Intranasal administration of a synthetic TLR4 agonist INI-2004 significantly reduces allergy symptoms following therapeutic administration in a murine model of allergic sensitization.

Introduction: Atopic diseases have been steadily increasing over the past decades and effective disease-modifying treatment options are urgently needed. These studies introduce a novel synthetic Toll-like receptor 4 (TLR4) agonist, INI-2004, with remarkable efficacy as a therapeutic intranasal treatment for seasonal allergic rhinitis.

Methods: Using a murine airway allergic sensitization model, the impact of INI-2004 on allergic responses was assessed.

Diamino Allose Phosphates: Novel, Potent, and Highly Stable Toll-like Receptor 4 Agonists.

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3--acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester.

Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives.

We report the synthesis and biological evaluation of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a-g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFNα inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist.

Characterization of TRIF selectivity in the AGP class of lipid A mimetics: role of secondary lipid chains.

TLR4 agonists that favor TRIF-dependent signaling and the induction of type 1 interferons may have potential as vaccine adjuvants with reduced toxicity. CRX-547 (4), a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of lipid A mimetics possessing three (R)-3-decanoyloxytetradecanoyl groups and d-relative configuration in the aglycon, selectively reduces MyD88-dependent signaling resulting in TRIF-selective signaling, whereas the corresponding secondary ether lipid 6a containing (R)-3-decyloxytetradecanoyl groups does not. In order to determine which secondary acyl groups are important for the reduction in MyD88-dependent signaling activity of 4, the six possible ester/ether hybrid derivatives of 4 and 6a were synthesized and evaluated for their ability to induce NF-κB in a HEK293 cell reporter assay.

Synthetic studies on ezomycins: stereoselective route to a thymine octosyl nucleoside derivative.

The ezomycins are Streptomyces-derived antifungal natural products, belonging to the complex peptidyl nucleoside family of antibiotics. Employing D-serine as a chiral platform, we report herein a novel synthetic route to the bicyclic octosyl nucleoside core of the ezomycins. A key step in the sequence involved a stereoselective 6-exo-trig oxymercurationoxidation of a strategic delta-hydroxy alkene derivative, toward construction of the trans-fused furopyran ring system as present in the target products.

Stereoselective route to the ezoaminuroic acid core of the ezomycins.

Starting from readily available (R)-glycidol, an efficient pathway to a strategically functionalized ezoaminuroic acid derivative of the antifungal ezomycins has been developed. A key transformation in the synthesis involves regio- and stereoselective conversion of the olefinic functionality of a 5,6-dihydropyran-2-one to the C-2, C-3 trans-1,2-amino alcohol moiety as present in ezoaminuroic acid.

An efficient and highly stereocontrolled route to bulgecinine hydrochloride.

(-)-Bulgecinine is a nonproteinogenic amino acid component present in bulgecins A, B, and C, antibiotic glycopeptides derived from Pseudomonas acidophila and Pseudomonas mesoacidophila. In combination with beta-lactam antibiotics, bulgecins exihibit a unique synergistic antibacterial activity against various Gram-negative microorganisms. Utilizing d-serine as a chiral template and employing a highly regio- and stereoselective intramolecular amidomercuration-oxidation protocol in the key pyrrolidine ring forming step, an efficient total synthetic route to enantiopure bulgecinine is reported herein.