From Ugi Multicomponent Reaction to Linkers for Bioconjugation

Bioconjugation is a key approach for the development of novel
molecular entities with clinical applications. The biocompatibility and specificity
of biomolecules such as peptides, proteins, and antibodies make these
macromolecules ideal carriers for selective targeted therapies. In this context,
there is a need to develop new molecular units that cover the requirements of the
next generation of targeted pharmaceuticals. Here, we present the design and
development of a versatile and stable linker based on a N-alkylated α,α-dialkyl
dipeptide for bioconjugation, with a particular focus on antibody-drug conjugates
(ADCs). Starting with the well-known Ugi multicomponent reaction, the
convenient chemical modification of the prepared adducts allowed us the
obtention of versatile bifunctional linkers for bioconjugation. A conjugation
strategy was tested to demonstrate the efficiency of the linker. In addition, a
novel cytotoxic anti-HER2 ADC was prepared using the Ugi-linker approach.