The influence of various wine parameters on the production and stability of xanthylium cation pigments in a wine‐like medium is reported. The xanthylium pigments have an absorbance maximum in the visible region at 440 nm that is close to the measured absorbance used by the wine industry to indicate the browning of wine (i.e. 420 nm). The results of this study show that iron is more efficient than copper in both the colouration and production of xanthylium cation pigments in wine‐like solutions of tartaric acid and (+)‐catechin. The non‐flavonoid caffeic acid can inhibit the accumulation of the xanthylium cation pigments, despite the presence of metal ions, and also influence the stability of the pigment. Sunlight leads to a decrease in the concentration of xanthylium cation pigments while a temperature difference of 20 oC in the absence of light was observed to have little influence on concentration. The results suggest that the xanthylium cations are more likely to be a transitory species during white wine oxidation rather than accumulating pigments based on their instability with caffeic acid.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the leadoptimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

A novel one-pot, three-component synthesis of N-acyl or Ncarbamoyl-α-amidosulfides 4 is described. The three-component reaction of aldehydes 1, primary carbamates (or amides) 2 and phenylsulfinic acid (6a) afforded α-amidosulfones 7, which after addition of sodium thiolate were in situ transformed into stable α-amidosulfides 4 in good to excellent

A general and practical N-iodosuccinimide (NIS)-promoted aza-Friedel-Crafts reaction of various aromatic nucleophiles with N-acylimines generated in situ from α-amidosulfides to give a rapid access to highly functionalized amines is described. The newly developed methodology is very mild, fast, efficient, and complementary.

Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five N2functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC 50 (0.5−20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and cocrystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3−10 μM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates.

A fifteen‐step synthesis of methyl cristatate is described. tert‐Butyl‐[(E)‐6‐iodo‐3‐methylhex‐2‐enyloxy)]diphenylsilane, synthesized from geraniol, was coupled with 2‐(diethoxymethyl)‐4‐lithiofuran and transformed – by acetal hydrolysis, Wittig olefination, and desilylation – into a sesquiterpene furan alcohol. This alcohol was converted into methyl cristatate by sequential condensation with carbonyldiimidazole and the enolate dianion derived from 2,2‐dimethyl‐6‐(2‐oxopropyl)‐4H‐1,3‐dioxin‐4‐one and subsequent Pd0‐catalyzed decarboxylative allylic migration, biomimetic aromatization, and transesterification with methanol.

A s y m m e t r i c S y n t h e s i s o f L e m o n o s eAbstract: L-Lemonose, the glycosidic part of (-)-lemonomycin, has been synthesized in ten steps with 18% overall yield from Dthreonine. The key steps are a double, highly diastereoselective Grignard addition to a Weinreb amide and a chemoselective oxidation of a primary alcohol in the presence of a secondary alcohol, a tertiary alcohol and a tertiary amine, leading directly to the lactol.