One-pot homologation of boronic acids : a platform for diversity-oriented synthesis

Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor

Enantiodivergent Formation of C−P Bonds: Synthesis of P‑Chiral Phosphines and Methylphosphonate Oligonucleotides

Phosphorus Incorporation (PI, abbreviated Π) reagents for the modular, scalable, and stereospecific synthesis of chiral phosphines and methylphosphonate nucleotides are reported. Synthesized from translimonene oxide, this reagent class displays an unexpected reactivity profile and enables access to chemical space distinct from that of the Phosphorus−Sulfur Incorporation reagents previously disclosed. Here, the adaptable phosphorus(V) scaffold enables sequential addition of carbon nucleophiles to produce a variety of enantiopure C−P building blocks. Addition of three carbon nucleophiles to Π, followed by stereospecific reduction, affords useful P-chiral phosphines; introduction instead of a single methyl group reveals the first stereospecific synthesis of methylphosphonate oligonucleotide precursors. While both Π enantiomers are available, only one isomer is requiredthe order of nucleophile addition controls the absolute stereochemistry of the final product through a unique enantiodivergent design

One-pot homologation of boronic acids : a platform for diversity-oriented synthesis

Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor

Spectroscopic studies of the Chan-Lam amination : a mechanism-inspired solution to boronic ester reactivity

We report an investigation of the Chan-Lam amination reaction. A combination of spectroscopy, computational modeling, and crystallography has identified the structures of key intermediates and allowed a complete mechanistic description to be presented, in-cluding off-cycle inhibitory processes, the source of amine and organoboron reactivity issues, and the origin of competing oxida-tion/protodeboronation side reactions. Identification of key mechanistic events has allowed the development of a simple solution to these issues: manipulating Cu(I)→Cu(II) oxidation and exploiting three synergistic roles of boric acid has allowed the development of a general catalytic Chan-Lam amination, overcoming long-standing and unsolved amine and organoboron limitations of this valuable transformation

One-pot homologation of boronic acids

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC).Formal homologation of sp2-hybridized boronic acids is achieved via cross-coupling of boronic acids with conjunctive haloaryl BMIDA components in the presence of a suitably balanced basic phase. The utility of this approach to provide a platform for diversity-oriented synthesis in discovery medicinal chemistry is demonstrated in the context of the synthesis of a series of analogues of a BET bromodomain inhibitor.Publisher PDFPeer reviewe

Human γδ T cells recognize CD1b by two distinct mechanisms

γδ T cells form an abundant part of the human cellular immune system, where they respond to tissue damage, infection, and cancer. The spectrum of known molecular targets recognized by Vδ1-expressing γδ T cells is becoming increasingly diverse. Here we describe human γδ T cells that recognize CD1b, a lipid antigen-presenting molecule, which is inducibly expressed on monocytes and dendritic cells. Using CD1b tetramers to study multiple donors, we found that many CD1b-specific γδ T cells use Vδ1. Despite their common use of Vδ1, three CD1b-specific γδ T cell receptors (TCRs) showed clear differences in the surface of CD1b recognized, the requirement for lipid antigens, and corecognition of butryophilin-like proteins. Several Vγ segments were present among the CD1b-specific TCRs, but chain swap experiments demonstrated that CD1b specificity was mediated by the Vδ1 chain. One of the CD1b-specific Vδ1+ TCRs paired with Vγ4 and shows dual reactivity to CD1b and butyrophilin-like proteins. αβ TCRs typically recognize the peptide display platform of MHC proteins. In contrast, our results demonstrate the use of rearranged receptors to mediate diverse modes of recognition across the surface of CD1b in ways that do and do not require carried lipids

Serine-Selective Bioconjugation.

This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods

Jugoslavija u međunarodnoj trgovini ribom, ribljim proizvodima i prerađevinama

Sulfonamides are profoundly important in pharmaceutical design. C–N cross-coupling of sulfonamides is an effective method for fragment coupling and structure–activity relationship (SAR) mining. However, cross-coupling of the important <i>N</i>-arylsulfonamide pharmacophore has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cu-catalysis (Chan–Lam cross-coupling). Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalable Chan–Lam <i>N</i>-arylation of primary and secondary <i>N</i>-arylsulfonamides at room temperature. We also demonstrate utility in the large scale synthesis of a key intermediate to a clinical hepatitis C virus treatment

Human Cellular Immune Response to the Saliva of Phlebotomus papatasi Is Mediated by IL-10-Producing CD8+ T Cells and Th1-Polarized CD4+ Lymphocytes

Cutaneous leishmaniasis affects millions of people worldwide and is caused by protozoa of the genus Leishmania. The parasite is transmitted during sand fly bites. While probing the skin for a blood meal, vectors salivate into the host's skin. Sand fly saliva contains several components that increase hemorrhage and interfere with the host's inflammatory response. Data obtained in mice originally indicate that immunization against saliva protected from leishmaniasis supporting possibility that leishmaniasis could be prevented by a vaccine based on sand fly saliva. Herein we investigated the nature and the importance of the cellular immune response developed against sand fly saliva by individuals at risk of cutaneous leishmaniasis due to Leishmania major. We demonstrated that the immunity against saliva is dominated by the activation of lymphocytes producing a suppressive cytokine called IL-10. These data may preclude the protective effect of sand fly saliva pre-exposure in humans. Further experiments revealed that the production of IL-10 masked the presence of a second kind of lymphocytes producing IFN-γ, a rather protective cytokine. The latter finding highlights the importance of the identification of the proteins activating the latter lymphocytes in order to develop vaccines based on selected proteins from the saliva of sand flies