- Generation of Oxidoreductases with Dual Alcohol Dehydrogenase and Amine Dehydrogenase Activity
-
The l-lysine-?-dehydrogenase (LysEDH) from Geobacillus stearothermophilus naturally catalyzes the oxidative deamination of the ?-amino group of l-lysine. We previously engineered this enzyme to create amine dehydrogenase (AmDH) variants that possess a new hydrophobic cavity in their active site such that aromatic ketones can bind and be converted into α-chiral amines with excellent enantioselectivity. We also recently observed that LysEDH was capable of reducing aromatic aldehydes into primary alcohols. Herein, we harnessed the promiscuous alcohol dehydrogenase (ADH) activity of LysEDH to create new variants that exhibited enhanced catalytic activity for the reduction of substituted benzaldehydes and arylaliphatic aldehydes to primary alcohols. Notably, these novel engineered dehydrogenases also catalyzed the reductive amination of a variety of aldehydes and ketones with excellent enantioselectivity, thus exhibiting a dual AmDH/ADH activity. We envisioned that the catalytic bi-functionality of these enzymes could be applied for the direct conversion of alcohols into amines. As a proof-of-principle, we performed an unprecedented one-pot “hydrogen-borrowing” cascade to convert benzyl alcohol to benzylamine using a single enzyme. Conducting the same biocatalytic cascade in the presence of cofactor recycling enzymes (i.e., NADH-oxidase and formate dehydrogenase) increased the reaction yields. In summary, this work provides the first examples of enzymes showing “alcohol aminase” activity.
- Tseliou, Vasilis,Schilder, Don,Masman, Marcelo F.,Knaus, Tanja,Mutti, Francesco G.
-
supporting information
p. 3315 - 3325
(2020/12/11)
-
- Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2
-
The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC50. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.
- Shan, Hengyue,Liu, Jianping,Shen, Jiali,Dai, Jialin,Xu, Gang,Lu, Kuankuan,Han, Chao,Wang, Yaru,Xu, Xiaolong,Tong, Yilun,Xiang, Huaijiang,Ai, Zhiyuan,Zhuang, Guanglei,Hu, Junhao,Zhang, Zheng,Li, Ying,Pan, Lifeng,Tan, Li
-
p. 855 - 9,865
(2021/05/18)
-
- Benzimidazole fragment containing Mn-complex catalyzed hydrosilylation of ketones and nitriles
-
The synthesis of a new bidentate (NN)–Mn(I) complex is reported and its catalytic activity towards the reduction of ketones and nitriles is studied. On comparing the reactivity of various other Mn(I) complexes supported by benzimidazole ligand, it was observed that the Mn(I) complexes bearing 6-methylpyridine and benzimidazole fragments exhibited the highest catalytic activity towards monohydrosilylation of ketones and dihydrosilylation of nitriles. Using this protocol, a wide range of ketones were selectively reduced to the corresponding silyl ethers. In case of unsaturated ketones, the chemoselective reduction of carbonyl group over olefinic bonds was observed. Additionally, selective dihydrosilylation of several nitriles were also achieved using this complex. Mechanistic investigations with radical scavengers suggested the involvement of radical species during the catalytic reaction. Stoichiometric reaction of the Mn(I) complex with phenylsilane revealed the formation of a new Mn(I) complex.
- Ganguli, Kasturi,Mandal, Adarsha,Sarkar, Bidisha,Kundu, Sabuj
-
supporting information
(2020/08/13)
-
- Mild palladium-catalysed highly efficient hydrogenation of CN, C-NO2, and CO bonds using H2 of 1 atm in H2O
-
Here we present the first example of a mild and high-efficiency protocol enabling a process in water using 1 atm of H2 for the efficient and selective hydrogenation of nitriles, nitro compounds, ketones, and aldehydes to yield primary amines and alcohols with satisfactory yields of up to >99%. Several palladium-based nanoparticle catalysts were prepared from K2PdCl4 and ligands, and one of them was found to be the best and most suitable for the hydrogenation of CN, C-NO2, and CO bonds. In addition, the catalyst Pd-NPs can be easily recycled and reused without losing their activity and selectivity. A plausible mechanism for the hydrogenation of a CN bond was also proposed, representing the first example that possesses great potential for sustainable industrial purposes.
- Liu, Yaxu,He, Shaopo,Quan, Ziyi,Cai, Huizhuo,Zhao, Yang,Wang, Bo
-
supporting information
p. 830 - 838
(2019/02/27)
-
- Bioproduction of benzylamine from renewable feedstocks via a nine-step artificial enzyme cascade and engineered metabolic pathways
-
Production of chemicals from renewable feedstocks has been an important task for sustainable chemical industry. Although microbial fermentation has been widely employed to produce many biochemicals, it is still very challenging to access non-natural chemicals. Two methods (biotransformation and fermentation) have been developed for the first bio-derived synthesis of benzylamine, a commodity non-natural amine with broad applications. Firstly, a nine-step artificial enzyme cascade was designed by biocatalytic retrosynthetic analysis and engineered in recombinant E. coli LZ243. Biotransformation of l-phenylalanine (60 mm) with the E. coli cells produced benzylamine (42 mm) in 70 % conversion. Importantly, the cascade biotransformation was scaled up to 100 mL and benzylamine was successfully isolated in 57 % yield. Secondly, an artificial biosynthesis pathway to benzylamine from glucose was developed by combining the nine-step cascade with an enhanced l-phenylalanine synthesis pathway in cells. Fermentation with E. coli LZ249 gave benzylamine in 4.3 mm concentration from glucose. In addition, one-pot syntheses of several useful benzylamines from the easily available styrenes were achieved, representing a new type of alkene transformation by formal oxidative cleavage and reductive amination.
- Zhou, Yi,Wu, Shuke,Mao, Jiwei,Li, Zhi
-
p. 2221 - 2228
(2018/10/20)
-
- Cobalt complex, preparation method thereof, and application thereof in selective catalysis of transfer hydrogenation reaction of cyano group
-
The invention discloses a cobalt complex, a preparation method thereof, and an application thereof in the selective catalysis of a transfer hydrogenation reaction of a cyano group. The structural formula of the cobalt complex is represented by formula I. The cobalt complex is prepared through a reaction of a cobalt salt and an NNP ligand or a PNP ligand under the protection of an inert atmosphere;and the chemical formula of the cobalt salt is CoX12, wherein X1 represents halogen, a sulfate radical, a perchlorate radical, a hexafluorophosphate radical, a hexafluoroantimonate radical, a tetrafluoroborate radical, a trifluoromethanesulfonate radical or a tetra(pentafluorophenyl)borate radical. The cobalt complex can be used in the selective catalysis of the transfer hydrogenation reaction ofthe cyano group to obtain a primary amine compound, a secondary amine compound and a tertiary amine compound, the primary amine compound, the secondary amine compound and the tertiary amine compoundare important intermediates in a series of subsequent functionalizing reactions, and the cobalt complex has a very high catalysis activity, and has great research values and a great application prospect.
- -
-
Paragraph 0157-0160
(2018/05/07)
-
- Highly Stable COF-Supported Co/Co(OH)2 Nanoparticles Heterogeneous Catalyst for Reduction of Nitrile/Nitro Compounds under Mild Conditions
-
Ordered nanoporosity in covalent organic framework (COF) offers excellent opportunity for property development. Loading nanoparticles (nPs) onto them is one approach to introducing tailor-made properties into a COF. Here, a COF–Co/Co(OH)2 composite containing about 16 wt% of 2 nPs is prepared on a N-rich COF support that catalyzes the release of theoretical equivalence of H2 from readily available, safe, and cheap NaBH4. Furthermore, the released H2 is utilized for the hydrogenation of nitrile and nitro compounds to amines under ambient conditions in a facile one-pot reaction. The COF “by choice” is built from “methoxy” functionalized dialdehydes which is crucial in enabling the complete retention of the COF structure under the conditions of the catalysis, where the regular Schiff bonds would have hydrolyzed. The N-rich binding pockets in the COF ensure strong nP–COF interactions, which provides stability and enables catalyst recycling. Modeling studies reveal the crucial role played by the COF in exposing the active facets and thereby in controlling the activation of the reducing agent. Additionally, via density functional theory, we provide a rational explanation for how these COFs can stabilize nanoparticles which grow beyond the limiting pore size of the COF and yet result in a truly stable heterogeneous catalyst – a ubiquitous observation. The study underscores the versatility of COF as a heterogeneous support for developing cheap and highly active nonnoble metal catalysts.
- Mullangi, Dinesh,Chakraborty, Debanjan,Pradeep, Anu,Koshti, Vijay,Vinod, Chathakudath P.,Panja, Soumendranath,Nair, Sunil,Vaidhyanathan, Ramanathan
-
-
- Versatile Dynamic Covalent Assemblies for Probing π-Stacking and Chirality Induction from Homotopic Faces
-
Herein we report for the first time the use of dynamic covalent reactions (DCRs) for building a π-stacking model system and further quantifying its substituent effects (SEs), which remain a topic of debate despite the rich history of stacking. A general DCR between 10-methylacridinium ion and primary amines was discovered, in which π-stacking played a stabilizing role. Facile quantification of SEs with in situ competing π-stacking systems was next achieved in the form of amine exchange exhibiting structural diversity by simply varying components. The linear correlation with σm in Hammett plots indicates the dominance of purely electrostatic SEs, and the additivity of SEs is in line with the direct interaction model. With α-chiral amines π-stacking within the adduct enabled chirality transfer from homotopic faces. The strategy of dynamic covalent assembly should be appealing to future research of probing weak interactions and manipulating chirality.
- Ye, Hebo,Hai, Yu,Ren, Yulong,You, Lei
-
supporting information
p. 3804 - 3809
(2017/03/27)
-
- Low-Pressure Hydrogenation of Nitriles to Primary Amines Catalyzed by Ruthenium Pincer Complexes. Scope and mechanism
-
The catalytic hydrogenation of nitriles to primary amines constitutes an environmentally benign and atom-economical methodology in synthetic organic chemistry. However, selective hydrogenation can be challenging, and usually elevated pressure and the use of various additives is required. Herein the hydrogenation of aromatic and aliphatic nitriles to form primary amines catalyzed by ruthenium pincer complexes is described. The reactions are conducted at low H2 pressure, low catalytic loadings and, in case of a variety of benzonitriles, under neutral conditions and without any additives. Mechanistic insight is provided.
- Mukherjee, Arup,Srimani, Dipankar,Ben-David, Yehoshoa,Milstein, David
-
p. 559 - 563
(2017/02/26)
-
- Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors
-
Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
- Dong, Guoqiang,Chen, Wei,Wang, Xia,Yang, Xinglin,Xu, Tianying,Wang, Pei,Zhang, Wannian,Rao, Yu,Miao, Chaoyu,Sheng, Chunquan
-
p. 7965 - 7983
(2017/10/18)
-
- Stereoelectronic effects in the reaction of aromatic substrates catalysed by: Halomonas elongata transaminase and its mutants
-
A transaminase from Halomonas elongata and four mutants generated by an in silico-based design were recombinantly produced in E. coli, purified and applied to the amination of mono-substituted aromatic carbonyl-derivatives. While benzaldehyde derivatives were excellent substrates, only NO2-acetophenones were transformed into the (S)-amine with a high enantioselectivity. The different behaviour of wild-type and mutated transaminases was assessed by in silico substrate binding mode studies.
- Contente, Martina Letizia,Planchestainer, Matteo,Molinari, Francesco,Paradisi, Francesca
-
p. 9306 - 9311
(2016/10/13)
-
- A method for the production of primary amines
-
The invention relates to the field of chemical industry and particularly relates to a method for preparing primary amine by using the raw materials including halogenated hydrocarbon (or hydrocarbon alcohol sulfonate) and ammonia water (or formamide). The method comprises the following three steps: (1) imidization: 3,4-diarylfuran-2,5-diketone (I) reacts with ammonia (or formamide) and the like to obtain 3,4-diaryl-1H-pyrrole-2,5-diketone (II); (2) N-hydrocarbylation: 3,4-diaryl-1H-pyrrole-2,5-diketone (II) generates an N-hydrocarbylation reaction with halogenated hydrocarbon (or hydrocarbon alcohol sulfonate) in the presence of alkali to obtain N-hydrocarbyl-3,4-diaryl-1H-pyrrole-2,5-diketone (III); and (3) hydrolysis: N-hydrocarbyl-3,4-diaryl-1H-pyrrole-2,5-diketone (III) is subjected to alkali hydrolysis to obtain primary amine and the generated 2,3-diaryl maleate is subjected to acid treatment and automatic ring closing to form 3,4-diaryl furan-2,5-diketone (I) which is subjected to imidization and directly applied to the N-hydrocarbylation reaction. The method provided by the invention has the characteristics that the 3,4-diaryl furan-2,5-diketone can be circularly used at a high recovery rate, the molar ratio of the raw materials is low, and the yield of the product primary amine is high.
- -
-
Paragraph 0237; 0257
(2016/10/09)
-
- Mild and Selective Cobalt-Catalyzed Chemodivergent Transfer Hydrogenation of Nitriles
-
Herein, we describe a selective cobalt-catalyzed chemodivergent transfer hydrogenation of nitriles to synthesize primary, secondary, and tertiary amines. The solvent effect plays a key role for the selectivity control. The general applicability of this procedure was highlighted by the synthesis of more than 70 amine products bearing various functional groups in high chemoselectivity. Moreover, this mild system achieved >2000 TONs (turnover numbers) for the transfer hydrogenation of nitriles.
- Shao, Zhihui,Fu, Shaomin,Wei, Mufeng,Zhou, Shaolin,Liu, Qiang
-
supporting information
p. 14653 - 14657
(2016/11/23)
-
- Selective hydrogenation of nitriles to primary amines catalyzed by a novel iron complex
-
Hydrogenation of nitriles to primary amines constitutes an atom-efficient and environmentally benign synthetic reaction. Herein we present a novel complex based on earth-abundant iron, and its application in the catalytic homogeneous hydrogenation of (hetero)aromatic, benzylic, and aliphatic nitriles to selectively form primary amines.
- Chakraborty, Subrata,Leitus, Gregory,Milstein, David
-
supporting information
p. 1812 - 1815
(2016/02/05)
-
- Selective Hydrogenation of Nitriles to Primary Amines Catalyzed by a Cobalt Pincer Complex
-
The catalytic hydrogenation of nitriles to primary amines represents an atom-efficient and environmentally benign reduction methodology in organic chemistry. This has been accomplished in recent years mainly with precious-metal-based catalysts, with a single exception. Here we report the first homogeneous Co-catalyzed hydrogenation of nitriles to primary amines. Several (hetero)aromatic, benzylic, and aliphatic nitriles undergo hydrogenation to the corresponding primary amines in good to excellent yields under the reaction conditions.
- Mukherjee, Arup,Srimani, Dipankar,Chakraborty, Subrata,Ben-David, Yehoshoa,Milstein, David
-
supporting information
p. 8888 - 8891
(2015/08/03)
-
- THIENOPYRIMIDINES
-
Thienopyrimidines of the formula (I) and their physiologically acceptable salts, in which R1, R2 and X are as defined in claim 1, exhibit phosphodiesterase V inhibition and can be employed for the treatment of illnesses of the cardiovascular system and for the treatment and/or therapy of impotence.
- -
-
-
- Synthesis of Primary Amines: First Homogeneously Catalyzed Reductive Amination with Ammonia
-
(Matrix Presented) The synthesis of primary amines via reductive amination of the corresponding carbonyl compounds with aqueous ammonia is achieved for the first time with soluble transition metal complexes. Up to an 86% yield and a 97% selectivity for benzylamines were obtained in the case of various benzaldehydes by using a Rh-catalyst together with water-soluble phosphine and ammonium acetate. In the case of aliphatic aldehydes, a bimetallic catalyst based on Rh/Ir gave improved results.
- Gross, Thoralf,Seayad, Abdul Majeed,Ahmad, Moballigh,Beller, Matthias
-
p. 2055 - 2058
(2007/10/03)
-
- 2-aminobenzoxazole derivatives and combinatorial libraries thereof
-
The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula: wherein R1 to R4 and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.
- -
-
-
- 2-aminopyridine derivatives and combinatorial libraries thereof
-
The present invention relates to novel 2-aminopyridine derivative compounds of the following formula: wherein R1to R5have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminopyridine derivative compounds.
- -
-
-
- Supported nickel-catalyzed hydrogenation of aromatic nitriles under low pressure conditions
-
Hydrogenation of aromatic nitriles takes place under the mild conditions using supported nickel catalysts to afford amino-methyl-substituted aromatics in good yields.
- Takamizawa,Wakasa,Fuchikami
-
p. 1623 - 1625
(2007/10/03)
-
- Inactivation of Leukocyte Elastase by Aryl Azolides and Sulfonate Salts. Structure-Activity Relationship Studies
-
The inhibitory activity of a series of aryl azolides and sulfonate salts toward human leukocyte elastase is reported.Several of the compounds were found to be potent inhibitors of the enzyme.Active compounds were obtained only when the specificity group and the reactive moiety were separated by a two-carbon chain.The introduction of hydrophobic groups enhanced the inhibitory activity of these compounds, with the exception of the sulfonate salts.The nature of the leaving group had had a profound effect on inhibitory activity, with compounds 23 and 26 being the most active (kobsd/ = 11722 and 13500 M-1 s-1, respectively).
- Groutas, W. C.,Brubaker, M. J.,Zandler, M. E.,Mazo-Gray, V.,Rude, S. A.,et al.
-
p. 1302 - 1305
(2007/10/02)
-
- Turning the product selectivity of nitrile hydrogenation from primary to secondary amines by precise modification of Pd/SiC catalysts using NiO nanodots
-
The selectivity of supported metal catalysts is mainly determined by the active metallic component, and thus turning the selectivity to a completely different product is rarely achieved by modification of the catalysts. Hydrogenation of nitriles is an efficient and environmentally benign route for the synthesis of valuable amines, but it usually produces mixtures of primary, secondary and even tertiary amines. Herein we report that the selectivity of Pd/SiC catalysts for the hydrogenation of nitriles with H2 can be turned from primary to secondary amines by modification of NiO nanodots. In the modified catalysts, the NiO nanodots act as reactive sites to consume hydrogen radicals on the Pd surface, and thus prolong the lifetime of an imine intermediate that determines the product selectivity. Under mild conditions (30 °C, atmospheric H2), Pd/SiC and NiO-Pd/SiC catalysts exhibit high selectivity to primary (94%) and secondary (99%) amines, respectively.
- -
-
-