d-Glycero-β-d-mannoheptose Phosphate 7-O-Modifications

Abstract

Pathogen-associated molecular patterns activate the immune system via pattern recognition receptors. Recently, newly discovered pathogen-associated molecular patterns, d-glycero-β-d-mannoheptose phosphate and d-glycero-β-d-mannoheptose 1,7-biphosphate, were shown to induce a TRAF-interacting protein with a forkhead-associated domain-dependent immune response in human embryonic kidney cells and colonic epithelial cells. Concurrently, ADP-heptose was shown to bind α-kinase 1 and activate TIFA via phosphorylation leading to an immune cascade to ultimately activate NF-κB. These pathogen-associated molecular patterns have raised interest in the pharmaceutical industry for their potential use as immunomodulators. However, little is understood about the host cell uptake of d-glycero-β-d-mannoheptose phosphate, d-glycero-β-d-mannoheptose 1,7-biphosphate, and ADP-heptose in vivo and derivatives of these molecules are needed to interrogate this. In this regard, herein we describe 7-O-modifications of d-glycero-β-d-mannoheptose phosphate to produce molecular probes toward the development of a useful toolbox for biologists. A convergent strategy that involves introduction of a substituent at O-7 before alkene oxidation was investigated and proved successful in the generation of a range of molecular probes.

Pathogen-Associated Molecular Patterns: The Synthesis of Heptose Phosphates and Derivatives

“…A patent application on the method related to the synthesis and use of molecular probe for metabolite 2 was preliminarily filed in 2018 and then published in a peer-reviewed journal in 2021 by Sauvageau and co-workers. 7d 28b In this instance, metabolite 2 was modified at O -7, with an aminoethyl linker. 28b This probe was designed to raise specific antibodies to metabolite 2 , additionally to perform pull-down assays to study protein interactions.…”

“…7d 28b In this instance, metabolite 2 was modified at O -7, with an aminoethyl linker. 28b This probe was designed to raise specific antibodies to metabolite 2 , additionally to perform pull-down assays to study protein interactions. Conversely to Scheme 13 , furanoside 60 (Scheme 14 ) was 7- O -alkylated with bromoacetonitrile and dihydroxylated using osmium tetroxide to afford nitrile 61 .…”

“…and 1-bromododecane. 28b 35 A pseudolipid containing a triazole was also obtained ( 106 ) after 7-azido- d - glycero -β- d - manno -heptopyranosyl phosphate was synthesized and subjected to alkyne and azide [3+2] cycloaddition with dec-1-yne. The activity of these compounds remains to be evaluated in vitro.…”

Stereoselective synthesis of d-glycero-d-manno-heptose-1β,7-bisphosphate (HBP) from d-mannurono-2,6-lactone

“…Noteworthy contributions include Sauvageau et al's synthesis of probes and derivatives to elucidate the inflammatory pathway induced by HBP, 6,7 and Vincent et al's synthesis of biotinylated analogs for identifying pathogen recognition receptor (PRRs) of bacterial metabolites, 8 and hydrolysis-resistant HBPs by substituting the anomeric oxygen with fluoromethylene. 9 We were also captivated by its intriguing bioactivity, prompting us to embark on the synthesis of the D-glycero-Dmanno-heptose skeleton and HBP through an innovative strategy.…”