Reaction-Based Fluorescent Probes for the Imaging of Nitroxyl (HNO

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Reaction-based fluorescent probes for the imaging of nitroxyl (HNO) in biological systems Baoli Dong, Xiuqi Kong, and Weiying Lin ACS Chem. Biol., Just Accepted Manuscript • DOI: 10.1021/acschembio.7b00901 • Publication Date (Web): 06 Dec 2017 Downloaded from http://pubs.acs.org on December 10, 2017

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Reaction-based fluorescent probes for the imaging of nitroxyl (HNO) in biological systems Baoli Dong, Xiuqi Kong, Weiying Lin*

Institute of Fluorescent Probes for Biological Imaging, School of Chemistry and Chemical Engineering, School of Materials Science and Engineering, University of Jinan, Shandong 250022, P.R. China. E-mail: [email protected] Abstract: Nitroxyl (HNO) has been identified as an important signaling molecule in biological systems, and plays critical roles in many physiological processes. Fluorescence imaging could provide a robust approach to explore the biological formation of HNO and its physiological functions. Herein, we summarize the organic reaction types for constructing HNO probes, and specifically focus on review of the recent advances in the development of the reaction-based HNO probes and their imaging applications in living systems. Keywords: Nitroxyl (HNO): a one-electron reduced and protonated product of nitric oxide (NO). HNO is a well-known signaling molecule in many physiological processes. Fluorescent probe: a tool that detects biomolecules, ions, microenvironment or particular biomolecular assemblies with high sensitivity and selectivity by fluorescence imaging. Reduction reaction: a chemical reaction that involves the gain of electrons by any chemical species, or the loss of oxygen from a compound. Staudinger ligation: a chemical reaction in which an azide reacts with a phosphine or phosphate to produce an iminophosphorane intermediate. Two-photon microscopy (TPM): a fluorescence imaging technique that typically uses near-infrared excitation light to visualize biomolecules in living systems. Near-infrared light: an electromagnetic radiation with wavelength in the range of 650 - 900 nm. Ratiometric fluorescence detection: a detection method that allows the measurement of the fluorescence intensities at two wavelengths and uses the ratio of these two signals as output. Mitochondria: an important double membrane-bound organelle in all eukaryotic cells. Fluorescence microscope: an optical microscope that employs fluorescence to generate images and has wide applications in the field of chemical biology.

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1. Introduction Nitroxyl (HNO) is the one-electron reduced and protonated product of nitric oxide (NO), which is a well-known signaling molecule in many physiological processes. Despite their very close structural similarity, recently it has been found that HNO shows different biological and chemical properties.[1-5] Due to its high chemical reactivity, HNO can avidly react with thiols to provide either disulfides or sulfinamides, and inhibit the enzyme’s activity.[6-7] HNO also exhibits the particular ability to activate cardiac sarcoplasmic ryanodine receptors, and may afford useful strategies for the treatment of cardiovascular diseases.[8-9] Although notable progresses regarding to biological chemistry of HNO have been achieved, the physiological and pathological effects of HNO still remain largely undiscovered. As a consequence, rapid and reliable detecting HNO in living biological systems is a crucial challenge, and has attracted the great attention of chemists. Traditionally, the commonly used methods for evaluating HNO level by detecting the by-products of HNO, include headspace gas chromatography, high-performance liquid-chromatography mass spectrometry (HPLC-MS) and electron paramagnetic resonance (EPR) spectroscopy.[10-14] These analytical techniques may provide appropriate sensitivity. Unfortunately, they are not suitable for the rapid and in situ detection of HNO in living systems. By contrast, fluorescence microscope is a modern and burgeoning technique for detecting bio-molecules because of its high sensitivity, excellent selectivity, and real-time analysis. [15-19] Fluorescence imaging of HNO in living systems could provide a robust approach to explore the formation of endogenous HNO and the physiological roles of HNO in complex biological processes. In this review, we discuss the recent developed fluorescent probes that have been used for the imaging of HNO in living systems. In the first section, the two main reaction types for constructing HNO probes, reduction reaction of Cu(II) to Cu(I) and Staudinger ligation, are introduced brieﬂy. Next, the recent advances of HNO probes based on these two reaction types are emphatically depicted, and the features of these probes are summarized in Supplemental Table 1. Finally, we present our perspective on the development of new probes for the imaging of HNO in living systems. 2. Reaction-based fluorescent probes for the imaging of HNO Currently, the fabrication of reaction-based fluorescent HNO probes is mainly on the basis of two reaction types, reduction reaction of Cu(II) to Cu(I) and Staudinger ligation (Scheme 1), respectively. For the former, because Cu(II) with the unpaired 2



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electron in a d orbital can quench the fluorescence of a fluorophore by photo-induced electron transfer (PET), thereby the fluorescent dyes binding with a paramagnetic Cu(II) complex usually display weak or no fluorescence. Selective reduction of Cu(II) to Cu(I) by HNO blocks PET by filling d orbital and thus recovers the fluorescence of the fluorophore. For the other mechanism, a 2-(diphenylphosphino)benzoate can react with HNO to provide hydroxyl by undergoing Staudinger ligation. After the response to HNO, conversion of 2-(diphenylphosphino)benzoate to hydroxyl restores the fluorescence of the fluorophore by spirolactone ring-closing mechanism or intramolecular charge transfer (ICT) effect.

Scheme 1. Two main design strategies for developing HNO fluorescent probes. 2.1 HNO probes based on reduction reaction of Cu(II) to Cu(I) In 2010, Lippard et al pioneered the construction of HNO probe 1 (Figure 1) based on the selective reduction of Cu(II) to Cu(I) by HNO. [20] 1 employed a BODIPY unit as fluorescence reporter and a tripodal Cu(II) complex as sensing site for HNO. 1 displayed weak fluorescence. After the treatment of 1 with excess Angeli’s salt (AS), a 4.3-fold fluorescence turn-on response was observed. 1 exhibited desirable selectivity over other biologically relevant species such as NO, H2O2 or ONOO-. Furthermore, this probe can be applied to detect HNO in living cells.

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Figure 1. a) Structure of 1 and mechanism of its reaction with HNO. b) HNO-induced fluorescence response in HeLa cells incubated with 1 µM 1 (A) and further treated with 200 µM AS after 1 min (B), 5 min (C), and 10 min (D). (Top) Brightfield images and (bottom) fluorescence images. Scale bar, 25 µm. Copyright 2010 American Chemical Society. Inspired by this pioneering Cu(II)-based HNO probe, structurally improved HNO probes emerged soon afterwards (Figure 2). Yao et al employed a coumarin fluorophore to develop a Cu(II)-based HNO probe 2.[21] This probe can serve as a dual-response HNO probe not only for fluorescence detection, but also for electron paramagnetic resonance (EPR) detection. Soon after, Yao et al made a simple improvement on 2, to develop an analogous HNO probe 3.[22] This probe can show improved cell membrane permeability, and exhibit rapid fluorescence response to HNO with high selectivity. Based on 1, Lippard et al designed a new kind of benzoresorufin-based copper(II) complexes (4-6) for detecting HNO. [23] These copper complexes had different metal-binding sites, and were employed for the imaging of HNO in living cells.

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Figure 2. Structures of Cu(II) complex-based HNO probes Compared with visible light, near-infrared (NIR) light is more attractive for imaging because of its less photodamage to biological sample, low background noise and deep tissue penetration. In 2014, Lippard et al developed the first NIR fluorescent probe for HNO (7, Figure 2). [24] The probe utilized a dihydroxanthene fluorophore as NIR signal reporter. 7 showed a 5-fold NIR fluorescence enhancement at 715 nm when reacting with HNO, and was highly selective for HNO over thiols and H2S. By the multicolor imaging experiments using 7 and a zinc-specific green-fluorescent probe simultaneously, the HNO-induced increase of intracellular mobile zinc levels was successfully tracked. By means of a facile solid-phase method, Lippard et al described a Cu(II)-based HNO probe 8 (Figure 2).[25] This probe utilized a tetramethyl-rhodamine scaffold as fluorescent platform. When 8 reacted with excess AS, the fluorescence at 580 nm displayed an immediate 4-fold increase. 8 remained selective for HNO over any other biologically relevant analytes, reducing agents such as ascorbate, and thiols. Moreover, 8 can be applied to selectively detect HNO in biological environment. Water solubility is an important point for designing HNO probes. Yoon et al descried a water-soluble HNO probe 9 (Figure 2).[26] Treatment of 9 with excess AS lead to a remarkable enhancement in emission intensity at 534 nm. Besides HNO, 9 also showed fluorescence response for NO, while it exhibited weak response to other

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biologically relevant ROS. Moreover, this probe was used for the imaging of NO and HNO in living cells. Recently, Xing et al developed a HNO probe 10 (Figure 2).[27] Treatment of 10 with excess AS, a significant enhancement of fluorescence at 595 nm was observed. A detection limit of 23.0 µM was obtained. Meanwhile, 10 also showed obvious fluorescence response to H2S. Furthermore, this probe can be used for the selective detection of HNO in liposomes, respectively. 2.2 HNO probes based on Staudinger ligation Reaction of phosphine with HNO based on Staudinger ligation is highly bioorthogonal because phosphines are generally abiotic and essentially unreactive toward biomolecules, and has been extensively applied for developing HNO probes.[28-29] Unlike Cu(II)-based HNO probes, the metal-free phosphine-based HNO probes are often reductant-resistant and generally present a greater fluorescence response. 2.2.1 Phosphine-based turn-on probes for HNO In 2013, Nakagawa et al fabricated the first phosphine-based probe 11 (Figure 3a) for HNO. [30] 11 was designed on the basis of rhodol with its amino group acylated by benzoic acid, and used triphenylphosphine moiety as the response site to HNO. Upon treatment of 11 with excess AS, the fluorescence at 526 nm increased significantly. Notably, the fluorescence of 11 was hardly influenced by the biologically relevant reductants, such as GSH, ascorbic acid (AA) and H2S. Furthermore, 11 can be applied for the imaging of HNO in living cells (Figure 3b).

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Figure 3. a) Structure of 11 and its sensing mechanism to HNO. b) Images of A549 cells incubated with 1 µM 11 before (A) and at 10 min (B), 15 min (C) and 20 min (D) after treatment with 2 µL of AS in 10 mM NaOH solution (200 µM). (top) FITC channels and (bottom) DIC images. Scale bars represent 20 µm. Copyright 2013 American Chemical Society. Following the pioneering probe 11, various small-molecule phosphine-based fluorescent probes for HNO have been developed. These probes can be classified into two types: turn-on probe (namely, intensity-based probe) and ratiometric probe. Turn-on probes are generally liable to provide a significant response, and often can be simply prepared by less steps. Ratiometric probes allow the measurement of fluorescence emission intensities at two different wavelengths, and the ratios of these two fluorescence signals can be independent of the environmental effects including probe concentration, and excitation intensity. Since the first phosphine-based probe for HNO was reported, various probes for HNO began to emerge. In 2014, Tan et al described a simple intensity-based fluorescent probe 12 (Figure 4) for HNO.[31] 12 showed a low detect limit of 20 nM, and exhibited a selective response to HNO over other biological reductants. King et al reported a fluorescein-based probe 13 for HNO (Figure 4).[32] When the probe was incubated with AS, the increase of the emission intensity at 520 nm can be observed. This probe can selectively react with HNO under physiological conditions with less interference from other biological redox species. Bhuniya et al developed a HNO probe 14 by using resorufin as the fluorophore (Figure 4).[33] Treated with excess AS, this probe displayed a significant fluorescence enhancement at 590 nm. A detect limit of 20 nM was achieved for HNO detection. Furthermore, the probe is capable of detecting HNO concentration in cellular milieus and in live specimen e.g. C. Elegan.

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Figure 4. Structures of phosphine-based turn-on probes for HNO. Considering the advantages of NIR light for biological imaging, Chen et al constructed a NIR probe 15 (Figure 4) for HNO.[34] Treatment of 15 with AS induced a significant enhancement in fluorescence intensity at 700 nm, and a detect limit was determined to be 60 nM. 15 possessed the ability to visualize lysosomal HNO in cells, and also can be applied to visualize HNO in mice. Soon after, Chen et al continued to develop another two NIR phosphine-based HNO probes 16 and 17 on the basis of 15.[35, 36] 16 and 17 both employed aza-BODIPY moiety as NIR fluorophore, showed high sensitivity with a detect limit of 30 nM, and excellent selectivity toward HNO, and were employed for the bio-imaging of HNO in living cells. Moreover, Sun et al and Yang et al also reported two NIR fluorescent probes 18 and 19 (Figure 4) for HNO by using a merocyanine skeleton as NIR fluorophore.[37, 38] 18 and 19 showed the detect limits of 43 and 60 nM, respectively. 18 can be used for the imaging of lysosomal HNO, while 19 can be applied for the detection of mitochondrial HNO with high specificity. In 2016, our group developed three green to NIR turn-on fluorescent probes 20-22 for the multicolour imaging of HNO in living cells.[39] After the treatment with AS, 20-22 showed three different turn-on fluorescence responses at 490 nm, 635 nm and 710 nm, respectively. 20-22 showed the detect limits of 6.48× 10-7 M, 6.08× 10-7 M and 6.22×10-7 M, respectively. By incubating of cells with these probes 8



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simultaneously, the multicolor imaging of cellular HNO with emission colors from green to NIR was successfully demonstrated. Two-photon microscopy (TPM) is a very attractive technique to visualize biomolecules in living systems, due to the significant advantages of two-photon fluorescence including less photodamage to biosamples, deep tissue penetration, and lower background fluorescence.[40] In 2015, our group reported a two-photon fluorescent probe 23 (Figure 4) for HNO. [41] The probe was designed on the basis of a two-photon dye. Upon treatment of 23 with AS, a remarkable enhancement in fluorescence intensity at 512 nm was observed clearly, and the detect limit was determined to be 5.90×10-7 M. Besides the two-photon imaging of HNO in living cells, 23 also can be employed for the two-photon imaging of HNO in living tissues. Lately, our group developed a two-photon red-emissive fluorescence probe 24 for HNO (Figure 4). [42] 24 itself displayed nearly no two-photon property, while it can show the maximum two-photon action value of about 90 GM after the addition of AS. 24 showed a detect limit of 65 nM, and can be used for the two-photon imaging of exogenous and endogenous HNO in living cells, as well as it can detect HNO in living tissues with a penetration depth of about 90 µm. In 2017, our group and Kim’s group described the mitochondria-targeted turn-on fluorescent probes for HNO (25 and 26), respectively.[43, 44] These two probes both employed triphenylphosphonium as the mitochondria-targeted site. After the treatment of 25 with AS, a significant enhancement (up to 125-fold) in the fluorescence intensity at 545 nm can be observed clearly. 25 and 26 showed the detect limits of 170 nM and 18 nM, respectively. 25 can be applied for the imaging of HNO in mitochondria, as well as the imaging of intracellular formed HNO in living cells. Upon addition of AS to 26 solution, the fluorescence intensity at 452 nm showed a gradual increase. 26 can be applied for the imaging of exogenous and endogenous HNO in the cellular mitochondria. 2.2.2 Phosphine-based ratiometric probes for HNO Taking advantage of intramolecular charge transfer (ICT) mechanism, Zhang et al developed a ratiometric fluorescent probe 27 (Figure 5) for HNO.[45] 27 displays blue-color fluorescence with maximum at 418 nm. Treatment of 27 with AS resulted in the decrease of the fluorescence intensity at 418 nm and the increase of the fluorescence intensity at 546 nm, and showed a detect limit of 0.5 µM. In 2017, the same group reported another ICT-based ratiometric probe 28 (Figure 5) for HNO.

[46]

Upon addition of AS, 28 showed a large red-shifted absorption spectrum of 185 nm, 9


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causing the solution color change from yellow to blue and the turn-on fluorescence response at 614 nm. Additionally, 28 showed a detect limit of 10 nM, and can be employed to the imaging of HNO in living cells. On the basis of a BODIPY-coumarin conjugate system, Zheng et al described a ratiometric HNO probe 29 (Figure 5). [47] 29 showed an intense emission band at 592 nm. After the reaction with AS, the emission at 463 nm gradually increased, and the emission at 592 nm decreased, indicating a ratiometric response with significant emission shift (up to 129 nm) to HNO. 29 showed a detect limit of 2.7×10-7 M, and was employed for the ratiometric imaging of HNO in living cells. Excited state intramolecular proton transfer (ESIPT) mechanism can provide an approach for developing ratiometric probes. Yin et al reported an ESIPT-based fluorescent probe 30 (Figure 5) for HNO.[48] After the treatment of 30 with AS, the fluorescence intensity at 460 nm increased gradually and the fluorescence intensity at 380 nm decreased slowly. 30 displayed a detect limit of 0.98 µM, and was employed for the ratiometric fluorescence detection of HNO in living cells. Zhu et al also reported an ESIPT-based fluorescent probe 31 with a detect limit of 0.128 µM (Figure 5),[49] and applied it for the fluorescence detection of HNO in aqueous solution and serum. Besides ICT and ESIPT mechanisms, Förster resonance energy transfer (FRET) is also a very important mechanism for constructing ratiometric probes. Sun et al reported the first FRET-based ratiometric probe 32 (Figure 5) for HNO.[50] 32 was designed on the basis of a coumarin-fluorescein FRET platform, in which the fluorescein moiety was protected by diphenylphosphino benzoate. Treatment of 32 with AS induced the fluorescence decrease at 470 nm and the fluorescence increase at 517 nm. 32 showed a detect limit of 1.4 µM, and can be used for the imaging of cellular HNO in a ratiometric manner. In combination with the advantages of TPM technique with the ratiometric probe, Tan et al constructed a FRET-based ratiometric two-photon fluorescent probe 33 for HNO (Figure 5).[51] In its FRET system, a two-photon naphthalene fluorophore acted as energy donor, and a rhodol fluorophore was selected as energy acceptor which was modified with a (diphenylphosphino)-benzoate moiety as a response site for HNO. Upon treatment with AS, a new emission at 541 nm appeared, while the emission at 448 nm displayed a decreased tendency, allowing a ratiometric fluorescent response for HNO with a detect limit of 1.9×10-7 M. More importantly, 33 can be employed for the two-photon fluorescence imaging of HNO in living cells and tissues.

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Very recently, Yang et al developed a two-photon ratiometric fluorescence probe 34 (Figure 5) for HNO by employing a benzo[h]chromene-rhodol FRET platform.[52] Upon introduction of AS, two-photon fluorescence at 540 nm increased obviously, and emission at 470 nm decreased gradually. 34 showed excellent sensitivity to HNO with a detection limit of 50 nM, and exhibited high selectivity to HNO over other biologically relevant species. Besides the two-photon ratiometric imaging of cellular HNO, 34 also can be used for visualizing the H2S/NO crosstalk in living cells and tissues.

Figure 5. Structures of phosphine-based ratiometric probes for HNO 3 Conclusion and perspectives Unceasingly discovered physiological and pathological effects of HNO spurred the rapid development of novel probes for the highly sensitive and selective imaging of HNO in biological systems. This review summarizes the recently developed HNO probes based on reduction of Cu(II) to Cu(I) and Staudinger ligation. These probes provide multiple imaging modes including two-photon, NIR and ratiometric imaging. They could pave the path for the deepgoing elucidation of the HNO-mediated mechanisms in physiology. Despite the great advances of HNO probes summarized herein, more eﬀorts are still needed to make them reach their full potential in practical application. First, nearly all of the developed HNO probes concentrate on the imaging of HNO in cells and tissues, instead of animals. Compared with the imaging in animals, visualizing biomolecules 11


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in cells or tissues can only intuitively offer the biomolecular distribution in a short time or in the local range, and may restrict its wide application in the long-term dynamic processes, such as disease progression. Detecting HNO in animals by NIR probes could be an important direction in the next step. Second, these developed probes are unsuitable for real-time monitoring HNO dynamics in living systems, mainly due to their irreversible sensing mechanisms. Reversible HNO probes could become the next generation of fluorescent HNO probes for ultimately settling the mysteries of HNO in biological systems.

■ AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] ORCID: Baoli Dong: 0000-0002-6173-9218 Xiuqi Kong: 0000-0003-0478-7982 Weiying Lin: 0000-0001-8080-4102 Notes: The authors declare no competing financial interest. ■ACKNOWLEDGMENTS This work was supported by NSFC (21472067, 21672083, 51602127), Taishan Scholar Foundation (TS 201511041), and the startup fund of the University of Jinan (309-10004). ■ ASSOCIATED CONTENT Supporting Information: The Supporting Information is available free of charge via the internet at http://pubs.acs.org. Supplemental Table 1.

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