Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems

Review DOI:10.1002/ijch.201600023 Thioether Coordination Chemistry for Molecular Imaging of Copper in Biological Systems Karla M. Ramos-Torres,[a] Safacan Kolemen,[a] and Christopher J. Chang*[a, b, c] We dedicate this submission to Harry Gray,who has beenateacher,mentor,friend, and inspiration to us all. Abstract:Copper is an essentialelement in biological sys- ular imaging agents for this metal, drawing inspirationfrom tems. Its potent redox activity renders it necessary for life, both biological binding motifsand synthetic model com- but at the same time, misregulationofits cellular pools can plexes that reveal thioether coordination as ageneral design lead to oxidative stress implicated in aging and various dis- strategy for selective andsensitive copper recognition. In ease states. Copper is commonly thought of as astatic co- this review,wesummarize some contributions,primarily factor buried in protein active sites;however,evidence of from our own laboratory,onfluorescence- and magnetic res- amore loosely bound, labile pool of copper has emerged. onance-based molecular-imaging probes for studying To help identify and understand new roles for dynamic copper in living systemsusingthioether coordination copper pools in biology,wehave developed selective molec- chemistry. Keywords: copper · fluorescent probes · molecular imaging · MR probes · thioether coordination 1. Introduction Copper is an essential element for life.[1] Owing to its as lipolysis,[20] and the activation of the mitogen-activated potent redox activity,the participationofthis metalas protein (MAP) kinase pathway relevant in normal physi- acatalytic and structural cofactor in enzymes that func- ology and in oncogenic serine/threonine-protein kinase tion in biological processes spanning energy generation, B-Raf (BRAF) signalingand tumorogenesis.[21,22] oxygen transport, cellularmetabolism, and signal trans- Against this backdrop,molecularimaging provides duction renders it vital for the life of eukaryotic organ- aversatile approach that can be used to monitorlabile isms.[2] However, this same redox promiscuity, when mis- metal fluxes in real timewith spatial and temporal resolu- regulated, can also lead to aberrant generation of reactive tion.[23–25] In combination with complementary biochemi- oxygen species (ROS) that have been linked to aging and cal and genetic methods,aswell as direct readoutsof different disease states,including genetic disorders like total metal content,small-molecule probes with different Menkes[3–5] and Wilsons[6–8] diseases,neurodegenerative readoutsignals, including fluorescence,colorimetric,and diseases like Alzheimers,[9–12] Parkinsons,[13] and Hun- magnetic resonance (MR) relaxivitymodalities,can be tingtons[14] diseases,and metabolic disorders such as dia- used effectively as pilotscreening tools for quicklyassess- betes and obesity.[15–17] Forthis reason,copper and other ing metalstatus in different physiological states.Assuch, redox-active metals have been canonically thought of as the development of metal-selective small-molecule buried cofactors within enzymeactive sites and part of probesprovides apotentially powerful toolbox that atightly bound metal pool.However, amore loosely allows for the mappingoflabile metalpools and the bound pool, termed the labile pool, in whichcopper and study of the roles of these dynamic fluxes.Inthis review, other metals can dynamically exchange withligands on timescales commensurate with signaling, has been ob- [a] K. M. Ramos-Torres, S. Kolemen, C. J. Chang served. This metal pool, in which rapid ligandexchange Department of Chemistry and changes in metal concentration gradients can mediate University of California Berkeley CA 94704 (USA) signaling processes,has been extensively studied in e-mail:[email protected] regard to redox-inactive alkali, alkaline earth and transi- [b] C. J. Chang tion metals,such as calcium,sodium, potassium,and zinc. Department of Molecular and Cell Biology Nonetheless,recent work from our lab and others has re- University of California Berkeley vealed that despite its high reactivity,dynamic copper CA 94704 (USA) fluxes are observed in important physiologicalprocesses, [c] C. J. Chang [18] such as neuronal calcium signaling pathways, spontane- Howard Hughes Medical Institute ous activity in neural circuits,[19] metabolic processes such Tel.:(+1) 510-642-4704 Isr.J.Chem. 2016,56, 724 –737 2016 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 724 Review we focus on the use of thioether coordination chemistry 2. Bioinspired Strategies for Selective Copper as ageneral design strategy for achieving copper-selective Recognition probes for molecular imaging –optical and magnetic resonance imaging, as an illustrative example of opportuni- Owing to environmentalheterogeneities in biological sys- ties at the interface between inorganic chemistry and tems,the development of small-moleculeprobes for bio- biology. logical use is inherently challenging. Because transition metals such ascopper are far less abundantthan their biologically relevant alkali/alkaline earth counterparts,selectivity poses one of the main challenges in probe design.Additionally for copper,redox specificity is re- Karla Ramos-Torres graduated from the quired,asitcan exist in two major oxidation states,Cu(I) University of Puerto Rico, RíoPiedras and Cu(II). In the cellular setting, most of the copper in 2011 with aB.S. in Chemistry.She is that is undergoing dynamicexchange is in the Cu(I)state, currently aPh.D. candidate at UC Ber- keley,where she works in the laboratory owing to the reducing intracellularenvironment (average [26] of Prof. Chris Chang. Her current re- potential of –0.25 V) buffered in partbythe thiol-con- search interests include the develop- taining low-molecular weight peptide glutathione (GSH). ment of molecular probes for the de- Preceding import across the plasma membrane, extracel- tection of biological copper.Outside of lular Cu(II) is reduced to the Cu(I)state by an insuffi- research, Karla enjoys playing volley- ciently understood mechanismthat presumably involves ball, hiking, and dancing. membrane reductases,[27] afterwhich intracellular accu- mulation of the metal ion is achieved primarily by the high-affinity Cu(I)-specific channel copper transporter Safacan Kolemen is apostdoctoral re- 1(CTR1). Theprevalence of the intracellular Cu(I) state searcher in the laboratory of Prof. Chris is further evidenced by the identification of Cu(I)-specific Chang at UC Berkeley.His work focus- metallochaperones such as Atox-1,[28] which delivers es on development of pH-sensitive and Cu(I) to the p-type ATPases ATP7A/B,the copper chap- copper-selective molecular probes. He erone for superoxide dismutase (CCS),[29,30] and the vari- received his Ph.D. in 2014 from Bilkent ous Sco[31] and Cox[32] copper chaperones for mitochondri- University,Turkey,where he worked al copper pools to metallate enzymes such as cytochrome under the supervision of Prof. Engin U. c oxidase (CcO). Thespecificity of this emerging class of Akkaya on designing photosensitizers for photodynamic therapy applications. proteins for copper binding is crucial for maintaining cellular homeostasisofthis metal. 2.1 Metal and Ligand Considerationsfor Copper Coordination Chris Chang is the Class of 1942 Chair Inspection of biological copper sites can give us insight Professor in the Departments of into its preferred modes of binding. Coordination in pro- Chemistry and Molecular and Cell Biol- ogy at UC Berkeley,Howard Hughes tein copper-binding sites is typically dominated by histi- Medical Institute Investigator,and Fac- dine,cysteine, and methionine residues.The makeupof ulty Scientist in the Chemical Sciences each ligand set depends on the specific role,copper trans- Division of Lawrence Berkeley National port or enzymatic activity,ofthe bindingsite.However, Laboratory.HeisaSenior Editor of the general use of these amino-acid side chains can be ACS Central Science.Chris received his viewed as also governed by the hard and soft acids and B.S. and M.S. from Caltech in 1997, bases (HSAB) principle.[33,34] In line with this theory,soft working with Harry Gray,studied as acid Cu(I) and borderline Cu(II) will preferentially bind aFulbright scholar in Strasbourg, ligandswith borderline to soft basicities,respectively, France with Jean-Pierre Sauvage, and leadingtoafavored use of amino-acid residues with ni- received his Ph.D. from MIT in 2002 with Dan Nocera. After post- doctoral studies with Steve Lippard, Chris joined the UC Berkeley trogen and sulfur donor atoms.Additionally,the number Faculty in 2004. His laboratory focuses on chemical biology and in- of donors,aswell as the coordination geometry,can also organic chemistry with particular interests in molecular imaging impart adegree of selectivity between the possible metal and catalysis applied to neuroscience and sustainable energy.His oxidation states for these bindingsites.Even though group’s work has been recognized by honors from the Dreyfus, Cu(I) does not have ageometric preference based on Beckman, Sloan, and Packard Foundations, Amgen, Astra Zeneca, alack of ligand field stabilizationenergy (LFSE), it is and Novartis, Technology Review,ACS (Cope Scholar,Eli Lilly, often foundinlow-coordinate systemswith 2, 3, or 4li- Nobel Laureate Signature, Baekeland), RSC (Transition Metal gands in linear, trigonal planar, or tetrahedralgeometries. Chemistry), SBIC, and the Blavatnik Foundation. Conversely,LFSE for Cu(II) results in higher coordinate Isr.J.Chem. 2016,56,

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