Article pubs.acs.org/ac
Photocalibrated NO Release from N‑Nitrosated Napthalimides upon One-Photon or Two-Photon Irradiation Ziqian Zhang,‡ Jiayao Wu,‡ Zhihao Shang,‡ Chao Wang,∥ Jiagao Cheng,§,‡ Xuhong Qian,†,‡ Yi Xiao,*,∥ Zhiping Xu,*,‡ and Youjun Yang*,†,‡ †
State Key Laboratory of Bioreactor Engineering; ‡Shanghai Key Laboratory of Chemical Biology; §Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China ∥ State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning 116024, China S Supporting Information *
ABSTRACT: NO donors are routinely used as the exogenous source in in vitro studies. However, the kinetics or the dose of NO release from the existing donors is not readily monitored. This complicates the elucidation of the involvement of NO in a biological response. We report herein a series of NO donors (NOD545a−g), whose NO release is triggered by UV light at 365 nm or a two-photon laser at 740 nm, and importantly, their NO release is accompanied by a drastic fluorescence turn-on, which has been harnessed to follow the kinetics and dose of NO release in a real-time fashion with spectroscopic methods or microscopic methods in in vitro studies. These merits have rendered NOD545a−g useful molecular tools in NO biology.
N
application are potentially conveniently monitored in a real-time fashion. Also, such a fluorescence based self-calibration mechanism is advantageous for its noninvasiveness and easy implementation to complex matrices. Existing photocalibrated NO donors are limited to a list of nitrosothiols tethered to a fluorophore, with DnsHCysNO as a notable example (Figure 1).52,53 The fluorescence of this donor is quenched via the
itric oxide (NO) donors have been routinely employed as the exogenous source of NO in numerous biomedical studies.1−9 Notable examples include organic nitrates, organic nitrites, metal-nitrosyl complexes, diazeniumdiolates (NONOates), C-/N-/O-/S-/metal-nitroso compounds, (benzo/)furoxans, sydnonimines, and hydroxyamines.10−25 The biological outcome of NO is profoundly influenced by its localization, flux, and dose.26−28 Therefore, it has attracted tremendous attention in developing NO donors, which release NO with a high spatiotemporal control, to facilitate interpretation of the NO involvement in physiological and pathological processes.29−40 However, even the topnotch NO donors (NONOates) are not satisfactory from this perspective.41−50 The decomposition halflives of many NONOates in simple neutral aqueous buffers have been measured to range from 1.3 min of DMA-NONOate to over 300 min of DPTA-NONOate. However, it is not as widely acknowledged as it should be that these values may not necessarily translate to a complex biological milieu, as the pH, polarity, and temperature of the system are presumably different from those parameters of the simple aqueous buffers. Li and Lancaster Jr. proposed the use of the oxymyoglobin (oxyMb) assay to calibrate the NO production from NONOates in biological systems.51 Though straightforward, this method has its limitations. First, it is based on UV−vis absorption spectroscopy and the direct use in a biological system is inconvenient due to the presence of biological background absorption. Also, with this method, nitric oxide is oxidized by oxyMb into nitrate and therefore prohibited from eliciting its biological activity. The difficulties with the calibration of NO release in vitro may be circumvented if the release of NO from a donor is accompanied by a fluorescence turn-on from a dark background. In this scenario, both the NO release kinetics and dose of © XXXX American Chemical Society
Figure 1. Decomposition pathways of DnsHCysNO.
photoinduced electron transfer mechanism (PET)54 and can potentially turn on if free cuprous ion (Cu+) is present in the biological system to catalyze the decomposition of nitrosothiols to release NO and disulfide.55−59 However, its fluorescence may also be erroneously turned on upon spontaneous transnitrosation without release of NO.60−63 We have rationally devised a novel mechanism to allow the release of NO to be triggered by light and accompanied by a drastic fluorescence turn-on to facilitate convenient in vitro quantitation of NO dose. NO release from these donors may be Received: April 23, 2016 Accepted: June 14, 2016
A
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry triggered by one-photon UV irradiation at 365 nm or by a twophoton laser at 740 nm. Importantly, such phototriggered and photocalibrated NO donors are stable to biothiols.
■
RESULTS AND DISCUSSION Electron-withdrawing substituted N-nitrosamines are known to homolyze upon photolysis to yield NO (Figure 2A).64−66 This
Figure 2. (A) The structure of 2° nitrosamine and its photolysis. (B) Pathway of NO release and fluorophore generation upon photolysis of NOD545a−g.
led to the design of N-nitrosated naphthalimides (NOD545a−g) as novel NO donors. Upon phototriggered decomposition, the byproduct, the anilinyl radical, is oxidative and expected to be readily reduced in situ to afford 4-amino naphthalimides (3a−g), which are highly fluorescent and can be used to monitor the dose of NO release (Figure 2B). Donors NOD545a−d differ from each other in the size of the alkyl group (−R2). NOD545a−f and their corresponding naphthalimide products (3a−f) were studied in phosphate buffer (40 mM, pH = 7.4) with DMSO as a cosolvent (20% for NOD545a−d and 1% for NOD545e−g). Donors NOD545e−f bear hydrophilic functionalities, exhibit improved aqueous solubility compared to NOD545a−d, and hence require a lower percentage of DMSO as a cosolvent. The maximum absorption of NOD545a is located at 345 nm with a molar absorptivity of 15 500 cm−1·M−1. NOD545a is essentially nonfluorescent with a diminishing fluorescence quantum yield of 0.0004. Compound 3a displays a red-shifted absorption with a maximum at 450 nm with a molar absorptivity of 18 700 cm−1·M−1. Upon excitation of 3a at 450 nm, an intense emission band with a maximum at 545 nm was observed with a fluorescence quantum yield of 0.26. Therefore, a fluorescence enhancement of up to ca. 800-fold is possible upon photolysis of those donors. The spectral and photophysical properties of other donors (NOD545b−g) and naphthalimides (3b−g) resemble those of NOD545a and 3a and are included in Table S2. Solutions of NOD545a−g (10 μM) in aqueous phosphate buffer (40 mM, pH = 7.4) with DMSO as a cosolvent were prepared. While NOD545a−d requires 20% DMSO, 1% is sufficient for NOD545e−g due to the presence of the hydrophilic group in their structure. These solutions were irradiated with UV light at 365 nm, and UV−vis absorption and fluorescence emission spectral changes were recorded intermittently. Take NOD545a as an example. Irradiation gradually led to disappearance of its absorption band peaked at 345 nm and appearance of the absorption band of 3a at 450 nm (Figure 3A).
Figure 3. Changes of the UV−vis absorption spectra and fluorescence emission spectra of solutions of NOD545a−g upon continuous UV irradiation at 365 nm (A, C, E, G, I, K, and M, respectively). The gradual enhancement of emission intensity at 545 nm of this NOD545a−g (B, D, F, H, J, L, and N) solution is plotted with respect to the duration of UV-irradiation. The slit widths are 2 nm for both excitation and emission.
The appearance of 3a was also monitored using fluorescence emission spectroscopy, with excitation wavelength at 450 nm (Figure 3A). A steady increase of emission of 3a at ca. 545 nm was observed and gradually leveled off (Figure 3B). This B
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry
This experiment further verifies that NO is indeed generated upon phototriggered decomposition of NOD545a. The identity of the fluorescent photodecomposition product from all donors was further confirmed using NMR and mass spectrometry. NOD545a (100 mg) was dissolved in 50 mL of MeOH, and the resulting solution was continuously irradiated with 365 nm light until its complete decomposition as indicated by TLC. The solution was then evaporated to dryness to afford a yellow solid, whose 1H NMR and MS spectra were acquired. The 1 H NMR spectrum of the isolated yellow solid contains only one set of peaks, indicating a clean conversion of NOD545a to a single chemical entity (Figure 5A), whose 1H NMR peaks are in
experiment was in agreement with the proposed decomposition pathway of this series of NO donors (Figure 2B). Phototriggered decompositions of NOD545b−g were also studied (Figure 3B− N). UV-light triggered NO release and fluorophore generation 3b−g from NOD545b−g also occurred smoothly. The fluorescence turn-on from NOD545a is comparatively slower than NOD545b−d, and NOD545g is slower than NOD545e,f (Figures S2 and S3). Both NOD545a and NOD545g have a methyl group attached to the nitrosamine moiety. The release of NO from these donors was confirmed by EPR spectroscopy with PTIO (2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide), with NOD545a as an example. PTIO is a persistent radical and has been routinely used as a spin trap for NO. It can quantitatively oxidize NO into NO2 and is concomitantly reduced to PTI (2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl), which is also a persistent radical (Figure 4A).67 The EPR signal of PTI differs from that of PTIO, and this
Figure 5. Overlay of the 1H-NMR spectra of (A) NOD545a, (B) 3a from independent synthesis, and (C) 3a from UV-triggered decomposition of NOD545a mixed with ca. 10% 3a from independent synthesis.
agreement with the structure of corresponding 3a (Figure 5B). We further acquired the 1H NMR spectrum of the resulting material with authentic 3a (Figure 5C). The presence of only one set of peaks, rather than two sets, further supports the identity of the resulting decomposition product to be 3a. This conclusion is further unambiguously supported by the MS data (not shown). This study further verifies the findings from the UV−vis and fluorescence spectroscopic studies that a clean phototriggered conversion from NOD545a to 3a has occurred. Similarly, we have confirmed that decompositions of other donors are also in agreement with our proposed mechanism (data not shown). Potent radical scavengers, i.e., resveratrol, hydroquinone, or ascorbic acid, were found to significantly accelerate the NO release from this class of NO donors. Their presence has dramatically shortened the duration needed for fluorescence enhancement to saturate. Take NOD545f as an example, its decomposition was completed in ca. 100 s, as compared to ca. 2000 s when those radical scavengers are not present (Figure 6). We propose that, upon photoexcitation, the donor can form an excited-state charge transfer complex with a reducing agent, to
Figure 4. (A) The reaction between PTIO and NO. (B) EPR signal of a solution containing NOD545a (10 μM) and PTIO (10 μM) in aqueous phosphate buffer (40 mM, pH = 7.4) with 20% DMSO. (C) EPR signal of this solution upon photolysis with 365 nm light for 1 min.
spectral change has been used to diagnose the presence of NO. The EPR spectra of a solution containing a stoichiometric amount of both NOD545a (10 μM) and PTIO (10 μM) was collected, and the characteristic signal of PTIO was observed (Figure 4B). Upon irradiation with 365 nm light for 1 min, the EPR signal of the solution changes to Figure 4C. This spectral change confirms that NO has indeed been released upon photoinduced decomposition of NOD545a. The release of NO from NOD545a upon UV-irradiation was also confirmed spectroscopically with a known fluorescence probe, 2,3-diaminonaphthalene.68 NOD545a (10 μM) and DAN (10 μM) were dissolved in neutral phosphate buffer containing 20% DMSO. The solution was then irradiated with UV light at 365 nm. The formation of 3a and NAT was monitored by fluorescence spectroscopy. The formation of compound NAT was monitored by following its emission at 415 nm upon excitation at 360 nm (Figure S4A,B). Formation of compound 3a was monitored by following its emission at 545 nm upon excitation at 450 nm (Figure S4C,D). It is clear that the fluorescence turn-on of 3a and NAT is essentially simultaneous.
Figure 6. Time dependent fluorescence enhancement of a solution of NOD545f (10 μM) in phosphate buffer (40 mM, pH = 7.4) with 1% DMSO, upon irradiation with 365 nm, with or without the presence of various reducing reagents. C
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry
to 40 μM of NOD545f for 24 h. Cell growth was not inhibited (Figure S5), and therefore, NOD545f exhibits minimal dark cytotoxicity, with a LC50 of ca. 48 μM. In vitro quantification of NO release from NOD545 series of donors can be conveniently carried out by microscopic methods, e.g., with a plate-reader in this study. Cells were incubated with different concentrations of 3f, the decomposition product from NOD545f, over a 96-well plate. This establishes the relationship between the fluorescence intensity and concentration of 3f in cell culture and constitutes a calibration curve for in vitro studies, against which doses of NO release can be conveniently estimated (Figure 8). The amount of NOD545f and duration of exposure
facilitate NO release. Tryptophan is comparatively much less effective, while thiols, e.g., glutathione and cysteine, are essentially ineffective. The message from this experiment is that the decomposition profile of a donor collected from a simple chemical system may not translate to a more complex matrix with high fidelity. This strongly demonstrates the advantage of such a fluorescence based calibration method, which can reliably and conveniently follow the flux and dose of NO release, regardless of the nature of medium. The formation of the fluorophore (3a−g) from the corresponding donor (NOD545a−g) is a two-step process, i.e., the homolysis of donor to an anilinyl radical species followed by its reduction. On the basis of the existing experimental results, it is very likely that the rate limiting step is the second step, i.e., reduction of the anilinyl radical. This is supported by both the spin-trapping experiment (Figure 4) and the NO release in the presence of reducing species (Figure 6). Transnitrosation may occur between a nitrosamine and a thiol, as have been noted in the literature.68,69 This would turn on fluorescence unexpectedly and deteriorate the control over NO release. Therefore, the reactivity of donors (NOD545a−g) toward thiols was tested, by stirring with various donors (10 μM) in neutral phosphate buffer (40 mM, pH = 7.4) containing 20% DMSO in the dark for 24 h with representative biorelevant thiols (up to 10 mM, which is the upper limit of physiological GSH), i.e., glutathione (GSH) and sodium sulfide. All donors totally resisted the potential nucleophilic attack from these chemicals (Figure S4). One-photon excitation triggered release of NO and onephoton imaging in vitro. NOD545f was used as an example to showcase the feasibility of these donors for biological applications, considering the fact that it is more soluble in aqueous media than NOD545a−e and its nitroso group is more sterically protected than that of NOD545g. The HeLa cell line is used in this UV-triggered release and one-photon imaging studies. A stock solution of NOD545f in DMSO was added into the cell culture and incubated for 15 min for the donor to diffuse through the cell membrane. Then, cells were washed and imaged with FITC filter sets. Essentially no background signal was observed (Figure 7B). Upon irradiation of the cells with light at 365 nm, green fluorescence emission from 3f was clearly captured with an inverted fluorescence microscope and the fluorescence intensity qualitatively increased with respect to the irradiation time (Figure 7C,D). Cytotoxicity of NOD545f was studied with the MTT assay. HeLa cells were incubated with up
Figure 8. On a 96-plate, HeLa cells were incubated with varying concentration of 3f; averaged fluorescence intensity of each concentration was used to build a calibration curve, against which dose of NO from NOD545f in in vitro studies is easily estimated.
to 365 nm are not necessary to calculate the dose of NO release. We emphasize that it is viable to use 3f to establish a calibration curve for in vitro application, because NOD545s decompose only in one well-defined pathway to yield NO and naphthalimide fluorophore (Figure 5). This method obviously does not extend to the probes bearing multiple decomposition pathways, e.g., fluorophore-labeled nitrosothiols.52,53 We tested the feasibility of our NO donors for two-photon triggered release of NO and for two-photon imaging, also with NOD545f as an example. First, the RAW264.7 cells were incubated with NOD545f (5 μM) for 15 min and were imaged upon excitation by a two-photon laser at 800 nm. Then, a dark image was collected (Figure 9B). We then irradiated the cell culture with a mercury lamp for 1 min and a two-photon image was acquired under the same setting (Figure 9C). Bright fluorescence was observed this time. This experiment suggests that a two-photon laser at 800 nm does not trigger decomposition of NOD545f, while 3f can be excited by a twophoton laser at 800 nm. We then found that a two-photon laser of shorter wavelength (740 nm) can induce decomposition of NOD545f (Figure 9E,F). This offers an alternative phototriggering approach to one-photon irradiation at 365 nm, in case potential cell damage from UV is a serious concern. Another potential advantage of the two-photon excitation is that only donor molecules within the minute volume of the focal point of the two-photon laser are selectively decomposed.70−72 This could serve as a spatio-control mechanism over NO release. In summary, we have developed a novel class of phototriggered NO donors (NOD545s). Their primary advantage over the existing phototriggered NO donors is that a drastic fluorescence turn-on (up to 800-fold) accompanies the release of NO, enabling convenient and reliable quantification of NO release even in complex biological matrices. Also, their
Figure 7. HeLa cells loaded with NOD545f (5 μM). Phase contrast (A) and fluorescence image without photoirradition (B) and with photoirradiation by 365 nm for the indicated duration (C, D). D
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry
Synthetic Scheme, Procedures, and Characterizations. All donors were readily synthesized in gram scale starting from 4bromo-1,8-naphthalic anhydride (1) in a three step cascade (Scheme 1). No tedious chromatographic separation has been Scheme 1. Synthetic Pathway of NOD545a−g
Figure 9. (A) Phase contrast of RAW 264.7 cells with NOD545f at 5 μM. (B) Cells were imaged with a two-photon laser at 800 nm. (C) Cells were irradiated with UV at 365 nm for 1 min and then imaged with a two-photon laser at 800 nm. Emission in the range of 380−560 nm was collected. (D) Phase contrast. (E) Cells were imaged with a two-photon laser at 800 nm. (F) Cells were irradiated with two-photon laser at 740 nm for 1 min and then imaged with a two-photon laser at 800 nm.
involved, and almost all intermediates and products can be purified by crystallization in high yields (Figure 1C). The X-ray crystal structure of NOD545a shows that the oxygen atom of the nitroso group is cis to the methyl group in the solid state (Figure S1). Yet, the NMR spectra indicates that both cis and trans conformations exist when they are in solution in a ratio of ca. 10:1, in agreement with the literature reports.74
decomposition pathway is singular and fully characterized using multiple spectroscopic methods. Third, biological thiols at their physiological concentrations do not induce spontaneous NO release and hence fluorescence turn-on from these donors. Fourth, both one-photon or two-photon excitation may induce their decomposition. Fifth, the resulting naphthalimide fluorophore may be imaged with both regular one-photon microscopy and two-photon microscopy. We have also found that potent biological radical scavengers can catalyze their photodecomposition kinetics. We expect these donors to receive wide applications.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.6b01603. General experimental methods, cell cytotoxicity study, crystal structure of NOD545a, photolysis of NOD545a−g in the presence of reducing agents, resistance of NOD545a−g toward biological thiols, cytotoxicity of NOD545f, and 1H NMR, 13C NMR, and HR-MS spectra (PDF) Crystallographic data of NOD545a in CIF format (CIF)
■
EXPERIMENTAL SECTION Spectroscopic Methods. UV−vis absorption spectra were acquired over a SHIMADZU UV-2600 spectrophotometer. Fluorescence spectra were collected on a PTI-QM4 steady-state fluorimeter, equipped with a 75 W Xeon arc lamp and a model 810 type PMT. The voltage of the PMT was set to 950 V. All spectra were collected with a 1 cm quartz cuvette (3.4 mL). Molar absorptivity was calculated with the Beer−Lambert law with absorption spectra of dilute solutions of each compound (O.D. < 0.05). Fluorescence quantum yields were calculated following literature procedures. 3b with a fluorescence quantum yield of 0.66 in ethanol was used as the reference.73 Cell Culture and Imaging. HeLa Cells and RAW264.7 cells were cultured in DMEM with 10% fetal bovine serum, 1% nonessential amino acids, 1% sodium pyruvate, and 1% penicillin/streptomycin. One-photon fluorescence images were collected on an inverted fluorescence microscope (DMI3000B, Leica) with standard FITC cubic filter sets (ex: 483 ± 15 nm; em: 535 ± 20 nm; dichroic cutoff: 506 nm). Two-photon imaging was carried out over an Olympus FV1000 system. Two-photon decomposition of NO donors was conducted by irradiation with two-photon laser at 740 nm of ∼5 mW. Two-photon fluorescence images were excited at 800 nm and collected at 380−560 nm. Cytotoxicities of NOD545s were studied with the MTT assay following literature procedures. The stock solution of NOD545f (5 mM) in DMSO was pipetted into the cell medium to result in a final concentration of 10 μM in cell medium. The concentration of DMSO in cell medium was 0.1%.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected] Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS The work is supported by the Fundamental Research Funds for the Central Universities (Nos. WY1514053 and WY1516017) and the National Natural Science Foundation of China (NOs. 21236002, 21372080 and 21572061).
■
REFERENCES
(1) Feelisch, M. Naunyn-Schmiedeberg's Arch. Pharmacol. 1998, 358, 113−122. (2) Hogg, N. Free Radical Biol. Med. 2000, 28, 1478−1486.
E
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry
(39) Wecksler, S. R.; Mikhailovsky, A.; Korystov, D.; Ford, P. C. J. Am. Chem. Soc. 2006, 128, 3831−3837. (40) Caruso, E. B.; Petralia, S.; Conoci, S.; Giuffrida, S.; Sortino, S. J. Am. Chem. Soc. 2007, 129, 480−481. (41) Switkes, E. G.; Dasch, G. A.; Ackermann, M. N. Inorg. Chem. 1973, 12, 1120−1123. (42) Hughes, M. N.; Wimbledon, P. E. J. Chem. Soc., Dalton Trans. 1977, 1650. (43) Akhtar, M. J.; Lutz, C. A.; Bonner, F. T. Inorg. Chem. 1979, 18, 2369. (44) Hrabie, J. A.; Klose, J. R.; Wink, D. A.; Keefer, L. K. J. Org. Chem. 1993, 58, 1472−1476. (45) Bettache, N.; Carter, T.; Corrie, J. E. T.; Ogden, D.; Trentham, D. R. In Methods in Enzymology; Packer, L., Ed.; Academic Press: New York, 1996; Vol. 268, pp 266−281. (46) Ramamurthi, A.; Lewis, R. S. Chem. Res. Toxicol. 1997, 10, 408− 413. (47) Schmidt, K.; Desch, W.; Klatt, P.; Kukovetz, W. r.; Mayer, B. Naunyn-Schmiedeberg's Arch. Pharmacol. 1997, 355, 457−462. (48) Dinh, B. T.; Dove, K.; Jappar, D.; Hrabie, J. A.; Morozov, V.; Hrabie, J. A.; Davies, K. M. Nitric Oxide 2005, 13, 204−209. (49) Dinh, B. T.; Price, S. E.; Majul, A.; El-Hajj, M.; Morozov, V.; Hrabie, J. A.; Davies, K. M. Nitric Oxide 2008, 18, 113−121. (50) Tai, L.-A.; Wang, Y.-C.; Yang, C.-S. Nitric Oxide 2010, 23, 60−64. (51) Li, Q.; Lancaster, J. R., Jr. Nitric Oxide 2009, 21, 69−75. (52) Chen, X.; Wen, Z.; Xian, M.; Wang, K.; Ramachandran, N.; Tang, X.; Schlegel, H. B.; Mutus, B.; Wang, P. G. J. Org. Chem. 2001, 66, 6064− 6073. (53) Ramachandran, N.; Root, P.; Jiang, X. M.; Hogg, P. J.; Mutus, B. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 9539−9544. (54) de Silva, A. P.; Gunaratne, H. Q.; Gunnlaugsson, T.; Huxley, A. J.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515− 1566. (55) Dicks, A. P.; Swift, H. R.; Williams, D. L. H.; Butler, A. R.; AlSa’doni, H. H.; Cox, B. G. J. Chem. Soc., Perkin Trans. 2 1996, 481−487. (56) Dicks, A. P.; Williams, D. L. H. Chem. Biol. 1996, 3, 655−659. (57) Williams, D. L. H. Acc. Chem. Res. 1999, 32, 869−876. (58) Stamler, J. S.; Toone, E. J. Curr. Opin. Chem. Biol. 2002, 6, 779− 785. (59) Baciu, C.; Cho, K. B.; Gauld, J. W. J. Phys. Chem. B 2005, 109, 1334−1336. (60) Barnett, D. J.; McAninly, J.; Williams, D. L. H. J. Chem. Soc., Perkin Trans. 2 1994, 1131−1133. (61) Liu, Z.; Rudd, M. A.; Freedman, J. E.; Loscalzo, J. J. Pharmacol. Exp. Ther. 1998, 284, 526−534. (62) Wang, K.; Wen, Z.; Zhang, W.; Xian, M.; Cheng, J. P.; Wang, P. G. Bioorg. Med. Chem. Lett. 2001, 11, 433−436. (63) Perissinotti, L. L.; Turjanski, A. G.; Estrin, D. A.; Doctorovich, F. J. Am. Chem. Soc. 2005, 127, 486−487. (64) Grover, T. A.; Ramseyer, J. A.; Piette, L. H. Free Radical Biol. Med. 1987, 3, 27−32. (65) Piech, K.; Bally, T.; Sikora, A.; Marcinek, A. J. Am. Chem. Soc. 2007, 129, 3211−3217. (66) Tanno, M.; Sueyoshi, S.; Miyata, N.; Umehara, K. Chem. Pharm. Bull. 1997, 45, 595−598. (67) Goldstein, S.; Russo, A.; Samuni, A. J. Biol. Chem. 2003, 278, 50949−50955. (68) Wink, D. A.; Cook, J. A.; Kim, S. Y.; Vodovotz, Y.; Pacelli, R.; Krishna, M. C.; Russo, A.; Mitchell, J. B.; Jourd’heuil, D.; Milesi, A. M.; Grisham, M. B. J. Biol. Chem. 1997, 272, 11147−11151. (69) Williams, D. L. H. Nitrosation Reactions and the Chemistry of Nitric Oxide; Elsevier: London, 2004. (70) Yanagimoto, T.; Toyota, T.; Matsuki, N.; Makino, Y.; Uchiyama, S.; Ohwada, T. J. Am. Chem. Soc. 2007, 129, 736−737. (71) So, P. T. C.; Dong, C. Y.; Masters, B. R.; Berland, K. M. Annu. Rev. Biomed. Eng. 2000, 2, 399−429. (72) Svoboda, K.; Yasuda, R. Neuron 2006, 50, 823−839. (73) Yuan, D.; Brown, R. G.; Hepworth, J. D.; Alexiou, M. S.; Tyman, J. H. P. J. Heterocycl. Chem. 2008, 45, 397−404.
(3) Jensen, M. S.; Nyborg, N. C.; Thomsen, E. S. Toxicol. Sci. 2000, 58, 127−134. (4) Webb, D. J.; Megson, I. L. Expert Opin. Invest. Drugs 2002, 11, 587− 601. (5) Ignarro, L. J.; Napoli, C.; Loscalzo, J. Circ. Res. 2002, 90, 21−28. (6) Al-Sa’doni, H. H.; Ferro, A. Mini-Rev. Med. Chem. 2005, 5, 247− 254. (7) Katsumi, H.; Nishikawa, M.; Hashida, M. Cardiovasc. Hematol. Agents Med. Chem. 2007, 5, 204−208. (8) Huerta, S.; Chilka, S.; Bonavida, B. Int. J. Oncol. 2008, 33, 909−927. (9) Serafim, R. A. M.; Primi, M. C.; Trossini, G. H. G.; Ferreira, E. I. Curr. Med. Chem. 2012, 19, 386−405. (10) Feldman, P. L. Tetrahedron Lett. 1991, 32, 875−878. (11) Feelisch, M.; Schoenafingeri, K.; Noack, E. Biochem. Pharmacol. 1992, 44, 1149−1157. (12) Kita, Y.; Hirasawa, Y.; Maeda, K.; Nishio, M.; Yoshida, K. Eur. J. Pharmacol. 1994, 257, 123−130. (13) Decout, J. L.; Roy, B.; Fontecave, M.; Muller, J. C.; Williams, P. H.; Loyaux, D. Bioorg. Med. Chem. Lett. 1995, 5, 973−978. (14) Rosenkranz, B.; Winkelmann, B. R.; Parnham, M. Clin. Pharmacokinet. 1996, 30, 372−384. (15) Singh, R. J.; Hogg, N.; Joseph, J.; Konorev, E.; Kalyanaraman, B. Arch. Biochem. Biophys. 1999, 361, 331−339. (16) Xu, L.-Y.; Yang, J.-S.; Link, H.; Xiao, B.-G. J. Immunol. 2001, 166, 5810−5816. (17) Stojanovic, M. O.; Ziolo, M. T.; Wahler, G. M.; Wolska, B. M. Am. J. Physiol. Cell Physiol. 2001, 281, C342−C349. (18) Ohwada, t.; Miura, M.; Tanaka, H.; Sakamoto, S.; Yamaguchi, K.; Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 2001, 123, 10164−10172. (19) Hrabie, J. A.; Keefer, L. K. Chem. Rev. 2002, 102, 1135−1154. (20) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J. Chem. Rev. 2002, 102, 1091−1134. (21) Goeldner, M., Givens, R., Eds. Dynamic Studies in Biology: Phototriggers, Photoswitches and Caged Biomolecules; Wiley-VCH: New York, 2005. (22) Halsey, C.; Roberts, I. A. G. Br. J. Haematol. 2003, 120, 177−186. (23) Wang, P. G., Cai, T. B., Taniguchi, N., Eds. Nitric Oxide Donors for Pharmaceutical and Biological Applications; Wiley-VCH: New York, 2005. (24) Berchner-Pfannschmidt, U.; Tug, S.; Hu, J.; Reyes, B. D.; Fandrey, J.; Kirsch, M. Biol. Chem. 2010, 391, 533−540. (25) Ieda, N.; Hotta, Y.; Miyata, N.; Kimura, K.; Nakagawa, H. J. Am. Chem. Soc. 2014, 136, 7085−7091. (26) Wink, D. A.; Vodovotz, Y.; Laval, J.; Laval, F.; Dewhirst, M. W.; Mitchell, J. B. Carcinogenesis 1998, 19, 711−721. (27) Ridnour, L. A.; Thomas, D. D.; Donzelli, S.; Espey, M. G.; Roberts, D. D.; Wink, D. A.; Isenberg, J. S. Antioxid. Redox Signaling 2006, 8, 1329−1337. (28) Thomas, D. D. Redox Biol. 2015, 5, 225−233. (29) Makings, L. R.; Tsien, R. Y. J. Biol. Chem. 1994, 269, 6282−6285. (30) Namiki, S.; Kaneda, F.; Ikegami, M.; Arai, T.; Fujimori, K.; Asada, S.; Hama, H.; Kasuya, Y.; Goto, K. Bioorg. Med. Chem. 1999, 7, 1695− 1702. (31) Works, C. F.; Ford, P. C. J. Am. Chem. Soc. 2000, 122, 7592−7593. (32) Fukuhara, K.; Kurihara, M.; Miyata, N. J. Am. Chem. Soc. 2001, 123, 8662−8666. (33) Ohwada, t.; Miura, M.; Tanaka, H.; Sakamoto, S.; Yamaguchi, K.; Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 2001, 123, 10164−10172. (34) Ruane, P. H.; Bushan, K. M.; Pavlos, C. M.; D’Sa, R. A.; Toscano, J. P. J. Am. Chem. Soc. 2002, 124, 9806−9811. (35) Bushan, K. M.; Xu, H.; Ruane, P. H.; D’Sa, R. A.; Pavlos, C. M.; Smith, J. A.; Celius, T. C.; Toscano, J. P. J. Am. Chem. Soc. 2002, 124, 12640−12641. (36) Pavlos, C. M.; Xu, H.; Toscano, J. P. Free Radical Biol. Med. 2004, 37, 745−752. (37) Wecksler, S.; Mikhailovsky, A.; Ford, P. C. J. Am. Chem. Soc. 2004, 126, 13566−13567. (38) Suzuki, T.; Nagae, O.; Kato, Y.; Nakagawa, H.; Fukuhara, K.; Miyata, N. J. Am. Chem. Soc. 2005, 127, 11720−11726. F
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
Article
Analytical Chemistry (74) O’Bannon, P. E.; Sulzle, D.; Dailey, W. P.; Schwarz, H. J. Am. Chem. Soc. 1992, 114, 344−345.
G
DOI: 10.1021/acs.analchem.6b01603 Anal. Chem. XXXX, XXX, XXX−XXX
