589-08-2Relevant articles and documents
The combined solid/solution-phase synthesis of nitrosamines: The evolution of the "libraries from libraries" concept
Yu, Yongping,Ostresh, John M.,Houghten, Richard A.
, p. 183 - 186 (2003)
The generation of diverse chemical libraries using the "libraries from libraries" concept by combining solid-phase and solution-phase methods is described. The central features of the approaches presented are the use of solid-phase synthesis methods for the generation of a combinatorial polyamine library. Following cleavage from the resin with HF, the polyamine library was reacted with ethyl nitrite in the solution phase to yield the desired nitrosamine library in good yield and purity. The approaches described enable the efficient syntheses of individual nitrosamines as well as mixture-based nitrosamine libraries.
Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
Mock, Elliot D.,Kotsogianni, Ioli,Driever, Wouter P. F.,Fonseca, Carmen S.,Vooijs, Jelle M.,Den Dulk, Hans,Van Boeckel, Constant A. A.,Van Der Stelt, Mario
, p. 481 - 515 (2021/02/05)
N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [ Mock et al. Nat Chem. Biol., 2020, 16, 667-675 ]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo.
Additive-freeN-methylation of amines with methanol over supported iridium catalyst
Liu, Xiang,Loh, Teck-Peng,Qiang, Wenwen,Wang, Jing,Ye, Sen,Zhu, Longfei
, p. 3364 - 3375 (2021/06/06)
An efficient and versatile zinc oxide-supported iridium (Ir/ZnO) catalyst was developed to catalyze the additive-freeN-methylation of amines with methanol. Mechanistic studies suggested that the high catalytic reactivity is rooted in the small sizes (1.4 nm) of Ir nanoparticles and the high ratio (93%) of oxidized iridium species (IrOx, Ir3+and Ir4+) on the catalyst. Moreover, the delicate cooperation between the IrOxand ZnO support also promoted its high reactivity. The selectivity of this catalyticN-methylation was controllable between dimethylation and monomethylation by carefully tuning the catalyst loading and reaction solvent. Specifically, neat methanol with high catalyst loading (2 mol% Ir) favored the formation ofN,N-dimethylated amine, while the mesitylene/methanol mixture with low catalyst loading (0.5 mol% Ir) was prone to producing mono-N-methylated amines. An environmentally benign continuous flow system with a recycled mode was also developed for the efficient production ofN-methylated amines. With optimal flow rates and amine concentrations, a variety ofN-methylamines were produced with good to excellent yields in this Ir/ZnO-based flow system, providing a starting point for the clean and efficient production ofN-methylamines with this cost-effective chemical process.
Mechanistic Insight into the Catalytic Promiscuity of Amine Dehydrogenases: Asymmetric Synthesis of Secondary and Primary Amines
Tseliou, Vasilis,Masman, Marcelo F.,B?hmer, Wesley,Knaus, Tanja,Mutti, Francesco G.
, p. 800 - 812 (2019/02/20)
Biocatalytic asymmetric amination of ketones, by using amine dehydrogenases (AmDHs) or transaminases, is an efficient method for the synthesis of α-chiral primary amines. A major challenge is to extend amination to the synthesis of secondary and tertiary amines. Herein, for the first time, it is shown that AmDHs are capable of accepting other amine donors, thus giving access to enantioenriched secondary amines with conversions up to 43 %. Surprisingly, in several cases, the promiscuous formation of enantiopure primary amines, along with the expected secondary amines, was observed. By conducting practical laboratory experiments and computational experiments, it is proposed that the promiscuous formation of primary amines along with secondary amines is due to an unprecedented nicotinamide (NAD)-dependent formal transamination catalysed by AmDHs. In nature, this type of mechanism is commonly performed by pyridoxal 5′-phosphate aminotransferase and not by dehydrogenases. Finally, a catalytic pathway that rationalises the promiscuous NAD-dependent formal transamination activity and explains the formation of the observed mixture of products is proposed. This work increases the understanding of the catalytic mechanism of NAD-dependent aminating enzymes, such as AmDHs, and will aid further research into the rational engineering of oxidoreductases for the synthesis of α-chiral secondary and tertiary amines.
