The ability to control the activation of prodrugs by
transition
metals has been shown to have great potential for controlled drug
release in cancer cells. However, the strategies developed so far
promote the cleavage of C–O or C–N bonds, which limits
the scope of drugs to only those that present amino or hydroxyl groups.
Here, we report the decaging of anortho-quinone
prodrug, a propargylated β-lapachone derivative, through a palladium-mediated
C–C bond cleavage. The reaction’s kinetic and mechanistic
behavior was studied under biological conditions along with computer
modeling. The results indicate that palladium (II) is the active species
for the depropargylation reaction, activating the triple bond for
nucleophilic attack by a water molecule before the C–C bond
cleavage takes place. Palladium iodide nanoparticles were found to
efficiently trigger the C–C bond cleavage reaction under biocompatible
conditions. In drug activation assays in cells, the protected analogue
of β-lapachone was activated by nontoxic amounts of nanoparticles,
which restored drug toxicity. The palladium-mediatedortho-quinone prodrug activation was further demonstrated in zebrafish
tumor xenografts, which resulted in a significant anti-tumoral effect.
This work expands the transition-metal-mediated bioorthogonal decaging
toolbox to include cleavage of C–C bonds and payloads that
were previously not accessible by conventional strategies.