35289-31-7Relevant articles and documents
Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains
Heberlig, Graham W.,Brown, Jesse T. C.,Simard, Ryan D.,Wirz, Monica,Zhang, Wei,Wang, Meng,Susser, Leah I.,Horsman, Mark E.,Boddy, Christopher N.
, p. 5771 - 5779 (2018)
A key missing tool in the chemist's toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Macrocyclic natural product biosynthesis offers an obvious starting point for biocatalyst discovery via the native macrocycle forming biosynthetic mechanism. Herein we demonstrate that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones and macrolactams. The TE domains responsible for zearalenone and radicicol biosynthesis successfully generate resorcylate-like 12- to 18-member macrolactones and a 14-member macrolactam. In addition these enzymes can also macrolactonize a non-resorcylate containing depsipeptide, suggesting they are versatile biocatalysts. Simple saturated omega-hydroxy acyl chains are not macrocyclized, nor are the alpha-beta unsaturated derivatives, clearly outlining the scope of the substrate tolerance. These data dramatically expand our understanding of substrate tolerance of these enzymes and are consistent with our understanding of the role of TEs in iterative polyketide biosynthesis. In addition this work shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known, accessing resorcylate lactone and lactams as well as cyclicdepsipeptides, which are highly biologically relevant frameworks.
4,4,16-Trifluoropalmitate: Design, Synthesis, Tritiation, Radiofluorination and Preclinical PET Imaging Studies on Myocardial Fatty Acid Oxidation
Colombano, Alessandro,Dall'Angelo, Sergio,Kingston, Lee,Gr?nberg, Gunnar,Correia, Claudia,Passannante, Rossana,Baz, Zuri?e,Morcillo, Miguel ángel,Elmore, Charles S.,Llop, Jordi,Zanda, Matteo
, p. 2317 - 2331 (2020/10/02)
Fatty acid oxidation (FAO) produces most of the ATP used to sustain the cardiac contractile work, although glycolysis is a secondary source of ATP under normal physiological conditions. FAO impairment has been reported in the advanced stages of heart failure (HF) and is strongly linked to disease progression and severity. Thus, from a clinical perspective, FAO dysregulation provides prognostic value for HF progression, the assessment of which could be used to improve patient monitoring and the effectiveness of therapy. Positron emission tomography (PET) imaging represents a powerful tool for the assessment and quantification of metabolic pathways in vivo. Several FAO PET tracers have been reported in the literature, but none of them is in routine clinical use yet. Metabolically trapped tracers are particularly interesting because they undergo FAO to generate a radioactive metabolite that is subsequently trapped in the mitochondria, thus providing a quantitative means of measuring FAO in vivo. Herein, we describe the design, synthesis, tritium labelling and radiofluorination of 4,4,16-trifluoro-palmitate (1) as a novel potential metabolically trapped FAO tracer. Preliminary PET-CT studies on [18F]1 in rats showed rapid blood clearance, good metabolic stability – confirmed by using [3H]1 in vitro – and resistance towards defluorination. However, cardiac uptake in rats was modest (0.24±0.04 % ID/g), and kinetic analysis showed reversible uptake, thus indicating that [18F]1 is not irreversibly trapped.
Quantitative Evaluation of the Effect of the Hydrophobicity of the Environment Surrounding Br?nsted Acid Sites on Their Catalytic Activity for the Hydrolysis of Organic Molecules
Miura, Hiroki,Kameyama, Shutaro,Komori, Daiki,Shishido, Tetsuya
, p. 1636 - 1645 (2019/01/21)
Sulfo-functionalized siloxane gels with a variety of surface hydrophobicities were fabricated to elucidate the effect of the environment surrounding the Br?nsted acid site on their catalytic activity for the hydrolysis of organic molecules. A detailed structural analysis of these siloxane gels by elemental analysis, X-ray photoelectron spectroscopy, Fourier-transformed infrared (FT-IR), and 29Si MAS NMR revealed the formation of gel catalysts with a highly condensed siloxane network, which enabled us to quantitatively evaluate the hydrophobicity of the environment surrounding the catalytically active sulfo-functionality. A sulfo group in a highly hydrophobic environment exhibited excellent catalytic turnover frequency for the hydrolysis of acetate esters with a long alkyl chain, whereas not only conventional solid acid catalysts but also liquid acids showed quite low catalytic activity. Detailed kinetic studies corroborated that the adsorption of oleophilic esters at the Br?nsted acid site was facilitated by the surrounding hydrophobic environment, thus significantly promoting hydrolysis under aqueous conditions. Furthermore, sulfo-functionalized siloxane gels with a highly hydrophobic surface showed excellent catalytic activity for the hydrolytic deprotection of silyl ethers.
