Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.

Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes

Protein quality control: the who’s who, the where’s and therapeutic escapes

In cells the quality of newly synthesized proteins is monitored in regard to proper folding and correct assembly in the early secretory pathway, the cytosol and the nucleoplasm. Proteins recognized as non-native in the ER will be removed and degraded by a process termed ERAD. ERAD of aberrant proteins is accompanied by various changes of cellular organelles and results in protein folding diseases. This review focuses on how the immunocytochemical labeling and electron microscopic analyses have helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the cellular protein quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones to rescue disease-causing trafficking defects of aberrant proteins

Carboxylate-Catalyzed C-Silylation of Terminal Alkynes

A carboxylate-catalyzed, metal-free C-silylation protocol for terminal alkynes is reported using a quaternary ammonium pivalate as the catalyst and commercially available N,O-bis(silyl)acetamides as silylating agents. The reaction proceeds under mild conditions, tolerates a range of functionalities, and enables concomitant O- or N-silylation of acidic OH or NH groups. A Hammett ρ value of +1.4 ± 0.1 obtained for para-substituted 2-arylalkynes is consistent with the proposed catalytic cycle involving a turnover-determining deprotonation step.peerReviewe

Carboxylate Catalysis : A Catalytic O-Silylative Aldol Reaction of Aldehydes and Ethyl Diazoacetate

A mild catalytic variant of the aldol reaction between ethyl diazoacetate and aldehydes is described using a combination of N,O-bis(trimethylsilyl)acetamide and catalytic tetramethylammonium pivalate as catalyst. The reaction proceeds rapidly at ambient temperature to afford the O-silylated aldol products in good to excellent yield, and the acetamide byproducts can be removed by simple filtration.peerReviewe

Carboxylate catalysis: a mild catalytic O-silylative aldol reaction of aldehydes and ethyl diazoacetate

A mild catalytic variant of the aldol reaction between ethyl diazoacetate and aldehydes is described using a combination of N,O-bis(trimethylsilyl)acetamide and catalytic tetramethylammonium pivalate as catalyst. The reaction proceeds rapidly at ambient temperature to afford the O-silylated aldol products in good to excellent yield, and the acetamide byproducts can be removed by simple filtration

Conjugates of Iron-Transporting N-Hydroxylactams with Ciprofloxacin

Screening of a library of novel N-hydroxylactams amenable by the Castagnoli-Cushman reaction identified four lead compounds that facilitated 55Fe transport into P. aeruginosa cells (one of these synthetic siderophores was found to be as efficient at promoting iron uptake as the natural siderophores pyoverdine, pyochelin or enterobactin). Conjugates of the four lead siderophores with ciprofloxacin were tested for antibacterial activity against P. aeruginosa POA1 (wild type) and the ∆pvdF∆pchA mutant strain. The antibacterial activity was found to be pronounced against the ∆pvdF∆pchA mutant strain grown in CAA medium but not for the POA1 strain. This may be indicative of these compounds being ‘Trojan horse’ antibiotics. Further scrutiny of the mechanism of the antibacterial action of the newly developed conjugates is warranted

Carboxylate Catalysis: A Catalytic <i>O</i>‑Silylative Aldol Reaction of Aldehydes and Ethyl Diazoacetate

A mild catalytic variant of the aldol reaction between ethyl diazoacetate and aldehydes is described using a combination of N,O-bis(trimethylsilyl)acetamide and catalytic tetramethylammonium pivalate as catalyst. The reaction proceeds rapidly at ambient temperature to afford the O-silylated aldol products in good to excellent yield, and the acetamide byproducts can be removed by simple filtration

Carboxylate Catalysis: A Catalytic <i>O</i>‑Silylative Aldol Reaction of Aldehydes and Ethyl Diazoacetate

A mild catalytic variant of the aldol reaction between ethyl diazoacetate and aldehydes is described using a combination of N,O-bis(trimethylsilyl)acetamide and catalytic tetramethylammonium pivalate as catalyst. The reaction proceeds rapidly at ambient temperature to afford the O-silylated aldol products in good to excellent yield, and the acetamide byproducts can be removed by simple filtration

Carboxylate catalyzed isomerization of β,γ-unsaturated NAC thioesters

We demonstrate herein the capacity of simple carboxylate salts – tetrametylammo-nium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect (k1H/k1D = 1.065±0.026) with a β,γ-deuterated substrate. Computational analysis of the mechanism provides a similar value (k1H/k1D = 1.05) with a mechanism where -reprotonation of the enolate intermediate is rate determining.We demonstrate herein the capacity of simple carboxylate salts – tetrametylammo-nium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect (k1H/k1D = 1.065±0.026) with a deuterated substrate. Computational analysis of the mechanism provides a similar value (k1H/k1D = 1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining

Carboxylate catalyzed isomerization of β,γ‐unsaturated N-acetylcysteamine thioesters

We demonstrate herein the capacity of simple carboxylate salts – tetrametylammonium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect ( k 1H / k 1D = 1.065±0.026) with a β,γ−deuterated substrate. Computational analysis of the mechanism provides a similar value ( k 1H / k 1D = 1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining.peerReviewe