This review assesses the mechanistic aspects of transition metal-mediated uncaging reactions, with the goal of aiding the rational development of new caging groups/catalysts for chemical biology and drug-delivery applications.
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.
An efficient sequential three-step reaction methodology for the synthesis of three new series-1-(prop-2-yn-1-yl)-1H-pyrroles, methyl 4-acetyl-1-((1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-3-carboxylates and 6-((1H-1,2,3-triazol-4-yl)methyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-ones-is reported. The methodology comprises: (i) N-alkylation reactions of polyfunctionalized 1H-pyrroles-which were previously obtained from (E)-methyl 2-azido-3-arylacrylates-with propargyl bromide in order to obtain 1H-pyrroles; (ii) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving organic azides (benzyl-, 4-methoxybenzyl-and 4-chlorobenzyl, as well as n-octyl azide) and N-propargylated 1H-pyrroles to give triazolyl derivatives, as methyl 1H-pyrrole-3-carboxylates (click chemistry); and (iii) [4 + 2] cyclocondensation reactions of the ketoesters in the presence of hydrazine hydrochloride in order to furnish the desired series of pyrrolo[3,4-d]pyridazin-1-ones at total yields up to 54%.
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