Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody–drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.
Design of the next-generation of therapeutics, biosensors, and molecular tools for basic research requires that we bring protein activity under control. Each protein has unique properties, and therefore, it is critical to tailor the current techniques to develop new regulatory methods and regulate new proteins of interest (POIs). This perspective gives an overview of the widely used stimuli and synthetic and natural methods for conditional regulation of proteins.
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 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-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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.