DC9: ELISA MARTINELLI (IT)
Partner of attachment: SANOFI (Sanofi GmbH) DE
Supervisor : Dr. Volker DERDAU
University of Attachment: UROS (University of Rostock) DE
Director of Thesis : Prof. Matthias BELLER

In drug discovery, isotopically labelled compounds are essential in many applications such as ADME (Absorption, Distribution, Metabolism, and Excretion) studies. In the last ten years an increasing number of biological drugs such as antibodies, proteins, ribonucleic acids (RNAs), became more prevalent in the pharmaceutical industry as important treatments for patients. Due to their nature, they are typically degraded at high temperature, at low or high pH values and are formulated in aqueous buffers.
For this reason, there is an increasing demand to transfer isotopically labelling methodologies for the introduction of deuterium or tritium in conditions that are compatible to these molecules.Since the middle of last century, Hydrogen Isotope Exchange (HIE) has been applied as a quick and effective method for introducing an isotope label into a developed drug candidate by simply substituting one hydrogen atom with a deuterium or tritium atom. Many HIE protocols use homogenous catalysis, meaning that the catalyst is completely dissolved in the reaction media. Among the various homogeneous metal catalysts, iridium(I) complexes have been widely studied, leading to their successful application to directed HIE reactions of aromatic and aliphatic substrates. The deuteration and tritiation is selective for a specific position in the molecule due to the coordination of the iridium catalyst with functional groups present in the substrate. While these catalysts were intensively studied in organic media, aqueous conditions have been sparsely evaluated so far.
We synthesized a pH-neutral water-soluble iridium(I) catalyst using modified phosphines as ligands. The modification consisted in the insertion of a chain composed of several units of polyethylene glycol (PEG). PEGs are commonly applied in the pharmaceutical sector, for example as excipient in tablets and pills. The catalyst was used in aqueous buffers to study directed HIE on aromatic compounds as well as to gain insights on the undesired reaction with water and other polar protic solvents such as ethanol or acetic acid. The different energies of the iridium-substrate complex formation in the different solvents gave a better understanding of the pH role in the reaction.
We found that the solvent and the pH have a strong impact on the side reaction of HDO formation occurring in the ligand sphere of the catalyst. The directed HIE reaction was successful for a variety of molecules with several directing groups where the nitrogen or oxygen atoms coordinated with the metal and allowed a selective deuteration of the molecule. This protocol was also applied to some marketed drugs such as an antibiotic for urinary tract infections (UTI) treatment and antihypertensive medications. Furthermore, the method was transferred to tritium reaction conditions labelling the antihypertensive drug telmisartan.
Our work will help studying new HIE catalysts in protic solvents and can be considered as a fundamental step towards finding suitable tritiation HIE reaction conditions for biologically active biological entities in the future.
