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.

Controlled In-Cell Generation of Active Palladium(0) Species for Bioorthogonal Decaging.

Owing to their bioorthogonality, transition metals have become very popular in the development of biocompatible bond-cleavage reactions. However, many approaches require design and synthesis of complex ligands or formulation of nanoparticles which often perform poorly in living cells. This work reports on a method for the generation of an active palladium species that triggers bond-cleaving reactions inside living cells. We utilized the water-soluble Na2 PdCl4 as a simple source of PdII which can be intracellularly reduced by sodium ascorbate to the active Pd0 species. Once generated, Pd0 triggers the cleavage of allyl ether and carbamate caging groups leading to the release of biologically active molecules. These findings do not only expand the toolbox of available bioorthogonal dissociative reactions but also provide an additional strategy for controlling the reactivity of Pd species involved in Pd-mediated bioorthogonal reactions.

Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation.

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.

Palladium Catalyst with Task-Specific Ionic Liquid Ligands: Intracellular Reactions and Mitochondrial Imaging with Benzothiadiazole Derivatives.

A water-soluble and charge-tagged palladium complex (PdMAI) was found to function inside breast cancer live cells of the MCF-7 lineage as an efficient catalyst for cross-coupling reaction. PdMAI, bearing two ionophilic task-specific ionic liquids as ligands, efficiently catalyzed both in cellulo Suzuki and Buchwald-Hartwig amination reactions. For the first time, therefore, the Buchwald-Hartwig amination is described to occur inside the highly complex cellular environment. The 2,1,3-benzothiadiazole (BTD) core was used as the base for the syntheses, and two π-extended fluorescent derivatives (BTD-2APy) and (BTD-1AN), which were found to emit in the green and red channels, had impressive mitochondrial affinity. These chromophores allowed for selective mitochondrial imaging and tracking.