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. 2019 Feb 7;13:478–487. doi: 10.1016/j.isci.2019.02.003

Firefly-Inspired Approach to Develop New Chemiluminescence Materials

Yuxing Yan 1,2,3, Shuo Wang 1,2,3, Fuli Xie 1,2, Xiaofeng Fang 1,2, Yu-Mo Zhang 1,2,4,∗, Sean Xiao-An Zhang 1,2
PMCID: PMC6441873  PMID: 30880044

Summary

Bioluminescence, wherein marine and terrestrial organisms chemically produce light for communication, is a burgeoning area of research. Herein, we demonstrate a new series of artificial chemiluminescent compounds inspired by the enol-degradation reaction of natural bioluminescent molecules, luciferins. Based on systematic optical experiments, isotope labeling, and theoretical calculations, the chemiluminescent mechanism of these new materials and the relationship of enol-degradation reaction and chemiluminescence are fully discussed. The color and efficiency of the artificial chemiluminescent materials can be easily adjusted, and blue (486 nm), yellow (565 nm), and near-infrared (756 nm) luminescence can thus be obtained. The findings and in-depth understanding herein may accelerate the development of bio/chemiluminescent materials for analytical applications and non-invasive bioluminescence imaging.

Subject Areas: Chemistry, Functional Group Chemistry, Organic Chemistry

Graphical Abstract

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Highlights

  • •

    New chemiluminescent materials inspired by bioluminescence have been designed

  • •

    A way to design new chemiluminescent materials is reported

  • •

    The relationship of enol-degradation and chemiluminescence is methodically discussed

Chemistry; Functional Group Chemistry; Organic Chemistry

Introduction

Bioluminescence as an amazing phenomenon is well known to most people, and can be found in many living organisms, such as firefly, mollusks, and jellyfishes (Tsarkova et al., 2016). Different species of marine and terrestrial organisms often use various proteins and substrates (Kaskova et al., 2016). Interestingly, many known bioluminescent reactions belong to an enol-degradation (ED) reaction as shown in Scheme 1, such as aldehydes catalyzed by horseradish peroxidase and imidazopyrazinone derivatives catalyzed by luciferase (Yue et al., 2012, Navizet et al., 2011). Specifically, the generally accepted bioluminescence mechanism involves the following steps: (1) the generation of the enolate form catalyzed by luciferase and (2) the emission of visible light through the decomposition of dioxetanone formed by the oxygenation and degradation of the enolate form with O2 (Scheme 1). Many novel luciferin analogs containing different substitutions with luminescent properties have been designed and successfully applied for the sensitive detection of harmful substances in vivo (Takakura et al., 2015, Van de Bittner et al., 2013), and for non-invasive bioluminescence imaging in preclinical cancer research (Kuchimaru et al., 2016, Rehemtulla et al., 2000, Luker et al., 2004, Heffern et al., 2016). Unfortunately, the relationship of ED reaction and luminescence is not entirely clear. It is still unclear why some ED reactions can emit light, whereas the others cannot and why most biomimetic chemiluminescent efforts via specially designed enol-degradable molecules have failed (Zhang et al., 2014, Zhang et al., 2017). Therefore, a great perplexity hereon is what actually are the key factors of ED reactions to re-transform chemical energy to light.

Scheme 1.

Scheme 1

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Substrates and Mechanisms of Known Bioluminescence Reactions (A) Firefly luciferin (B) Fridericia heliota luciferin (C) Cypridina luciferin (D) Latia luciferin (E) Bacteria luciferin (F) Euphausiid luciferin.

Chemiluminescent materials, similar to bioluminescent materials without external light excitation, offer many obvious advantages over fluorescence materials based on photon emission, such as high signal-to-noise ratio and significantly reduced photodamage and photobleaching (Moddord et al., 2014, Jones et al., 2017). Thus chemiluminescence is a well-established technology applied to many areas of biological analysis. However, limited diversity restricts the development of the chemiluminescence. One important method to develop a new class of chemiluminescent materials is the simulation of bioluminescent ED reactions. For example, enol forms of acridinium esters oxidized by hydrogen peroxide have been used in analytical applications (Natrajan et al., 2014). Herein, we present a novel series of artificial chemiluminescent materials inspired by the amazing ED reaction of natural bioluminescent molecules. Eighteen molecules have been studied, and the structural features and essential influencing factors of the ED reactions to achieve chemiluminescence have been discussed in depth by contrasting ED with light emission and ED without light emission.

Results

Chemiluminescence

For an in-depth study of the relationship of ED reactions and luminescence, 18 molecules containing structural feature of a-H with different leaving groups and rigid structures were synthesized and prepared in Supplemental Information. For this, XA-O and XA-C synthesized by a rigid xanthoic acid with phenol (XA-O) or phenyl (XA-C) were first chosen as examples. The enzyme's function of proton extraction was imitated by chemical base to simplify the bioluminescent model that was used before by eminent researchers for studying the bioluminescence mechanism(White et al., 1980, Nakatani et al., 2007, Vacher et al., 2018, Freeman et al., 2011). To our great surprise, bright blue-white light at 486 nm was observed in XA-O solution stimulated by base (potassium tert-butoxide [KTB]) under an oxygen atmosphere in Figure 1A. After adding base under an oxygen atmosphere, the luminescence intensity increased rapidly to a peak value and then decreased to zero, as shown in the chemiluminescent kinetic curve of Figure 1A. However, no light emission can be detected by base or oxygen alone. The degradation process was investigated by absorption spectroscopy (Figure S1). After adding the base, new absorption peaks at 376 and 312 nm were instantly observed corresponding to the enolate form of XA-O, indicating that the deprotonation of XA-O was the first degradation step. Then after exposure to oxygen, the intensity of both peaks 312 and 376 nm were decreased over time and disappeared finally, along with the appearance of new peaks at 337, 326, and 279 nm assigned as the characteristic peaks of the degradation products of XA-O.

Figure 1.

Figure 1

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Chemiluminescent Properties of XA-O and XA-C

(A and B) Chemiluminescent spectra of (A) XA-O and (B) XA-C stimulated by KTB under oxygen (black curve), TKB alone (red curve), and oxygen alone (blue curve) in dimethylformamide (DMF). Inset: chemiluminescence kinetics and images.

(C) Photoluminescence spectra of xanthone, o-ethoxyphenol, xanthoic acid, the mixture of the three compounds, and the degradation mixture in the presence of 20 equiv. KTB and oxygen in DMF.

(D) Chemiluminescent spectrum (black curve) of a mixture of XA-O and fluorescein, and photoluminescence spectrum (blue curve) of fluorescein in DMF in the presence of KTB.

XA-C, which possessed a similar structure as XA-O, did not exhibit any chemiluminescent properties (Figure 1B). Interestingly, XA-C underwent similar degradation process after stimulation with base and oxygen as shown in Figure S2. The enolate form of XA-C with characteristic peaks at 374 and 300 nm was generated first after adding base in nitrogen atmosphere, and then new peaks characteristic of degradation products appeared after being exposed to oxygen. Such differences inspired us to explore the detailed relationship of the ED reaction and luminescence and to deeply understand the key factors of ED reactions for luminescence.

The Chemiluminescence Mechanism

To understand the ED mechanism, three observable degradation products of XA-O, containing xanthone, o-ethoxyphenol, and xanthoic acid, were carefully isolated by column chromatography, which were confirmed further by nuclear magnetic resonance (NMR) (Figure S3). These results were also supported by the absorption peaks of the degradation solution, comparing the characteristic peaks of xanthone, o-ethoxyphenol, and xanthoic acid in Figure S1.

The mass spectrum (MS) of the ED solution of XA-O under an 18O2 atmosphere without further post-treatment was measured then. In Figure 2A (positive mode) and Figure S4 (negative mode), the major peak at 199.07 was assigned to xanthone [(M+2)+H]+. Also, other peaks at 139.13, 227.07, and 181.07 were identical to the theoretical molecular weights of o-ethoxyphenol [M + H]+ and xanthoic acid [M + H]+ [M-CO2]+ compared with the MS of xanthoic acid in Figure S4. The appearance of [18O]-labeled xanthone suggested that the enolate of XA-O was oxidized by the addition of two oxygen atoms and then decomposed to xanthone. Considering [18O]-labeled xanthone and [16O]-labeled o-ethoxyphenol as degradation products, the mass difference of 12 amu indicated the loss of a single carbon atom, which agreed with the reactions of O2 addition and CO2 release. Carbon dioxide elimination was a dominant dissociation pathway in ED (i.e., for luciferin). Therefore the ED mechanism of XA-O was proposed as shown in Figure 2C. First, the four-ring structure (Int 2) of XA-O was formed by the oxygenation of the enolate form generated by the surrounding base. Then, Int 2 was decomposed into dioxetanone as a high-energy intermediate and 4-ethoxyphenolate. Finally, carbon dioxide, xanthone, and light were produced by the decomposition of dioxetanone. The decomposition mechanism of dioxetanone is discussed below.

Figure 2.

Figure 2

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Mechanisms of ED Reactions

(A–D) MS of (A) XA-O (positive MS) and (B) XA-C (negative MS) stimulated by KTB under an 18O2 atmosphere without further post-treatment. Proposed mechanisms for the ED of (C) XA-O and (D) XA-C.

Owing to the generation of xanthoic acid, we can infer that the hydrolysis of XA-O occurred. Next, the hydrolysis of XA-O was observed to confirm the relationship between hydrolysis and chemiluminescence. XA-O hydrolyzed completely after the addition of a base in a methanol-water solution under oxygen atmosphere. However, light cannot be detected during the reference reactions, as shown in the chemiluminescent kinetic curves and image in Figure S5. This result indicated clearly that the hydrolysis of XA-O was a side reaction for the emission of light.

Surprisingly, we discovered that the chemiluminescence spectrum of XA-O was the same as the photoluminescence spectrum of dual-ionized xanthoic acid (486 nm, the form of xanthoic acid under 20 equiv. KTB, which was undoubtedly proven by its fluorescence and NMR spectra in Figure S6), instead of that of xanthone in Figure 1C (the emission peak of xanthone was at 425 nm without base, and fluorescence quantum yield [QY] is zero under 20 equiv. KTB in Figure S6). These strongly supported that the decomposition mechanism of dioxetanone was intermolecular chemically initiated electron exchange, not unimolecular decomposition based on many excellent articles about decomposition of 1,2-dioxetanones (Vacher et al., 2018, Augusto et al., 2013, Stevani et al., 2000). Thus, we proposed the decomposition mechanism of dioxetanone as shown in Figure 2. The 1,2-dioxetanone was decomposed into carbon dioxide and the xanthone radical anion catalyzed by electron transfer from the xanthoic acid dianon as an activator. Then, the excited singlet state of xanthoic acid was generated through electron backtransfer from the xanthone radical anion. This mechanism was further confirmed by the mixture of fluorescein (as an activator) in Figure 1D. A delightful fluorescence of fluorescein was detected when it was mixed into the XA-O solution. At the same time, light cannot be detected when hydrolysis reaction of XA-O was avoided in anhydrous dimethylformamide (DMF) (Transparent Methods); nevertheless, light can appear when mixing fluorescein in anhydrous DMF (Figure S7).

The ED products (xanthone and p-anisic acid) of XA-C without chemiluminescent properties were isolated by column chromatography and confirmed by NMR spectroscopy in Figure S8. Then, MS of the ED solution under an 18O2 atmosphere without further post-treatment was also obtained. As shown in Figure 2B (negative mode) and Figure S4 (positive mode), two major peaks at 198.01 and 152.98 were assigned to xanthone [M+2]+ and p-anisic acid [(M+2)-H]+. The appearance of [18O]-labeled xanthone and p-anisic acid indicated that the enolate of XA-C was also oxidized by the addition of two oxygen atoms and then decomposed to form xanthone and p-anisic acid. Therefore the degradation mechanism of XA-C was proposed (Figure 2D). First, the enolate form was generated under basic conditions. Then, oxygen was captured to form an Int 2, which was immediately decomposed to a carboxylic acid and ketone.

In the two ED mechanisms, Int 2 formed by the addition of two oxygen atoms was a common high-energy unstable intermediate. However, the decomposition path was considerably different. For chemiluminescent XA-O, dioxentanone was formed in ED reaction, and the C-O bond linking the carbonyl and leaving group (phenol) was broken. For non-chemiluminescent XA-C, there was no dioxentanone intermediate, and the C-C bond linking the carbonyl and α-C was broken. That means, we can propose that the formation of dioxentanone and the cleavage energies of these two bonds were crucial to understand the degradation path and chemiluminescent properties.

In addition, femtosecond transient absorption spectroscopy (FTAS) was attempted to verify the formation of dioxetanone, which was a very difficult issue in research of bio/chemiluminescence mechanism (Usami and Isobe, 1996). M11 and M12 as reference molecules containing 400-nm absorbances were synthesized and detected by FTAS (Figures S9 and S10), owing to the limit of the 400-nm excitation light source. Fortunately, a new peak at 511 nm was detected only in the ED process of M11, compared with the spectra of the ED process of M12. Maybe, the 511-nm peak was an evidence to support the identity of the dioxetanone.

Density Functional Theory Analysis

To further understand the relationship of the ED pathway and the reactant structures, the potential energy surfaces of the ED reactions for XA-O and XA-C were analyzed by UCAM-B3LYP/6-31G(d,p) (Frisch et al., 2009). As shown in Figure 3, XA-C and XA-O both had two possible pathways (I and II) and three energy barriers, including molecular oxygen capture and the formation and decomposition of Int 2.

Figure 3.

Figure 3

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Potential Energy Surfaces of XA-O and XA-C and Chemiluminescent Properties of M3-M18

(A and B) Potential energy surfaces of the generation and degradation taking different pathways for (A) XA-O and (B) XA-C computed at the UCAM-B3LYP/6-31G(d,p) level.

(C) Dependency of chemiluminescence excitation quantum yield on the QY of the activator.

(D) Dependency of chemiluminescence excitation quantum yield on the ED percent.

(E) Chemiluminescent spectra of M8 solution mixed with xanthoic acid (blue curve), fluorescein (green curve), and 2-(2-(4-hydroxystyryl)-4H-chromen-4-ylidene)malononitrile (red curve).

The oxygen molecule (triplet) first attacked the enolate form of XA-O to form a C2-O1 bond and peroxide anion (Int 1) through a single electron transfer mechanism (Liu et al., 2009), which is discussed in detail in Figure S11. Then new C1-O2 bond and four-membered ring (Int 2) were formed by overcoming a small barrier of 0.1 kcal/mol. Two possible reaction pathways were studied for the decomposition of Int 2. In path I, the C1-C2 bond was stretched and 18.6 kcal/mol energy had to be overcome to generate xanthone and the carbonate compound (P1). However, [18O]-labeled P1 ([M+2]: 184.06) cannot be detected by MS (Figure 2A). In path II, only 12.9 kcal/mol energy was needed, and the C1-X (C1-O) bond was first stretched. Thus path II was preferred based on the thermomechanical analysis. The highest energy barrier was only 12.9 kcal/mol in the entire potential energy curve of ED of XA-O, which meant that this process was a spontaneous thermodynamic reaction.

The potential energy curves of the ED process of XA-C is shown in Figure 3B. XA-C and XA-O had similar potential energy curves before the decomposition of Int 2. The difference was the decomposition path of Int 2. By analyzing the decomposition pathway of Int 2, path I was preferred based on thermomechanical analysis, which was consistent with our experimental results. Compared with potential energy curves of XA-C and XA-O, the degradation pathway was dependent on the breakage energy difference of the C-C (C1-C2 for XA-O and XA-C linking the carbonyl and α-C) and C-X bonds (C1-O for XA-O and C1-C for XA-C linking the carbonyl and leaving group). In path I, the decomposition of C-C was easier than that of the C-X bond. However, C-X was preferentially decomposed over the C-C bond to form dioxetanone in path II. Thus the formation of the dioxetanone for ED reaction required the C-X bond to be preferentially cleaved and depended on the leaving group. This means, we can predict the chemiluminescent property of the ED reaction and the formation of dioxetanone by comparing the energies of TS2 of path I and TS3 of path II.

To further verify this inference, optical properties and bond cleavage energy barriers of 16 other molecules with different leaving groups were also studied in Table 1. Compared with M3, M4, M6, and M10 containing the same C-O linking group between the carbonyl and the different leaving groups, chemiluminescence can be observed only if the energy of TS3 was smaller than that of TS2. This means that the chemiluminescent property was not dependent on the kind of linking bond. We also found that the bond cleavage energy barrier can be affected by the electron-withdrawing ability of the leaving group. For example, the energy of TS2 of M3 with ethyl group as leaving group was 10.7 kcal/mol, which was smaller than that of TS3 (54.9 kcal/mol). However, M10 with ethyl group substituted by quaternary ammonium salt exhibited contrary result. The energies of TS2 and TS3 were 17.2 kcal/mol and 14.8 kcal/mol, respectively. Therefore, Int 2 of M10 preferentially underwent C-O bond cleavage over C-C bond cleavage, indicating that M10 would exhibit chemiluminescence consistent with our experimental results observed by the chemiluminescent image in Table 1. Other molecules also followed the rule that TS2 was smaller than TS3 for chemiluminescence. For example, the energy of TS2 of amide-linked M5 was 11.8 kcal/mol and that of TS3 was 21.5 kcal/mol, as shown in the potential energy curves of M5 (Figure S12). Therefore Int 2 of M5 preferentially underwent C-C bond cleavage over C-N bond cleavage, and the ED of M5 would occur through path I, similar to XA-C. This calculation result indicated that the dioxetanone was not formed and M5 did not exhibit chemiluminescence, which was consistent with our experimental results (Table 1). All the molecules proved that the formation of the dioxetanone and chemiluminescence required that the C-X linking the carbonyl and the different leaving group was more prone to breakage.

Table 1.

The Structures, Calculated Energy Barriers (Kcal/mol) of Decomposition of Int 2 in Path I (TS2) and II (TS3), Pathway Predicted by DFT, Chemiluminescent (CL) Images, the Maximum Wavelength of Chemiluminescence (λem), the Chemiluminescence (ФCL), and Singlet (ФS) Excitation Quantum Yield of XA-O, XA-C, and M3–M18

graphic file with name fx2.gif
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Chemiluminescent Intensity and Color

Based on the chemiluminescence mechanism of the new compounds, we can speculate that the chemiluminescent intensity of the ED reaction depended on the fluorescence QY of the activator, the percent of enolate form, and ED reaction. Regarding this, the pKa of α-H was key for the amount of enolate form, and the relationship of pKa and enol-ketone equilibrium reaction had been thoroughly discussed by many excellent works (Sloop et al., 2006, Jimenez-Cruz et al., 2015, Belova et al., 2010). In this work, to study exactly the relationship of ED reaction and chemiluminescence, and to avoid the interference of enol-ketone equilibrium reaction, excess base (20 equiv. t-BuOK) in our experiments was used to confirm that the enol-ketone equilibrium reaction was not the rate-determining step for ED reaction and ketone form had been transferred into enolate form completely.

The chemiluminescence and the singlet excitation QYs of the chemiluminescent compounds were measured using the luminol standard for photomultiplier calibration (Augusto et al., 2013, Stevani et al., 2000). As shown in Table 1, the new compounds exhibited the desirable intensity (Augusto et al., 2013). Compared with M8, M7, and M11 containing the same leaving group and different acid as activator, the chemiluminescence and the singlet excitation QYs were proportional to the QY of activator in Figure 3C. QY of dual-ionized form of 2,2-bis(4-(9H-carbazol-9-yl)phenyl)acetic acid as the activator for M11 was 30.2%, which was more than four times that of 9H-fluoren-9-one (7.3%) as the activator for M7; also, the chemiluminescence and the singlet excitation QYs of M11 (3.9×10−2/1.29×10−1 E/mol) were hundreds of times larger than those of M7 (1.4×10−4/5.0×10−3 E/mol). M8 did not exhibit chemiluminescent property, and therefore its QY was zero, although the formation of the dioxetanone was verified to be predicted by DFT method in Table 1. In addition, QY of dual-ionized xanthoic acid was about 50%, but its chemiluminescence and singlet excitation QY (7.8×10−4/1.6×10−3 E/mol) was smaller than that of M11, which indicated that the chemiluminescent intensity was affected by multiple factors.

Hydrolysis, as a competing reaction for ED reaction, was also a factor for the chemiluminescent intensity. Molecules containing the same leaving group with different substituents were designed to study the influence of hydrolysis, labeled as M13–M18 in Table 1. M18 containing nitro as electron-withdrawing substituent exhibited high percentage of hydrolysis, about 75%, and low percentage of degradation, about 25%. Also, its chemiluminescence and singlet excitation QY was about 7.8×10−4 E/mol and 1.6×10−3 E/mol, respectively. The chemiluminescence and singlet excitation QY can increase more than 30 times by removing the electron-withdrawing substituent, such as M13. As shown in Figure 3D, the chemiluminescence and singlet excitation QYs were proportional to the percent of ED reaction regulated by the electron-donating ability of substituent, and were inversely proportional to hydrolysis percent.

Based on the abovementioned discussion, we can confirm that the chemiluminescent intensity of these new compounds exhibited plenty of room by optimizing the electron-donating ability of substituents to regulate the ED percent and optimizing QY of acid as the activator. The chemiluminescent color depended on the color of the activator in the ED reaction. As shown in Figure 3E, the color was blue (486 nm) when xanthoic acid was mixed into the ED solution of M8, which cannot emit light alone. Meanwhile, the color was turned to yellow (565 nm) or red (756 nm) when fluorescein or (E)-2-(2-(4-hydroxystyryl)-4H-chromen-4-ylidene) malononitrile, respectively, was mixed. Thus the color can be fine-tuned by mixing fluorescent materials with different colors.

Discussion

In this study, the relationship of ED and luminescence was systematically confirmed for the first time. Two important factors for bio/chemiluminescence via ED are clearly demonstrated: the formation of dioxetanone intermediates, which is dependent on the leaving group, and the QY of the activator. The luminescence intensity and color rests with the QY and color of the activator. These findings demonstrate a new way to fabricate new luminescent materials. We believe that this work not only will accelerate research to deeply understand the mechanism and evolution of bioluminescence but also will open new methods to synthesize new chemiluminescent materials to develop novel artificial light systems, analytical tools, and non-invasive bioluminescence imaging.

Limitations of the Study

To verify the relationship of ED and chemiluminescence and to design new chemiluminescent materials inspired by ED of bioluminescence, we used isotope labeling method and theoretical calculations to discuss systematically the ED mechanism. However, dioxetanone as the intermediate was not captured by NMR or MS. Therefore it is necessary to use new characterization methods to investigate the mechanism in further work.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21602075), by Natural Science Foundation of Jilin Province (CN) (No. 20180520155JH), and by Young Elite Scientist Sponsorship Program by Jilin Province (CN) (181903).

Author Contributions

Y.Y., S.W., X.F., and F.X. performed all the experiments; Y.Y., S.W., and Y.-M.Z. analyzed the experimental data; Y.-M.Z. conducted the theoretical computations and analyzed the data; and Y.M. Z. and S. X.-A Z. reviewed and co-wrote the manuscript.

Declaration of Interests

Authors declare no conflict of interest.

Published: March 14, 2019

Footnotes

Supplemental Information includes Transparent Methods, 46 figures, and 1 data file and can be found with this article online at https://doi.org/10.1016/j.isci.2019.02.003.

Supplemental Information

Document S1. Transparent Methods and Figures S1–S46
mmc1.pdf (4.3MB, pdf)
Data S1. Cartesian Coordinates, Related to Figures 3
mmc2.xlsx (1.2MB, xlsx)

References

  1. Augusto F.A., de Souza G.A., de Souza Junior S.P., Khalid M., Baader W.J. Efficiency of electron transfer initiated chemiluminescence. Photochem. Photobiol. 2013;89:1299–1317. doi: 10.1111/php.12102. [DOI] [PubMed] [Google Scholar]
  2. Belova N.V., Sliznev V.V., Oberhammer H., Girichev G.V. Tautomeric and conformational properties of β-diketones. J. Mol. Struct. 2010;978:282–293. [Google Scholar]
  3. Van de Bittner G.C., Bertozzi C.R., Chang C.J. Strategy for dual-analyte luciferin imaging: in vivo bioluminescence detection of hydrogen peroxide and caspase activity in a murine model of acute inflammation. J. Am. Chem. Soc. 2013;135:1783–1795. doi: 10.1021/ja309078t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Freeman R., Liu X., Willner I. Chemiluminescent and chemiluminescence resonance energy transfer (CRET) detection of DNA, metal ions, and aptamer–substrate complexes using hemin/G-quadruplexes and CdSe/ZnS quantum dots. J. Am. Chem. Soc. 2011;133:11597–11604. doi: 10.1021/ja202639m. [DOI] [PubMed] [Google Scholar]
  5. Frisch M.J., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Mennucci B., Petersson G.A., Nakatsuji H. Gaussian Inc.; 2009. GAUSSIAN 09. [Google Scholar]
  6. Heffern M.C., Park H.M., Au-Yeung H.Y., Van de Bittner G.C., Ackerman C.M., Stahl A., Chang C.J. In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease. Proc. Natl. Acad. Sci. U S A. 2016;113:14219–14224. doi: 10.1073/pnas.1613628113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Jimenez-Cruz F., Ríos-Olivares H., García-Gutierrez J.L., Fragoza Mar L. Electronic effects on ketoeenol tautomerism of p-substituted aryl-1,3-diketone malonates. J. Mol. Struct. 2015;1101:162–169. [Google Scholar]
  8. Jones K.A., Porterfield W.B., Rathbun C.M., McCutcheon D.C., Paley M.A., Prescher J.A. Orthogonal luciferase-luciferin pairs for bioluminescence imaging. J. Am. Chem. Soc. 2017;139:2351–2358. doi: 10.1021/jacs.6b11737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kaskova Z.M., Tsarkova A.S., Yampolsky I.V. 1001 lights: luciferins, luciferases, their mechanisms of action and applications in chemical analysis, biology and medicine. Chem. Soc. Rev. 2016;45:6048–6077. doi: 10.1039/c6cs00296j. [DOI] [PubMed] [Google Scholar]
  10. Kuchimaru T., Lwano S., Kiyama M., Mitsumata S., Kadonosono T., Niwa H., Maki S., Kizaka-Kondoh S.A. A luciferin analogue generating near-infrared bioluminescence achieves highly sensitive deep-tissue imaging. Nat. Commun. 2016;7:11856. doi: 10.1038/ncomms11856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Liu F., Liu Y., De Vico L., Lindh R. Theoretical study of the chemiluminescent decomposition of dioxetanone. J. Am. Chem. Soc. 2009;131:6181–6188. doi: 10.1021/ja808511t. [DOI] [PubMed] [Google Scholar]
  12. Luker K.E., Smith M.C.P., Luker G.D., Gammon S.T., Piwnica-Worms H., Piwnica-Worms D. Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. Proc. Natl. Acad. Sci. U S A. 2004;101:12288–12293. doi: 10.1073/pnas.0404041101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Moddord D.M., Reddy G.R., Miller S.C. Latent luciferase activity in the fruit fly revealed by a synthetic luciferin. Proc. Natl. Acad. Sci. U S A. 2014;111:4443–4448. doi: 10.1073/pnas.1319300111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nakatani N., Hasegawa J.Y., Nakatsuji H. Red light in chemiluminescence and yellow-green light in bioluminescence: color-tuning mechanism of firefly, Photinus pyralis, studied by the symmetry-adapted cluster-configuration interaction method. J. Am. Chem. Soc. 2007;129:8756–8765. doi: 10.1021/ja0611691. [DOI] [PubMed] [Google Scholar]
  15. Natrajan A., Wen D., Sharpe D. Synthesis and properties of chemiluminescent acridinium ester labels with fluorous tags. Org. Biomol. Chem. 2014;12:3887–3901. doi: 10.1039/c4ob00456f. [DOI] [PubMed] [Google Scholar]
  16. Navizet I., Liu Y.J., Ferre N., Raca-Sanjuan D., Lindh R. The chemistry of bioluminescence: an analysis of chemical functionalities. ChemPhysChem. 2011;12:3064–3076. doi: 10.1002/cphc.201100504. [DOI] [PubMed] [Google Scholar]
  17. Rehemtulla A., Stegman L.D., Cardozo S.J., Gupta S., Hall D.E., Contag C.H., Ross B.D. Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. Neoplasia. 2000;2:491–495. doi: 10.1038/sj.neo.7900121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sloop J.C., Bumgardner C.L., Washington G., Loehle W.D., Sankar S.S., Lewis A.B. Keto–enol and enol–enol tautomerism in trifluoromethyl-b-diketones. J. Fluor. Chem. 2006;127:780–786. [Google Scholar]
  19. Stevani C.V., Silva S.M., Baader W.J. Studies on the mechanism of the excitation step in peroxyoxalate system. Eur. J. Org. Chem. 2000;24:4037–4046. [Google Scholar]
  20. Takakura H., Kojima R., Kamiya M., Kobayashi E., Komatsu T., Ueno T., Terai T., Hanaoka K., Nagano T., Urano Y. New class of bioluminogenic probe based on bioluminescent enzyme-induced electron transfer: BioLeT. J. Am. Chem. Soc. 2015;137:4010–4013. doi: 10.1021/ja511014w. [DOI] [PubMed] [Google Scholar]
  21. Tsarkova A.S., Kaskova Z.M., Yampolsky I.V. A tale of two luciferins: fungal and earthworm new bioluminescent systems. Acc. Chem. Res. 2016;49:2372–2380. doi: 10.1021/acs.accounts.6b00322. [DOI] [PubMed] [Google Scholar]
  22. Usami K., Isobe M. Low-temperature photooxygenation of coelenterate luciferin analog synthesis and proof of 1,2-dioxetanone as luminescence intermediate. Tetrahedron. 1996;52:12061–12090. [Google Scholar]
  23. Vacher M., Galván I.F., Ding B.-W., Schramm S., Berraud-Pache R., Naumov P., Ferré N., Liu Y.J., Navizet I., Roca-Sanjuán D. Chemi- and bioluminescence of cyclic peroxides. Chem. Rev. 2018;118:6927–6974. doi: 10.1021/acs.chemrev.7b00649. [DOI] [PubMed] [Google Scholar]
  24. White E.H., Steinmetz M.G., Miano J.D., Wildes P.D., Morland R. Chemi- and bioluminescence of firefly luciferin. J. Am. Chem. Soc. 1980;102:3199–3208. doi: 10.1021/ja01036a093. [DOI] [PubMed] [Google Scholar]
  25. Yue L., Liu Y.J., Fang W.H. Mechanistic insight into the chemiluminescent decomposition of firefly dioxetanone. J. Am. Chem. Soc. 2012;134:11632–11639. doi: 10.1021/ja302979t. [DOI] [PubMed] [Google Scholar]
  26. Zhang Y.M., Wang X., Li W., Zhang W., Li M., Zhang S.X.A. Bio-inspired enol-degradation for multipurpose oxygen sensing. Chem. Commun. (Camb) 2014;50:13477–13480. doi: 10.1039/c4cc05831c. [DOI] [PubMed] [Google Scholar]
  27. Zhang Y.M., Zhang J., Zhang S.X.A. Luciferin inspired oxygen sensing with alternant change of color and fluorescence. Dyes Pigm. 2017;138:1–6. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Transparent Methods and Figures S1–S46
mmc1.pdf (4.3MB, pdf)
Data S1. Cartesian Coordinates, Related to Figures 3
mmc2.xlsx (1.2MB, xlsx)

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