IMCN thesis defence - Mathieu SOETENS

IMCN Thesis Defence Mathieu SOETENS "Development of transition metal catalyst for bioorthogonal reactions"

Cancer is a metabolic disease characterized by immortal cells which develop in a non-controlled and anarchic fashion after undergoing mutations and alterations in their DNA. These cells tend to grow in masses which are called tumours. It has emerged as one of the ten main causes of mortality along with cardiovascular diseases. A lot of effort has been put both into academia and into industry to respond to this societal challenge in order to both understand their biology and to find a way to selectively kill these cells.
A lot of cytotoxic agents and metallodrugs target DNA as cancer cells divide faster than healthy cells, but severe side effects are observed on patients. The next generation of chemotherapy will be more selective to avoid side effects. Our response to this challenge is to use transition metal catalysis to selectively activate anti-cancer molecules inside cancer cells.
Initially, iridium catalysts capable of reducing imines with the metabolic cofactor NADH were developed. Following this, palladium catalysts capable of deprotecting allyl carbamates in a buffered aqueous medium using the glutathione cofactor were developed. We showed that we were able to activate fluorescent molecules selectively inside cancer cells. Our best candidates were stable, cell permeable and non-toxic in addition to remaining active in the cellular medium.
Then, with satisfactory catalysts in hand, we moved on to therapeutical applications. In one hand, we attempted to catalytically inhibit enzymes using our catalysts and in the other hand, we tried to gain selectivity by making prodrugs capable of recognizing cancer-specific proteins at the cell surface.