Metal ions play critical roles in numerous fundamental life processes. Hence, there is a great need to effectively monitor and image metal ions. Fluorescent probes are one of the most effective methods for measuring metal ions. In general, according to the different recognition mechanisms of fluorescent probes, they can be divided into two categories: reversible probes and irreversible probes. Among the various fluorophores, rhodamine and fluorescein, as the typical representatives of xanthene, have been paid much attention in biological imaging due to their high absorption coefficient, high fluorescence quantum yield, and water solubility. This review highlights the recent advances on chelation-based xanthene fluorescent probes that have been used for detecting metal ions. The focus has been on the design strategies to improve the selectivity and sensitivity of fluorescent probes by introducing different recognition moieties. Meanwhile, their recognition mechanism and applications are particularly highlighted.
Metal ions play pivotal roles in numerous fundamental life processes (Carter et al. 2014, Properzi and Marcantoni 2014, Chen et al. 2015, Lee et al. 2015, Singha et al. 2015, Yin et al. 2015, Jung et al. 2016, Zhang et al. 2016b), including osmotic regulation, metabolism, biomineralization, and signaling. There are mainly two kinds of metal ions: (1) biologically essential metal ions, including Ca2+, Fe3+, Zn2+, and Cu2+, should be maintained within a suitable range to guarantee their normal biochemical functions and (2) biologically toxic metal ions, such as Hg2+ and Pb2+, need to be detected with high sensitivity both in vivo and in vitro (Ye et al. 2013, Cui et al. 2015, Qian and Xu 2015). The change of these metal ion concentrations can affect the normal body and physiological functions directly (Figure 1). As a result, the detection and quantitative determination of these metal ions have emerged as the permanent research goal (Ding et al. 2015). Conventional methods, such as atomic absorption spectroscopy, high-performance liquid chromatography, and inductively coupled plasma-mass spectroscopy, have basic limitations in terms of cost, sample processing, and run times, which pose challenges or render them impractical for high-throughput clinical or research purpose. However, fluorescent sensing system has been recognized as one of the most efficient measures to monitor biological events in vitro and in vivo for its low-cost convenient pretreatment, rapid response, high sensitivity, and excellent selectivity (Zhou et al. 2011, Vendrell et al. 2012, Yang et al. 2013a, Li et al. 2014). In addition, when served as the reactant associated with the targeted analyte, it can provide a reliable fluorescent response, which can be detected using a fluorometer or even more conveniently under a portable UV lamp.
Until now, various fluorescent probes have been developed based on a diverse range of fluorophores, such as cyanine, BODIPY, xanthene, coumarin, pyrene, and 1,8-naphthalimide, with different excitation and emission wavelengths (Chen et al. 2012). In general, according to the different recognition mechanisms of these reported fluorescent probes, they can be divided into two categories: reversible and irreversible probes (Kartha et al. 2015, Moon et al. 2016). Reversible probes, usually called chelation-based probes, are typically based on the binding equilibrium between probe molecules and the target, and such processes of the coordination and release of the target result in the occurrence and disappearance of the reversible fluorescence signal. Irreversible probes are typically based on the extent of the chemical conversions between the probe molecules and the target, and such processes of the specific chemical reactions result in the fluorescence signal change, and the altered signals are maintained.
Rhodamine and fluorescein, as the typical representatives of xanthene, have been paid much attention in biological imaging due to their high absorption coefficient, high fluorescence quantum yield, and water solubility (Kim et al. 2008, Chen et al. 2010). Their carboxyl group can be easily converted to the spirolactam or spirolactone moiety, which could be used as a molecular scaffold to construct an excellent reversible fluorescent probe. Although such spirocyclic derivatives of rhodamine and fluorescein dyes are nonfluorescent, as shown in Figure 2, they will elicit the fluorescence emission via the ring-opening reaction of the corresponding spirocyclic (the spirocyclic C–X bond breaks, X=N, O, S) after the targeted metal ions are added (Shi and Ma 2008, Zhan et al. 2008, Huang et al. 2014b). If the metal ions are removed, the fluorescence signal will be recovered to its original state. Therefore, they have potential applications in detecting metal ions as reversible fluorescence probes. Especially, over the past decade, fluorescent probes based on xanthene have been focused on detecting those metal ions in living systems (Kikuchi 2010, Hayashi and Okamoto 2013, He et al. 2015). These efforts have uncovered many promising probes that have important applications (Li et al. 2015a, Lin et al. 2015, Tang et al. 2015, Fernandez and Vendrell 2016).
In addition, many researchers make an effort to the design strategies in developing a variety of highly selective and sensitive fluorescent probes that are of good applicability to biological systems. Generally speaking, for the probes derived from rhodamine B and 6G, the modification of molecules is most commonly concentrated on the N-terminus of spirolactam commonly, which could be linked to various receptors for metal ions. In contrast, the corresponding modification is most commonly concentrated on the hydroxyl group of the fluorescein derivate. Therefore, the aim of this review is to highlight the advances on xanthene-based fluorescent probes for metal ions, which cover mostly works published since 2011.
Xanthene fluorescent probes with the Schiff base structure
The most representative example of fluorescent probes based on xanthene for Cu2+ was reported by Czarnik’s group in 1997, which attracts a great deal of attention (Dujols et al. 1997). Schiff base structural motif, a good ligand, can be used for the identification of metal ions and quantitative analysis of the content of metal ions because of the electron-rich property. Hydrazone compounds, a kind of Schiff base compound obtained by modified hydrazide compound, have better biological activity and lower toxicity to organisms. As a result, based on previous work, lots of xanthene hydrazone probes are designed, improved, and synthesized by introducing different aldehydes or ketones.
Probes for Cu2+
Most of the xanthene hydrazone probes could be applied in the identification of Cu2+ because of the good affinity of nitrogenous and oxygenous recognition moiety to Cu2+ according to the soft-hard acid-base theory. Copper ions, a kind of transition metal ions, play an essential role in a variety of fundamental physiological processes in organisms ranging from bacteria to mammals, and its distribution is strictly controlled in vivo. On the one hand, excess copper can cause a highly toxic state and lead to serious infant liver damage, such as Wilson’s disease. On the other hand, the loss of copper homeostasis can result in Alzheimer’s disease and Menkes disease. A comprehension of the physiological and pathological functions of Cu2+ in living cells is very significant (Liu et al. 2012b, Ge et al. 2013b, Goswami et al. 2014). Therefore, fluorescent probes for the detection of copper ion have been widely explored. Among them, the most interesting, selective, and sensitive probes are those that are based on xanthene hydrazone (Figure 3).
In 2011, Zhao et al. described the development of a rhodamine chromene-based fluorescence probe 1 to monitor the intracellular Cu2+ level in living HeLa cells, which exhibited a fluorescence response toward Cu2+ under physiological conditions with high sensitivity and selectivity (Liu et al. 2011). The fluorescence intensity was significantly increased by about 40-fold with 10 equivalents of added Cu2+. The data from Job’s method exhibited a maximum absorbance when the molecular fraction of 1 was close to 50%, which also suggests a 1:1 stoichiometry for the 1-Cu2+ complex (Figure 4).
In the same year, a new probe 2 based on the spirolactam form of rhodamine 101 hydrazone was reported by Xie’s group, which exhibited a highly selective and sensitive response toward Cu2+ in aqueous solutions (Xie et al. 2011). The structural rigidity introduced by multiple n-propylene bridges of rhodamine 101 moieties can shift the absorption and emission maxima to longer wavelengths, with higher molar extinction coefficients and higher quantum yields compared to rhodamine B. The fluorescence of probe 2 can be detected in a low concentration (2×10−6 mol/l) of Cu2+. The results revealed that probe 2 is a good colorimetric probe to Cu2+ in the red region (Figure 5).
8-Hydroxyquinoline-based ligands with extended conjugated fluorophores can form luminescent chelates with a number of metal ions. Therefore, a novel rhodamine-quinoline derivative-based probe 3 was designed and synthesized by Feng et al. which exhibited highly selective and sensitive colorimetric and “turn-on” fluorescent responses toward Cu2+ ions in aqueous solution (Feng et al. 2012). The good linear relationship was easily obtained from the fluorescence changes and the concentrations in the range of 20–120 mm. The fluorescence change was remarkable for the Cu2+ ion detection even in the presence of other metal ions, such as Ca2+, Cd2+, Co2+, Hg2+, Ni2+, Zn2+, Ba2+, Mg2+, and Pb2+.
In 2012, a new probe 4 based on rhodamine B with 1,2,4-triazole as subunit was synthesized and characterized by Zhang (Zhang et al. 2012). Because of the 1,2,4-triazole subunit containing lone electron pairs on N, the semirigid ligand could effectively chelate Cu2+ according to the ionic radius and limit the geometric structure of the complex. Probe 4 exhibited high selectivity and sensitivity for Cu2+ in ethanol/water (6:4, v/v) of pH 7.0 HEPES buffer solution and underwent ring opening mechanism, and a 2:1 metal-ligand complex was formed. Probe 4 displayed a linear response to Cu2+ in the range between 1.0×10−7 and 1.0×10−6m with a detection limit of 4.5×10−8m. Its capability of biological application was also evaluated and the results showed that probe 4 could be successfully employed as a Cu2+-selective probe in the fluorescence imaging of living MCF-7 cells (Figure 6).
Zhao et al. described the development of a rhodamine chromene-based “turn-on” fluorescence probe 5 to monitor the intracellular Cu2+ level in living cells (Liu et al. 2012a). The new fluorescent probe with a chlorine group in chromene moiety exhibited good membrane-permeable property because the predicted lipophilicity of the present probe is strong, and a fluorescence response toward Cu2+ under physiological conditions with high sensitivity and selectivity facilitates the naked-eye detection of Cu2+ (Figure 7). The fluorescence quantum yield of 5 with 15 equivalents of Cu2+ was 0.26 at an excitation wavelength of 530 nm, which was higher than what was previously reported. The results showed a linear response range covering a concentration range of Cu2+ from 0.1×10−5 to 7.0×10−5m and the correlation coefficient R is 0.9896. The detection limit was 2.3×10−7m. The fluorescence intensity was remarkably increased upon the addition of Cu2+ within 1 or 2 min, whereas the other 16 metal ions (Na+, Mg2+, Al3+, K+, Ca2+, Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Hg2+, Zn2+, Ba2+, Pb2+, Ag+, and Cd2+) caused no significant effect.
In 2013, Thennarasu et al. reported two new rhodamine-indole conjugates 6 and 7 (Chereddy et al. 2013b). They have provided evidence to show that both the sensitivity and the selectivity of probes 6 and 7 were tunable by choosing appropriate solvent systems. Compared to probe 6, probe 7 had higher selectivity and sensitivity for Cu2+ and had excellent stability in physiological pH conditions. The limit of detection of Cu2+ (3×10−8m) was lower than the values reported for several other rhodamine-based Cu2+ probes. Moreover, probe 7 is not toxic up to ~10 mm and can be used for the detection of Cu2+ in live fibroblast cells. To explore the importance of the chelating ring size, nature, and orientation of coordinating atoms in the metal ion selective complex formation, they further synthesized three fluorescent probes 8–10 using a similar strategy (Chereddy et al. 2013a). The electrospray ionization-mass spectrometry (ESI-MS) data of the Cu2+ complexes of probes 8 and 9 suggested a 1:2 stoichiometry for both complexes. However, as the triazole (pKa=0.3) is slightly more basic than pyridine (pKa=5.2), probe 10 containing a triazole group instead of the pyridine group should favor the formation of the 10-Cu2+ complex in a 1:1 stoichiometry. Meanwhile, the interference from Fe3+ ions observed in the cases of probes 8 and 9 was not observed in the case of probe 10. Therefore, probe 10 is highly selective toward Cu2+, forms a 1:1 Cu2+-complex, and allows the spectrometric as well as naked-eye detection of Cu2+ in aqueous and biological samples. It is useful for the detection of intracellular Cu2+ levels in live keratinocyte cells because probe 10 is stable at physiological pH and is nontoxic to NIH 3T3 cells at low concentrations (Figure 8).
Based on the FRET mechanism, Das et al. have synthesized a new indole functionalized rhodamine probe 11, which binds to Cu2+ with visually observable changes in their electronic and fluorescence spectral behavior (Kar et al. 2013). Probe 11 emitted only weak fluorescence at 490 nm when excited at 340 nm, whereas it resulted in a decrease in the fluorescence intensity at 490 nm and an increase in the fluorescence intensity at 587 nm upon the addition of Cu2+ to a solution containing 11 (Figure 9). These spectral changes are significant enough in the near-infrared (NIR) and visible regions of the spectrum and thus enable naked-eye detection. The spectral change is due to the formation of the 11-Cu complex and the deprotonation of the indole unit occurs simultaneously with the addition of Cu2+. The apparent binding constant for the formation of 11-Cu complex was calculated by considering a 1:1 binding stoichiometry. Studies manifested that 11-Cu complex is selective and fully reversible in the presence of sulfide anions. As determined by confocal fluorescence microscopy, probe 11 could also be used as an imaging probe for the detection of Cu2+ in HeLa cells.
In 2013, Long et al. developed a rhodamine-based fluorescent probe 12 for Cu2+ bearing the 8-hydroxyquinoline unit (Wang et al. 2013). Probe 12 formed a 1:1 complex with Cu2+ by cooperating the O and N of the 8-hydroxyquinoline unit and carbonyl O and N of rhodamine hydrazide unit. Therefore, it exhibited favorable features, including reversibility, high sensitivity with a large fluorescence enhancement (80-fold) and a low detection limit of 0.19 μm, high selectivity for Cu2+ over other heavy and transition metal (HTM) ions in Tris-HCl/ethanol (7:3, v/v, pH 7.4), working well at physiological pH, and good cell membrane permeability. Finally, probe 12 can be applied in the imaging of Cu2+ in living cells (Figure 10).
Tang et al. (2013) reported the synthesis and photophysical properties of a new rhodamine B-based probe 13, which exhibited high selectivity, sensitivity, and rapid recognition behavior toward Cu2+ via colorimetric and fluorescent detection mode. The detection limit of probe 13 was evaluated to be 7.96×10−8m. The Cu2+ recognition process is reversible and barely interfered by other coexisting metal ions, including Hg2+, Ag+, Pb2+, Sr2+, Ba2+, Cd2+, Ni2+, Co2+, Fe2+, Fe3+, Mn2+, Cu2+, Zn2+, Al3+, Cr3+, Mg2+, K+, and Na+.
In 2014, Dong et al. synthesized a novel rhodamine fluorescent probe 14 by reacting rhodamine B hydrazide with 3-bromo-5-methylsalicylaldehyde, which has been developed as a new colorimetric probe for the selective and sensitive detection of Cu2+ (Zhang et al. 2014). Experimental results indicated that probe 14 can provide a rapid, selective, and sensitive response to Cu2+ with a linear dynamic range from 0.667 to 240 μmol/l. Common interferential ions did not show any interference on Cu2+ determination. It was anticipated that probe 14 can be a good candidate probe and has potential applications for Cu2+ determination. Besides, the proposed probe 14 exhibited the following advantages: a quick, simple, and facile synthesis (Figure 11).
In 2015, an “off-on” rhodamine-based fluorescent probe 15 for the selective detection of Cu2+ has been designed and synthesized by Mao et al. which showed a highly Cu2+-selective fluorescence enhancement response in an aqueous pH 7 (Mao et al. 2015). Under optimum conditions, the increase of fluorescence intensity was linearly proportional to the concentration of Cu2+ over a wide range, and the limit of detection was 29 nm. The study indicated that a 1:1 stoichiometry complex was obtained by the copper ion chelated with vanillin-O, carbonyl-O, and rhodamine 6G hydrazide-N (Figure 12). Therefore, the present method could be applied for the analysis of Cu2+ in an aqueous system.
Yang et al. reported a damantane-modified salicylrhodamine B and β-cyclodextrin-modified Fe3O4@SiO2 assembled by host-guest interactions, which induced novel inclusion complex magnetic nanoparticles (SFIC MNPs) colorimetric sensitive for Cu2+ (Zhang et al. 2015b). Probe 16 exhibited a clear color change from colorless to pink selectively and sensitively with the addition of Cu2+ in the experiments of UV-visible spectra, and the detection limit was measured up to 5.99×10−6m in solutions of CH3CN/H2O (1:10). The SFIC MNPs were superparamagnetic according to magnetic measurements and could be separated and collected easily with a commercial magnet in 9 s. In addition, microspheres have also shown a good ability of separating for other ions from aqueous solutions due to a large number of hydroxyl groups on the surface (Figure 13).
Levels of lysosomal copper are closely related to the human body. However, there is one major limitation of detection methods for monitoring dynamic changes in copper pools that are unable to diagnostically assess the influence of copper accumulation on health status. Fortunately, Yang et al. reported a rhodamine fluorescent probe 17 activated by the presence of lysosomal Cu2+ in 2015 (Li et al. 2015b). Upon activation by lysosomal acidic pH, probe 17 bound with Cu2+ by spiropyran-based proton activation, promoting rhodamine ring-opening, which showed a “switched on” fluorescence signal (Figure 14). This strategy resolved some common challenges of chemical probes in biosensing, such as spatial resolution in cell imaging, solubility and stability in biological system, and interference from intracellular species. The new design, allowing one to track on a location-specific basis and visualizing lysosomal Cu2+, could offer a potentially rich opportunity to examine copper physiology in both healthy and diseased states.
In 2016, a new rhodamine probe 18 with a high selectivity for Cu2+ was synthesized by Wang et al. (Zhang et al. 2016a). The analytical results obtained by UV-vis and fluorescence spectrophotometry show that the linear range of probe 18 for Cu2+ is 0.50–20.00 and the limit of detection is 0.11 μm. The 1:1 stoichiometric structure between probe 18 and Cu2+ could be formed because the copper ions are cooperated with the O atom of introduced moiety, O atom of carbonyl, and N atom of rhodamine B hydrazide. Meanwhile, it can be easily seen by the naked eye that the pink color of a 18-Cu2+ solution immediately disappeared after the addition of excess sodium EDTA, with the fluorescence intensity returning to the original state. Probe 18 can be employed as a reversible fluorescent probe for Cu2+ in drinking water and living HeLa cells.
In 2013, our group reported three new rhodamine Schiff base probes 19–21 (Yang et al. 2013b). The probes displayed remarkably Cu2+-selective orange fluorescence and pink color switch over a wide range of tested metal ions in ethanol-PBS (5/5, v/v, pH 7.4) solution. Job’s method was applied to study the binding stoichiometry of 19 and Cu2+. The 2:1 stoichiometry is the binding mode of the probe and Cu2+ because the introduced cinnamyl aldehyde has no heteroatom. The coordination was also investigated to be a reversible process because the fluorescence disappeared when excess ethylenediamine was added to the colored solution of complex. Confocal laser scanning microscopy experiments revealed that the probes demonstrated the value for sensitive and selective detection of intracellular Cu2+ in living HeLa cells (Figure 15).
The above-mentioned strategy was subsequently extended that we have conducted comprehensive studies to explore the structure-property relationships of these probes 19–27, which contain differently substituted cinnamyl aldehyde with a C=N Schiff base structural motif (She et al. 2016). Extensive work has been focused on the structure-property relationships of this probe model and has investigated the change of optical properties caused by different electronic effects and steric effect of the recognition group. More importantly, density functional theory (DFT) calculation simulates the ring-closed and ring-open forms of these modular Schiff base Cu2+ fluorescent probes. In addition, confocal laser scanning microscopy experiments suggested that all the probes would be a powerful tool for the sensitive and selective detection and mapping of Cu2+ adsorbed in environmental microbial systems. This approach provides a significant strategy for studying structure-property relationships and guiding the synthesis of probes with various optical properties (Figure 16).
Probes for detecting Hg2+
To date, probes containing Schiff base structural motif have been developed successfully to detect Cu2+. Therefore, there is a series of xanthene thiohydrazone probes that would be applied in detecting Hg2+ when the carbonyl oxygen atom is replaced by sulfur atom. Mercury ion is one of the most toxic metal ions. Mercury overload can cause serious damage to the brain, nervous system, endocrine system, and even the kidneys because of its toxic effects. Based on the soft-hard acid-base theory, Hg2+ is a representative example of soft acid and sulfur is a soft base. Therefore, a sulfur-based functional group must be a good candidate as the S is strong binding site for Hg2+. Based on the above reasons, xanthene thiohydrazone probes, where the carbonyl oxygen atom is replaced by sulfur atom, were designed and synthesized (Figure 17).
In 2011, a novel fluorescent probe 28 has been reported by Jiang to detect Hg2+ in aqueous buffer solution, which demonstrated high selectivity for sensing Hg2+ with about 383-fold enhancement in fluorescence emission intensity and micromolar sensitivity (Kd=7.5×10−6 mol/l; Wang et al. 2011a). In addition, in the presence of other metal ions, such as alkali and alkaline earth metal ions (K+, Na+, Mg2+, and Ca2+) and other transition metal ions (Mn2+, Ni2+, Co2+, Cu2+, Zn2+, Cd2+, Ag+, Pb2+, Cr3+, and Fe3+), there was no evident fluorescence intensity enhancement because Hg2+ could be distinguished from other metal ions. Probe 28 is cell permeable and can visualize the changes of intracellular mercury ions in living cells using fluorescence microscopy (Figure 18).
In the same year, Yang et al. reported a novel rhodamine-based highly sensitive and selective colorimetric “off-on” fluorescent probe 29 for Hg2+ ions designed and prepared using the well-known thiospirolactam rhodamine chromophore and furfural hydrazone as signal-reporting groups (Wang et al. 2011b). The photophysical characterization and Hg2+-binding properties of probe 29 in neutral N,N-dimethylformamide (DMF) aqueous solution were also investigated. The signal change of probe 29 was based on a specific metal ion-induced reversible ring-opening mechanism of the rhodamine spirolactam. The response of probe 29 for Hg2+ ions was instantaneous and reversible. Moreover, this probe is applied for in vivo imaging in rat Schwann cells to confirm that it can be used as a fluorescent probe for monitoring Hg2+ in living cells with satisfying results, which further demonstrates its value of practical applications in environmental and biological systems (Figure 19).
Also in 2011, a novel fluorescent probe 30 based on rhodamine has been designed and synthesized by Li et al. for the detection of Hg2+ ions, which exhibited high sensitivity and selectivity over other metal ions (K+, Na+, Ca2+, Mg2+, Ba2+, Zn2+, Cd2+, Cu2+, and Pb2+) in aqueous solution and living cells (Wang et al. 2011c). Upon the addition of increasing concentrations of Hg2+, a new emission band peaking at 555 nm appeared and developed, which could be ascribed to the delocalized xanthene moiety of rhodamine group. The fluorescence response of probe 30 to other metal ions under the same condition was also investigated. There was no significant spectral change of probe 30 observed. It indicated that probe 30 could recognize Hg2+ from other metal ions even those that exist in high concentrations.
In 2012, Zhang et al. had a significant innovation in a new fluoroionphore-ionic liquid hybrid-based strategy to improve the performance of classic fluoroionphores via a synergistic extraction effect and realize simultaneous instrument-free detection and removal of heavy metal ions (HMIs; Jin et al. 2012). Hg2+ was chosen as a model HMI, and a rhodamine thiospirolactam was chosen as a model fluoroionphore to construct bifunctional fluoroionphore-ionic liquid hybrid probe 31. The novel strategy provided a general platform for the highly sensitive detection and removal of various HMIs in aqueous samples and held promise for environmental and biomedical applications (Figure 20).
In 2013, Zhou et al. reported a novel rhodamine-pyrene-conjugated probe 32, which exhibited lower detection limit, shorter response time, and advantageous reversibility (Chu et al. 2013). On the gradual addition of Hg2+ to a solution of probe 32, a new fluorescence emission band centered at 594 nm appeared, which was due to the ring opening of the rhodamine thiospirolactam. Subsequently, the emission band changed with a blue shift in the maximum to 582 nm, which might be accounted for the intermolecular electron transfer between probe 32 and Hg2+. Upon interaction with Hg2+, the result showed a 1:1 stoichiometry for the Hg2+ complex accompanied with a weakened fluorescence resonance energy transfer (FRET) behavior. Moreover, probe 32 could be well applied in the water sample for the detection of Hg2+.
A novel probe 33, 3′,6′-bis(diethylamino)-2-((2,4-dimethoxybenzylidene)amino)spiro[isoindoline-1,9′-xanthene]-3-thione, was designed and synthesized in 2013 by Gao et al. (Liu et al. 2013). Probe 33 displayed highly selective and sensitive recognition of Hg2+. Adding mercury ions into the aqueous solution, its fluorescence intensity was enhanced significantly, whereas its color was changed from colorless to pink. Therefore, a new fluorescence method of detection of Hg2+ was proposed. Satisfying results were obtained when the probe was applied in detecting Hg2+ in tap water, river water, and soil samples (Figure 21).
In 2014, Han et al. synthesized 2-carboxybenzaldehyde rhodamine B thiohydrazine, a fluorescent probe 34, to recognize Hg2+ in DMF/H2O (1:9, v/v) solution with high selectivity (Han et al. 2014). Most importantly, probe 34 could be employed to monitor Hg2+ in living cells using fluorescent imaging technique with satisfied results.
Emrullahoglu et al. described in 2014 the design and synthesis of a molecular probe 35 based on a rhodamine/BODIPY platform that displayed differential fluorescence responses toward Hg2+ and Au3+ and demonstrated its utility in intracellular ion imaging (Karakus et al. 2014). It exhibited a dual emission mode for the detection of Au3+ and a single emission mode for the detection of Hg2+ (Figure 22).
In the same year, a rhodamine-based optical probe 36 has been developed for the selective detection of Hg2+ in aqueous solution as well as in living cells by Guo et al. (Aydin et al. 2014). Live cell confocal imaging study demonstrates that probe 36 is also capable of imaging the presence of Hg2+ ions as well as its dynamic changes in live cells (Figure 23).
A core-shell structured inorganic-organic hybrid nanocomposite for Hg(II) sensing and removal was designed and fabricated in 2015 by Yang, where the core was composed of superparamagnetic Fe3O4 and the shell consisted of molecular silica sieve MCM-41 (Jiqu and Qixia 2015). A rhodamine-derived probe 37 was grafted onto the backbone of MCM-41 through a silane coupling reagent to control its loading content. This probe functionalized core-shell structure was confirmed and characterized by X-ray diffraction (XRD) analysis, electron microscopy images, IR spectra, thermogravimetry, and N2 adsorption/desorption isotherms. It was found that the emission of this composite increased with increasing Hg2+ concentrations but was immune to other metal ions, showing good selectivity and high sensitivity toward Hg2+ ions. A linear Stern-Volmer curve was observed with short response time. In addition, this composite possessed good Hg2+ removing and recycling performance (Figure 24).
He et al. focused in 2015 on the Hg2+-sensing behavior of rhodamine-derived probe 38 (Shen et al. 2015). The up-conversion NaYF4 nanocrystals were constructed and applied as the excitation host so that probe 38 could be lightened by the 980 nm excited up-conversion emission, aiming at better probe photostability. The efficient energy transfer between the up-conversion host and the probes was analyzed and confirmed by spectral analysis and emission decay lifetime comparison. It was found that the probe emission linearly increased with increasing Hg2+ where it was immune to other common metal ions, showing emission “turn-on” effect toward Hg2+ with good selectivity. The probe followed a simple complexation stoichiometry of 1:1 with Hg2+ ions (Figure 25).
A new rhodamine B-based fluorescent probe 39 containing pyrene moiety was designed and synthesized by Yao in 2016, which showed a colorimetric and fluorometric sensing ability for Hg2+ with high selectivity over other metal ions (Rui et al. 2016). The binding analysis using Job’s plot suggested 1:1 stoichiometry for the complexes formed for Hg2+. Probe 39 exhibited the linear fluorescence quenching to Hg2+ in the range of 0.3–4.8 μm (λex=365 nm) and 0.3–5.4 μm (λex=515 nm), and the detection limit was 0.72 μm. In addition, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that probe 39 had low cytotoxicity and was successfully used to monitor intracellular Hg2+ levels in living cells (Figure 26).
Xanthene fluorescent probes with amide structure
As the most abundant trace element, iron plays an obligatory role in many biochemical processes at the cellular level. The transfer, storage, and balance of Fe3+ are associated with living organisms. Either its excess or deficiency has a great influence on human and animal health. Iron at high level can lead to the formation of reactive oxygen species (ROS) by the Fenton reaction, which can impair lipids, nucleic acids, and proteins. Cellular toxicity caused by iron has been related to some serious diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. On the contrary, the scarcity of iron can cause anemia and breathing problems (Sahoo et al. 2012). Thus, many fluorescent probes for Fe3+ have been designed and synthesized in recent years (Figure 27).
In 2011, our group introduced benzothiazole moiety for the first time to synthesize a “turn-on” probe 40 based on rhodamine B exhibiting high sensitivity and selectivity toward Fe3+ in methanol solution (Yin et al. 2011). The addition of Fe3+ to the probe solution showed an approximately 193-fold enhancement in the fluorescence intensity at 580 nm when excited at 500 nm. The sensing mechanism was proposed to involve that the addition of Fe3+ induced the N atom of spirolactam to attack the C atom of carbonyl and the ring opening of the spirolactam of rhodamine because Fe3+ coordinates with N atom of benzothiazole of probe 40 by DFT calculations. Thereby, it is formed by the optimized geometry of the 1:1 1-Fe3+ complex. In an additional effort, in 2012, we respectively developed a probe 41 (She et al. 2012) and three probes 42–44 (Yang et al. 2012) based on rhodamine for the detection of Fe3+ and offered high selectivity and sensitivity toward Fe3+ over other metal ions such as Li+, Na+, K+, Ba2+, Ca2+, Cd2+, Mg2+, Co2+, Mn2+, Zn2+, Pb2+, Ni2+, Hg2+, Ag+, Cu+, Cu2+, Fe2+, and Cr3+. These probes have a similar recognition mechanism toward Fe3+ that the coordination of Fe3+ is more inclined to occur at the N atom on the thiazole ring rather than at the O atom of the carbonyl moiety, which also can be supported by IR spectra that the amide carbonyl oxygen was actually not involved in the coordination. In addition, what deserves to be mentioned the most is that the single crystal structure of probe 44-Fe3+ complex fully proved that recognition mechanism (Figure 28A). Upon coordination with Fe3+, probes 41–44 displayed good brightness and fluorescent enhancement. A linear relationship was observed to exist between the relative fluorescence intensity of probes 41–44 and the concentration of Fe3+ in the range of 5–20 μm with a detection limit of 5 μm. Moreover, confocal laser scanning microscopy experiments have proven that probes 41–44 can be applied to monitor Fe3+ in living HeLa cells (Figure 28B).
In 2013, Zhao et al. have developed a new ratiometric fluorescence probe 45 based on rhodamine B and coumarin to monitor Fe3+ with high sensitivity and selectivity (Ge et al. 2013a). Upon the addition of Fe3+ to the aqueous solution of the probe, two fluorescence peaks at 580 and 460 nm were observed, which belong to rhodamine B and coumarin, respectively. This is a novelty design of the ratiometric probe of Fe3+ due to the CHEF process generated along with the PET process suppressed simultaneously. The fluorescence intensity at 580 nm was significantly increased by about 120-fold with 5 equivalents of Fe3+ added in aqueous solution (Figure 29).
In 2014, Qian et al. introduced rigid 8-aminoquinoline moiety and flexible 2-aminopyridine into rhodamine chromophore to synthesize fluorescent probes to evaluate the effect of complexation with cations (Huang et al. 2014a). The experiments demonstrated that probe 46 with rigid 8-aminoquinoline moiety has higher selectivity and sensitivity for monitoring Fe3+ in aqueous solution. In the presence of Fe3+, the O atom of carbanyl group is binding with Fe3+, which promotes aggregation leading to a strong fluorescence at 590 nm. The recognition mode of probe 46 with Fe3+ was proven to be 2:1 on account that Fe3+ is bonded with quinolyl N and carbonyl O, which is concluded from Job’s plot, 1D and 2D COSY H-H experiments (Figure 30). Finally, in vivo imaging demonstrated that probe 46 could be successfully applied as a bioimaging agent for monitoring Fe3+ in living cells.
Based on our previous work, in 2015, we presented two rhodamine-based probes 47 and 48 for the specific monitoring of Fe3+ in cellular systems with sufficient high selectivity and sensitivity (Ma et al. 2015). The fluorescence intensities were shown to be linearly related to the concentration of Fe3+ in the range of 0.9–20 μm for probe 47 and 5.0–20 μm for probe 48. In addition, probe 47 was also found to be more sensitive with a detection limit of 0.9 μm than the 5.0 μm limitation of probe 48, indicating the superior properties of probe 47. A feasible mechanism was proposed that Fe3+ cooperated with the O atom of carbonyl and N atom of amide in the probe to form the 1:1 complexes. The titration of the complexes with ethylenediamine was also presented to determine the reversible nature of the binding process. This phenomenon likely resulted from the removal of Fe3+ from the binding complexes, resulting in the reconstitution of the spirolactam ring in the probes, thus indicating the reversible property of the probes. Finally, the obvious fluorescence image obtained from confocal laser scanning microscopy of the detection of Fe3+ in living L929 cells demonstrate that probes 47 and 48 could contribute to significant breakthroughs in understanding the critically important functions of Fe3+ in related cells and biological organs (Figure 31).
Yang et al. developed two probes 49 and 50 exhibiting prominent sensitive and selective response to Fe3+ more than other commonly coexistent metal ions in methanol/water (1:1, v/v) (Yang et al. 2015). The other metal ions include Na+, K+, Ca2+, Cd2+, Mg2+, Co2+, Mn2+, Cu2+, Al3+, Zn2+, Ni2+, Fe2+, Hg2+, and Cr3+. An obvious fluorescent enhancement at about 580 nm was observed in the presence of Fe3+ and accompanied by significant color changes, which can be used for “naked-eye” detection. They studied the mechanism through IR and 1H nuclear magnetic resonance (NMR) spectra, which revealed that the carbonyl oxygen was actually involved in coordination with Fe3+ and accompanied by the opening of the spirolactam ring. Moreover, confocal laser scanning microscopy experiments have proven that the probes were successfully used for fluorescence imaging in HepG2 cells (Figure 32).
Besides, there is a special structure that rhodamine binding with hydroxylamine forms hydroxamate, which has a strong chelation with Fe3+. Fe3+ could remain in many proteins and enzymes because ferrichrome siderophores contain three hydroxamate units as binding sites. The ferrichrome-Fe3+ complex is shown in Figure 33. We can easily find that Fe3+ could be cooperated with the O atoms of hydroxamate. Recently, some “turn-on” fluorescent probes have been developed based on the biomimetic hydroxamate binding unit coupled with rhodamine.
Hu et al. developed an acetyl rhodamine-hydroxamate fluorescent probe 51 to respond to Fe3+ ions (Hu et al. 2011). Upon mixing with Fe3+ in CH3CN/H2O (1:1, v/v), the spirolactam of 51 was opened, which resulted in the dramatic enhancement with 55 equivalents of added Fe3+, both fluorescence and absorbance intensity as well as the color change of the solution. The detection limit of probe 51 for Fe3+ was estimated to be about 7.0×10−8m (S/N≥3), which was sufficiently low for the detection of Fe3+ ions found in many chemical and biological systems. Confocal laser scanning microscopy experiments showed that probe 51 could be used to detect Fe3+ in living cells (Figure 34).
Xanthene fluorescent probes with 2,2-dipicolylamine (DPA) structure
Zn2+ is a biologically essential element that should be maintained within a suitable concentration range in living systems. The disorder of zinc metabolism has been correlated to epilepsy, diabetes, infantile diarrhea, and Alzheimer’s disease because of its significance in many biological processes, for example, neural-signal transmissions and pathology, regulation of metalloenzymes, gene transcription, immune function, and mammalian reproduction. Therefore, there is an increasing demand for highly sensitive and selective analytical methods to detect Zn2+ ion.
Fortunately, a DPA unit can be developed as fluorescent probes for Zn2+ with advantages of tunable emission wavelengths, high selectivity, excellent sensitivity, and good cell permeability. A DPA unit is well known to be a classical receptor for zinc ions, which has been widely used for the design and development of various fluorescent probes for monitoring Zn2+ ion. Importantly, Lippard’s group made a lot of effort in this filed (Chang et al. 2004, Nolan et al. 2004, Woodroofe et al. 2004, Goldsmith and Lippard 2006, Tomat et al. 2008). However, there is a major limit on the application of these small-molecule ratiometric probes in quantifying mobile zinc due to the complex syntheses, small dynamic ranges, and narrow gaps between the wavelengths. To overcome this challenge, subsequent studies on the design of fluorescent probes for zinc ions were performed by Lippard’s group (Figure 35).
In 2014, Lippard et al. reported the synthesis and photophysical properties of probes 52 and 53, which are the first ditopic resorufin-based probes for mobile zinc (Loas et al. 2014). Upon binding with Zn2+, probes 52 and 53 exhibited 14- and 41-fold enhancements of their red fluorescence emission, respectively. The synthetic strategy employed in the design of the ditopic probes offers distinct advantages toward facile structural modifications of both the fluorophore and the Zn2+-binding motifs. An envisioned homologous series will help improve the stability in solution, tune the photophysical and zinc-binding properties, and, of course, advance the understanding of the factors determining spontaneous localization in live cells (Figure 35).
Zhang et al. devised a strategy for repurposing existing intensity-based probes for quantitative applications (Zhang et al. 2015a). Using solid-phase peptide synthesis, they conjugated a zinc-sensitive derivative and a zinc-insensitive 7-hydroxycoumarin derivative onto opposite ends of a rigid P9K peptide scaffold to design a ratiometric fluorescent probe 54 for mobile zinc (Figure 35). Probe 54 could be applied to quantify the mobile zinc in epithelial prostatic cells and showed that both normal and tumorigenic cells maintain buffered mobile zinc levels even when challenged with exogenous zinc. Besides, it was used to measure mobile zinc levels in human seminal plasma and reveal a positive correlation between the total and mobile zinc levels.
Xanthene fluorescent probes with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid moiety (BAPTA) structure
Since Tsien reported the first intracellular calcium sensor (Tsien 1980), BAPTA binding unit has been employed along with a series of fluorophores to construct fluorescent calcium probes. Based on the high selectivity of the BAPTA ligand, an optically controlled Ca2+ probe was developed to mimic natural calcium oscillations (Wu et al. 2011). Probe 55, a spiroamido-rhodamine derivative of BAPTA, underwent cycles of reversible transitions between a colorless closed state and a fluorescent open ring (Figure 36). The closed-state exhibited a high affinity for Ca2+ (Kd=509 nm) with excellent selectivity over Mg2+ (Kd=19 mm). The open isomer had a 350-fold lower Ca2+ affinity (Kd=181 μm), whereas the Mg2+ affinity was not significantly affected (Kd=14 mm).
Although BAPTA is a highly selective ligand for calcium, the sensitivity of probes possessing the moiety still needs to be improved. By considering the NIR response of Si-rhodamine, it was used by Nagano et al. to construct a BAPTA-based Si-rhodamine calcium probe 56 and its cell-permeable derivative 57 (Figure 37; Egawa et al. 2011). Probe 56 displayed red fluorescence at 660–670 nm when it was complexed with calcium ions in MOPS buffer solution containing KCl and ethylene glycol tetracetic acid (pH 7.2). In addition, probe 56 exhibited high selectivity to calcium without interference from other metal ions. Furthermore, its high tissue penetration ability, low background autofluorescence, and phototoxicity suggested that probe 56 is applicable in the biological systems and demonstrated that it could be used in monitoring the action potentials of calcium increase in neuronal cell body. Moreover, probe 57 has high cell membrane permeability to make it useful for multicolor fluorescence imaging of action potentials in brain slices loaded with sulforhodamine 101 and potentially applicable to neuroscience studies.
The concentration change of calcium that is closely correlated to many physiological phenomena and the ability of simultaneously monitoring cytoplasmic calcium and other metal ions or proteins are of importance in studies of biological signaling pathways. Hanaoka et al. designed a series of Si-rhodamine-based calcium probes 58–60 based on a PET mechanism (Figure 37; Egawa et al. 2013). These probes, in which a benzo-amide unit is linked to BAPTA, were employed to study protein-expressing animals and cultured cells. Moreover, fluorescence images of histamine-induced calcium oscillations in HeLa cells using these probes were employed to visualize changes in cytoplasmic calcium concentration.
Conclusion and perspectives
In this review, representative examples of metal ion fluorescent probes based on xanthene reported from 2011 to 2016 were discussed. In particular, the design strategies, recognition mechanism, and application of such fluorescent probes were illustrated. Xanthene, as a molecular scaffold that was employed to design novel probes for the selective recognition of metal ions, have become a very attractive sensing system for intracellular detection. Current efforts on xanthene fluorescent probes have been focused on improving the sensitivity and selectivity, expanding the family of detectable metal ions, developing new sensing mechanisms, and further developing in biochemical and biomedical sciences, clinical medicine, and so on.
Although a large variety of fluorescent probes that have high sensitivity and specificity for the detection of metal ions have been developed, what remains lacking is the practical application of the probes. Because metal ions are very important in living organisms, new probes that are compatible with in vivo imaging are urgently required. Therefore, future efforts in this area need to be addressed in the design of such type of probes that can be successfully employed in detecting and monitoring targeted metal ions in in vivo imaging and in the environment. In addition, more efforts should be directed to the areas of calculation. It is expected that the future development of metal ion probes will become more theory application driven. A rapid development in the research of fluorescent metal ion probes is thus anticipated in the coming years. We hope that this review entices the scientific community into designing ever more highly sensitive and selective fluorescent probes for metal ions and might educate students new to the field as well as provide guidance in the selection of appropriate molecular modes for future applications in the environment and bioimaging.
We thank the National Natural Science Foundation of China (NSFC Grant Nos. 21572177, 21272184, 21103137, and J1210057), the Shaanxi Provincial Natural Science Fund Project (Nos. 2015JZ003 and 2016JZ004), the Xi’an City Science and Technology Project [No. CXY1511(3)], and the Northwest University Science Foundation for Postgraduate Students (Nos. YZZ14052, YZZ15040, YZZ15045, and YZZ15006) for financial support.
Aydin, Z.; Wei, Y.; Guo, M. An “off-on” optical sensor for mercury ion detection in aqueous solution and living cells. Inorg. Chem. Commun.2014, 50, 84–87. Search in Google Scholar
Carter, K. P.; Young, A. M.; Palmer, A. E. Fluorescent sensors for measuring metal ions in living systems. Chem. Rev.2014, 114, 4564–4601. Search in Google Scholar
Chang, C. J.; Jaworski, J.; Nolan, E. M.; Sheng, M.; Lippard, S. J. A tautomeric zinc sensor for ratiometric fluorescence imaging: application to nitric oxide-induced release of intracellular zinc. Proc. Natl. Acad. Sci. U. S. A.2004, 101, 1129–1134. Search in Google Scholar
Chen, X.; Zhou, Y.; Peng, X.; Yoon, J. Fluorescent and colorimetric probes for detection of thiols. Chem. Soc. Rev.2010, 39, 2120–2135. Search in Google Scholar
Chen, X.; Pradhan, T.; Wang, F.; Kim, J. S.; Yoon, J. Fluorescent chemosensors based on spiroring-opening of xanthenes and related derivatives. Chem. Rev.2012, 112, 1910–1956. Search in Google Scholar
Chen, K.; Shu, Q.; Schmittel, M. Design strategies for lab-on-a-molecule probes and orthogonal sensing. Chem. Soc. Rev.2015, 44, 136–160. Search in Google Scholar
Chereddy, N. R.; Korrapati, P. S.; Thennarasu, S.; Mandal, A. B. Tuning copper(II) ion selectivity: the role of basicity, size of the chelating ring and orientation of coordinating atoms. Dalton Trans.2013a, 42, 12873–12877. Search in Google Scholar
Chereddy, N. R.; Janakipriya, S.; Korrapati, P. S.; Thennarasu, S.; Mandal, A. B. Solvent-assisted selective detection of sub-micromolar levels of Cu2+ ions in aqueous samples and live-cells. Analyst2013b, 138, 1130–1136. Search in Google Scholar
Chu, K.-H.; Zhou, Y.; Fang, Y.; Wang, L.-H.; Li, J.-Y.; Yao, C. Rhodamine-pyrene conjugated chemosensors for ratiometric detection of Hg2+ ions: different sensing behavior between a spirolactone and a spirothiolactone. Dyes Pigm.2013, 98, 339–346. Search in Google Scholar
Cui, J.; Li, D.-P.; Shen, S.-L.; Liu, J.-T.; Zhao, B.-X. A simple and effective fluorescent probe based on rhodamine B for determining Pd2+ ions in aqueous solution. RSC Adv.2015, 5, 3875–3880. Search in Google Scholar
Ding, Y.; Tang, Y.; Zhu, W.; Xie, Y. Fluorescent and colorimetric ion probes based on conjugated oligopyrroles. Chem. Soc. Rev.2015, 44, 1101–1112. Search in Google Scholar
Dujols, V.; Ford, F.; Czarnik, A. W. A long-wavelength fluorescent chemodosimeter selective for Cu(II) ion in water. J. Am. Chem. Soc.1997, 119, 7386–7387. Search in Google Scholar
Egawa, T.; Hanaoka, K.; Koide, Y.; Ujita, S.; Takahashi, N.; Ikegaya, Y.; Matsuki, N.; Terai, T.; Ueno, T.; Komatsu, T.; Nagano, T. Development of a far-red to near-infrared fluorescence probe for calcium ion and its application to multicolor neuronal imaging. J. Am. Chem. Soc.2011, 133, 14157–14159. Search in Google Scholar
Egawa, T.; Hirabayashi, K.; Koide, Y.; Kobayashi, C.; Takahashi, N.; Mineno, T.; Terai, T.; Ueno, T.; Komatsu, T.; Ikegaya, Y.; Matsuki, N.; Nagano, T.; Hanaoka, K. Red fluorescent probe for monitoring the dynamics of cytoplasmic calcium ions. Angew. Chem. Int. Ed. Engl.2013, 52, 3874–3877. Search in Google Scholar
Feng, L.; Li, H.; Lv, Y.; Guan, Y. Colorimetric and “turn-on” fluorescent determination of Cu2+ ions based on rhodamine-quinoline derivative. Analyst2012, 137, 5829–5833. Search in Google Scholar
Fernandez, A.; Vendrell, M. Smart fluorescent probes for imaging macrophage activity. Chem. Soc. Rev.2016, 45, 1182–1196. Search in Google Scholar
Ge, F.; Ye, H.; Zhang, H.; Zhao, B.-X. A novel ratiometric probe based on rhodamine B and coumarin for selective recognition of Fe(III) in aqueous solution. Dyes Pigm.2013a, 99, 661–665. Search in Google Scholar
Ge, F.; Ye, H.; Luo, J.-Z.; Wang, S.; Sun, Y.-J.; Zhao, B.-X.; Miao, J.-Y. A new fluorescent and colorimetric chemosensor for Cu(II) based on rhodamine hydrazone and ferrocene unit. Sens. Actuators B Chem.2013b, 181, 215–220. Search in Google Scholar
Goldsmith, C. R.; Lippard, S. J. 6-Methylpyridyl for pyridyl substitution tunes the properties of fluorescent zinc sensors of the Zinpyr family. Inorg. Chem.2006, 45, 555–561. Search in Google Scholar
Goswami, S.; Maity, S.; Maity, A. C.; Maity, A. K.; Das, A. K.; Saha, P. A FRET-based rhodamine-benzimidazole conjugate as a Cu2+-selective colorimetric and ratiometric fluorescence probe that functions as a cytoplasm marker. RSC Adv.2014, 4, 6300. Search in Google Scholar
Han, Z.-X.; Zhu, B.-S.; Wu, T.-L.; Yang, Q.-Q.; Xue, Y.-L.; Zhang, Z.; Wu, X.-Y. A fluorescent probe for Hg2+ sensing in solutions and living cells with a wide working pH range. Chin. Chem. Lett.2014, 25, 73–76. Search in Google Scholar
Hayashi, G.; Okamoto, A. Probe design for the effective fluorescence imaging of intracellular RNA. Chem. Rec.2013, 13, 209–217. Search in Google Scholar
He, X. P.; Zang, Y.; James, T. D.; Li, J.; Chen, G. R. Probing disease-related proteins with fluorogenic composite materials. Chem. Soc. Rev.2015, 44, 4239–4248. Search in Google Scholar
Hu, Z.-Q.; Feng, Y.-C.; Huang, H.-Q.; Ding, L.; Wang, X.-M.; Lin, C.-S.; Li, M.; Ma, C.-P. Fe3+-selective fluorescent probe based on rhodamine B and its application in bioimaging. Sens. Actuators B Chem.2011, 156, 428–432. Search in Google Scholar
Huang, J.; Xu, Y.; Qian, X. Rhodamine-based fluorescent off-on sensor for Fe3+ in aqueous solution and in living cells: 8-aminoquinoline receptor and 2:1 binding. Dalton Trans.2014a, 43, 5983–5989. Search in Google Scholar
Huang, Y.; Wang, M.; She, M.; Yang, Z.; Liu, P.; Li, J.; Shi, Z. Recent progress in the fluorescent probe based on spiro ring opening of xanthenes and related derivatives. Chin. J. Org. Chem.2014b, 34, 1–25. Search in Google Scholar
Jin, Z.; Xie, D. X.; Zhang, X. B.; Gong, Y. J.; Tan, W. Bifunctional fluoroionphore-ionic liquid hybrid for toxic heavy metal ions: improving its performance via the synergistic extraction strategy. Anal. Chem.2012, 84, 4253–4257. Search in Google Scholar
Jiqu, H.; Qixia, Y. A core-shell structured inorganic-organic hybrid nanocomposite for Hg(II) sensing and removal. Spectrochim. Acta. A Mol. Biomol. Spectrosc.2015, 149, 487–493. Search in Google Scholar
Jung, H. S.; Verwilst, P.; Kim, W. Y.; Kim, J. S. Fluorescent and colorimetric sensors for the detection of humidity or water content. Chem. Soc. Rev.2016, 45, 1242–1256. Search in Google Scholar
Kar, C.; Adhikari, M. D.; Ramesh, A.; Das, G. NIR- and FRET-based sensing of Cu2+ and S2- in physiological conditions and in live cells. Inorg. Chem.2013, 52, 743–752. Search in Google Scholar
Karakus, E.; Ucuncu, M.; Emrullahoglu, M. A rhodamine/BODIPY-based fluorescent probe for the differential detection of Hg(II) and Au(III). Chem. Commun. (Camb.)2014, 50, 1119–1121. Search in Google Scholar
Kartha, K. K.; Sandeep, A.; Praveen, V. K.; Ajayaghosh, A. Detection of nitroaromatic explosives with fluorescent molecular assemblies and pi-gels. Chem. Rec.2015, 15, 252–265. Search in Google Scholar
Kikuchi, K. Design, synthesis and biological application of chemical probes for bio-imaging. Chem. Soc. Rev.2010, 39, 2048–2053. Search in Google Scholar
Kim, H. N.; Lee, M. H.; Kim, H. J.; Kim, J. S.; Yoon, J. A new trend in rhodamine-based chemosensors: application of spirolactam ring-opening to sensing ions. Chem. Soc. Rev.2008, 37, 1465–1472. Search in Google Scholar
Lee, M. H.; Kim, J. S.; Sessler, J. L. Small molecule-based ratiometric fluorescence probes for cations, anions, and biomolecules. Chem. Soc. Rev.2015, 44, 4185–4191. Search in Google Scholar
Li, X.; Gao, X.; Shi, W.; Ma, H. Design strategies for water-soluble small molecular chromogenic and fluorogenic probes. Chem. Rev.2014, 114, 590–659. Search in Google Scholar
Li, J.; Cheng, F.; Huang, H.; Li, L.; Zhu, J.-J. Nanomaterial-based activatable imaging probes: from design to biological applications. Chem. Soc. Rev.2015a, 44, 7855–7880. Search in Google Scholar
Li, Y.; Zhao, Y.; Chan, W.; Wang, Y.; You, Q.; Liu, C.; Zheng, J.; Li, J.; Yang, S.; Yang, R. Selective tracking of lysosomal Cu2+ ions using simultaneous target- and location-activated fluorescent nanoprobes. Anal. Chem.2015b, 87, 584–591. Search in Google Scholar
Lin, V. S.; Chen, W.; Xian, M.; Chang, C. J. Chemical probes for molecular imaging and detection of hydrogen sulfide and reactive sulfur species in biological systems. Chem. Soc. Rev.2015, 44, 4596–4618. Search in Google Scholar
Liu, W. Y.; Li, H. Y.; Zhao, B. X.; Miao, J. Y. Synthesis, crystal structure and living cell imaging of a Cu2+-specific molecular probe. Org. Biomol. Chem.2011, 9, 4802–4805. Search in Google Scholar
Liu, W. Y.; Li, H. Y.; Lv, H. S.; Zhao, B. X.; Miao, J. Y. A rhodamine chromene-based turn-on fluorescence probe for selectively imaging Cu2+ in living cell. Spectrochim. Acta. A Mol. Biomol. Spectrosc.2012a, 95, 658–663. Search in Google Scholar
Liu, W. Y.; Li, H. Y.; Zhao, B. X.; Miao, J. Y. A new fluorescent and colorimetric probe for Cu2+ in live cells. Analyst2012b, 137, 3466–3469. Search in Google Scholar
Liu, S.; Zhang, L.; Gao, J.; Zhou, J. Synthesis and analytical application of a novel fluorescent Hg2+ probe 3′,6′-bis(diethylamino)-2-((2,4-dimethoxybenzylidene)amino) spiro[isoindoline-1,9′-xanthene]-3-thione. J. Fluoresc.2013, 23, 989–996. Search in Google Scholar
Loas, A.; Radford, R. J.; Lippard, S. J. Addition of a second binding site increases the dynamic range but alters the cellular localization of a red fluorescent probe for mobile zinc. Inorg. Chem.2014, 53, 6491–6493. Search in Google Scholar
Ma, S.; Yang, Z.; She, M.; Sun, W.; Yin, B.; Liu, P.; Zhang, S. Y.; Li, J. L. Design and synthesis of functionalized rhodamine based probes for specific intracellular fluorescence imaging of Fe3+. Dyes Pigm.2015, 115, 120–126. Search in Google Scholar
Mao, J.; Cheng, J.; Wang, X.; Wang, S.; Cheng, N.; Wang, J. A rhodamine-based fluorescent probe for Cu(II) determination in aqueous solution. Luminescence2015, 30, 221–227. Search in Google Scholar
Moon, H.; Park, J.; Tae, J. Fluorescent probes based on rhodamine hydrazides and hydroxamates. Chem. Rec.2016, 16, 124–140. Search in Google Scholar
Nolan, E. M.; Burdette, S. C.; Harvey, J. H.; Hilderbrand, S. A.; Lippard, S. J. Synthesis and characterization of zinc sensors based on a monosubstituted fluorescein platform. Inorg. Chem.2004, 43, 2624–2635. Search in Google Scholar
Properzi, R.; Marcantoni, E. Construction of heterocyclic structures by trivalent cerium salts promoted bond forming reactions. Chem. Soc. Rev.2014, 43, 779–791. Search in Google Scholar
Qian, X.; Xu, Z. Fluorescence imaging of metal ions implicated in diseases. Chem. Soc. Rev.2015, 44, 4487–4493. Search in Google Scholar
Rui, Q. Q.; Zhou, Y.; Fang, Y.; Yao, C. Spirolactone and spirothiolactone rhodamine-pyrene probes for detection of Hg2+ with different sensing properties and its application in living cells. Spectrochim. Acta. A Mol. Biomol. Spectrosc.2016, 159, 209–218. Search in Google Scholar
Sahoo, S. K.; Sharma, D.; Bera, R. K.; Crisponi, G.; Callan, J. F. Iron(III) selective molecular and supramolecular fluorescent probes. Chem. Soc. Rev.2012, 41, 7195–7227. Search in Google Scholar
She, M.; Yang, Z.; Yin, B.; Zhang, J.; Gu, J.; Yin, W.; Li, J.; Zhao, G.; Shi, Z. A novel rhodamine-based fluorescent and colorimetric “off-on” chemosensor and investigation of the recognizing behavior towards Fe3+. Dyes Pigm.2012, 92, 1337–1343. Search in Google Scholar
She, M.; Yang, Z.; Hao, L.; Wang, Z.; Luo, T.; Obst, M.; Liu, P.; Shen, Y.; Zhang, S.; Li, J. A novel approach to study the structure-property relationships and applications in living systems of modular Cu2+ fluorescent probes. Sci. Rep.2016, 6, 28972. Search in Google Scholar
Shen, L.; He, Y.; Yang, X.; Ma, W. The synthesis and mercury-recognizing skill of two emission “turn-on” rhodamine derivatives excited by rare earth up-conversion lattice. Spectrochim. Acta. A Mol. Biomol. Spectrosc.2015, 135, 172–179. Search in Google Scholar
Shi, W.; Ma, H. Rhodamine B thiolactone: a simple chemosensor for Hg2+ in aqueous media. Chem. Commun. (Camb.)2008, 1856–1858. Search in Google Scholar
Singha, S.; Kim, D.; Seo, H.; Cho, S. W.; Ahn, K. H. Fluorescence sensing systems for gold and silver species. Chem. Soc. Rev.2015, 44, 4367–4399. Search in Google Scholar
Tang, L.; Guo, J.; Wang, N. A new rhodamine B hydrazide hydrazone derivative for colorimetric and fluorescent “off-on” recognition of copper(II) in aqueous media. Bull. Kor. Chem. Soc.2013, 34, 159–163. Search in Google Scholar
Tang, Y.; Lee, D.; Wang, J.; Li, G.; Yu, J.; Lin, W.; Yoon, J. Development of fluorescent probes based on protection-deprotection of the key functional groups for biological imaging. Chem. Soc. Rev.2015, 44, 5003–5015. Search in Google Scholar
Tomat, E.; Nolan, E. M.; Jaworski, J.; Lippard, S. J. Organelle-specific zinc detection using Zinpyr-labeled fusion proteins in live cells. J. Am. Chem. Soc.2008, 130, 15776–15777. Search in Google Scholar
Tsien, R. Y. New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures. Biochemistry1980, 19, 2396–2404. Search in Google Scholar
Vendrell, M.; Zhai, D.; Er, J. C.; Chang, Y. T. Combinatorial strategies in fluorescent probe development. Chem. Rev.2012, 112, 4391–4420. Search in Google Scholar
Wang, H.-H.; Xue, L.; Yu, C.-L.; Qian, Y.-Y.; Jiang, H. Rhodamine-based fluorescent sensor for mercury in buffer solution and living cells. Dyes Pigm.2011a, 91, 350–355. Search in Google Scholar
Wang, H.; Li, Y.; Xu, S.; Li, Y.; Zhou, C.; Fei, X.; Sun, L.; Zhang, C.; Li, Y.; Yang, Q.; Xu, X. Rhodamine-based highly sensitive colorimetric off-on fluorescent chemosensor for Hg2+ in aqueous solution and for live cell imaging. Org. Biomol. Chem.2011b, 9, 2850–2855. Search in Google Scholar
Wang, Y.; Huang, Y.; Li, B.; Zhang, L.; Song, H.; Jiang, H.; Gao, J. A cell compatible fluorescent chemosensor for Hg2+ based on a novel rhodamine derivative that works as a molecular keypad lock. RSC Adv.2011c, 1, 1294. Search in Google Scholar
Wang, J.; Long, L.; Xie, D.; Song, X. Cu2+-selective “off-on” chemsensor based on the rhodamine derivative bearing 8-hydroxyquinoline moiety and its application in live cell imaging. Sens. Actuators B Chem2013, 177, 27–33. Search in Google Scholar
Woodroofe, C. C.; Masalha, R.; Barnes, K. R.; Frederickson, C. J.; Lippard, S. J. Membrane-permeable and -impermeable sensors of the Zinpyr family and their application to imaging of hippocampal zinc in vivo. Chem. Biol.2004, 11, 1659–1666. Search in Google Scholar
Wu, L.; Dai, Y.; Marriott, G. Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator. Org. Lett.2011, 13, 2018–2021. Search in Google Scholar
Xie, P.; Guo, F.; Li, C.; Xiao, Y. A new chemosensor based on rhodamine 101 hydrazone for Cu(II) in the red region. Can. J. Chem.2011, 89, 1364–1369. Search in Google Scholar
Yang, Z.; She, M.; Yin, B.; Cui, J.; Zhang, Y.; Sun, W.; Li, J.; Shi, Z. Three rhodamine-based “off-on” chemosensors with high selectivity and sensitivity for Fe3+ imaging in living cells. J. Org. Chem.2012, 77, 1143–1147. Search in Google Scholar
Yang, Y.; Zhao, Q.; Feng, W.; Li, F. Luminescent chemodosimeters for bioimaging. Chem. Rev.2013a, 113, 192–270. Search in Google Scholar
Yang, Z.; She, M.; Zhang, J.; Chen, X.; Huang, Y.; Zhu, H.; Liu, P.; Li, J.; Shi, Z. Highly sensitive and selective rhodamine Schiff base “off-on” chemosensors for Cu2+ imaging in living cells. Sens. Actuators B Chem.2013b, 176, 482–487. Search in Google Scholar
Yang, M.; Meng, W.; Ding, Q.; Su, N.; Liu, X.; Zhang, M.; Yang, B. Novel fluorescent probes based on rhodamine for naked-eye detection of Fe3+ and their application of imaging in living cells. N. J. Chem.2015, 39, 4790–4795. Search in Google Scholar
Ye, H.; Ge, F.; Chen, X.-C.; Li, Y.; Zhang, H.; Zhao, B.-X.; Miao, J.-Y. A new probe for fluorescent recognition of Hg2+ in living cells and colorimetric detection of Cu2+ in aqueous solution. Sens. Actuators B Chem.2013, 182, 273–279. Search in Google Scholar
Yin, W.; Cui, H.; Yang, Z.; Li, C.; She, M.; Yin, B.; Li, J.; Zhao, G.; Shi, Z. Facile synthesis and characterization of rhodamine-based colorimetric and “off-on” fluorescent chemosensor for Fe3+. Sens. Actuators B Chem.2011, 157, 675–680. Search in Google Scholar
Yin, J.; Hu, Y.; Yoon, J. Fluorescent probes and bioimaging: alkali metals, alkaline earth metals and pH. Chem. Soc. Rev.2015, 44, 4619–4644. Search in Google Scholar
Zhan, X. Q.; Qian, Z. H.; Zheng, H.; Su, B. Y.; Lan, Z.; Xu, J. G. Rhodamine thiospirolactone. Highly selective and sensitive reversible sensing of Hg(II). Chem. Commun. (Camb.)2008, 16, 1859–1861. Search in Google Scholar
Zhang, J.; Yu, C.; Qian, S.; Lu, G.; Chen, J. A selective fluorescent chemosensor with 1,2,4-triazole as subunit for Cu (II) and its application in imaging Cu (II) in living cells. Dyes Pigm.2012, 92, 1370–1375. Search in Google Scholar
Zhang, J.; Zhang, L.; Wei, Y.; Chao, J.; Shuang, S.; Cai, Z.; Dong, C. A selectively rhodamine-based colorimetric probe for detecting copper(II) ion. Spectrochim. Acta. A Mol. Biomol. Spectrosc.2014, 132, 191–197. Search in Google Scholar
Zhang, D. Y.; Azrad, M.; Demark-Wahnefried, W.; Frederickson, C. J.; Lippard, S. J.; Radford, R. J. Peptide-based, two-fluorophore, ratiometric probe for quantifying mobile zinc in biological solutions. ACS Chem. Biol.2015a, 10, 385–389. Search in Google Scholar
Zhang, Y.; Wang, W.; Li, Q.; Yang, Q.; Li, Y.; Du, J. Colorimetric magnetic microspheres as chemosensor for Cu2+ prepared from adamantane-modified rhodamine and β-cyclodextrin-modified Fe3O4@SiO2 via host-guest interaction. Talanta2015b, 141, 33–40. Search in Google Scholar
Zhang, B.; Diao, Q.; Ma, P.; Liu, X.; Song, D.; Wang, X. A sensitive fluorescent probe for Cu2+ based on rhodamine B derivatives and its application to drinking water examination and living cells imaging. Sens. Actuators B Chem.2016a, 225, 579–585. Search in Google Scholar
Zhang, W.; Zhu, S.; Luque, R.; Han, S.; Hu, L.; Xu, G. Recent development of carbon electrode materials and their bioanalytical and environmental applications. Chem. Soc. Rev.2016b, 45, 715–752. Search in Google Scholar
Zhou, Y.; Xu, Z.; Yoon, J. Fluorescent and colorimetric chemosensors for detection of nucleotides, FAD and NADH: highlighted research during 2004–2010. Chem. Soc. Rev.2011, 40, 2222–2235. Search in Google Scholar
©2017 Walter de Gruyter GmbH, Berlin/Boston
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.