Specificity of Saliva Esterases by Wine Carboxylic Esters and Inhibition by Wine Phenolic Compounds Under Simulated Oral Conditions

The specificity of human esterase activity (EA) from the stimulated (SS) and non-stimulated (NSS) saliva toward different typical wine odorant carboxylic esters and its inhibition by the wine phenolic compounds has been evaluated. For the specificity, six p-nitrophenyl linked esters with different carbon chain lengths (from 2 to 12 carbons) were employed. The five single phenolic compounds (catechin, quercetin, kaempferol, myricetin, and resveratrol) at typical wine concentrations were assayed in the salivary EA inhibition study. Additionally, the inhibition exerted by the mixtures of wine polyphenols was evaluated using four commercial phenolic extracts [a grape seed extract (GSE), the monomers and oligomer fraction of the GSE, and a red wine extract (RWE)]. Finally, the saliva EA under the wine consumption conditions (pH = 5 and 11.3% ethanol) was evaluated. The results showed a higher EA in SS than NSS. It was also shown that the EA was higher toward the smaller than bigger esters regardless of the saliva types (SS or NSS). However, the inhibition exerted on saliva EA by the individual and mixtures of phenolic compounds was proven. Catechin was the phenolic compound that mostly inhibited saliva EA, while resveratrol showed the lowest EA inhibition. This inhibition was mainly related to the concentration of the phenolic compounds, but also with its structure. Finally, under simulated wine consumption, a decrease in EA was produced, which was mainly provoked by the decrease in the salivary pH. Nonetheless, since salivary pH recovers a few seconds after wine consumption, saliva EA might be relevant for the long-lasting perception of wine esters.

Novel CYP11B-ligand [123/131I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience

Purpose Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [123/131I]iodometomidate ([123/131I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. Methods Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [123I]IMTO and the most promising compound (R)-1-[1-(4-[123I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([123I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [131I]IMAZA in one of these patients was performed. Results We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [131I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. Conclusion We developed the new radiopharmaceutical [123/131I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.

N-Heterocyclic carbene catalyzed asymmetric [3 + 3] cycloaddtion of β,β-disubstituted, α,β-unsaturated carboxylic esters with 3-aminobenzofurans

An NHC-catalyzed β-carbon functionalization reaction to afford enantioenriched benzofuran fused δ-lactams bearing an all-carbon quaternary stereocenter is documented.