38 research outputs found
Unprecedented Directing Group Ability of Cyclophanes in Arene Fluorinations with Diaryliodonium Salts
For the first time it is shown that exceptionally electron-rich arene rings can be fluorinated exclusively during the reductive elimination reactions of diaryliodonium fluorides. The 5-methoxy[2.2]paracyclophan-4-yl directing group simultaneously reduces unproductive aryne chemistry and eliminates ligand exchange reactions by a combination of steric and electronic effects. Use of the cyclophane directing group permits an unprecedented degree of control in fluorination reactions of diaryliodonium salts.
Includes Supporting Information (50 pp.
Improved Arene Fluorination Methodology for I(III) Salts
The use of low polarity aromatic solvents (benzene or toluene) and/or the removal of inorganic salts results in dramatically improved yields of fluorinated arenes from diaryliodonium salts. This methodology is shown to “scale down” to the conditions used typically for radiotracer synthesis
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Imaging Active Infection in vivo Using D-Amino Acid Derived PET Radiotracers.
Occult bacterial infections represent a worldwide health problem. Differentiating active bacterial infection from sterile inflammation can be difficult using current imaging tools. Present clinically viable methodologies either detect morphologic changes (CT/ MR), recruitment of immune cells (111In-WBC SPECT), or enhanced glycolytic flux seen in inflammatory cells (18F-FDG PET). However, these strategies are often inadequate to detect bacterial infection and are not specific for living bacteria. Recent approaches have taken advantage of key metabolic differences between prokaryotic and eukaryotic organisms, allowing easier distinction between bacteria and their host. In this report, we exploited one key difference, bacterial cell wall biosynthesis, to detect living bacteria using a positron-labeled D-amino acid. After screening several 14C D-amino acids for their incorporation into E. coli in culture, we identified D-methionine as a probe with outstanding radiopharmaceutical potential. Based on an analogous procedure to that used for L-[methyl-11C]methionine ([11C] L-Met), we developed an enhanced asymmetric synthesis of D-[methyl-11C]methionine ([11C] D-Met), and showed that it can rapidly and selectively differentiate both E. coli and S. aureus infections from sterile inflammation in vivo. We believe that the ease of [11C] D-Met radiosynthesis, coupled with its rapid and specific in vivo bacterial accumulation, make it an attractive radiotracer for infection imaging in clinical practice
Synthetic biology approaches in drug discovery and pharmaceutical biotechnology
Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology
Unprecedented Directing Group Ability of Cyclophanes in Arene Fluorinations with Diaryliodonium Salts
An improved radiosynthesis of O-(2-[<sup>18</sup> F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer.
Highly efficient no-carrier-added Fluorine-18-functionalization of electron rich arenes and applications of hypervalent iodine
Positron Emission Tomography (PET) is a valuable imaging technique which provides a 3-dimensional real-time image of a biochemical process in vivo, non-invasively. The scope of PET is currently limited by the inability to provide clinically relevant radiotracers to appropriately diagnose the phenotype characteristic of a respective disease. Many clinically relevant radiotracers require functionalization of electron-rich arenes with [18F]-fluoride. Due to the short half-life of [18F] (t1/2 = 109.5 min), the late-stage incorporation of [18F]-fluoride is highly desirable. However, direct nucleophilic aromatic substitution is extremely difficult due to inherent nucleophilic properties of fluoride anion and conditions required for radiochemical syntheses. The work in this thesis provides the first general late-stage methodology of functionalizing electron rich arenes with [18F]fluoride through reductive elimination of diaryliodonium salts. Significant precedence exists for the preparation of diaryliodonium salts; however, most are limited by functional group tolerance or the use of toxic heavy metals. Regiospecific functionalization of highly activated aromatic systems by direct electrophilic aromatic substitution (EAS) or nucleophilic aromatic substitution (SNAr) is often difficult or impossible to achieve without the use of other accessory groups, which requires multiple steps and painstaking purifications. In this thesis, we show an electrophilically tunable I (III) reagent is mild enough to prepare regioisomerically pure diaryliodonium salts by direct EAS. Furthermore, regioselective iodination of electron rich arenes can be achieved from reductive elimination of the corresponding diaryliodonium salt. Therefore, we propose this simple, mild process to be a convenient alternative to the classic, Sandmeyer-type reaction
Improved Arene Fluorination Methodology for I(III) Salts
The use of low polarity aromatic solvents (benzene or toluene) and/or the removal of inorganic salts results in dramatically improved yields of fluorinated arenes from diaryliodonium salts. This methodology is shown to “scale down” to the conditions used typically for radiotracer synthesis
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An improved radiosynthesis of O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate: A first‐in‐class cholinesterase PET tracer
O-(2-Fluoroethyl)-O-(p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [18 F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [18 F]1, was obtained in a non-decay-corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [18 F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo