RESUMO
Binding of antigen to IgE-high affinity FcεRI complexes on mast cells and basophils results in the release of preformed mediators such as histamine and de novo synthesis of cytokines causing allergic reactions. Src-like adapter protein (SLAP) functions co-operatively with c-Cbl to negatively regulate signaling downstream of the T cell receptor, B cell receptor, and receptor tyrosine kinases (RTK). Here, we investigated the role of SLAP in FcεRI-mediated mast cell signaling, using bone marrow derived mast cells (BMMCs) from SLAP knock out (SLAP KO) mice. Mature SLAP-KO BMMCs displayed significantly enhanced antigen induced degranulation and synthesis of IL-6, TNFα, and MCP-1 compared to wild type (WT) BMMCs. In addition, SLAP KO mice displayed an enhanced passive cutaneous anaphylaxis response. In agreement with a negative regulatory role, SLAP KO BMMCs showed enhanced FcεRI-mediated signaling to downstream effector kinases, Syk, Erk, and Akt. Recombinant GST-SLAP protein binds to the FcεRIß chain and to the Cbl-b in mast cell lysates, suggesting a role in FcεRI down regulation. In addition, the ubiquitination of FcεRIγ chain and antigen mediated down regulation of FcεRI is impaired in SLAP KO BMMCs compared to the wild type. In line with these findings, stimulation of peripheral blood human basophils with FcεRIα antibody, or a clinically relevant allergen, resulted in increased SLAP expression. Together, these results indicate that SLAP is a dynamic regulator of IgE-FcεRI signaling, limiting allergic responses.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Mastócitos/imunologia , Proteínas Proto-Oncogênicas pp60(c-src)/sangue , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Receptores de IgE/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Animais , Basófilos/imunologia , Basófilos/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Citocinas/biossíntese , Dinitrofenóis/farmacologia , Feminino , Humanos , Imunoglobulina E/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Anafilaxia Cutânea Passiva/genética , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Albumina Sérica/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
An expansion of methodologies aimed at the formation of versatile organonitriles, via the intramolecular aminocyanation of unactivated alkenes, is herein reported. Importantly, the need for a rigid tether in these reactions has been obviated. The ease-of-synthesis and viability of substrates bearing flexible backbones has permitted for diastereoselective variants as well. We demonstrated the utility of this methodology with the formation of pyrrolidones, piperidinones, isoindolinones, and sultams. Furthermore, subsequent transformation of these motifs into medicinally relevant molecules is also demonstrated. A double crossover 13C-labeling experiment is consistent with a fully intramolecular cyclization mechanism. Deuterium labeling experiments support a mechanism involving syn-addition across the alkene.
Assuntos
Alcenos/química , Nitrilas/química , Paládio/química , Ftalimidas/síntese química , Pirrolidinonas/síntese química , Alcenos/síntese química , Aminação , Catálise , Ciclização , Deutério/química , Ácidos de Lewis/química , Modelos Moleculares , Nitrilas/síntese química , Ftalimidas/química , Pirrolidinonas/química , EstereoisomerismoRESUMO
Alkene oxyacylation is a new strategy for the preparation of ß-oxygenated ketones. Now, with Ir catalysis and low-cost salicylate esters, alkene oxyacylation can be promoted by simple and versatile hydroxyl directing groups. This paper discusses catalyst optimization, substituent effects, mechanistic experiments, and the challenges associated with asymmetric catalysis. Crossover experiments point to several key steps of the mechanism being reversible, including the most likely enantiodetermining steps. The oxyacylation products are also prone to racemization without catalyst when heated alone; however, crossover is not observed without catalyst. These observations account for the low levels of enantioinduction in alkene oxyacylation. The versatility of the hydroxyl directing group is highlighted by demonstrating further transformations of the products.
RESUMO
Reported here is a palladium catalyzed intramolecular acylcyanation of alkenes using α-iminonitriles. Through this method, highly functionalized indanones are synthesized in moderate to high yields using Pd(PPh3)4, without need for any additional ligands, and a common Lewis acid (ZnCl2). Additionally, the reaction tolerates substitution at various positions on the aromatic ring including electron donating and electron withdrawing groups.
Assuntos
Alcenos/química , Paládio/química , Catálise , Cloretos/química , Nitrilas/química , Compostos de Zinco/químicaRESUMO
A metal-free, Lewis acid promoted intramolecular aminocyanation of alkenes was developed. B(C6F5)3 activates N-sulfonyl cyanamides, thus leading to a formal cleavage of the N-CN bonds in conjunction with vicinal addition of sulfonamide and nitrile groups across an alkene. This method enables atom-economical access to indolines and tetrahydroquinolines in excellent yields, and provides a complementary strategy for regioselective alkene difunctionalizations with sulfonamide and nitrile groups. Labeling experiments with (13)C suggest a fully intramolecular cyclization pattern due to the lack of label scrambling in double crossover experiments. Catalysis with Lewis acid is realized and the reaction can be conducted under air.
Assuntos
Alcenos/química , Aminas/química , Cianetos/química , HidróliseRESUMO
A new coordination polymer of polyoxomolybdate, {[Cu(4)(bbp)(5)Mo(6)O(22)]·(H(2)O)(4)}(∞) (bbp = 1,4-bis(benzoimidazol-1-yl)phenyl), has been synthesized under solvothermal reaction, which represents a double-bridging interpenetrating α-Po network based on the bimetallic cluster {Cu(4)Mo(6)}. The thermogravimetric and electrochemical behaviors have also been studied.
RESUMO
Sparked by the strategy of pillared-layer MOFs, three formate coordination polymers, {[Ni(2)(HCO(2))(3)(L)(2)](NO(3)).2H(2)O}(infinity) (1), {[Co(2)(HCO(2))(3)(L)(2)](HCO(2)).2H(2)O}(infinity) (2), and {[Cu(2)(HCO(2))(3)(L)(2)](HCO(2)).2H(2)O}(infinity) (3), have been synthesized by employing the rodlike ligand 4,4'-bis(imidazol-1-yl)biphenyl (L) as the pillar. Structural analysis indicates that the title complexes 1-3 are isostructural compounds, which possess metal-formate 2D layers perpendicularly pillared by the ligand L to afford a 3D open framework. This is an interesting example of a Kagome lattice based on the formate mediator. Moreover, the formate anion of this 2D Kagome layer exhibits various bridging modes: anti-anti, syn-anti, and 3.21 modes. Their magnetic measurements reveals that only complex 1 presents the spin canting phenomenon, while its isostructural Co(II) and Cu(II) complexes are simply paramagnets with antiferromagnetic coupling.