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Understanding Bioorthogonal Palladium Catalysis in Living Systems: From Mechanistic Constraints to in situ Drug Assembly by Marine Lefèvre -
Jeudi 28 mai 2026 à 16h00 - Auditoire SUD01 - Croix du Sud - 1348 Louvain-la-Neuve -
The context-dependent activation of palladium catalysts in biological environments is a key challenge in bioorthogonal catalysis. Palladium offers a broad catalytic repertoire for bond-cleavage reactions, prodrug activation, and in situ drug assembly, making it attractive for the development of cancer-relevant therapeutic strategies. However, in living systems, palladium reactivity is difficult to predict because the metal can interact with thiols, proteins, reducing agents, and other biological components that influence its speciation, accessibility, catalytic activity, and cytotoxicity.
This work reports the study of several factors governing palladium-mediated bioorthogonal catalysis in cancer-relevant environments, namely: i) thiol-mediated Pd(II) activation; ii) catalyst architecture and ligand effects; iii) oxygen availability; iv) medium-driven reactivity; v) micellar confinement; and vi) the structure of the prodrug or precursor to be activated.
Fluorogenic allyl deprotection reactions were first used as functional reporters to compare palladium behavior in aqueous buffers, culture media, and living cells. These studies showed that Pd(II) precatalysts can become catalytically competent under biologically relevant conditions, particularly in thiol-rich environments, but that this activation cannot be reduced to a simple on/off process. These mechanistic insights were then applied to preliminary therapeutic models based on palladium-triggered prodrug activation and intracellular drug generation. Importantly, these studies showed that the biological outcome of palladium-mediated activation depends not only on the molecule released or assembled, but also on the catalyst itself, since different palladium systems can lead to distinct cytotoxicity patterns.
Overall, this work highlights the importance of studying palladium speciation, accessibility, and context-dependent reactivity in biological systems for therapeuthic applications. It shows that future applications of palladium bioorthogonal catalysis should not aim simply to increase catalytic activity, but to control the productive palladium species responsible for the desired therapeutic output.
Jury members :
Prof. Olivier Riant (Supervisor)
Prof. Olivier Feron (Supervisor)
Prof. Michel Devillers (UCLouvain) (Chairperson)
Prof. Michael Singleton (UCLouvain) (Secretary)
Prof. Raphael Frederick (UCLouvain)
Prof. Céline Marmion (Royal College of Surgeons in Ireland)
Prof. Gilles Gasser (Chimie ParisTech-PSL)
Pay attention : the public defense of Marine Lefèvre will also take place in the form of a videoconference - Meeting ID 3751240896547 - Passcode vU9TM7Wu
