Fluorescent Probes for Selective Recognition of Hypobromous Acid: Achievements and Future Perspectives

molecules Review Fluorescent Probes for Selective Recognition of Hypobromous Acid: Achievements and Future Perspectives Yuyu Fang 1,2 and Wim Dehaen 2,* 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; [email protected] 2 Department of Chemistry, KU Leuven, Celestijnenlaan 200f-bus 02404, 3001 Leuven, Belgium * Correspondence: [email protected] Abstract: Reactive oxygen species (ROS) have been implicated in numerous pathological processes and their homeostasis facilitates the dynamic balance of intracellular redox states. Among ROS, hypobromous acid (HOBr) has a high similarity to hypochlorous acid (HOCl) in both chemical and physical properties, whereas it has received relatively little attention. Meanwhile, selective recognition of endogenous HOBr suffers great challenges due to the fact that the concentration of this molecule is much lower than that of HOCl. Fluorescence-based detection systems have emerged as very important tools to monitor biomolecules in living cells and organisms owing to distinct advantages, particularly the temporal and spatial sampling for in vivo imaging applications. To date, the development of HOBr-specific fluorescent probes is still proceeding quite slowly, and the research related to this area has not been systematically summarized. In this review, we are the first to review the progress made so far in fluorescent probes for selective recognition and detection of HOBr. The molecular structures, sensing mechanisms, and their successful applications of these probes as bioimaging agents are discussed here in detail. Importantly, we hope this review will call for more attention to this rising field, and that this could stimulate new future achievements. Keywords: fluorescent probes; selective recognition; ROS; hypobromous acid Citation: Fang, Y.; Dehaen, W. Fluorescent Probes for Selective Recognition of Hypobromous Acid: Achievements and Future 1. Introduction Perspectives. Molecules 2021, 26, 363. https://doi.org/10.3390/ Nature contains a complex collection of elements, molecules, and ions that play irre- molecules26020363 placeable roles in a wide range of chemical and biological processes. Selective recognition of these specific guests is a significant research area in supramolecular chemistry [1,2]. Received: 8 December 2020 Among the various guests, reactive oxygen species (ROS), which have higher reactivity Accepted: 7 January 2021 than molecular oxygen in the ground state, as their name suggests, are groups of reactive Published: 12 January 2021 neutral and anionic small molecules [3]. In particular, intracellular ROS are produced within many cell types upon incomplete reduction of oxygen through multiple electron Publisher’s Note: MDPI stays neu- transfer reactions, depending on the cell and tissue types [4]. tral with regard to jurisdictional clai- One of the major sources of intracellular ROS is NADPH oxidase process (Figure1a ), ms in published maps and institutio- and the commonly seen ROS include hydrogen peroxide (H2O2), hypohalous acids (HOCl/ nal affiliations. − − 1 ClO ), superoxide anion (O2• ), hydroxyl radical (•OH), singlet oxygen ( O2), peroxyni- − trite (ONOO ) and ozone (O3)[5]. It has been widely demonstrated that endogenous ROS are involved in numerous biological signaling pathways [6–8]. However, excess production of ROS can lead to oxidative damage to a wide range of biomolecules such as carbohydrates, Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. proteins, nucleic acids, and lipids, which has been implicated in physiological and patho- This article is an open access article physiological processes such as cancer, aging, cardiovascular disease, diabetes mellitus, distributed under the terms and con- gastrointestinal diseases, Alzheimer’s disease (AD), and so on [9–11]. ROS concentrations ditions of the Creative Commons At- within an expected threshold facilitate the dynamic balance of intracellular redox state. tribution (CC BY) license (https:// Undoubtedly, selective recognition and detection of those species have attracted a great creativecommons.org/licenses/by/ deal of attention [12–14]. Not surprisingly, biologists and chemists have made joint efforts 4.0/). to conceive feasible ROS-related therapeutic approaches in the past decades. Nevertheless, Molecules 2021, 26, 363. https://doi.org/10.3390/molecules26020363 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 19 Molecules 2021, 26, 363 2 of 18 chemists have made joint efforts to conceive feasible ROS-related therapeutic approaches in the past decades. Nevertheless, the monitoring and quantitation of ROS remains a challenging taskthe monitoringnot only due and to quantitationtheir high re ofactivity ROS remains and short a challenging lifetime, but task also not to only the due to their low concentrationshigh reactivity in vivo. and short lifetime, but also to the low concentrations in vivo. Figure 1. (a) TheFigure intracellular 1. (a) The generationintracellular of generation reactive oxygen of reactive species oxygen (ROS) species and (b )(ROS) the formation and (b) the of endogenousformation of hypobromous acid (HOBr)endogenous catalyzed hypobromous by eosinophil acid peroxidase (HOBr) catalyzed (EPO) or myeloperoxidaseby eosinophil peroxidase (MPO). (EPO) or myeloperoxidase (MPO). Hypobromous acid (HOBr) is an important ROS with a high similarity to HOCl Hypobromousin both acid chemical (HOBr) and is physicalan important properties. ROS with In a organelles, high similarity HOBr to is HOCl generated in from the − both chemicalperoxidation and physical of bromideproperties. anions In (Brorganelles,) with H HOBr2O2 (Figure is generated1b), whose from reaction the pe- is catalyzed by roxidation ofthe bromide heme peroxidasesanions (Br−) suchwith as H eosinophil2O2 (Figure peroxidase 1b), whose (EPO) reaction or myeloperoxidase is catalyzed by (MPO) [15]. the heme peroxidasesImportantly, such HOBr as eosinophil is a potent peroxidase oxidizer with(EPO) effective or myeloperoxidase antibacterial activity,(MPO) and is also [15]. Importantly,regarded HOBr as anis a integral potent factoroxidizer in thewith neutrophil effective hostantibacterial defense system.activity, Forand instance, is HOBr also regardedparticipates as an integral in the factor formation in the ofneutrophil sulfilimine host cross-links defense insystem. collagen For IV, instance, whose scaffolds are HOBr participatesessential in the to theformation formation of sulfil and functionimine cross-links of basement in collagen membranes IV, whose (BMs) scaf-in vivo [16]. In a folds are essentialsimilar to fashion the formation to other and ROS, function excessive of generationbasement membranes of HOBr will (BMs) injure in organisms,vivo which [16]. In a similaralways fashion results to in other inflammatory ROS, excessive tissue damagegeneration and of a varietyHOBr will of diseases injure organ- [17–19]. Increasing isms, which alwaysevidence results reveals in thatinflammatory the EPO levels tissue in damage serum ofand asthmatic a variety patients of diseases is three [17– times higher 19]. Increasingthan evidence that in healthyreveals individualsthat the EP [20O ].levels Considering in serum that of theasthmatic bromide patients concentration is in blood three times higherand plasma than that is far in lower healthy than individuals that of chloride [20]. Considering (ca. 1000-fold) that [the21], bromide the concentration of concentrationendogenous in blood and HOBr plasma is relatively is far lower lower than than that HOCl, of chloride which renders(ca. 1000-fold) the selective [21], recognition the concentrationof endogenous of endogenous HOBr HOBr more is challenging relatively lower than other than ROS.HOCl, which renders the selective recognitionAmong of endogenous various analytical HOBr more techniques, challenging fluorescent than other probes ROS. have emerged as indispens- Among ablevarious tools analytical to monitor techniques, biomolecules fluorescent in living cellsprobes and have organisms emerged owing as toindis- the high sensitiv- pensable toolsity, to non-invasive monitor biom imaging,olecules real-time in living detection, cells and low organisms cost, and owing superb to spatio-temporal the high resolu- sensitivity, non-invasivetion [22–25]. Particularly,imaging, real-t the probesime detection, with near-infrared low cost, (NIR) and emissionsuperb (650–900spa- nm) are tio-temporal highlyresolution favored [22–25]. for in Particularly, bio-imaging the due probes to their with distinct near-infrared ability of tissue (NIR) penetration emis- [26–28]. sion (650–900Meanwhile, nm) are highly ratiometric favored fluorescent for in bio-imaging probes are due highly to their desirable distinct because ability these of molecules tissue penetrationcould [26–28]. overcome Meanwhile, the ambiguities ratiomet ofric single fluorescent fluorescence probes intensity are highly and desira- offer quantitative measurements via self-calibration of two emission bands [29]. In addition, in contrast to ble because these molecules could overcome the ambiguities of single fluorescence in- aggregation-caused quenching (ACQ) that is quite common in most conjugated fluorescent tensity and offer quantitative measurements via self-calibration of two emission bands molecular systems, the aggregation-induced emission (AIE) first discovered by Tang’s [29]. In addition, in contrast to

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