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Iridium-Catalyzed CH-Functionalization : Development and Applications of Innovative Strategies for Hydrogen Isotope Exchange on Small Molecules and Biotherapeutic Drugs for Drug Discovery

Authors
  • Valero, Mégane
Publication Date
Jan 17, 2020
Source
HAL-Descartes
Keywords
Language
English
License
Unknown
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Abstract

The development of new efficient, fast and easy-to-handle methods to label drug compounds with deuterium or tritium in one single step is of great importance in academia and industry. These labelled compounds are for example an essential part in drug discovery and help to speed up the generation of the safety profile of a drug candidate. Classical isotope labeling mainly relies on the transformation of precursors which require multistep synthesis, a drawback which may be overcome by late-stage functionalization. We reported the first efficient catalytic protocol for ortho-selective iridium(I)-catalysed Hydrogen Isotope Exchange (HIE) reactions of pharmacologically important phenylacetic acid esters and amides with D2 or T2 under very mild reaction conditions (room temperature). We have demonstrated that by applying the optimized combination of different iridium catalysts and reaction temperatures (-60 to 130°C), different HIE reaction outcomes in selectivity and reactivity can be achieved. Together with DFT calculations, we have postulated a guideline for directing group strength of several functional groups, to predict the outcome of HIE reactions in the competition situation of complex molecules. Starting from a complex tritium labelling of the maytansine DM4 drug, the HIE reaction on a series of common linker side chains of antibody-drug-conjugates proceeded with high chemical yields, high regioselectivity and with deuterium incorporations up to 99%. The scope of the method was further extended to amino acids, di- and tripeptides, with deuterium incorporation up 95%D in the glycine moiety. Finally, in collaboration with CEA-Saclay and CNRS, air-stable and easy-to-handle iridium NHC-ligated nanoparticles were developed for the first time and used in HIE reactions of complex anilines. The usefulness of the methods developed all along the PhD was demonstrated by tritiation of DM4, Camylofine, Benalaxyl and the Volixibat pharmacophore.

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