Development of a bioorthogonal tsuji- trost reaction targeting cancer hypoxia

Cancer is currently the second leading cause of death worldwide. Patients suffering from this disorder present abnormal cells which grow and divide uncontrollably into a tumour mass. Within this proliferating mass, hypoxia arises in areas presenting a low partial pressure of oxygen. These regions are located too far from blood vessels to receive a sufficient oxygen supply to fulfil their demand. Furthermore, hypoxic cancer cells are associated with a more invasive phenotype and resistance to radio- and chemotherapy. Targeting such malignancies represents a major challenge in therapy today in attempting to kill cancerous cells without harming the healthy surrounding tissue. To tackle this challenge, our strategy entails the use of transition metal catalysts to selectively activate anticancer molecules inside hypoxic cells. Therefore, first biocompatible organometallic complexes were designed. Their action in cellulo was then studied based on their ability to liberate a fluorescent molecule from a non-fluorescent precursor. Then, by comparing the results under normoxic and hypoxic conditions, only catalysts that were active in low-oxygen settings were isolated. This provided a level of selectivity towards hypoxic cancer cell targeting. Finally, the possibility was explored to synthesise inactive drugs from known pharmacophores to target proteins involved in the energy metabolism of hypoxic cancer cells.