10.1021/jm000496v
The research focuses on the synthesis, structure-activity relationships (SARs), and pharmacokinetic profiles of nonpeptidic r-keto heterocycles as novel inhibitors of human chymase, a chymotrypsin-like serine protease with potential roles in cardiovascular diseases and inflammatory conditions. The study hypothesizes that a pyrimidinone scaffold combined with heterocycles as P1 carbonyl-activating groups can effectively inhibit chymase, leading to the design and synthesis of various 5-amino-6-oxo-1,6-dihydropyrimidine derivatives with different heterocycles. The compounds were evaluated for their in vitro inhibitory activity against human heart chymase and other proteases using spectrophotometric assays monitoring the release of p-nitroaniline from synthetic substrates. The most potent compound, 2r (Y-40079), was further subjected to pharmacokinetic studies in rats, assessing its absorption, bioavailability, and metabolic stability. The experiments involved various reactants such as acetone cyanohydrin, HCl, monoethanolamine, and palladium-carbon for synthesis, and employed techniques like NMR, MS, and elemental analysis for compound characterization. The inhibitory constants (Ki), association rate constants (kon), and dissociation constants (koff) were determined through progress curve analysis and nonlinear regression. The research aimed to develop a potent, selective, and metabolically stable nonpeptidic chymase inhibitor, which could serve as a therapeutic agent or a tool for understanding chymase-related pathophysiology.
10.1021/acs.orglett.1c02143
The research presents a novel synthetic pathway for allylic substitution reactions. The study focuses on a nickel-catalyzed tandem reaction that involves the isomerization of alkenyl alcohols followed by allylic cyanation. Key chemicals involved in this research include acetone cyanohydrin as the cyanation agent, nickel complexes such as Ni(cod)2 and Ni(4?tBustb)3 as catalysts, and a specific diphosphite ligand (L3) that plays a crucial role in the reaction's success. Methanol is used as the solvent, which is essential for achieving high yields of the desired products. The methodology demonstrated high potential through a gram-scale regioconvergent experiment and the formal synthesis of quebrachamine. The catalytic system tolerates a variety of functional groups and is efficient even when olefins migrate across up to eight carbons. Deuterium labeling experiments provided insights into the reaction mechanism, supporting a sequential alkene isomerization (chain-walking) followed by allylic cyanation.
10.1007/BF00948247
The study focuses on the reaction dynamics of α,β-unsaturated aldehydes with acetone cyanohydrin in the presence of diethylamine. It explores how the structure of the reactants influences the reaction's direction, continuing previous investigations. The research demonstrates that aldehydes like crotonaldehyde and 3,3-dimethylacrylaldehyde react with acetone cyanohydrin and diethylamine to form aminonitriles while maintaining their trans configuration. However, acrolein and certain other aldehydes tend to polymerize under the same conditions. The study also observes a shift in the double bond position in the reaction with trans-octatriene-2,4,6-al, leading to the formation of cyanenamine. The products' structures were confirmed through IR, PMR, and mass spectrometry, along with elemental analysis. The study further investigates the reactions at elevated temperatures, leading to the formation of saturated derivatives of cyanamines. The experimental section details the methods used for GLC analysis, PMR and IR spectroscopy, and mass spectrometry, providing a comprehensive approach to understanding the reaction mechanisms and product characterization.
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T+:Very toxic;
