Letter pubs.acs.org/acssensors
Aromatization of 9,10-Dihydroacridine Derivatives: Discovering a Highly Selective and Rapid-Responding Fluorescent Probe for Peroxynitrite Zhi-heng Li,† Rui Liu,† Zheng-li Tan,† Lan He,§ Zhong-lin Lu,*,† and Bing Gong*,†,¶ †
College of Chemistry, Beijing Normal University, Beijing 100875, China Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States § National Institute for Food and Drug Control, Beijing 100050, China ¶
S Supporting Information *
ABSTRACT: As part of an effort to develop generally applicable strategies for creating probes suitable for detecting important molecular and ionic species, the oxidative aromatization of nonfluorescent 9,10-dihydroacridine derivatives triggered by peroxynitrite (ONOO−) led to the identification of compound 2H, 9-phenyl-9,10-dihydroacridine-4-carboxylic acid, as a rapidresponding fluorescent probe capable of detecting ONOO− with an extraordinary selectivity. Adding a little more than 1 equiv of ONOO− to a solution of 2H resulted in over 100-fold fluorescence enhancement. In sharp contrast, treating 2H with excessive amounts of other oxidants that often interfere with the detection of ONOO− failed to lead to noticeable fluorescence increase. The reaction of ONOO− with 2H shows a similar efficiency in the pH range of 2−8. Low cytotoxicity was observed for 2H and its aromatized product. Bioimaging experiments revealed the promising potential of 2H as a new fluorescent probe for the selective detection of intracellular ONOO−. KEYWORDS: dihydroacridine, aromatization, fluorescent probe, peroxynitrite, rapid-response, high selectivity A number of small-molecule fluorescent probes for detecting ONOO− based on peroxynitrite-triggered reactions have been reported over the last two decades. Early examples of known ONOO− probes include 2,7-dichlorodihydrofluorescein and dihydrorhodamine 123, which could be oxidized to fluorescent products by ONOO−.10 Unfortunately, these two probes suffer from limited selectivity for ONOO−. Subsequent efforts led to the development of probes with improved selectivity and time response; the majority of these probes are based on the release of otherwise quenched fluorescence chromophores by cleaving off11 or modifying12 attached quenchers. One unique approach, based on the formation of a fluorescent aromatic core via two consecutive oxidative steps, the second being specific to ONOO−, led to a selective peroxynitrite probe.13 Other than small molecules, probes for ONOO− based on modified fluorescent proteins, duplex RNAs, and quantum dots have also been reported.14 In spite of the progress made thus far, due to the extremely short half-life (about 10 ms) of ONOO− and the many reaction pathways involving this ion in biological systems,6a,7 developing probes that allow the detection of ONOO− with desired
F
luorescence probes are among the most sensitive and efficient analytical tools featured by simplicity, high temporal and spatial resolutions, and real-time, nondestructive nature, that allow the detection and imaging of very small quantities of chemically, biologically, and environmentally important molecules and ions.1,2 For example, probes that selectively detect nitric oxide (NO) have led to both fundamental understanding and important biomedical applications.3 Since its discovery in 1990,4 peroxynitrite (ONOO−) generated from the diffusion-controlled radical coupling reaction of NO and superoxide5 has been recognized as a powerful in vivo oxidizing and nitrating agent. This biologically important anion, formed intracellularly mainly in the mitochondria,6 react with a variety of biomolecules and is implicated in many pathogenic processes. As a result, ONOO− level provides a central pathogenic indicator for a number of human diseases.7 Recent studies indicate that ONOO− also plays a positive role in the immune system8 and the signal transduction pathways of living cells.9 ONOO− is believed to provide the key to understanding related biological processes and diagnosing relevant diseases. To elucidate the mechanisms by which ONOO− plays its distinctive biological roles, the development of sensitive, selective, and rapid-response detection techniques for this ion is urgently needed. © XXXX American Chemical Society
Received: March 6, 2017 Accepted: March 22, 2017 Published: March 22, 2017 A
DOI: 10.1021/acssensors.7b00139 ACS Sens. XXXX, XXX, XXX−XXX
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ACS Sensors sensitivity, selectivity, and time response still represents a major challenge. As part of our effort to develop generalizable, readily adaptable strategies for creating fluorescence probes for bioimaging applications,15 we report herein the discovery of a highly selective and rapidly responding fluorescent probe, based on the aromatization of a readily available derivative of 9, 10dihydroacridine, compound 2H, for detecting peroxynitrite. Derivatives of acridine provide an important class of fluorescent dyes16 such as acridine organge, acridine yellow, proflavine, and acriflavine. With their extended aromatic core, acridine dyes are fluorescent and have relatively high quantum yields. Compared to acridines, 9,10-dihydroacridines should be much less fluorescent due to the absence of an extended aromatic system. It is known that 9,10-dihydroacridine derivatives, like 1,4-dihydropyridine derivatives,15 undergo aromatization upon being oxidized.17 The ready conversion between derivatives of acridine and 9,10-dihydroacridine and the expected difference in their fluorescent behavior prompted us to explore the possibility of developing fluorescent probes for reactive species that play important roles in biological processes, based on the oxidative aromatization of 9,10dihydroacridine derivatives. Examining the reduction of acridine (Ac) into 9,10dihydroacridine (AcH2, 95%) proceeded smoothly with NaBH4 in ethanol (Scheme 1). Two widely used dyes, acridine
Compounds 1, 2, and 3 were synthesized and reduced into 1H, 2H, and 3H (Supporting Information and Schemes 1 and S1). Dihydroacridines 1H, 2H, and 3H exhibited very good stability when exposed to air and light, suggesting that these dihydro-derivatives are sufficiently stable and thus suitable candidates for being practically useful probes. Compounds 1, 2, and 3 show very different emission intensities (Figure 1A) with that of 2 being the strongest,
Scheme 1. Structures of the Target Molecules
followed by the much weaker emission of 1 and the weakest intensity of 3. Because of the strong emission of 2, we decided to further explore 2H as a possible fluorescence probe for reactive oxygen and nitrogen species based on its oxidative aromatization. As shown in Figure 1B, compound 2H, as expected, is essentially nonfluorescent (Φ = 0.0001). In contrast, compound 2 gives a much stronger emission band (Φ = 0.1667 at 496 nm). The nonfluorescent 2H, along with the fairly strong emission of 2, suggests that the conversion of 2H to 2 could provide an off−on switch for detecting oxidative species. Compound 2H (2 μM) was then screened against a series of reactive oxygen and nitrogen species including 1O2, ·O2−, H2O2, ·OH, NO2−, NO3−, ClO−, NO, and ONOO− (Figure 2A). Among these oxidants, ONOO− (1 equiv), upon mixing with 2H, resulted in a significant fluorescence enhancement over that of the blank. In sharp contrast, treating 2H with 10 equiv of each of the other analytes failed to reveal any fluorescence signal that is noticeably above that of the control (blank). Given that oxidants such as H2O2, ClO−, and ·OH, that may interfere with the detection of ONOO−, did not cause detectable fluorescence enhancement above that of the control at a much higher concentration, the high selectivity of 2H toward ONOO− is extraordinary. Equally intriguing is the fact that ·OH or NO3−, which may result from the hemolysis or isomerization of ONOOH or ONOO−, do not cause any fluorescence enhancement. This suggests that ONOO− oxidizes 2H without going through its decomposed reactive species. A possible mechanism involves an initial one-electron transfer from the N lone pair of 2H to ONOO−, which leads to a cation radical that, upon homolysis of the C9−H bond, completes the aromatization process to give 2 (Figure S26). That the fluorescence species formed from treating 2H (2 μM) with ONOO− (2 μM) was indeed 2 was confirmed by examining the reaction mixture with ESI-HRMS (Figure S27),
Figure 1. Fluorescence emission spectra of (A) compounds 1, 2, and 3 (2 μM/each) and (B) 2 and 2H (2 μM/each). The spectra were measured in PBS buffer (50 mM, pH 7.4, with 0.1% DMSO) at 25 °C (1.0 cm quartz cuvette; slits: 5/5 nm; for 1: λex = 356 nm, λem = 516 nm; for 2: λex = 356 nm, λem = 496 nm; for 3: λex = 360 nm, λem = 580 nm).
orange (3,6-dimethylaminoacridine) and proflavine (3,6diaminoacridine), were chosen as potential candidates for developing fluorescent probes. Monitoring the reduction of either dye indicated that, upon treating with NaBH4 in ethanol, as the reactant disappeared, a new, nonfluorescent species appeared. However, after completion of the reaction, the nonfluorescent product gradually disappeared and a fluorescent species corresponding to the original reactant reappeared. This observation suggests that the reduced products of acridine orange and proflavine do not have the stabilities that are suitable for practical applications. The instability observed for the reduced product of acridine orange or proflavine was likely due to the presence of the dimethylamino or amino groups that enhances the electron richness of, and thus susceptibility toward oxidation by, the dihydro-derivative. Compounds 1, 2, and 3, and the dihydroderivatives 1H, 2H, and 3H (Scheme 1), each of which bears at least one electron-withdrawing group, were designed based on the following reasoning: (1) attaching electron-withdrawing group(s) to the dihydroacridine core should improve the stability of the corresponding derivatives; (2) having substituents placed at positions adjacent to the N atom of the dihydroacridine core may enhance the selectivity of the corresponding derivatives toward different oxidative species; (3) to avoid undesired modification upon oxidation and to also facilitate the aromatization process, a phenyl group is introduced at the 9-position of the acridine or dihydroacridine core. B
DOI: 10.1021/acssensors.7b00139 ACS Sens. XXXX, XXX, XXX−XXX
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ACS Sensors
which a 104-fold enhancement of fluorescence intensity over that of blank was observed. The detection limit of 2H for ONOO− was estimated to be 16 nM under the experimental conditions. The pH values inside different organelles of living cells are known to vary, ranging from 4.5 to 7.4.18 The fluorescence intensities of 2, 2H, and 2H mixed with ONOO− at different pH values were examined (Figure S28). Compound 2H gave a very weak emission from pH 2.0 to 10.0, while 2, or 2H in the presence of ONOO−, showed strong emissions between pH 2.0 and 8.0. These results suggest that compound 2H can serve as a ONOO− probe that functions well in a wide pH range, especially in physiological and weakly acidic environment. Incubating mouse RAW264.7 macrophages with 2 and 2H indicated that >80% cells remain viable when either compound was present at concentrations from 2 to 40 μM (Figure S29), suggesting that 2 and 2H have low cytotoxicity. The feasibility of using 2H to visualize ONOO− in living cells was then evaluated with RAW264.7 macrophages. Cells were first treated with different inducers, and then with probe 2H (5 μM, mixed with 5 μM of dioleoylphosphatidyl ethanolamine, DOPE), followed by incubation for another 15 min. Nitric oxide synthase 2 (NOS2) can be induced by interferon-γ (IFNγ) and lipopolysaccharide (LPS) and result in the generation of intracellular peroxynitrite. The activity of NOS2 can be partially inhibited by aminoguanidine (AG), a NOS inhibitor.19 Extraneous ONOO− can also be produced by adding 3morpholinosydnonimine (SIN-1), a ONOO− donor.20 Besides, hydroxyl radical (·OH) can be produced by the addition of phorbol 12-myristate 13-acetate (PMA).21 As shown in Figure 4, the presence of compound 2 leads to the imaging of cells, while compound 2H alone could not result in any detectable intracellular fluorescence emission. In contrast, strong fluorescence in the green emission channel was observed in 2H-loaded cells in which peroxynitrite was produced either by treating the macrophages with LPS and IFN-γ (Figure 4C), or with added SIN-1 (Figure 4E). However, almost no fluorescence emission was observed with LPS and IFN-γ in the presence of AG (Figure 4D). Very weak or no detectable fluorescence emission was observed with ClO− (Figures 4F), H2O2 (Figure S30A), NO (Figure S30B), and · OH (Figure S30C). These results clearly demonstrate that probe 2H could specific ally detect intracellular ONOO−. In summary, based on its oxidative aromatization, compound 2H has been identified as a highly selective and rapid-response fluorescent probe for peroxynitrite. Along with 2, compound 2H provides a prototype that offers multiple sites for further structural and functional modifications, which should lead to probes with enhanced performance. For example, probes with improved solubility, specific cellular targeting, and ready membrane-permeability can be envisioned by attaching substituents to the carboxyl or the 9-phenyl substituent of 2 and 2H. Such synthetic modification does not involve the acridine or 9,10-dihydroacridine backbone and thus should not alter the reactivity or the fluorescence behavior of the resultant derivatives. Given the ready synthetic availability of acridine derivatives and their convenient reduction into 9,10-dihydroacridines, along with the nonfluorescent nature and the expedient oxidative aromatization of the latter back into the fluorescent acridine derivatives, the approach described in this paper should be generalizable and evolvable to the screening and discovery of fluorescent probes for a variety of biologically or environmentally important reactive oxidative species.
Figure 2. (A) Fluorescence response of 2H (2 μM) to ONOO− (2 μM) and other oxidants (20 μM). Bars represent fluorescence intensity (496 nm) 30 min after addition of oxidants. (1) Blank (2H only); (2) 1O2; (3) ClO−; (4) H2O2; (5) NO; (6) NO2−; (7) NO3−; (8) ·O2−; (9) ·OH; (10) ONOO−. (B) Time-dependent fluorescence intensity response upon adding ONOO− (2 μM, indicated by arrow) to a solution of 2H (2 μM). All data were acquired in PBS buffer (50 mM, pH 7.4, with 0.1% DMSO) at 25 °C. (1.0 cm quartz cuvette, slits: 5/5 nm, λex = 356 nm, λem = 496 nm).
which revealed a dominant peak (m/z = 300.1) given by the [M + H+] ion of 2. In line with the highly favorable aromatization process, a rapid time-dependent change in fluorescence intensity at 496 nm was observed upon adding 1 equiv of ONOO− into a solution of 2H (2 μM) (Figure 2B). The reaction completed within 5 s, with a 74-fold fluorescence enhancement being observed. Treating 2H with ONOO− revealed that fluorescence intensity increased linearly with 0 to 1 equiv of ONOO− (Figure 3) and plateaued beyond ∼1.3 equiv of ONOO−, at
Figure 3. (A) Change in fluorescence intensity (at 496 nm) of the solution of 2H (2 μM) with increasing equivalents concentration of ONOO−. (B) Fluorescence intensity at 496 nm vs concentration of ONOO−. Data for (A) and (B) were acquired in 50 mM PBS, pH 7.4, with 0.1% DMSO, at 25 °C. λex = 356 nm, λem = 496 nm. C
DOI: 10.1021/acssensors.7b00139 ACS Sens. XXXX, XXX, XXX−XXX
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Letter
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ACKNOWLEDGMENTS This work was supported by the Natural Science Foundation of China (21372032 and 91227109), and the US National Science Foundation (CBET-1066947).
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Figure 4. Fluorescence microscopic images of RAW264.7 macrophages loaded with 2 or 2H. Cells were treated with 2 or 2H (5 μM) and mixed with 5 μM of dioleoylphosphatidyl ethanolamine (DOPE) without any inducer for 15 min, or first with different induces and then loaded with probe 2H (5 μM, mixed with 5 μM of dioleoylphosphatidyl ethanolamine, DOPE) for 15 min: (A) 2 only. (B) 2H only. (C) 2H, LPS (1 μg/mL), and IFN-γ (50 ng/mL) for 4 h. (D) 2H, LPS (1 μg/mL), IFN-γ (50 ng/mL), and AG (1 mM) for 4 h. (E) 2H and SIN-1 (1 mM) for 0.5 h. (F) 2H and NaClO (50 μM) for 0.5 h. Scale bars: 50 μm.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssensors.7b00139. Chemical structures, general methods, synthesis and characterization data, scans of original mass spectra, proposed reaction mechanism, ESI-HRMS spectrum of the reaction mixture of ONOO− with 2H, cell viability assays of 2H and 2 (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail: bgong@buffalo.edu. ORCID
Zhi-heng Li: 0000-0002-1077-5278 Bing Gong: 0000-0002-4155-9965 Notes
The authors declare no competing financial interest. D
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DOI: 10.1021/acssensors.7b00139 ACS Sens. XXXX, XXX, XXX−XXX
