1199266-89-1Relevant articles and documents
Multi-enzyme pyruvate removal system to enhance (: R)-selective reductive amination of ketones
Li, Chao,Song, Hao,Zhang, Jinhua,Zhao, Yanshu
, p. 28984 - 28991 (2020)
Biocatalytic transamination is widely used in industrial production of chiral chemicals. Here, we constructed a novel multi-enzyme system to promote the conversion of the amination reaction. Firstly, we constructed the ArR-ωTA/TdcE/FDH/LDH multi-enzyme system, by combination of (R)-selective ω-transaminase derived from Arthrobacter sp. (ArR-ωTA), formate dehydrogenase (FDH) derived from Candida boidinii, formate acetyltransferase (TdcE) and lactate dehydrogenase (LDH) derived from E. coli MG1655. This multi-enzyme system was used to efficiently remove the by-product pyruvate by TdcE and LDH to facilitate the transamination reaction. The TdcE/FDH pathway was found to dominate the by-product pyruvate removal in the transamination reaction. Secondly, we optimized the reaction conditions, including d-alanine, DMSO, and pyridoxal phosphate (PLP) with different concentration of 2-pentanone (as a model substrate). Thirdly, by using the ArR-ωTA/TdcE/FDH/LDH system, the conversions of 2-pentanone, 4-phenyl-2-butanone and cyclohexanone were 84.5%, 98.2% and 79.3%, respectively.
Engineering of amine dehydrogenase for asymmetric reductive amination of ketone by evolving Rhodococcus phenylalanine dehydrogenase
Ye, Li Juan,Toh, Hui Hung,Yang, Yi,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
, p. 1119 - 1122 (2015)
Triple mutant K66Q/S149G/N262C (TM-pheDH) of Rhodococcus phenylalanine dehydrogenase (pheDH) was engineered by directed evolution as the first enzyme for the highly enantioselective reductive amination of phenylacetone 1 and 4-phenyl-2-butanone 3, giving (R)-amphetamine 2 and (R)-1-methyl-3-phenylpropylamine 4 in >98% ee, respectively. The new amine dehydrogenase TM-pheDH with special substrate specificity is a valuable addition to the amine dehydrogenase family with very limited number, for asymmetric reductive amination of ketone, an important reaction in sustainable pharmaceutical manufacturing. Molecular docking provided insight into the role of key mutations of pheDH, being useful for engineering new amine dehydrogenases with higher activity and unique substrate scope. (Chemical Equation Presented).
One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald–Hartwig N-Arylation
Ahmed, Syed T.,Cosgrove, Sebastian C.,Parmeggiani, Fabio,Thompson, Matthew P.,Turner, Nicholas J.
, p. 18156 - 18160 (2020)
The combination of biocatalysis and chemo-catalysis increasingly offers chemists access to more diverse chemical architectures. Here, we describe the combination of a toolbox of chiral-amine-producing biocatalysts with a Buchwald–Hartwig cross-coupling reaction, affording a variety of α-chiral aniline derivatives. The use of a surfactant allowed reactions to be performed sequentially in the same flask, preventing the palladium catalyst from being inhibited by the high concentrations of ammonia, salts, or buffers present in the aqueous media in most cases. The methodology was further extended by combining with a dual-enzyme biocatalytic hydrogen-borrowing cascade in one pot to allow for the conversion of a racemic alcohol to a chiral aniline.
Studies on the photostability and in vitro phototoxicity of Labetalol
Andrisano, Vincenza,Ballardini, Roberto,Hrelia, Patrizia,Cameli, Norma,Tosti, Antonella,Gotti, Roberto,Cavrini, Vanni
, p. 495 - 504 (2001)
The purpose of this study was to obtain information on the photochemical and phototoxic properties of Labetalol, a beta-blocker drug. Preliminary information on the drug photoreactivity was achieved using a flow system with a photochemical reactor on-line with a diode array detection system. Photophysical and photochemical investigations on the drug were performed in aqueous solutions at different pH values using spectrophotometric and fluorimetric methods; the photodegradation quantum yield was found to be 2.7×10-3 at pH 5.8 and 1.5×10-2 at pH 11.5. Forced photodegradation of labetalol solutions under exposure to UVA-UVB radiations (xenon arc lamp) was monitored by reversed-phase liquid chromatography. The main photodegradation products were isolated and characterized by NMR and mass spectrometry; labetalol was found to give 3-amino-1-phenylbutane and salicylamide-4-carboxaldehyde as the main photoproducts. Preliminary phototoxic testings on human keratinocyte cultures were performed evaluating the viability of the cells by the neutral-red uptake assay; mutagenic and photomutagenicity tests were also carried out based on Salmonella typhimurium strains. As a result, labetalol was found to be photolabile,mainly in alkaline medium, but evidences of significant phototoxic and photomutagenic effects by the drug were not observed. Copyright
A Process Concept for High-Purity Production of Amines by Transaminase-Catalyzed Asymmetric Synthesis: Combining Enzyme Cascade and Membrane-Assisted ISPR
B?rner, Tim,Rehn, Gustav,Grey, Carl,Adlercreutz, Patrick
, p. 793 - 799 (2015)
For the amine transaminase (ATA)-catalyzed synthesis of chiral amines, the choice of donor substrate is of high importance for reaction and process design. Alanine was investigated as an amine donor for the reductive amination of a poorly water-soluble ketone (4-phenyl-2-butanone) in a combined in situ product removal (ISPR) approach using liquid-membrane extraction together with an enzyme cascade. This ISPR strategy facilitates very high (>98%) product purity with an integrated enrichment step and eliminates product as well as coproduct inhibition. In the presented proof-of-concept alanine shows the following advantages over the other frequently employed amine donor isopropyl amine: (i) nonextractability of alanine affords high product purity without any additional downstream step and no losses via coextraction, (ii) higher maximum reaction rates, and (iii) broader acceptance among ATAs.
Mild dynamic kinetic resolution of amines by coupled visible-light photoredox and enzyme catalysis
Yang, Qiong,Zhao, Fengqian,Zhang, Na,Liu, Mingke,Hu, Huanhuan,Zhang, Jingjie,Zhou, Shaolin
, p. 14065 - 14068 (2018)
Herein, we described photoenzymatic dynamic kinetic resolution (DKR) of amines under mild conditions. The racemization of amines via a photoredox-mediated hydrogen atom transfer (HAT) protocol in conjunction with an enzyme catalyst to achieve the DKR of amines allows a variety of primary amines to be converted into a single enantiomer in high yield and with excellent enantioselectivity. Notably, this protocol can also be extended to 1,4-diamine derivatives with high levels of diastereo- and enantioselectivity.
Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates
Chen, Hui,Cai, Rong,Patel, Janki,Dong, Fangyuan,Chen, Hsiaonung,Minteer, Shelley D.
, p. 4963 - 4971 (2019)
Enantiomerically pure chiral amines are of increasing value in the preparation of bioactive compounds, pharmaceuticals, and agrochemicals. ω-Transaminase (ω-TA) is an ideal catalyst for asymmetric amination because of its excellent enantioselectivity and wide substrate scope. To shift the equilibrium of reactions catalyzed by ω-TA to the side of the amine product, an upgraded N2 fixation system based on bioelectrocatalysis was developed to realize the conversion from N2 to chiral amine intermediates. The produced NH3 was in situ reacted with l-alanine dehydrogenase to generate alanine with NADH as a coenzyme. ω-TA transferred the amino group from alanine to ketone substrates and finally produced the desired chiral amine intermediates. The cathode of the upgraded N2 fixation system supplied enough reducing power to synchronously realize the regeneration of reduced methyl viologen (MV?+) and NADH for the nitrogenase and l-alanine dehydrogenase. The coproduct, pyruvate, was consumed by l-alanine dehydrogenase to regenerate alanine and push the equilibrium to the side of amine. After 10 h of reaction, the concentration of 1-methyl-3-phenylpropylamine achieved 0.54 mM with the 27.6% highest faradaic efficiency and >99% enantiomeric excess (eep). Because of the wide substrate scope and excellent enantioselectivity of ω-TA, the upgraded N2 fixation system has great potential to produce a variety of chiral amine intermediates for pharmaceuticals and other applications.
Determination of labetalol hydrochloride in drug formulations by spectrophotometry
Rahman, Nafisur,Rahman, Habibur,Azmi, Syed Najmul Hejaz
, p. 185 - 196 (2007)
A validated, selective and sensitive spectrophotometric method has been developed for the determination of labetalol hydrochloride in commercial dosage forms. The method is based on the coupling reaction of positive diazonium ion of 4-aminobenzenesulfonic acid with phenolate ion of labetalol to form a colored azo compound which absorbs maximally at 395 nm. Under the optimized experimental conditions, the color is stable up to 2 h and Beer's law is obeyed in the concentration range of 0.8-17.6 μg mL-1 with a linear regression equation of A = 4.84 × 10-4 + 7.864 × 10-2 C and coefficient of correlation, r = 0.9999. The molar absorptivity and Sandell's sensitivity are found to be 2.874 × 104 L mol-1 cm-1 and 0.013 μg cm-2 per 0.001-absorbance unit, respectively. The limits of detection and quantitation of the proposed method are 0.08 and 0.23 μg mL-1, respectively. The intra-day and inter-day precision variation and accuracy of the proposed method is acceptable with low values of standard analytical error. The recovery results obtained by the proposed method in drug formulations are acceptable with mean percent recovery ± RSD of 99.97 ± 0.52 - 100.03 ± 0.63%. The results of the proposed method compared with those of Bilal's spectrophotometric method indicated excellent agreement with acceptable true bias of all samples within ± 2.0%.
Immobilization of ω-transaminases by encapsulation in a sol-gel/celite matrix
Koszelewski, Dominik,Mueller, Nicole,Schrittwieser, Joerg H.,Faber, Kurt,Kroutil, Wolfgang
, p. 39 - 44 (2010)
Commercially available ω-transaminases ω-TA-117, -113, and Vibrio fluvialis (Vf-AT) have been immobilized in a sol-gel matrix. Improved results were obtained by employing Celite 545 as additive. The immobilized ω-transaminases ω-TA-117, -113, and V. fluvialis (Vf-AT) were tested in the kinetic resolution of α-chiral primary amines. In contrast to the free enzyme ω-TA-117, the sol-gel/celite immobilized enzyme showed activity even at pH 11. Recycling of the sol-gel/Celite 545 immobilized ω-transaminase ω-TA-117 was performed over five reaction cycles without any substantial loss in enantioselectivity and conversion. Finally, the immobilized ω-TA 117 was employed in a one-pot two-step deracemization of rac-mexiletine and rac-4-phenyl-2-butylamine, two pharmacologically relevant amines. The corresponding optically pure (S)-amines were obtained in up to 95% isolated yield (>99% ee).
Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D2O as a Deuterium Source
Ning, Lei,Li, Hengzhao,Lai, Zemin,Szostak, Michal,Chen, Xingyue,Dong, Yanhong,Jin, Shuhui,An, Jie
, p. 2907 - 2916 (2021)
Selective introduction of the deuterium atom into the α-position of amines is important for the development of all types of novel deuterated drugs and agrochemicals due to the pervasive presence of amines. In this study, we report the first general single-electron-transfer reductive deuteration of both ketoximes and aldoximes using SmI2 as an electron donor and D2O as a deuterium source for the synthesis of α-deuterated primary amines with excellent levels of deuterium incorporations (>95% [D]). This protocol exhibits excellent chemoselectivity and tolerates a variety of functional groups. The potential application of this new method was showcased in the synthesis of deuterated drugs, such as rimantadine-d4, the tebufenpyrad analogue, derivatives of nabumetone and pregnenolone, and a series of building blocks for the rapid and general assembly of deuterated drugs and pesticides.
