RESUMO
The enantioselective copper-catalyzed oxidative coupling of alkenols with styrenes for the construction of dihydropyrans, isochromans, pyrans and morpholines is reported. A concise formal synthesis of a σ1 receptor ligand using this alkene carboetherification methodology was demonstrated. Ligand, solvent and base all impact reaction efficiency. DFT transition state calculations are presented.
RESUMO
Necroptosis is a form of cell death characterized by receptor-interacting protein kinase activity and plasma membrane permeabilization via mixed-lineage kinase-like protein (MLKL). This permeabilization is responsible for the inflammatory properties of necroptosis. We previously showed that very long chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially through protein fatty acylation. Here, we define the scope of protein acylation by saturated VLCFAs during necroptosis. We show that MLKL and phosphoMLKL, key for membrane permeabilization, are exclusively acylated during necroptosis. Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting that acylation by VLCFAs contributes to their membrane localization. Acylation of phosphoMLKL occurs downstream of phosphorylation and oligomerization and appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also show that disruption of endosomal trafficking increases cell viability during necroptosis, possibly by preventing recruitment, or removal, of phosphoMLKL from the plasma membrane.
Assuntos
Aciltransferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/farmacologia , Acilação/efeitos dos fármacos , Aciltransferases/metabolismo , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/química , Ácidos Graxos/química , Células HT29 , Humanos , Necroptose/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
The copper-catalyzed enantioselective intramolecular hydroalkoxylation of unactivated alkenes for the synthesis of tetrahydrofurans, phthalans, isochromans, and morpholines from 4- and 5-alkenols is reported. The substrate scope is complementary to existing enantioselective alkene hydroalkoxylations and is broad with respect to substrate backbone and alkene substitution. The asymmetric induction and isotopic labeling studies support a polar/radical mechanism involving enantioselective oxycupration followed by C-[Cu] homolysis and hydrogen atom transfer. Synthesis of the antifungal insecticide furametpyr was accomplished.
Assuntos
Alcenos/química , Antifúngicos/síntese química , Benzofuranos/síntese química , Cobre/química , Éteres Cíclicos/química , Éteres Cíclicos/síntese química , Inseticidas/síntese química , Pirazóis/síntese química , Antifúngicos/química , Benzofuranos/química , Catálise , Furanos/química , Hidrogênio/química , Inseticidas/química , Estrutura Molecular , Pirazóis/química , EstereoisomerismoRESUMO
Necroptosis is a form of regulated cell death which results in loss of plasma membrane integrity, release of intracellular contents, and an associated inflammatory response. We previously found that saturated very long chain fatty acids (VLCFAs), which contain ≥20 carbons, accumulate during necroptosis. Here, we show that genetic knockdown of Fatty Acid (FA) Elongase 7 (ELOVL7) reduces accumulation of specific very long chain FAs during necroptosis, resulting in reduced necroptotic cell death and membrane permeabilization. Conversely, increasing the expression of ELOVL7 increases very long chain fatty acids and membrane permeabilization. In vitro, introduction of the VLCFA C24 FA disrupts bilayer integrity in liposomes to a greater extent than a conventional C16 FA. To investigate the microscopic origin of these observations, atomistic Molecular Dynamics (MD) simulations were performed. MD simulations suggest that fatty acids cause clear differences in bilayers based on length and that it is the interdigitation of C24 FA between the individual leaflets that results in disorder in the region and, consequently, membrane disruption. We synthesized clickable VLCFA analogs and observed that many proteins were acylated by VLCFAs during necroptosis. Taken together, these results confirm the active role of VLCFAs during necroptosis and point to multiple potential mechanisms of membrane disruption including direct permeabilization via bilayer disruption and permeabilization by targeting of proteins to cellular membranes by fatty acylation.
Assuntos
Membrana Celular/metabolismo , Ácidos Graxos/metabolismo , Bicamadas Lipídicas/metabolismo , Lipossomos/metabolismo , Necroptose/fisiologia , Acilação , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácidos Graxos/química , Técnicas de Silenciamento de Genes , Células HT29 , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Estrutura MolecularRESUMO
Spirocyclic ethers can be found in bioactive compounds. This copper-catalyzed enantioselective alkene carboetherification provides 5,5-, 5,6- and 6,6-spirocyclic products containing fully substituted chiral carbon centers with up to 99 % enantiomeric excess. This reaction features the formation of two rings from acyclic substrates, 1,1-disubstituted alkenols functionalized with either arenes, alkenes, or alkynes, and clearly constitutes a powerful way to synthesize chiral spirocyclic ethers.
Assuntos
Cobre/química , Éteres/química , Propanóis/química , Compostos de Espiro/química , Alcenos/química , Alcinos/química , Catálise , Cristalografia por Raios X , Éteres/síntese química , Conformação Molecular , Propanóis/síntese química , EstereoisomerismoRESUMO
A unique method to affect intramolecular aminooxygenation and dioxygenation of allenols and allenylsulfonamides is described. These operationally simple reactions occur under neutral or basic conditions where copper(II) carboxylates serve as reaction promoter, oxidant, and carboxylate source. Moderate to high yields of heterocycle-functionalized vinyl carboxylate esters are formed with moderate to high levels of diastereoselectivity. Such vinyl carboxylate esters could serve as precursors to α-amino and α-oxy ketones and derivatives thereof.