

137

102

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The interactions between sugar-containing molecules from the bacteria cell wall and pattern recognition receptors (PRR) on the plasma membrane or cytosol of specialized host cells are the first molecular events required for the activation of higher animal’s immune response and inflammation. This review focuses on the role of carbohydrates of bacterial endotoxin (lipopolysaccharide, LPS, lipooligosaccharide, LOS, and lipid A), in the interaction with the host Toll-like receptor 4/myeloid differentiation factor 2 (TLR4/MD-2) complex. The lipid chains and the phosphorylated disaccharide core of lipid A moiety are responsible for the TLR4 agonist action of LPS, and the specific interaction between MD-2, TLR4, and lipid A are key to the formation of the activated complex (TLR4/MD-2/LPS)2, which starts intracellular signalling leading to nuclear factors activation and to production of inflammatory cytokines. Subtle chemical variations in the lipid and sugar parts of lipid A cause dramatic changes in endotoxin activity and are also responsible for the switch from TLR4 agonism to antagonism. While the lipid A pharmacophore has been studied in detail and its structure-activity relationship is known, the contribution of core saccharides 3-deoxy-d-manno-octulosonic acid (Kdo) and heptosyl-2-keto-3-deoxy-octulosonate (Hep) to TLR4/MD-2 binding and activation by LPS and LOS has been investigated less extensively. This review focuses on the role of lipid A, but also of Kdo and Hep sugars in LPS/TLR4 signalling.

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Discovery and Structure–Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists

Cited by 33 publications

References 65 publications

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

Spirofused and Annulated 1,2,4‐Trioxepane‐, 1,2,4‐Trioxocane‐, and 1,2,4‐Trioxonane‐Cyclohexadienones: Cyclic Peroxides with Unusual Ring Conformation Dynamics

The Role of Carbohydrates in the Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4) Signalling

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