1190-73-4Relevant articles and documents
Synthesis of HIV-1 capsid protein assembly inhibitor (CAP-1) and its analogues based on a biomass approach
Romashov, Leonid V.,Ananikov, Valentine P.
, p. 10593 - 10598 (2016)
A biomass-derived platform chemical was utilized to access a demanded pharmaceutical substance with anti-HIV activity (HIV, human immunodeficiency virus) and a variety of structural analogues. Step economy in the synthesis of the drug core (single stage from cellulose) is studied including flexible variability of four structural units. The first synthesis and X-ray structure of the inhibitor of HIV-1 capsid protein assembly (CAP-1) is described.
Formicins, N-Acetylcysteamine-Bearing Indenone Thioesters from a Wood Ant-Associated Bacterium
Byun, Woong Sub,Du, Young Eun,Hong, Suckchang,Hwang, Sunghoon,Jang, Yong-Joon,Lee, Sang Kook,Lee, Seok Beom,Oh, Dong-Chan,Shin, Bora,Shin, Jongheon,Shin, Yern-Hyerk
, (2020)
Formicins A-C (1-3) were discovered from Streptomyces sp. associated with wood ants. The structures of 1 and 2 were elucidated as indenone thioesters bearing N-acetylcysteamine based on spectroscopic analysis. The configurations of 1-3 were determined by the analysis of ROESY correlations, the phenylglycine methyl ester method, and chemical derivatization from 3 to 2. Formicin A inhibited the growth of human triple-negative breast cancer cells by regulating the liver kinase B1-mediated AMPK signaling pathway.
Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies
Hahn, Frank,Ro?, Theresa,Schr?der, Marius,Wunderlich, Johannes
, (2020)
Studies on the biosynthetic processing of polyene thioester intermediates are complicated by limited access to appropriate substrate surrogates. We present a step-economic synthetic access to biomimetic β-ketopolyene thioesters that is based on an Ir-catalyzed reductive Horner-Wadsworth-Emmons olefination. New β-ketotriene and pentaenethioates of pantetheine and N-acetylcysteamine were exemplarily synthesized via short and concise routes. The usefulness of these compounds was demonstrated in an in vitro assay with the ketoreductase domain MycKRB from mycolactone biosynthesis.
Identification of crucial bottlenecks in engineered polyketide biosynthesis
Grote, Marius,Kushnir, Susanna,Pryk, Niclas,M?ller, David,Erver, Julian,Ismail-Ali, Ahmed,Schulz, Frank
, p. 6374 - 6385 (2019)
The concept of combinatorial biosynthesis promises access to compound libraries based on privileged natural scaffolds. Ever since the elucidation of the biosynthetic pathway towards the antibiotic erythromycin A in 1990, the predictable manipulation of type I polyketide synthase megaenzymes was investigated. However, this goal was rarely reached beyond simplified model systems. In this study, we identify the intermediates in the biosynthesis of the polyether monensin and numerous mutated variants using a targeted metabolomics approach. We investigate the biosynthetic flow of intermediates and use the experimental setup to reveal the presence of selectivity filters in polyketide synthases. These obstruct the processing of non-native intermediates in the enzymatic assembly line. Thereby we question the concept of a truly modular organization of polyketide synthases and highlight obstacles in substrate channeling along the cascade. In the search for the molecular origin of a selectivity filter, we investigate the role of different thioesterases in the monensin gene cluster and the connection between ketosynthase sequence motifs and incoming substrate structures. Furthermore, we demonstrate that the selectivity filters do not apply to new-to-nature side-chains in nascent polyketides, showing that the acceptance of these is not generally limited by downstream modules.
Preprogramming Complex Hydrogel Responses using Enzymatic Reaction Networks
Postma, Sjoerd G. J.,Vialshin, Ilia N.,Gerritsen, Casper Y.,Bao, Min,Huck, Wilhelm T. S.
, p. 1794 - 1798 (2017)
The creation of adaptive matter is heavily inspired by biological systems. However, it remains challenging to design complex material responses that are governed by reaction networks, which lie at the heart of cellular complexity. The main reason for this slow progress is the lack of a general strategy to integrate reaction networks with materials. Herein we use a systematic approach to preprogram the response of a hydrogel to a trigger, in this case the enzyme trypsin, which activates a reaction network embedded within the hydrogel. A full characterization of all the kinetic rate constants in the system enabled the construction of a computational model, which predicted different hydrogel responses depending on the input concentration of the trigger. The results of the simulation are in good agreement with experimental findings. Our methodology can be used to design new, adaptive materials of which the properties are governed by reaction networks of arbitrary complexity.
Enzymatic extender unit generation for in vitro polyketide synthase reactions: Structural and functional showcasing of Streptomyces coelicolor MatB
Hughes, Amanda J.,Keatinge-Clay, Adrian
, p. 165 - 176 (2011)
In vitro experiments with modular polyketide synthases (PKSs) are often limited by the availability of polyketide extender units. To determine the polyketide extender units that can be biocatalytically accessed via promiscuous malonyl-CoA ligases, structural and functional studies were conducted on Streptomyces coelicolor MatB. We demonstrate that this adenylate-forming enzyme is capable of producing most CoA-linked polyketide extender units as well as pantetheine- and N-acetylcysteamine-linked analogs useful for in vitro PKS studies. Two ternary product complex structures, one containing malonyl-CoA and AMP and the other containing (2R)-methylmalonyl-CoA and AMP, were solved to 1.45 A and 1.43 A resolution, respectively. MatB crystallized in the thioester-forming conformation, making extensive interactions with the bound extender unit products. This first structural characterization of an adenylate-forming enzyme that activates diacids reveals the molecular details for how malonate and its derivatives are accepted. The orientation of the α-methyl group of bound (2R)-methylmalonyl-CoA, indicates that it is necessary to epimerize α-substituted extender units formed by MatB before they can be accepted by PKS acyltransferase domains. We demonstrate the in vitro incorporation of methylmalonyl groups ligated by MatB to CoA, pantetheine, or N-acetylcysteamine into a triketide pyrone by the terminal module of the 6-deoxyerythronolide B synthase. Additionally, a means for quantitatively monitoring certain in vitro PKS reactions using MatB is presented.
Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis
Klopries, Stephan,Sundermann, Uschi,Schulz, Frank
, p. 664 - 674 (2013)
Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes. Individual malonic acid derivatives are typically required to be activated as coenzyme A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase. Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity. One requirement for this endeavor is the supplementation of the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates. The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose. Here, the incorporation efficiency into different polyketides of N-acetylcysteamine activated methylmalonate is studied and quantified, showing a surprisingly high and transferable activity of these polyketide synthase substrate analogues in vivo.
Iodate oxidation of n-acetyl l-cysteine: Application in drug determination and characterization of its oxidation and degradation product by mass spectrometry
Siddiqui, Masoom Raza,Wabaidur, Saikh Mohammad,Alothman, Zied A.,Rahman, Habibur,Alam, Md.Sarfaraz,Ali, Md.Sajid
, p. 2303 - 2307 (2014)
A kinetic spectrophotometric method based on the initial rate measurement has been developed for the determination of N-acetyl L-cysteine. The developed method is based on the oxidation of N-acetyl L-cysteine with iodate. The reaction product was studied and characterized using the mass spectrometry and the structure of the product was proposed. From the mass spectrometric studies it was concluded that the oxidation of the drug resulted in the formation of a disulfide. The developed method was validated as per the guidelines of international conference on harmonization. The developed initial rate method was found to be linear in the concentration range of 1.25-30 μg ml-1. The detection and quantitation limits were found to be 0.018 and 0.056 μg ml-1. In the current study, the degradation product of N-acetyl L cysteine was also prepared and identified using mass spectrometry.
Monitoring biocatalytic transformations mediated by polyketide synthase enzymes in cell lysate via fluorine NMR
Piasecki, Shawnk.,Keatinge-Clay, Adrian T.
, p. 1840 - 1842 (2012)
The biocatalytic employment of modular polyketide synthase enzymes in cell lysate has become a viable route to preparative quantities of synthetically valuable polyketide fragments. We report the quantitative, uninvasive, and continuous monitoring of such biocatalytic reactions by observing trifluoromethyl-bearing substrates via 19F NMR spectroscopic analysis. To demonstrate the utility of this technique, we followed reactions catalyzed by a thioesterase and several ketoreductases.
HOT MELT EXTRUDED SOLID DISPERSIONS CONTAINING A BCL2 INHIBITOR
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Page/Page column 73, (2021/09/04)
A pro-apoptotic solid dispersion comprises, a Bcl -2 family protein inhibitory compound of Formula A as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier, and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises subjecting to elevated temperature the compound of Formula A, the water-soluble polymeric carrier, and the surfactant to provide an extrudable semi-solid mixture; extruding the semi-solid mixture; and cooling the resulting extrudate to provide a solid matrix comprising the polymeric carrier, and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl -2 family proteins, for example cancer or an immune or autoimmune disease.
