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-O-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. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.

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. An (R)-3-decanoyloxytetradecanoyl group on the 3-position of the d-glucosamine unit was found to be indispensable for maintaining low NF-κB activity irrespective of the substitutions (decyl or decanoyl) on the other two secondary positions. These results suggest that the carbonyl group of the 3-secondary lipid chain may impede homodimerization and/or conformational changes in the TLR4-MD2 complex necessary for MyD88 binding and pro-inflammatory cytokine induction.

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. In contrast to the known carbohydrate-based synthetic routes to the above furopyranyl fragment, the present amino acid chiral template approach is expected to offer a more flexible pathway toward potential SAR-targeted structural/stereochemical modifications of this central bicyclic nucleoside component of the ezomycins.

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.