Pseudomonas aeruginosa (PA) is a Gram-negative pathogen that the World Health Organization has ranked as a priority 1 (critical) threat. One potential prophylactic approach to preventing or reducing the incidence of PA would be development of a long sought-after vaccine. Both antibody and CD4+ T-cell responses have been noted as playing key roles in protection against infection. In these studies, we have designed a prototype vaccine consisting of several known linear B-cell epitopes derived from an outer membrane porin F (OprF). The resulting thiol-containing protein was conjugated to a version of the lipopeptide-based Toll-like receptor agonist Pam3CysSK4Mal (10) containing a maleimide moiety and formulated into dipalmitoylphosphatidylcholine (DPPC)/cholesterol (Chol) liposomes. Mice immunized with the resulting vaccine generated antibodies that bound PA14 (serotype O10) in vitro and induced opsonization in the presence of rabbit complement and murine macrophage RAW264.7 cells. The liposome was optimized to contain 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG), Chol, Pam3CysSK4-OprF (12) and the Quillaja saponaria-derived saponin adjuvant QS-21. The resulting vaccine formulation produced significantly higher antibody titers, increased the IgG2a antibody isotype, and increased the number of IgG-producing B-cells as well as splenic primed T-cells. In summary, the liposomal vaccine platform was found highly useful for the generation of a robust and balanced TH1/TH2 response.

We disclose here practical strategies toward the synthesis of morpholines and Claisen rearrangement products based on the divergent reactivity of a common halonium intermediate. These reactions employ widely available alkenes in a Lewis acid-catalyzed halo-etherification process that can then transform them into the desired products with exceptional regioselectivity for both activated and unactivated olefins. Our mechanistic probe reveals an interesting regiochemical kinetic resolution process.

A novel iodide-catalyzed intermolecular aminooxygenation strategy is described here. Amide is used as the O- and N- source to probe for regiocontrol strategies. Notably, simple additives can be selectively introduced to achieve regiodivergent oxyamination processes for electronically activated alkenes while being regio-complementary for unactivated alkenes. Our preliminary data demonstrates that this regiocontrol strategy based on nucleophile can also be applied in asymmetric processes using chiral hypervalent iodine catalysis.

An aerobic catalytic oxidation process is described for the olefin oxyamination using acids and primary amines as the sources of O and N. Our mechanistic findings point to the formation of triiodide as a critical catalytic intermediate to account for the tolerance of electron-rich nucleophiles. This dual iodide and copper catalytic system is suitable for a formal [5+1] annulation process to access valuable lactam structures and highlighted by the synthesis of the pharmaceutical Zamifenacin.

The utilization of a halogen bond in a number of chemical fields is well-known. Surprisingly, the incorporation of this useful noncovalent interaction in chemical reaction engineering is rare. We disclose here an uncommon use of halogen bonding to induce intermolecular C-sp(3)-H amination while enabling a hydrogen atom transfer relay strategy to access privileged pyrrolidine structures directly from alkanes. Mechanistic studies support the presence of multiple halogen bond interactions at distinct reaction stages.

A group of hydroxytolans were previously found capable of suppressing tumor cell growth. The most current study further evaluated their regulatory effects on inflammation, a common factor in many diseases including cancer, arthritis and cardiovascular disorders. The study focused on macrophages, an immune cell type responsible for chronic inflammation. Cell viability assays were conducted to assess the effect of hydroxytolans, at various concentrations for 24h, on murine macrophage cell line RAW 264.7, compared to murine fibroblast L292 cells. Quantitative RT PCR analysis was conducted to detect activation of inflammatory genes (TNFα, IL-1, IL-6 and iNOS) in response to LPS stimulation (2.5 μg/mL, 2h) after hydroxytolan treatment (50 μg/mL, 0.5h). NF-κB activation is one of the underlying mechanisms for LPS-induced inflammation, and its regulation was investigated by using a luciferase assay on RAW 264.7 cells following hydroxytolan treatment (50 μg/mL, 0.5h) and LPS stimulation (2.5 μg/mL, 6h). In addition, phosphorylation of JNK, one of the key molecules driving the signal pathway for induction of pro-inflammatory cytokine was assessed by Western blot analysis after hydroxytolan treatment (50 μg/mL, 0.5h) and LPS stimulation (2.5 μg/mL, 0.5h). RAW 264.7 macrophages were more susceptible to 4,4'-dihydroxytolan in terms of cell viability, compared to non-macrophage L292 cells. Pre-treating RAW 264.7 with both 4,4'-dihydroxytolan and 3,4',5-trihydroxytolan attenuated LPS-induced expression of cytokines and iNOS, NF-κB activation, and JNK phosphorylation. Together our data implicated that these drug candidates exhibited an inhibitory effect on macrophages, suggesting a therapeutic potential of hydroxytolans for the treatment of macrophage-medicated inflammatory diseases.

An alkene sulfenoamination reaction with 2-aminothiophenol is developed using iodide catalysis. This reaction renders access to useful 1,4-benzothiazines with good functional group compatibility including both electron-donating and electron-withdrawing substituents. The reaction is proposed to proceed through an inversion of the polarity of the thiol functionality. Our mechanistic studies reveal that both thiiranium and thiyl radical pathways are plausible and that the disulfide reagent can also function as a viable substrate in this reaction.

A new class of intermolecular olefin aminooxygenation reaction is described. This reaction utilizes the classic halonium intermediate as a regio- and stereochemical template to accomplish the selective oxyamination of both activated and unactivated alkenes. Notably, urea chemical feedstock can be directly introduced as the N and O source and a simple iodide salt can be utilized as the catalyst. This formal [3+2] cycloaddition process provides a highly modular entry to a range of useful heterocyclic products with excellent selectivity and functional-group tolerance.

Saturated heterocycles are important structural motifs in a range of pharmaceuticals and agrochemicals. As a result of their importance, syntheses of these molecules have been extensively investigated. Despite the progress in this area, the most adopted strategies are still often characterized with inefficiency or relying on functionalizations with specialized precursors and pre-existing cores. This review highlights a dynamic synthetic strategy for the direct synthesis of saturated heterocycles from intermolecular alkene difunctionalizations. These coupling processes are highly modular, and therefore, offer perhaps the most convenient means to prepare diverse heterocyclic structures in compound libraries for bioactivity evoluations.

An intermolecular sulfenoamination reaction utilizing a stable sulfur precursor with a broad range of alkene structures is described. More importantly, these reactions proceed in a highly regio- and stereoselective manner to afford interesting heterocyclic motifs ready for biological studies. In addition, a highly regiodivergent approach to access the opposite regioisomers for styrene derivatives was also developed.

A convenient synthesis of a privileged pharmaceutical motif, thiazoline is accomplished. This reaction utilizes simple and readily available alkene and thioamide substrates in an intermolecular fashion via a simple one-pot procedure. A wide range of functional groups is tolerated, and the thiazoline product has been further utilized for the synthesis of the corresponding β-aminothiol and thiazole from routine hydrolysis and oxidation protocols.