​Frédéric Taran's laboratory has long experience of bioorthogonal chemistry, a young discipline referring to any chemical reaction that can occur within living systems. Following the discovery in 2017 of a bioorthogonal reaction between mesoionic compounds, iminosydnones and cyclooctynes, which leads to the release of a ligation product and a cleavage product, Frédéric Taran and his colleagues have optimised this 'click-and-release' reaction for healthcare applications such as the controlled release of active compounds in vivo (see previous Joliot news).

BEHIND BIOORTHOGONAL CHEMISTRY

In this new study published in Angewandte Chemie, the researchers go one step further and establish a proof of concept applied to the synthesis of an FDA-approved anti-cancer drug inside living cells. They demonstrate that it is possible to synthesise sorafenib in cells using nanomicelles constructed with amphiphiles containing bioorthogonal reagents for the synthesis of a first chemical species (an isocyanate) which will then react, in a non-bioorthogonal manner in the confined environment of the micelle, with a second compound (an amine) to generate a bioactive urea derivative that will then diffuse outside the micelle to exert its biological activity at the heart of the cancer cell.

By demonstrating that both types of chemistry (bioorthogonal activation of reactive micelles and non-bioorthogonal activation in the confined space of the micelle) occurred inside living cancer cells, leading to biological effects identical to those induced by native sorafenib, the authors propose a new paradigm for drug synthesis in living systems. This innovative approach represents a fundamental extension of the concept of biorthogonal chemistry and holds great promise for pioneering developments in therapeutic applications.

Contacts: Frédéric Taran (frederic.taran@cea.fr); Sébastien Papot (sebastien.papot@univ-poitiers.fr) ​