title: Synthesis and selective2H-,13C-, and15N-labeling of the Tau protein binder THK-523.
abstract: A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to13C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound. Iridium-catalyzed hydrogen isotope exchange (HIE) reactions were performed on THK-523 and its13C-labeled analog providing access to 4 additional analogues labeled with deuterium as well. Finally, by applying a Buchwald-Hartwig coupling, we were able to prepare a15N-THK-523 variant with the isotope label in the quinoline ring system.
authors.affiliation: Carbon Dioxide Activation Center (CADIAC), Department of Chemistry and the Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark.
authors.forename: Karoline T
authors.initials: KT
authors.lastname: Neumann
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Department of Engineering, Aarhus University, Aarhus, Denmark.
authors.forename: Anders T
authors.initials: AT
authors.lastname: Lindhardt
authors.affiliation: Lundbeck Research, Danmark H. Lundbeck A/S, Valby, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: Carbon Dioxide Activation Center (CADIAC), Department of Chemistry and the Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark.
authors.forename: Troels
authors.initials: T
authors.lastname: Skrydstrup
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D002247:Carbon Isotopes / Q000737:chemistry*; D003903:Deuterium / Q000737:chemistry*; D009587:Nitrogen Isotopes / Q000737:chemistry*; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D016875:tau Proteins / Q000378:metabolism
chemical_list: C559040:2-(4-aminophenyl)-6-(2-fluoroethoxy)quinoline; D000814:Aniline Compounds; D002247:Carbon Isotopes; D009587:Nitrogen Isotopes; D011804:Quinolines; D019275:Radiopharmaceuticals; D016875:tau Proteins; D003903:Deuterium
keywords: alzheimer disease; buchwald-Hartwig coupling; carbonylative sonogashira coupling; hydrogen isotope exchange; isotope labeling; tau binder