Abstract
Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.
Highlights
Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis
Transition metal mediated bioorthogonal reactions are of particular interest as they enable an array of non-natural chemical transformations that can be used to modulate living systems.[5,6]
We reported a water soluble NHC–Pd catalyst coupled to a cell penetrating peptide, which was able to remove a propargyloxycarbonyl group from a pro-fluorophore in cells, demonstrating the first intracellular application of NHC–Pd chemistry.[37]
Summary
Bioorthogonal reactions enable the selective visualisation and manipulation of biological processes in living systems and have been widely used in a number of applications.[1,2,3,4]Transition metal mediated bioorthogonal reactions are of particular interest as they enable an array of non-natural chemical transformations that can be used to modulate living systems.[5,6] Reactions mediated by copper,[7,8] iron,[9] gold,[10,11,12] ruthenium,[12,13,14,15,16] and iridium[17] have all found applications in living systems, palladium is perhaps the most utilised metal in a biological setting.[18]Palladium has gained popularity in bioorthogonal chemistry due its ability to perform catalytic cross-coupling reactions, enabling the generation of carbon–carbon and carbon– heteroatom bonds under mild, biological conditions,[19,20,21] and more recently in vivo.[22,23] Palladium catalysts have been used to initiate a range of intracellular reactions including dealkylation,[24] decaging of propargyloxycarbonyl groups,[19,24,25] as well as Suzuki–Miyaura cross-couplings.[20,26,27,28] palladium mediated reactions have been used to selectively activate enzymes through deprotection of modified amino acids within proteins,[21,29] to synthesise anticancer agents in cellulo from two benign precursors,[19] as well as activate produgs;[20,21,22,24] to date, the majority of the examples have used palladium nanoparticles entrapped within a polymeric support,[19,20,22,23,24,26,27,30] simple palladium salts such as Pd(OAc)[2,31,32,33] or designed targeted palladium ligands.[34]. Chen used an NHC–Pd catalyst (with imidazolium-based ligands bearing hydrophilic quaternary ammonium salts) to mediate the Suzuki–Miyaura coupling reaction between a boronic acid functionalised biotin and 4-iodophenylalanine modified cell surface proteins, enabling subsequent imaging of the cell surface with fluorescently labelled streptavidin.[33] Recently, we reported a water soluble NHC–Pd catalyst coupled to a cell penetrating peptide, which was able to remove a propargyloxycarbonyl group from a pro-fluorophore in cells, demonstrating the first intracellular application of NHC–Pd chemistry.[37] While catalyst loading was carried out on the solid-phase, the synthesis of the NHC ligand required multistep synthesis in solution, purification, and conjugation to a solid support.
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