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Transition‐metal‐catalyzed bioorthogonal reactions emerged a decade ago as a novel strategy to implement spatiotemporal control over enzymatic functions and pharmacological interventions. The use of this methodology in experimental therapy is driven by the ambition of improving the tolerability and PK properties of clinically‐used therapeutic agents. The preclinical potential of bioorthogonal catalysis has been validated in vitro and in vivo with the in situ generation of a broad range of drugs, including cytotoxic agents, anti‐inflammatory drugs and anxiolytics. In this article, we report our investigations towards the preparation of solid‐supported Cu(I)‐microdevices and their application in bioorthogonal uncaging and click reactions. A range of ligand‐functionalized polymeric devices and off‐on Cu(I)‐sensitive sensors were developed and tested under conditions compatible with life. Last, we present a preliminary exploration of their use for the synthesis of PROTACs through CuAAC assembly of two heterofunctional mating units. [ABSTRACT FROM AUTHOR]

Being recognized as the best‐tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly‐catalytic Au‐polymer composite by assembling ultrasmall Au‐nanoparticles at the protein‐repelling outer layer of a co‐polymer scaffold via electrostatic loading. Illustrating the in vivo‐compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled ‐for the first time‐ modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal. [ABSTRACT FROM AUTHOR]

SN‐38, the active metabolite of irinotecan, is released upon liver hydrolysis to mediate potent antitumor activity. Systemic exposure to SN‐38, however, also leads to serious side effects. To reduce systemic toxicity by controlling where and when SN‐38 is generated, a new prodrug was specifically designed to be metabolically stable and undergo rapid palladium‐mediated activation. Blocking the phenolic OH of SN‐38 with a 2,6‐bis(propargyloxy)benzyl group led to significant reduction of cytotoxic activity (up to 44‐fold). Anticancer properties were swiftly restored in the presence of heterogeneous palladium (Pd) catalysts to kill colorectal cancer and glioma cells, proving the efficacy of this novel masking strategy for aromatic hydroxyls. Combination with a Pd‐activated 5FU prodrug augmented the antiproliferative potency of the treatment, while displaying no activity in the absence of the Pd source, which illustrates the benefit of achieving controlled release of multiple approved therapeutics—sequentially or simultaneously—by the same bioorthogonal catalyst to increase anticancer activity. Palladium‐functionalized microdevices were used to uncage newly developed prodrug that releases SN‐38 (irinotecan′s active metabolite) in combination with previously known anticancer prodrug of 5FU. [ABSTRACT FROM AUTHOR]

Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs. [ABSTRACT FROM AUTHOR]

Systemic side effects limit the efficacy of chemotherapy regimens. To reduce toxicity, a metabolically stable prodrug of SN‐38 (irinotecan's active metabolite) has been designed to be exclusively activated by Pd‐functionalized microdevices that can be implanted into tumors. It is also shown the first concomitant uncaging of two drugs used in clinical combinations by the same bioorthogonal method. More information can be found in the Full Paper by P. M. Brennan, A. Unciti‐Broceta, et al. on page 16783 ff. [ABSTRACT FROM AUTHOR]

Thiole sind allgegenwärtig in lebenden Systemen, und ihre starke Bindung an Goldoberflächen hält andere funktionelle Gruppen fast vollständig von diesen fern. In ihrer Zuschrift auf S. 12727 berichten J. Santamaría, A. Unciti ‐ Broceta et al. über Gold ‐ Heterogenkatalysatoren für die bioorthogonale Aktivierung zugelassener Tumortherapeutika (durch O/N ‐ Depropargylierung) in Krebszellkulturen und die erste Aktivierung einer bioorthogonalen Sonde im Gehirn von Zebrafischen. [ABSTRACT FROM AUTHOR]

Thiols are ubiquitous in living systems where they bind strongly to gold surfaces and render interactions with other functional groups basically non‐existent. In their Communication on page 12548 ff., J. Santamaría and A. Unciti‐Broceta et al. describe heterogeneous gold catalysts that enable bioorthogonal uncaging (by O/N‐depropargylation) of clinically approved anticancer drugs in cancer cell culture, and the first intracranial activation of a bioorthogonal probe in a zebrafish. [ABSTRACT FROM AUTHOR]