Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C-C Bond Cleavage Reactions.

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 an ortho-quinone prodrug, a propargylated ß-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 ß-lapachone was activated by nontoxic amounts of nanoparticles, which restored drug toxicity. The palladium-mediated ortho-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.

Mechanistic insights into transition metal-mediated bioorthogonal uncaging reactions.

Cleavage of C-O and C-N bonds mediated by transition metals is a promising bioorthogonal approach to rescue the activity of caged molecules, such as proteins and cytotoxic drugs, under biological conditions. However, the precise mechanism of such uncaging reactions remains elusive. This review provides mechanistic insights into metal-mediated bond-cleavage reactions, with the goals of understanding the main factors that influence the reaction and aiding the rational development of new caging groups/catalysts for chemical biology and drug-delivery applications.

Interplay of chloride levels and palladium(ii)-catalyzed O-deallenylation bioorthogonal uncaging reactions.

The palladium-mediated uncaging reaction of allene substrates remains a promising yet often overlooked strategy in the realm of bioorthogonal chemistry. This method exhibits high kinetic rates, rivaling those of the widely employed allylic and propargylic protecting groups. In this study, we investigate into the mechanistic aspects of the C-O bond-cleavage deallenylation reaction, examining how chloride levels influence the kinetics when triggered by Pd(ii) complexes. Focusing on the deallenylation of 1,2-allenyl protected 4-methylumbelliferone promoted by Allyl2Pd2Cl2, our findings reveal that reaction rates are higher in environments with lower chloride concentrations, mirroring intracellular conditions, compared to elevated chloride concentrations typical of extracellular conditions. Through kinetic and spectroscopic experiments, combined with DFT calculations, we uncover a detailed mechanism that identifies AllylPd(H2O)2 as the predominant active species. These insights provide the basis for the design of π-allylpalladium catalysts suited for selective uncaging within specific cellular environments, potentially enhancing targeted therapeutic applications.