Using Ligand-Accelerated Catalysis to Repurpose Fluorogenic Reactions for Platinum or Copper

Abstract

The development of a fluorescent probe for a specific metal has required exquisite design, synthesis, and optimization of fluorogenic molecules endowed with chelating moieties with heteroatoms. These probes are generally chelation- or reactivity-based. Catalysis-based fluorescent probes have the potential to be more sensitive; however, catalytic methods with a biocompatible fluorescence turn-on switch are rare. Here, we have exploited ligand-accelerated metal catalysis to repurpose known fluorescent probes for different metals, a new approach in probe development. We used the cleavage of allylic and propargylic ethers as platforms that were previously designed for palladium. After a single experiment that combinatorially examined >800 reactions with two variables (metal and ligand) for each ether, we discovered a platinum- or copper-selective method with the ligand effect of specific phosphines. Both metal–ligand systems were previously unknown and afforded strong signals owing to catalytic turnover. The fluorometric technologies were applied to geological, pharmaceutical, serum, and live cell samples and were used to discover that platinum accumulates in lysosomes in cisplatin-resistant cells in a manner that appears to be independent of copper distribution. The use of ligand-accelerated catalysis may present a new blueprint for engineering metal selectivity in probe development.

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

“…The authors used the cleavage of allylic and propargylic ethers as platforms to systematically screen metals and ligands to discover fast and efficient BCRs. 59 After examining over 800 reactions, several previously unknown metal–ligand pairs were disclosed, indicating that the selectivity/reactivity of the metals can be tuned by specific phosphine ligands and that the cleavage reaction can be efficiently conducted using a catalytic amount of the metal catalyst. 59 Nevertheless, the potential toxicity of metal ions to living systems needs to be considered.…”

“… 59 After examining over 800 reactions, several previously unknown metal–ligand pairs were disclosed, indicating that the selectivity/reactivity of the metals can be tuned by specific phosphine ligands and that the cleavage reaction can be efficiently conducted using a catalytic amount of the metal catalyst. 59 Nevertheless, the potential toxicity of metal ions to living systems needs to be considered. In addition, these transition-metal-triggered BCRs are often sensitive to the reaction conditions, rendering it difficult to adopt the optimized reaction to a more complex environment.…”

“…As one of the most widely used metals for catalyzing bioorthogonal ligation reactions, such as CuAAC, Cu has recently been used to trigger BCRs ,− (Figure , entries 5, 9, and 11). Inspired by the in vitro deprotection of the dimethyl propargyl group using Cu­(I) by Finn et al in 2013, we employed this bioorthogonal cleavage pair for the manipulation of cell surface interactions .…”

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

“…We anticipated that some drawbacks of the vinyl ether moiety could be resolved using a different masking group. Allyl ether was previously reported as a Ru‐ [16] or Pt‐labile [17] caging group in living cells, however, decaging of allyl ethers mediated by Pd under biocompatible conditions has not been reported yet.…”

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

“…[4a] We anticipated that some drawbacks of the vinyl ether moiety could be resolved using a different masking group. Allyl ether was previously reported as a Ru- [16] or Pt-labile [17] caging group in living cells, however, decaging of allyl ethers mediated by Pd under biocompatible conditions has not been reported yet.…”