Copper is a required metal nutrient for life, but global or local alterations in its homeostasis are linked to diseases spanning genetic and metabolic disorders to cancer and neurodegeneration. Technologies that enable longitudinal in vivo monitoring of dynamic copper pools can help meet the need to study the complex interplay between copper status, health, and disease in the same living organism over time. Here, we present the synthesis, characterization, and in vivo imaging applications of Copper-Caged Luciferin-1 (CCL-1), a bioluminescent reporter for tissue-specific copper visualization in living animals. CCL-1 uses a selective copper(I)-dependent oxidative cleavage reaction to release d-luciferin for subsequent bioluminescent reaction with firefly luciferase. The probe can detect physiological changes in labile Cu+ levels in live cells and mice under situations of copper deficiency or overload. Application of CCL-1 to mice with liver-specific luciferase expression in a diet-induced model of nonalcoholic fatty liver disease reveals onset of hepatic copper deficiency and altered expression levels of central copper trafficking proteins that accompany symptoms of glucose intolerance and weight gain. The data connect copper dysregulation to metabolic liver disease and provide a starting point for expanding the toolbox of reactivity-based chemical reporters for cell- and tissue-specific in vivo imaging.

Iron is an essential metal for living organisms, but misregulation of its homeostasis at the cellular level can trigger detrimental oxidative and/or nitrosative stress and damage events. Motivated to help study the physiological and pathological consequences of biological iron regulation, we now report a reaction-based strategy for monitoring labile Fe2+ pools in aqueous solution and in living cells. Iron Probe 1 (IP1) exploits a bioinspired, iron-mediated oxidative C–O bond cleavage reaction to achieve a selective turn-on response to Fe2+ over a range of cellular metal ions in their bioavailable forms. We show that this first-generation chemical tool for fluorescence Fe2+ detection can visualize changes in exchangeable iron stores in living cells upon iron supplementation or depletion, including labile iron pools at endogenous, basal levels. Moreover, IP1 can be used to identify reversible expansion of labile iron pools by stimulation with vitamin C or the iron regulatory hormone hepcidin, providing a starting point for further investigations of iron signaling and stress events in living systems as well as future probe development.

A reaction-based strategy exploiting cobalt-mediated oxidative C-O bond cleavage affords a selective turn-on fluorescent probe for paramagnetic Co(2+) in water and in living cells.

A new type of neutral donor-acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either buildingblock concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane.dynamic combinatorial chemistry ͉ molecular recognition W e report here the spontaneous assembly of a donoracceptor (D-A) [2]-catenane from a dynamic combinatorial library (DCL) in water. Unusually, this is a D-A catenane that contains the electron-deficient and electron-rich aromatic moieties in the same ring. Owing to their complex topology and the resulting synthetic challenge, mechanically interlocked molecules such as catenanes have captivated chemists for a long time (1). With advances in the efficient templated synthesis of these interlocked structures, applications of these interesting molecules have been found in molecular electronic devices, such as switches, motors, color displays, and molecular memory (2-5).Conventional catenane synthesis relies on the use of noncovalent interactions to preorganize precursors in a suitable configuration that favors the formation of an interlocked structure, employing an irreversible, kinetically controlled chemical reaction as the final catenating step (for recent examples, see 6-9). The recent rise of dynamic covalent chemistry (10) using reversible chemical reactions under thermodynamic control has led to an increasing number of catenane syntheses that are either designed to lead to a particular structure (for recent examples, see 9, 11-19) or result from unpredictable dynamic combinatorial selection (20,21). The advantage of either of these dynamic strategies is the possibility of recycling un-interlocked components, hence increasing the yield of the desired structure.Interactions between electron-rich aromatics, such as dialkoxynaphthalene (DN) and tetrathiafulvalene (TTF), and electron deficient aromatics, like naphthalenediimide (NDI) and paraquat, have been extensively used in the preparation of catenanes (9,22,23). The vast majority of these catenane constructions rely on kinetically controlled reactions. Some examples of thermodynamically controlled syntheses of these structures include the neutral [2]-catenanes featuring zincpyridine coordination (24) and alkene metathesis as the ringclosing reactions (25). More recently, Stoddart and coworkers reported the iodide-catalyzed self-assembly of paraquat-based cationic D-A [2]-(16) and [3]-catenanes (14) from separate -donor and -acceptor rings using thermodynamically controlled nucleophilic substitution. Most of the examples of D-A catenane syntheses depend on a preformed, -rich crown ether ring containing electron-donor units, and the subsequent formation of new electron-deficient rings followed by catenation. Hence, the resulting catenanes...

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.

For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5'-untranslated regions (5'-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5'-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe -specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe ) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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Two donor-acceptor [2]catenanes have been synthesized and characterized from a single dynamic combinatorial library in water. One of these catenanes is different from earlier related interlocked molecules in that two donor units stack on each other in an unexpected order. Shifting the equilibrium by choosing the right conditions resulted in a significant increase in the yields of the individual catenanes.