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Bright and Light-Up Sensing of Benzo[c,d]indole-oxazolopyridine Cyanine Dye for RNA and Its Application to Highly Sensitive Imaging of Nucleolar RNA in Living Cells
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  • Kei Higuchi
    Kei Higuchi
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
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  • Yusuke Sato*
    Yusuke Sato
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
    *Phone: (81) 22-795-6551. Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-5824-1654
  • Nao Togashi
    Nao Togashi
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
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  • Michiyuki Suzuki
    Michiyuki Suzuki
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
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  • Yukina Yoshino
    Yukina Yoshino
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
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  • Seiichi Nishizawa*
    Seiichi Nishizawa
    Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
    *Phone: (81)22-795-6549. Email: [email protected]
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ACS Omega

Cite this: ACS Omega 2022, 7, 27, 23744–23748
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https://doi.org/10.1021/acsomega.2c02408
Published June 29, 2022

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Abstract

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Small molecular weight probes that can show a fluorescence signaling response upon binding to RNAs are promising for RNA imaging in living cells. Live-cell RNA imaging probes that can achieve a large light-up ability (>100-fold) and high Φbound value for RNA (>0.50) have been rarely reported to date. Here, benzo[c,d]indole-oxazolopyridine (BIOP), an unsymmetrical monomethine cyanine analogue, was newly developed as a bright and large light-up probe for imaging of nucleolar RNA in living cells. BIOP served as a yellow-emissive probe (λem = 570 nm) and exhibited a significant light-up response upon RNA binding (770-fold) with a high Φbound value (0.52). We demonstrated the advantages of BIOP over a commercially available RNA-staining probe, SYTO RNA select, for robust and sensitive RNA sensing by a systematic comparison of fluorescent properties for RNA. In addition, BIOP was found to possess high membrane permeability and low cytotoxicity in living cells. The examination of live-cell imaging revealed that BIOP exhibited emission in the nucleolus upon binding to nucleolar RNA much stronger than that of SYTO RNA select. Furthermore, BIOP facilitated the highly sensitive imaging of nucleolar RNA, in which 50 nM BIOP can stain nucleolar RNA in living cells with a 20 min incubation.

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Introduction

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With increasing knowledge about the diverse roles of RNA within cells, much attention has been paid to RNA-binding fluorescent probes as powerful and versatile tools for the study of RNA functions. (1) In comparison to protein-based (2) and oligonucleotide-based probes, (3) small molecular weight probes for RNA analysis have been less developed despite their versatility and easy-to-use properties. (4) This is mainly because this class of probes usually shows the binding preference for DNA over RNA. (5) SYTO RNA select is one of the commercially available probes with RNA selectivity. While SYTO RNA is almost nonfluorescent in solution, its emission is greatly enhanced by more than 100-fold upon binding to RNA. Such a light-up ability renders this probe useful as a sensitive RNA-sensing probe. (6) On the other hand, the usefulness of SYTO RNA select as an RNA-imaging probe in cells has been severely limited. This probe has low photostability (4,7) and a relatively short emission wavelength (λem = 530 nm) that suffers interference from cellular autofluorescence. Moreover, the low cellular permeability of SYTO RNA select is also problematic, resulting in less applicability toward the RNA imaging in living cells. (8)
Considerable work has been done in order to overcome these drawbacks of SYTO RNA select, resulting in the realization of improved photostability, long emission wavelength, and compatibility with live-cell imaging. (9) Several probes were shown to be applicable to the staining of nucleolar RNA in living cells, offering useful tools for the analysis of nucleolar RNA dynamics. (9a) (9b) On the other hand, less attention has been paid to the brightness and light-up property of this class of probes despite the fact that these factors are crucial for achieving sensitive imaging. Indeed, live-cell RNA-imaging probes to meet the large light-up ability (>100-fold) and high Φbound value for RNA (>0.50) have been rarely reported to date. In this context, Wang et al. recently developed a new styryl dye-based green-emissive probe (λem = 511 nm), PI2, that exhibited a large light-up response and high Φbound for RNA (Φfree = 0.0039, Φbound = 0.577). (10) However, a high concentration of PI2 (5.0 μM) was required for live-cell imaging experiments, presumably due to its low permeability in living cells. It was reported that the viability of 3T3 cells was decreased to 70–75% with an incubation concentration of 5–20 μM P12 for 24 h. (10) Our group designed unsymmetrical monomethine cyanine-based probes with a distinct light-up switch for RNA. (11) Benzo[c,d]indole-quinoline (BIQ) showed a significant enhancement of the emission by more than 100-fold upon binding to RNA, (11a) whose fluorogenic “off–on” ability in deep-red region (λem > 650 nm) is outstanding among small probes for live-cell RNA imaging. We also demonstrated nucleolar RNA staining in living MCF7 cells even with 500 nM of the BIQ derivative with improved binding affinity. (11b) However, BIQ analogues have a relatively moderate fluorescence quantum yield in the bound state with RNA (Φbound < 0.02), resulting in low brightness of the probe in live-cell imaging.
In this work, we report on a new benzo[c,d]indole-containing monomethine cyanine with improved brightness and light-up properties for RNA sensing. We focused on the oxazolopyridine heterocycle for the probe design because cyanine dyes containing this heterocycle exhibited a large fluorescence quantum yield in the bound state with nucleic acids. (12) Here, the oxazolo[5,4-c]pyridine heterocycle was conjugated with a benzo[c,d]indole unit (Scheme 1), yielding the benzo[c,d]indole-oxazolopyridine (BIOP) probe. BIOP works as a yellow-emissive probe (λem = 570 nm) and exhibits a significant light-up response upon RNA binding (770-fold) with a high Φbound value (0.52). Based on such promising signaling functions, we demonstrate the potential of BIOP for nucleolar RNA imaging in living cells.

Scheme 1

Scheme 1. Synthesis of Benzo[c,d]indole-oxazolo[5,4-c]pyridine (BIOP)a
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aReagents and conditions: (a) potassium ethyl xanthate, EtOH, reflux, 93%; (b) iodomethane, DMF, 61%; (c) methyl p-toluenesulfonate, 130 °C, 28%; (d) 1,2-dimethylbenzo[c,d]indol-1-ium iodide (3), NEt3, MeCN, 40 °C, 14%.

Results and Discussion

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Synthesis of BIOP

For the synthesis of BIOP (Scheme 1), 5-methyl-2-(methylthio)oxazolo[5,4-c]pyridin-5-ium tosylate (2) was first prepared in three steps from the commercially available 4-aminopyridin-3-ol (1) (Scheme S1). (13,14) Compound 2 was then combined with the benzo[c,d]indole unit (3) (11,15) by a condensation reaction, which affords BIOP (purity >95%) as characterized by 1H NMR and ESI-MS (Figures S1 and S2). Further details of the synthesis are shown in the Supporting Information.

Fluorescence Response of BIOP for RNA

First, we investigated the fluorescence response of BIOP (1.0 μM) to calf thymus DNA orEscherichia coli (E. coli) total RNA, as these nucleic acids from biological species were utilized in many studies for RNA-targeting fluorescent probes. (9) Measurements were done at 25 °C in a 10 mM sodium phosphate buffer (pH 7.0). As shown in Figure 1, we observed negligible emission in the absence of nucleic acid (fluorescence quantum yield (Φfree) = 0.00038). This can be explained by the nonradiative energy loss through free rotation around the monomethine linker between corresponding heterocycles, as typically observed for various monomethine cyanine dyes. (16) The addition of E. coli total RNA (1.0 mM per nucleotide) resulted in a significant fluorescence enhancement of BIOP in the yellow spectral range (λem = 570 nm). We observed a hyperchromicity and a red shift of the absorption band of BIOP when bound to RNA (Figure S3), which suggests the intercalative binding mode of BIOP for RNA. Thus, the observed light-up response would arise from the suppressed rotation upon intercalation into the base pairs in the RNA. (16,17) The light-up factor (I/I0, where I and I0 denote the fluorescence intensities in the presence and absence of a target, respectively) of BIOP is determined to be 770-fold. Such a large light-up property is well reflected in the remarkable increase in the fluorescence quantum yield upon binding to RNA. Significantly, the fluorescence quantum yield of BIOP in the bound state (Φbound) was determined to be 0.52. This value is 1 order of magnitude larger compared to that of BIQ derivatives that were previously developed by us. (11) The brightness, defined as the product of the fluorescence quantum yield and molecular extinction coefficient, reaches 1.1 × 104 for BIOP bound to RNA (Table 1). Apparently, the integration of the oxazolopyridine unit into the monomethine cyanine scaffold leads to large Φbound value for RNA binding. In addition, the response for RNA is larger than that for DNA (Figure 1), which indicates the selective response of BIOP toward RNA like BIQ derivatives. (11)

Figure 1

Figure 1. Fluorescence spectra of BIOP (1.0 μM) in the absence (a) and presence of (b) 1.0 mM E. coli total RNA or (c) 1.0 mM ctDNA. Measurements were done in 10 mM sodium phosphate buffer solution (pH 7.0) containing 100 mM NaCl and 1.0 mM EDTA. Excitation: 530 nm. Temperature: 25 °C.

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Table 1. Photophysical Properties and Fluorescence Signaling Ability for RNA Sensing
 BIOPSYTO RNA select
emission wavelengtha570 nm530 nm
light-up factorb770500
Φboundb0.520.36
εabs,maxa2.2 × 104 cm–1 M–13.9 × 104 cm–1 M–1
brightness (εabs, max × Φbound)1.1 × 1041.4 × 104
photostabilitybhighlow
a

Values obtained in 10 mM sodium phosphate buffer solution (pH 7.0) containing 100 mM NaCl and 1.0 mM EDTA.

b

[Probe] = 1.0 μM, [E. coli total RNA] = 1.0 mM.

In order to gain further insights into binding of BIOP to RNA, we examined the fluorescence response for synthetic double-stranded (ds) and single-stranded (ss) RNA (Figure S4). The fluorescence intensity was much enhanced for rG/rC and rA/rU compared to that of rC, rA, and rU. It is thus highly likely that BIOP binding arises from the intercalation into the base pairs in the RNA. (16,17) The comparison with synthetic DNA reveals the selective response for RNA, which is consistent with the results for biological nucleic acids (cf. Figure 1). We note that BIOP displayed a strong light-up response for both rG and dG, presumably due to the possible binding to G-quadruplex structures similar to various monomethine cyanines. (11,18) We then estimate the binding affinity of BIOP for the rG/rC duplex by fluorescence titration experiments (Figure S5). The apparent dissociation constant (Kd) was determined to be 8.1 ± 1.6 μM (N = 3). The binding affinity of BIOP is stronger than BIQ having a quinoline counterpart (Kd > 22 μM), (11a) indicating that the use of oxazolo[5,4-c]pyridine is also advantageous for the enhanced binding affinity.

Comparison with SYTO RNA Select

Here, the response properties of BIOP were directly compared with those of commercially available SYTO RNA select for E. coli total RNA under the identical conditions (cf. Figure 1). We found several advantages of BIOP over SYTO RNA select (Figure S6 and Table 1). Taken together with the longer emission wavelength compared to that of SYTO RNA select, both light-up properties and Φbound values for BIOP are superior by more than 1.4-fold compared to those of SYTO RNA select (I/I0 = 500-fold and Φbound = 0.36). These results indicate more favorable fluorescence signaling ability of BIOP over SYTO RNA select for RNA sensing. In addition, BIOP possesses a stronger resistance to photobleaching than that of SYTO RNA select (Figure S7). The fluorescence intensity of SYTO RNA select bound to RNA decreased by as much as 75% after 160 min continuous irradiation, whereas the decrease in the fluorescence intensity of BIOP was very small (7%). While the clear selectivity for RNA over DNA is a promising function of SYTO RNA select in solutions (Figure S6), a distinct advantage of BIOP can be seen when applied to live-cell imaging.

Fluorescence Imaging of Living Cells

Figure 2A shows the fluorescence image of living MCF7 cells after incubation of 0.5 μM BIOP for 20 min using TRITC filter sets in the fluorescence microscopy. We observed strong emission in the yellow spectral region in the nucleolus and cytoplasm. This indicates good cell plasma and nuclear membrane permeability of BIOP in living cells. Considering the abundance of RNA, such as rRNA, in the nucleolus, (4,7−11) it is highly likely that the observed signal in the nucleolus originates from the light-up response of BIOP for nucleolar RNA. Meanwhile, the emission in the cytoplasm was found to be due to the accumulation of BIOP in the mitochondria by examination of a series of organelle-selective staining probes (Figure S8, Pearson’s correlation coefficient: 0.78). This would be due to possible interaction of cationic BIOP with a negative mitochondria membrane, as observed for various cyanine analogues. (19) In order to confirm the origin of the emission in the nucleolus, deoxyribonuclease (DNase) and ribonuclease (RNase) digestion experiments were done in fixed and permeabilized MCF7 cells (Figure 2B). BIOP exhibited strong emission in the nucleolus in fixed and permeabilized cells, similar to the case of living cells. The fluorescence signal of BIOP in the nucleolus dramatically diminished in the case of RNase, whereas the signal remained almost unaffected after the DNase treatment. These results showed that BIOP exhibited strong emission by binding to nucleolar RNA. We also noticed the emission disappearance in the mitochonria after the DNase treatment. This result suggests that the emission observed in the mitochondria originates from the binding of BIOP to mitochondrial DNA. (20)

Figure 2

Figure 2. (A) Fluorescence image of living MCF7 cells incubated with 0.5 μM BIOP for 20 min. Fluorescence intensity profile along the white line is also shown, where the fluorescence in the nucleolus is highlighted. (B) Fluorescence images of fixed-permeabilized MCF7 cells stained with 0.5 μM BIOP before (control) and after treatment of RNase or DNase. Fluorescence intensity profiles along the white line are also shown. (C) Fluorescence image of living MCF7 cells incubated with 0.5 μM SYTO RNA select for 20 min. Fluorescence intensity profile along the white line is also shown. Scale bar: 15 μm.

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The live-cell imaging performance of BIOP for MCF7 cells was then compared with that of SYTO RNA select under the identical measurement conditions ([probe] = 0.5 μM, 20 min incubation). In sharp contrast to BIOP, SYTO RNA select displayed negligible emission in the nucleolus, whereas we observed weak emission in the cytoplasm (Figure 2C). The observed imaging pattern of SYTO RNA select is consistent with the previous reports. (8b) (9c) Clearly, BIOP can serve as a more useful probe for the imaging of nucleolar RNA in living cells compared to SYTO RNA select.
Significantly, the excellent imaging properties of BIOP enable the staining of nucleolar RNA even at a concentration as low as 50 nM (Figure 3). The emission in the nucleolus is clearly observed and can be distinguishable from that in the nucleus. Several fluorescent probes have been so far shown to possess an imaging performance for nucleolar RNA in living cells better than that with SYTO RNA select; (7−11,21) however, to the best of our knowledge, nucleolar RNA imaging has never been accomplished at a 50 nM probe concentration. Thus, BIOP can work as the most sensitive imaging probe for nucleolar RNA in living cells. The high RNA-sensing ability of BIOP would contribute to this improved imaging sensitivity of nucleolar RNA. In addition, it is highly likely that the high membrane permeability of BIOP also provides a better imaging performance. Low probe concentration should be beneficial as it can greatly reduce the damage to the biological systems inside the cells. (8a,22)

Figure 3

Figure 3. Fluorescence image of living MCF7 cells incubated with 50 nM BIOP for 20 min. Fluorescence intensity profile along the white line is also shown, where the fluorescence in the nucleolus is highlighted. Scale bar: 15 μm.

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Cytotoxicity of live-cell imaging probes is also an important factor for the practical use toward accurate analysis of living cells. We assessed the cytotoxicity of BIOP after 20 min incubation in living MCF7 cells with the Alamar blue assay (Figure S9A). Negligible cytotoxicity was found for the BIOP concentration below 5.0 μM, which shows that the nucleolar RNA staining with 20 min incubation of BIOP has no influence on the cell viability. In addition, more than 90% cell viability was observed in the case of 24 h incubation of 1.0 μM BIOP (Figure S9B). It is consistent with the observation that BIOP clearly stained the nucleolus without any morphological change after 24 h incubation (Figure S10). BIOP thus holds great potential for the long-term monitoring of nucleolar RNA in living cells, which offers a useful tool for the analysis of nucleolar RNA dynamics during mitosis and apotosis induced by anticancer drugs. (9a)
It should be also noted that BIOP has a good counterstaining compatibility with the nuclear selective Hoechst 33342, a blue-emissive DNA-staining probe (Figure S11, Pearson’s correlation coefficient: 0.12). As the excitation and emission profiles of BIOP are orthogonal to Hoechst 33342, the combination of these probes allows the simultaneous visualization of DNA and RNA distribution in living cells. (7a,9a,c) We also demonstrated the applicability of BIOP to living HeLa cells (Figure S12). As observed for MCF7 cells, BIOP was able to stain the nucleolar RNA under the above condition ([BIOP] = 1.0 μM, 20 min incubation). This shows the versatility of BIOP as a useful imaging probe for nucleolar RNA in living cells.

Conclusions

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In summary, benzo[c,d]indole-oxazolopyridine, BIOP, was newly developed as a useful probe for RNA sensing and nucleolar RNA imaging in living cells. BIOP has brighter and larger light-up response for RNA as well as higher photostability compared to that of SYTO RNA select. Highly sensitive imaging of nucleolar RNA in living cells was achieved by virtue of the excellent RNA-sensing properties and high membrane permeability. This sensitivity of BIOP is superior compared to the previously developed probes with better imaging performance for nucleolar RNA in living cells over SYTO RNA select. Moreover, BIOP possesses low cytotoxicity in living cells. While there is some room for improvement of the probe function, such as the Stokes shift (9a) and nucleolus-targeting ability, we believe that BIOP can be the most useful candidate for practical use toward spatiotemporal analysis of nucleolar RNA in living cells.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02408.

  • Experimental details, absorption spectra, fluorescence response, photostability, live-cell imaging, cytotoxicity of BIOP (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Kei Higuchi - Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
    • Nao Togashi - Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
    • Michiyuki Suzuki - Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
    • Yukina Yoshino - Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
  • Author Contributions

    K.H. and Y.S. conceived the study. K.H. and M.S. designed and performed all experiments with help from N.T. and Y.Y. K.H., Y.S., and S.N. wrote the manuscript. Y.S. and S.N. supervised the research.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by Grant-in-Aid for Challenging Research (Pioneering) (No. 21K18207) and for Young Scientists (A) (No. 17H04881) from the Japan Society for the Promotion of Science (JSPS).

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    The RNA genomes of a no. of pathogenic RNA viruses, such as HIV-1, have extensive folded conformations with imperfect A-form duplexes that are essential for virus function and could serve as targets for structure-specific antiviral drugs. As an initial step in the discovery of such drugs, the interactions with RNA of a wide variety of compds., which are known to bind to DNA in the minor groove, by classical or by threading intercalation, have been evaluated by thermal melting and viscometric analyses. The corresponding sequence RNA and DNA polymers, poly(A)·poly(U) and poly(dA)·poly(dT), were used as test systems for anal. of RNA binding strength and selectivity. Compds. that bind exclusively in the minor groove at AT sequences of DNA (e.g., netropsin, distamycin, and a zinc porphyrin deriv.) do not have significant interactions with RNA. Compds. that bind in the minor groove in AT sequences of DNA but have other favorable interactions in GC sequences of DNA (e.q., Hoechst 33258, DAPI, and other arom. diamidines) can have very strong RNA interactions. A group of classical intercalators and a group of intercalators with unfused arom. ring systems contain compds. that intercalate and have strong interactions with RNA. At this time, no clear pattern of mol. structure that favors RNA over DNA interactions for intercalators has emerged. Compds. that bind to DNA by threading intercalation generally bind to RNA by the same mode, but none of the threading intercalators tested to date have shown selective interactions with RNA.
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    (b) Sato, Y.; Ichihashi, T.; Nishizawa, S.; Teramae, N. Strong and selective binding of amiloride to an abasic site in RNA duplexes: Thermodynamic characterization and microRNA detection. Angew. Chem. Int. Ed 2012, 51, 6369– 6372,  DOI: 10.1002/anie.201201790
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    5b
    Strong and selective binding of amiloride to an abasic site in RNA duplexes: Thermodynamic characterization and microRNA detection
    Sato, Yusuke; Ichihashi, Toshiki; Nishizawa, Seiichi; Teramae, Norio
    Angewandte Chemie, International Edition (2012), 51 (26), 6369-6372, S6369/1-S6369/9CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The binding characteristics of amiloride to abasic (AP) site-contg. duplex RNA were examd. by fluorescence, CD (CD), and isothermal titrn. calorimetry (ITC) measurements, and the obtained data were compared with the corresponding AP site-contg. DNA duplexes (AP-DNA). Addn. of AP-RNA causes a significant enhancement in the fluorescence intensity of amiloride, whereas no response is obsd. for a fully-matched RNA duplex having no AP sites as well as single-stranded RNAs consisting of AP-RNA, indicate highly selective binding of amiloride to the AP site of AP-RNA. The titrn. curve was well fitted by a 1:1 binding isotherm, which gives a dissocn. const. Ki of (9.5 ± 0.66) nM. The addn. of amiloride to AP-RNA causes little change in the CD spectrum, indicating that the resulting amiloride/AP-RNA complex remains in the A-form without any drastic conformational change. The A-form geometry in the nucleic acids allows more extensive base-base overlap and provides more efficient stacking interactions of nucleotides than the B-form geometry of AP-DNA. Thermodn. characterization by isothermal titrn. calorimetry (ITC) supports the efficient stacking interaction at the AP site of AP-RNA. Moreover, amiloride is applicable to the detection of microRNAs (miRNAs) that have been assocd. with various diseases, based on the sensitive fluorescence response of the amiloride binding to the AP site in RNA duplexes.
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  6. 6
    (a) Wu, Y.; Liu, Y.; Lu, C.; Lei, S.; Li, J.; Du, G. Quantification of RNA by a fluorometric method using the SYTO RNA Select stain. Anal. Biochem. 2020, 606, 113857,  DOI: 10.1016/j.ab.2020.113857
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    6a
    Quantitation of RNA by a fluorometric method using the SYTO RNASelect stain
    Wu, Yexu; Liu, Yanfeng; Lu, Chuanchuan; Lei, Senlin; Li, Jianghua; Du, Guocheng
    Analytical Biochemistry (2020), 606 (), 113857CODEN: ANBCA2; ISSN:0003-2697. (Elsevier B.V.)
    Quantitation of even trace amts. of RNA has biol. significance. However, existing methods of RNA estn. are not capable of eliminating the interference of other impurities, esp. DNA. The authors developed a rapid and sensitive method for fluorometric estn. of RNA using an RNA-specific dye, SYTO RNASelect. A good linear correlation between the fluorescence intensity and RNA concn. was obsd. using this method. The maximal fluorescence intensity of DNA was only 2.9% of the fluorescence intensity of 40μg/mL RNA, demonstrating the high RNA specificity of the SYTO RNASelect method.
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    (b) de Voogt, W. S.; Tanenbaum, M. E.; Vader, P. Illuminating RNA trafficking and functional delivery by extracellular vesicles. Adv. Drug Delivery Rev. 2021, 174, 250– 264,  DOI: 10.1016/j.addr.2021.04.017
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    6b
    Illuminating RNA trafficking and functional delivery by extracellular vesicles
    de Voogt, Willemijn S.; Tanenbaum, Marvin E.; Vader, Pieter
    Advanced Drug Delivery Reviews (2021), 174 (), 250-264CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. RNA-based therapeutics are highly promising for the treatment of numerous diseases, by their ability to tackle the genetic origin in multiple possible ways. RNA mols. are, however, incapable of crossing cell membranes, hence a safe and efficient delivery vehicle is pivotal. Extracellular vesicles (EVs) are endogenously derived nano-sized particles and possess several characteristics which make them excellent candidates as therapeutic RNA delivery agent. This includes the inherent capability to functionally tRNAs in a selective manner and an enhanced safety profile compared to synthetic particles. Nonetheless, the fundamental mechanisms underlying this selective inter- and intracellular trafficking and functional transfer of RNAs by EVs are poorly understood. Improving our understanding of these systems is a key element of working toward an EV-based or EV-mimicking system for the functional delivery of therapeutic RNA. In this review, state-of-the-art approaches to detect and visualize RNA in situ and in live cells are discussed, as well as strategies to assess functional RNA transfer, highlighting their potential in studying EV-RNA trafficking mechanisms.
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  7. 7
    (a) Lu, Y.-J.; Deng, Q.; Hu, D.-P.; Wang, Z.-Y.; Huang, B.-H.; Du, Z.-Y.; Fang, Y.-X.; Wong, W.-L.; Zhang, K.; Chow, C.-F. A molecular fluorescent dye for specific staining and imaging of RNA in live cells: A novel ligand integration from classical thiazole orange and styryl compounds. Chem. Commun. 2015, 51, 15241– 15244,  DOI: 10.1039/C5CC05551B
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    7a
    A molecular fluorescent dye for specific staining and imaging of RNA in live cells: a novel ligand integration from classical thiazole orange and styryl compounds
    Lu, Yu-Jing; Deng, Qiang; Hu, Dong-Ping; Wang, Zheng-Ya; Huang, Bao-Hua; Du, Zhi-Yun; Fang, Yan-Xiong; Wong, Wing-Leung; Zhang, Kun; Chow, Cheuk-Fai
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (83), 15241-15244CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A new RNA-selective fluorescent dye (I) integrated with a thiazole orange and a p-(methylthio)styryl moiety shows better nucleolus RNA staining and imaging performance in live cells than the com. stains. I also exhibits excellent photostability, cell tolerance, and counterstain compatibility with 4',6-diamidino-2-phenylindole for specific RNA-DNA colocalization in bioassays.
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    (b) Liu, J.; Zhang, S.; Zhang, C.; Dong, J.; Shen, C.; Zhu; Xu, H.; Fu, M.; Yang, G.; Zhang, X. A water-soluble two-photon ratiometric triarylboron probe with nucleolar targeting by preferential RNA binding. Chem. Commun. 2017, 53, 11476– 11479,  DOI: 10.1039/C7CC06045A
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    7b
    A water-soluble two-photon ratiometric triarylboron probe with nucleolar targeting by preferential RNA binding
    Liu, Jun; Zhang, Shilu; Zhang, Chenghua; Dong, Jun; Shen, Chengyi; Zhu, Jiang; Xu, Huajun; Fu, Mingkai; Yang, Guoqiang; Zhang, Xiaoming
    Chemical Communications (Cambridge, United Kingdom) (2017), 53 (83), 11476-11479CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    By functionalizing triarylboron with cyclen, we developed a two-photon fluorescence probe, TAB-2 (I), which can selectively bind RNA with a ratiometric readout. We tested I in NIH/3T3 fibroblast cells, and demonstrated its capability in visualizing nucleoli and analyzing microenvironment polarity by two-photon and fluorescence-lifetime imaging microscopy.
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  8. 8
    (a) Li, Q.; Kim, Y.; Namm, J.; Kulkarni, A.; Rosania, G. R.; Ahn, Y.-H.; Chang, Y.-T. RNA-selective, live cell imaging probes for studying nuclear structure and function. Chem. Biol. 2006, 13, 615– 623,  DOI: 10.1016/j.chembiol.2006.04.007
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    8a
    RNA-Selective, Live Cell Imaging Probes for Studying Nuclear Structure and Function
    Li, Qian; Kim, Yunkyung; Namm, Joshua; Kulkarni, Amita; Rosania, Gus R.; Ahn, Young-Hoon; Chang, Young-Tae
    Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (6), 615-623CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
    The higher-order structural organization of the cell nucleus reflects the underlying genome-wide transcriptional activity and macromol. transport processes. To study the microscopic organization of RNA distribution within the nucleus, a combinatorial library of fluorescent styryl mols. was synthesized and screened for an in vitro RNA response and live cell nuclear imaging. Four different cell lines (HeLa, A549, 3T3, and 3T3-L1) were analyzed in terms of higher-order nuclear organization. The authors identified RNA-selective dyes with better imaging properties relative to com. available SYTORNASelect dye; the selected dyes were also cell permeant, photostable, and well tolerated by the cells. The authors' dyes also had very good counterstain compatibility with Hoechst and DAPI, which could help to image the DNA distribution in relation to RNA distribution in live cells and therefore reveal different patterns of RNA-DNA colocalization.
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    (b) Cao, C.; Wei, P.; Li, R.; Zhong, Y.; Li, X.; Xue, F.; Shi, Y.; Yi, T. Ribosomal RNA-selective light-up fluorescent probe for rapidly imaging the nucleolus in live cells. ACS Sens 2019, 4, 1409– 1416,  DOI: 10.1021/acssensors.9b00464
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    8b
    Ribosomal RNA-Selective Light-Up Fluorescent Probe for Rapidly Imaging the Nucleolus in Live Cells
    Cao, Chunyan; Wei, Peng; Li, Ruohan; Zhong, Yaping; Li, Xiang; Xue, Fengfeng; Shi, Yibing; Yi, Tao
    ACS Sensors (2019), 4 (5), 1409-1416CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
    RNA-based fluorescent probes are currently limited by their low selectivity toward RNA vs. DNA, and low specificity to different RNA structures. Poor membrane permeability is another defect of existing fluorogenic RNA probes for intracellular imaging. In this work, a naphthalimide deriv., probe I, was developed for the rapid and selective detection of intracellular rRNA. Probe I exhibited a 32-fold fluorescent enhancement in response to rRNA binding and showed desirable selectivity for rRNA vs. DNA and other nucleic acids in phosphate buffer at pH 7.2. Importantly, probe I displayed excellent permeability of the nucleolus, could be taken up in 1 min by four different cell lines, and may be the fastest nucleolus dye. The excellent selectivity of probe I toward rRNA is attributed to the specific interaction between the complicated 3D structures of rRNA, which was confirmed by quantum calcns. using mol. docking simulations. An appropriate lipophilic balance in I with the hydrophilic amine group and hydrophobic naphthalimide, as well as its high water soly., guarantees the high permeability of I in cell membranes and nucleolus pores, compared to other analogs (e.g., probes 2-8 in this work). Furthermore, enlarged confocal laser micro images of nucleoli and RNase digestion tests revealed that I remained highly selective toward rRNA, even for intracellular imaging. As a live cell probe, I also exhibited better photostability than the com. RNA dye, SYTO RNA select.
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  9. 9
    (a) Zhou, B.; Liu, W.; Zhang, H.; Wu, J.; Liu, S.; Xu, H.; Wang, P. Imaging nucleolar RNA in living cells using a highly photostable deep-red fluorescent probe. Biosens. Bioelectron 2015, 68, 189– 196,  DOI: 10.1016/j.bios.2014.12.055
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    9a
    Imaging of nucleolar RNA in living cells using a highly photostable deep-red fluorescent probe
    Zhou, Bingjiang; Liu, Weimin; Zhang, Hongyan; Wu, Jiasheng; Liu, Sha; Xu, Haitao; Wang, Pengfei
    Biosensors & Bioelectronics (2015), 68 (), 189-196CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    A new crescent-shape fluorescent probe (named here as CP) that selectively stains RNA in nucleoli of living cells is prepd. CP shows a deep-red emission (658 nm) and a large Stokes shift because of the introduction of rigid-conjugated coumarin moiety into the mol. structure. Cell imaging expts. indicate that CP can rapidly stain nucleoli in living cells by binding with nucleolar RNA, showing performance superior to com. available nucleoli dye SYTO RNASelect in terms of high photostability and selectivity. More significantly, these excellent properties together with low cytotoxicity enable CP to monitor nucleolar RNA changes during mitosis, and after treating with anti-cancer drugs cisplatin, actinomycin D and α-amanitin. Thus, CP could be a potential tool for real-time, long-term visualization of the dynamic changes for nucleolar RNA and evaluation of the therapeutic effect for anti-cancer drugs that targeted RNA polymerase I (Pol I).
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    (b) Yao, Q.; Li, H.; Xian, L.; Xu, F.; Xia, J.; Fan, J.; Du, J.; Wang, J.; Peng, X. Differentiating RNA from DNA by a molecular fluorescent probe based on the “door-bolt” mechanism biomaterials. Biomaterials 2018, 177, 78– 87,  DOI: 10.1016/j.biomaterials.2018.05.050
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    9b
    Differentiating RNA from DNA by a molecular fluorescent probe based on the "door-bolt" mechanism biomaterials
    Yao, Qichao; Li, Haidong; Xian, Liman; Xu, Feng; Xia, Jing; Fan, Jiangli; Du, Jianjun; Wang, Jingyun; Peng, Xiaojun
    Biomaterials (2018), 177 (), 78-87CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    Although excellent fluorescent probes have been developed for DNA, good probes for RNA remain lacking. The shortage of reported and com. RNA probes is attributable to their severe interference from DNA. As DNA and RNA have similar structures but different functions, it has been an imperative challenge to develop RNA probes that differentiate from DNA. In this study, an NIR fluorescent probe, NBE, is described, which contains a bulky julolidine group that can fit in a spacious RNA pocket and emit intense fluorescence. However, NBE has no response to DNA, as it cannot intercalate into the double strands or even in the DNA minor groove. The sensing mechanism is similar to the effect of a door-bolt. NBE shows excellent performance in RNA sensing (outstanding photostability, high selectivity and fast response), whether in aq. buffers, fixed cells or living cells. These findings might provide not only a potential imaging tool but also a new design strategy for the recognition of RNA while avoiding interference from DNA.
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    (c) Guo, L.; Chan, M. S.; Xu, D.; Tam, D. Y.; Bolze, F.; Lo, P. K.; Wong, M. S. Indole-based cyanine as a nuclear RNA-selective two-photon fluorescent probe for live cell imaging. ACS Chem. Biol. 2015, 10, 1171– 1175,  DOI: 10.1021/cb500927r
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    9c
    Indole-based Cyanine as a Nuclear RNA-Selective Two-Photon Fluorescent Probe for Live Cell Imaging
    Guo, Lei; Chan, Miu Shan; Xu, Di; Tam, Dick Yan; Bolze, Frederic; Lo, Pik Kwan; Wong, Man Shing
    ACS Chemical Biology (2015), 10 (5), 1171-1175CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    The subcellular targeting properties of the indole-based cyanines can be tuned by the functional substituent attached onto the indole moiety in which the first example of a highly RNA-selective and two-photon active fluorescent light-up probe for high contrast and brightness TPEF images of rRNA in the nucleolus of live cells has been developed. It is important to find that this cyanine binds much stronger toward RNA than DNA in a buffer soln. as well as selectively stains and targets to rRNA in the nucleolus. Remarkably, the TPEF brightness (Φσmax) is dramatically increased with 11-fold enhancement in the presence of rRNA, leading to the record high Φσmax of 228 GM for RNA. This probe not only shows good biocompatibility and superior photostability but also offers general applicability to various live cell lines including HeLa, HepG2, MCF-7, and KB cells and excellent counterstaining compatibility with com. available DNA or protein trackers.
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  10. 10
    Wang, C.; Lu, Y.-J.; Cai, S.-Y.; Long, W.; Zheng, Y.-Y.; Lin, J.-W.; Yan, Y.; Huang, X.-H.; Wong, W.-L.; Zhang, K.; Chow, C. F. Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach. Sens. Actuators B 2018, 262, 386– 394,  DOI: 10.1016/j.snb.2018.02.004
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    10
    Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach
    Wang, Cong; Lu, Yu-Jing; Cai, Sen-Yuan; Long, Wei; Zheng, Yuan-Yuan; Lin, Jing-Wen; Yan, Yan; Huang, Xuan-He; Wong, Wing-Leung; Zhang, Kun; Chow, Cheuk-Fai
    Sensors and Actuators, B: Chemical (2018), 262 (), 386-394CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
    The cell permeable small fluorescent org. mols. possessing RNA-specific binding property were synthesized for the study of structural influence on two detg. factors of binding affinity and specificity. The newly developed and structurally simple ligands show much higher RNA-binding affinity (equil. binding const.: PI1, K = 4.50 × 105 M-1; PI2, K = 4.48 × 105 M-1) than that of a well-studied RNA-selective dye E36 (K = 0.89 × 105 M-1) by the introduction of an aminoethylpiperidine group on the quinolinium scaffold. In addn., the in vivo study of live cell imaging (human prostate cancer cells) indicated that these small mols. are able to provide strong interaction signals when binding with RNA in the region of nucleolus and cytoplasm. The interaction specificity of the mol. towards RNA is found much higher than other types of nucleic acids, which was further supported by the digest tests with RNase (RNase). The exptl. results of the present study not only provide important cues on the fluorescent signaling, binding affinity, and specificity advancement with the small RNA-specific binding ligands through structurally refinement of mol. scaffolds, but also give complementary information in searching lead ligands for targeting RNA sequence using high-throughput compd. screening techniques and mol. modeling studies.
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  11. 11
    (a) Yoshino, Y.; Sato, Y.; Nishizawa, S. Deep-red light-up signaling of benzo[c,d]indole-quinoline monomethine cyanine for imaging of nucleolar RNA in living cells and for sequence-selective RNA analysis. Anal. Chem. 2019, 91, 14254– 14260,  DOI: 10.1021/acs.analchem.9b01997
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    11a
    Deep-Red Light-up Signaling of Benzo[c,d]indole-Quinoline Monomethine Cyanine for Imaging of Nucleolar RNA in Living Cells and for Sequence-Selective RNA Analysis
    Yoshino, Yukina; Sato, Yusuke; Nishizawa, Seiichi
    Analytical Chemistry (Washington, DC, United States) (2019), 91 (22), 14254-14260CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    RNA-binding small probes with deep-red emission are promising for RNA anal. in biol. media without suffering from background fluorescence. Here benzo[c,d]indole-quinoline (BIQ), an asym. monomethine cyanine analog, was newly developed as a novel RNA-selective probe with light-up signaling ability in the deep-red spectral range. BIQ features a significant light-up response (105-fold) with an emission max. at 657 nm as well as improved photostability over the com. available RNA-selective probe, SYTO RNA select. BIQ was successfully applied to the fluorescence imaging of nucleolar RNAs in living cells with negligible cytotoxicity. Furthermore, we found the useful ability of BIQ as a base surrogate integrated in peptide nucleic acid (PNA) oligonucleotides for RNA sequence anal. BIQ base surrogate functioned as a deep-red light-up base surrogate in forced intercalation (FIT) and triplex-forming FIT (tFIT) systems for the sequence-selective detection of single-stranded and double-stranded RNAs, resp.
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    (b) Sato, Y.; Igarashi, Y.; Suzuki, M.; Higuchi, K.; Nishizawa, S. Deep-red fluorogenic cyanine dyes carrying an amino-group-terminated side chain for improved RNA detection and nucleolar RNA imaging. RSC Adv. 2021, 11, 35436– 35439,  DOI: 10.1039/D1RA05872J
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    11b
    Deep-red fluorogenic cyanine dyes carrying an amino group-terminated side chain for improved RNA detection and nucleolar RNA imaging
    Sato, Yusuke; Igarashi, Yugo; Suzuki, Michiyuki; Higuchi, Kei; Nishizawa, Seiichi
    RSC Advances (2021), 11 (56), 35436-35439CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    The introduction of an amino-group-terminated side chain into deep-red emissive benzo[c,d]indole-quinoline monomethine cyanine dye has led to the improved detection of RNAs as well as the imaging of nucleolar RNAs in cells.
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  12. 12
    (a) Kovalska, V. B.; Tokar, V. P.; Losytskyy, M. Y.; Deligeorgiev, T.; Vassilev, A.; Gadjev, N.; Drexhage, K. H.; Yarmoluk, S. M. Studies of monomeric and homodimeric oxazolo[4,5-b]pyridinium cyanine dyes as fluorescent probes for nucleic acids visualization. J. Biochem. Biophys. Methods 2006, 68, 155– 165,  DOI: 10.1016/j.jbbm.2006.04.006
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    12a
    Studies of monomeric and homodimeric oxazolo[4,5-b]pyridinium cyanine dyes as fluorescent probes for nucleic acids visualization
    Kovalska, V. B.; Tokar, V. P.; Losytskyy, M. Yu.; Deligeorgiev, T.; Vassilev, A.; Gadjev, N.; Drexhage, K.-H.; Yarmoluk, S. M.
    Journal of Biochemical and Biophysical Methods (2006), 68 (3), 155-165CODEN: JBBMDG; ISSN:0165-022X. (Elsevier Ltd.)
    The series of recently synthesized monomeric and homodimeric cyanine dyes based on monomethine cyanine chromophore with oxazolo[4,5-b]pyridinium and quinoline end groups were studied as possible fluorescent probes for nucleic acids detection. Significant fluorescence enhancement and intensity level (quantum yield up to 0.75) was obsd. for all the dyes in the presence of DNA. The oxazolo[4,5-b]pyridinium cyanines demonstrated high sensitivity as fluorescent stains for post-electrophoretic visualization of nucleic acids in agarose gels upon both VIS and UV transillumination, and the visualized band contained 0.8 ng of dsDNA.
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    (b) Hövelmann, F.; Gaspar, I.; Ephrussi, A.; Seitz, O. Brightness enhanced DNA FIT-probes for wash-free RNA imaging in tissues. J. Am. Chem. Soc. 2013, 135, 19025– 19032,  DOI: 10.1021/ja410674h
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    12b
    Brightness enhanced DNA FIT-probes for wash-free RNA imaging in tissue
    Hovelmann Felix; Gaspar Imre; Ephrussi Anne; Seitz Oliver
    Journal of the American Chemical Society (2013), 135 (50), 19025-32 ISSN:.
    Fluorogenic oligonucleotides enable RNA imaging in cells and tissues. A high responsiveness of fluorescence is required when unbound probes cannot be washed away. Furthermore, emission should be bright in order to enable detection against autofluorescent background. The development of fluorescence-quenched hybridization probes has led to remarkable improvement of fluorescence responsiveness. Yet, comparably little attention has been paid to the brightness of smart probes. We describe hybridization probes that combine responsiveness with a high brightness of the measured signal. The method relies upon quencher-free DNA forced intercalation (FIT)-probes, in which two (or more) intercalator dyes of the thiazole orange (TO) family serve as nucleobase surrogates. Initial experiments on multi-TO-labeled probes led to improvements of responsiveness, but self-quenching limited their brightness. To enhance both brightness and responsiveness the highly responsive TO nucleoside was combined with the highly emissive oxazolopyridine analogue JO. Single-stranded TO/JO FIT-probes are dark. In the probe-target duplex, quenching caused by torsional twisting and dye-dye contact is prevented. The TO nucleoside appears to serve as a light collector that increases the extinction coefficient and transfers excitation energy to the JO emitter. This leads to very bright JO emission upon hybridization (F/F0 = 23, brightness = 43 mL mol(-1) cm(-1) at λex = 516 nm). TO/JO FIT-probes allowed the direct fluorescence microscopic imaging of oskar mRNA within a complex tissue. Of note, RNA imaging was feasible under wide-field excitation conditions. The described protocol enables rapid RNA imaging in tissue without the need for cutting-edge equipment, time-consuming washing, or signal amplification.
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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c3isVykuw%253D%253D&md5=8b4239a014ba2e025b6ad898fa255419
  13. 13
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    A red fluorescent probe, PFB, is designed and synthesized, which presents several remarkable features including a large Stokes shift (85nm), long emission wavelength, high photostability and good biocompatibility. PFB also displays the solvent-dependent effect, which is verified by the d. functional theory (DFT) calcns. Addnl., PFB can act as a fluorescent probe for cellular imaging with high uptake efficiency and highly sensitive detection toward RNA under low optimum concn. (1μM), which enables it to achieve cancer cell tracing in vitro and tumor growth monitoring in vivo. The results of real-time tracking expt. reveal that PFB can be traced in stained HepG-2 cells for 11 generations and monitor tumor growth for 18 days. This work highlights the potential application of PFB as a promising alternative to the com. RNA fluorescent probes.
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    Chemical Communications (Cambridge, United Kingdom) (2013), 49 (37), 3890-3892CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Hydrogen sulfide (H2S) is emerging as an important gasotransmitter but remains difficult to study. Here we report a novel two-photon fluorescent probe with NIR emission for H2S detection. It was successfully used to realize H2S imaging in bovine serum, living cells, tissues as well as in living mice.
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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of Benzo[c,d]indole-oxazolo[5,4-c]pyridine (BIOP)a
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    aReagents and conditions: (a) potassium ethyl xanthate, EtOH, reflux, 93%; (b) iodomethane, DMF, 61%; (c) methyl p-toluenesulfonate, 130 °C, 28%; (d) 1,2-dimethylbenzo[c,d]indol-1-ium iodide (3), NEt3, MeCN, 40 °C, 14%.

    Figure 1

    Figure 1. Fluorescence spectra of BIOP (1.0 μM) in the absence (a) and presence of (b) 1.0 mM E. coli total RNA or (c) 1.0 mM ctDNA. Measurements were done in 10 mM sodium phosphate buffer solution (pH 7.0) containing 100 mM NaCl and 1.0 mM EDTA. Excitation: 530 nm. Temperature: 25 °C.

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    Figure 2

    Figure 2. (A) Fluorescence image of living MCF7 cells incubated with 0.5 μM BIOP for 20 min. Fluorescence intensity profile along the white line is also shown, where the fluorescence in the nucleolus is highlighted. (B) Fluorescence images of fixed-permeabilized MCF7 cells stained with 0.5 μM BIOP before (control) and after treatment of RNase or DNase. Fluorescence intensity profiles along the white line are also shown. (C) Fluorescence image of living MCF7 cells incubated with 0.5 μM SYTO RNA select for 20 min. Fluorescence intensity profile along the white line is also shown. Scale bar: 15 μm.

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    Figure 3

    Figure 3. Fluorescence image of living MCF7 cells incubated with 50 nM BIOP for 20 min. Fluorescence intensity profile along the white line is also shown, where the fluorescence in the nucleolus is highlighted. Scale bar: 15 μm.

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  • References

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      A review. Sequence-specific detection of intracellular RNA is one of the most important approaches to understand life phenomena. However, it is difficult to detect RNA in living cells because of its variety and scarcity. In the last three decades, several chem. probes have been developed for RNA detection in living cells. These probes are composed of DNA or artificial nucleic acid and hybridize with the target RNA in a sequence-specific manner. This hybridization triggers a change of fluorescence or a chem. reaction. In this review, we classify the probes according to the assocd. fluorogenic mechanism, i.e., interaction between fluorophore and quencher, environmental change of fluorophore, and template reaction with/without ligation. In addn., we introduce examples of RNA imaging in living cells.
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      Low molecular weight fluorescent probes with good photostability for imaging RNA-rich nucleolus and RNA in cytoplasm in living cells
      Song, Guofen; Sun, Yuming; Liu, Yong; Wang, Xiankun; Chen, Meiling; Miao, Fang; Zhang, Weijia; Yu, Xiaoqiang; Jin, Jianling
      Biomaterials (2014), 35 (7), 2103-2112CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      We have synthesized two low mol. wt. org. mols., PY and IN successfully, which selectively stain nucleolus and cytoplasm of living cells in 30 min, with a much lower uptake in the nucleus. Nucleic acids electrophoresis and digest test of RNase indicate their markedly higher affinity for RNA, esp. PY. Moreover their RNA localization in cells is further supported by digest test of RNase, namely, the nucleolar fluorescence signal is distinctly lost upon treatment with RNase. And, the fact that live cells stained by PY and IN still possess physiol. function can be confirmed: MTT assay demonstrates that the mitochondria of cells stained remains its electron mediating ability, and double assay of PY/IN and propidium iodide as well as trypan blue testing show that the membrane of cells stained still is intact. Importantly, compared with the only com. RNA probe, SYTO RNA-Select, PY and IN exhibit much better photostability when continuously illuminated with 488 nm laser and mercury lamp. These results prove that PY and IN are very attractive staining reagents for visualizing RNA in living cells.
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      The search for structure-specific nucleic acid-interactive drugs: Effects of compound structure on RNA versus DNA interaction strength
      Wilson, W. David; Ratmeyer, Lynda; Zhao, Min; Strekowski, Lucjan; Boykin, David
      Biochemistry (1993), 32 (15), 4098-104CODEN: BICHAW; ISSN:0006-2960.
      The RNA genomes of a no. of pathogenic RNA viruses, such as HIV-1, have extensive folded conformations with imperfect A-form duplexes that are essential for virus function and could serve as targets for structure-specific antiviral drugs. As an initial step in the discovery of such drugs, the interactions with RNA of a wide variety of compds., which are known to bind to DNA in the minor groove, by classical or by threading intercalation, have been evaluated by thermal melting and viscometric analyses. The corresponding sequence RNA and DNA polymers, poly(A)·poly(U) and poly(dA)·poly(dT), were used as test systems for anal. of RNA binding strength and selectivity. Compds. that bind exclusively in the minor groove at AT sequences of DNA (e.g., netropsin, distamycin, and a zinc porphyrin deriv.) do not have significant interactions with RNA. Compds. that bind in the minor groove in AT sequences of DNA but have other favorable interactions in GC sequences of DNA (e.q., Hoechst 33258, DAPI, and other arom. diamidines) can have very strong RNA interactions. A group of classical intercalators and a group of intercalators with unfused arom. ring systems contain compds. that intercalate and have strong interactions with RNA. At this time, no clear pattern of mol. structure that favors RNA over DNA interactions for intercalators has emerged. Compds. that bind to DNA by threading intercalation generally bind to RNA by the same mode, but none of the threading intercalators tested to date have shown selective interactions with RNA.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXltlSqsro%253D&md5=b8fcae2a762911d46c65dfcf069df884
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      Strong and selective binding of amiloride to an abasic site in RNA duplexes: Thermodynamic characterization and microRNA detection
      Sato, Yusuke; Ichihashi, Toshiki; Nishizawa, Seiichi; Teramae, Norio
      Angewandte Chemie, International Edition (2012), 51 (26), 6369-6372, S6369/1-S6369/9CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The binding characteristics of amiloride to abasic (AP) site-contg. duplex RNA were examd. by fluorescence, CD (CD), and isothermal titrn. calorimetry (ITC) measurements, and the obtained data were compared with the corresponding AP site-contg. DNA duplexes (AP-DNA). Addn. of AP-RNA causes a significant enhancement in the fluorescence intensity of amiloride, whereas no response is obsd. for a fully-matched RNA duplex having no AP sites as well as single-stranded RNAs consisting of AP-RNA, indicate highly selective binding of amiloride to the AP site of AP-RNA. The titrn. curve was well fitted by a 1:1 binding isotherm, which gives a dissocn. const. Ki of (9.5 ± 0.66) nM. The addn. of amiloride to AP-RNA causes little change in the CD spectrum, indicating that the resulting amiloride/AP-RNA complex remains in the A-form without any drastic conformational change. The A-form geometry in the nucleic acids allows more extensive base-base overlap and provides more efficient stacking interactions of nucleotides than the B-form geometry of AP-DNA. Thermodn. characterization by isothermal titrn. calorimetry (ITC) supports the efficient stacking interaction at the AP site of AP-RNA. Moreover, amiloride is applicable to the detection of microRNAs (miRNAs) that have been assocd. with various diseases, based on the sensitive fluorescence response of the amiloride binding to the AP site in RNA duplexes.
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      (a) Wu, Y.; Liu, Y.; Lu, C.; Lei, S.; Li, J.; Du, G. Quantification of RNA by a fluorometric method using the SYTO RNA Select stain. Anal. Biochem. 2020, 606, 113857,  DOI: 10.1016/j.ab.2020.113857
      6a
      Quantitation of RNA by a fluorometric method using the SYTO RNASelect stain
      Wu, Yexu; Liu, Yanfeng; Lu, Chuanchuan; Lei, Senlin; Li, Jianghua; Du, Guocheng
      Analytical Biochemistry (2020), 606 (), 113857CODEN: ANBCA2; ISSN:0003-2697. (Elsevier B.V.)
      Quantitation of even trace amts. of RNA has biol. significance. However, existing methods of RNA estn. are not capable of eliminating the interference of other impurities, esp. DNA. The authors developed a rapid and sensitive method for fluorometric estn. of RNA using an RNA-specific dye, SYTO RNASelect. A good linear correlation between the fluorescence intensity and RNA concn. was obsd. using this method. The maximal fluorescence intensity of DNA was only 2.9% of the fluorescence intensity of 40μg/mL RNA, demonstrating the high RNA specificity of the SYTO RNASelect method.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsF2qtb7I&md5=6cab265414aecba3241af65473076a08
      (b) de Voogt, W. S.; Tanenbaum, M. E.; Vader, P. Illuminating RNA trafficking and functional delivery by extracellular vesicles. Adv. Drug Delivery Rev. 2021, 174, 250– 264,  DOI: 10.1016/j.addr.2021.04.017
      6b
      Illuminating RNA trafficking and functional delivery by extracellular vesicles
      de Voogt, Willemijn S.; Tanenbaum, Marvin E.; Vader, Pieter
      Advanced Drug Delivery Reviews (2021), 174 (), 250-264CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. RNA-based therapeutics are highly promising for the treatment of numerous diseases, by their ability to tackle the genetic origin in multiple possible ways. RNA mols. are, however, incapable of crossing cell membranes, hence a safe and efficient delivery vehicle is pivotal. Extracellular vesicles (EVs) are endogenously derived nano-sized particles and possess several characteristics which make them excellent candidates as therapeutic RNA delivery agent. This includes the inherent capability to functionally tRNAs in a selective manner and an enhanced safety profile compared to synthetic particles. Nonetheless, the fundamental mechanisms underlying this selective inter- and intracellular trafficking and functional transfer of RNAs by EVs are poorly understood. Improving our understanding of these systems is a key element of working toward an EV-based or EV-mimicking system for the functional delivery of therapeutic RNA. In this review, state-of-the-art approaches to detect and visualize RNA in situ and in live cells are discussed, as well as strategies to assess functional RNA transfer, highlighting their potential in studying EV-RNA trafficking mechanisms.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVGht7zP&md5=04ec3269a2348bd0276bee180e225f0b
    7. 7
      (a) Lu, Y.-J.; Deng, Q.; Hu, D.-P.; Wang, Z.-Y.; Huang, B.-H.; Du, Z.-Y.; Fang, Y.-X.; Wong, W.-L.; Zhang, K.; Chow, C.-F. A molecular fluorescent dye for specific staining and imaging of RNA in live cells: A novel ligand integration from classical thiazole orange and styryl compounds. Chem. Commun. 2015, 51, 15241– 15244,  DOI: 10.1039/C5CC05551B
      7a
      A molecular fluorescent dye for specific staining and imaging of RNA in live cells: a novel ligand integration from classical thiazole orange and styryl compounds
      Lu, Yu-Jing; Deng, Qiang; Hu, Dong-Ping; Wang, Zheng-Ya; Huang, Bao-Hua; Du, Zhi-Yun; Fang, Yan-Xiong; Wong, Wing-Leung; Zhang, Kun; Chow, Cheuk-Fai
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (83), 15241-15244CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A new RNA-selective fluorescent dye (I) integrated with a thiazole orange and a p-(methylthio)styryl moiety shows better nucleolus RNA staining and imaging performance in live cells than the com. stains. I also exhibits excellent photostability, cell tolerance, and counterstain compatibility with 4',6-diamidino-2-phenylindole for specific RNA-DNA colocalization in bioassays.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOrt7fK&md5=98958a1a49f8c744c23faa554543d662
      (b) Liu, J.; Zhang, S.; Zhang, C.; Dong, J.; Shen, C.; Zhu; Xu, H.; Fu, M.; Yang, G.; Zhang, X. A water-soluble two-photon ratiometric triarylboron probe with nucleolar targeting by preferential RNA binding. Chem. Commun. 2017, 53, 11476– 11479,  DOI: 10.1039/C7CC06045A
      7b
      A water-soluble two-photon ratiometric triarylboron probe with nucleolar targeting by preferential RNA binding
      Liu, Jun; Zhang, Shilu; Zhang, Chenghua; Dong, Jun; Shen, Chengyi; Zhu, Jiang; Xu, Huajun; Fu, Mingkai; Yang, Guoqiang; Zhang, Xiaoming
      Chemical Communications (Cambridge, United Kingdom) (2017), 53 (83), 11476-11479CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      By functionalizing triarylboron with cyclen, we developed a two-photon fluorescence probe, TAB-2 (I), which can selectively bind RNA with a ratiometric readout. We tested I in NIH/3T3 fibroblast cells, and demonstrated its capability in visualizing nucleoli and analyzing microenvironment polarity by two-photon and fluorescence-lifetime imaging microscopy.
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    8. 8
      (a) Li, Q.; Kim, Y.; Namm, J.; Kulkarni, A.; Rosania, G. R.; Ahn, Y.-H.; Chang, Y.-T. RNA-selective, live cell imaging probes for studying nuclear structure and function. Chem. Biol. 2006, 13, 615– 623,  DOI: 10.1016/j.chembiol.2006.04.007
      8a
      RNA-Selective, Live Cell Imaging Probes for Studying Nuclear Structure and Function
      Li, Qian; Kim, Yunkyung; Namm, Joshua; Kulkarni, Amita; Rosania, Gus R.; Ahn, Young-Hoon; Chang, Young-Tae
      Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (6), 615-623CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
      The higher-order structural organization of the cell nucleus reflects the underlying genome-wide transcriptional activity and macromol. transport processes. To study the microscopic organization of RNA distribution within the nucleus, a combinatorial library of fluorescent styryl mols. was synthesized and screened for an in vitro RNA response and live cell nuclear imaging. Four different cell lines (HeLa, A549, 3T3, and 3T3-L1) were analyzed in terms of higher-order nuclear organization. The authors identified RNA-selective dyes with better imaging properties relative to com. available SYTORNASelect dye; the selected dyes were also cell permeant, photostable, and well tolerated by the cells. The authors' dyes also had very good counterstain compatibility with Hoechst and DAPI, which could help to image the DNA distribution in relation to RNA distribution in live cells and therefore reveal different patterns of RNA-DNA colocalization.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFGqsL0%253D&md5=34b4697433dcb0b49d7db4adc7da5dd8
      (b) Cao, C.; Wei, P.; Li, R.; Zhong, Y.; Li, X.; Xue, F.; Shi, Y.; Yi, T. Ribosomal RNA-selective light-up fluorescent probe for rapidly imaging the nucleolus in live cells. ACS Sens 2019, 4, 1409– 1416,  DOI: 10.1021/acssensors.9b00464
      8b
      Ribosomal RNA-Selective Light-Up Fluorescent Probe for Rapidly Imaging the Nucleolus in Live Cells
      Cao, Chunyan; Wei, Peng; Li, Ruohan; Zhong, Yaping; Li, Xiang; Xue, Fengfeng; Shi, Yibing; Yi, Tao
      ACS Sensors (2019), 4 (5), 1409-1416CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      RNA-based fluorescent probes are currently limited by their low selectivity toward RNA vs. DNA, and low specificity to different RNA structures. Poor membrane permeability is another defect of existing fluorogenic RNA probes for intracellular imaging. In this work, a naphthalimide deriv., probe I, was developed for the rapid and selective detection of intracellular rRNA. Probe I exhibited a 32-fold fluorescent enhancement in response to rRNA binding and showed desirable selectivity for rRNA vs. DNA and other nucleic acids in phosphate buffer at pH 7.2. Importantly, probe I displayed excellent permeability of the nucleolus, could be taken up in 1 min by four different cell lines, and may be the fastest nucleolus dye. The excellent selectivity of probe I toward rRNA is attributed to the specific interaction between the complicated 3D structures of rRNA, which was confirmed by quantum calcns. using mol. docking simulations. An appropriate lipophilic balance in I with the hydrophilic amine group and hydrophobic naphthalimide, as well as its high water soly., guarantees the high permeability of I in cell membranes and nucleolus pores, compared to other analogs (e.g., probes 2-8 in this work). Furthermore, enlarged confocal laser micro images of nucleoli and RNase digestion tests revealed that I remained highly selective toward rRNA, even for intracellular imaging. As a live cell probe, I also exhibited better photostability than the com. RNA dye, SYTO RNA select.
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    9. 9
      (a) Zhou, B.; Liu, W.; Zhang, H.; Wu, J.; Liu, S.; Xu, H.; Wang, P. Imaging nucleolar RNA in living cells using a highly photostable deep-red fluorescent probe. Biosens. Bioelectron 2015, 68, 189– 196,  DOI: 10.1016/j.bios.2014.12.055
      9a
      Imaging of nucleolar RNA in living cells using a highly photostable deep-red fluorescent probe
      Zhou, Bingjiang; Liu, Weimin; Zhang, Hongyan; Wu, Jiasheng; Liu, Sha; Xu, Haitao; Wang, Pengfei
      Biosensors & Bioelectronics (2015), 68 (), 189-196CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      A new crescent-shape fluorescent probe (named here as CP) that selectively stains RNA in nucleoli of living cells is prepd. CP shows a deep-red emission (658 nm) and a large Stokes shift because of the introduction of rigid-conjugated coumarin moiety into the mol. structure. Cell imaging expts. indicate that CP can rapidly stain nucleoli in living cells by binding with nucleolar RNA, showing performance superior to com. available nucleoli dye SYTO RNASelect in terms of high photostability and selectivity. More significantly, these excellent properties together with low cytotoxicity enable CP to monitor nucleolar RNA changes during mitosis, and after treating with anti-cancer drugs cisplatin, actinomycin D and α-amanitin. Thus, CP could be a potential tool for real-time, long-term visualization of the dynamic changes for nucleolar RNA and evaluation of the therapeutic effect for anti-cancer drugs that targeted RNA polymerase I (Pol I).
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      (b) Yao, Q.; Li, H.; Xian, L.; Xu, F.; Xia, J.; Fan, J.; Du, J.; Wang, J.; Peng, X. Differentiating RNA from DNA by a molecular fluorescent probe based on the “door-bolt” mechanism biomaterials. Biomaterials 2018, 177, 78– 87,  DOI: 10.1016/j.biomaterials.2018.05.050
      9b
      Differentiating RNA from DNA by a molecular fluorescent probe based on the "door-bolt" mechanism biomaterials
      Yao, Qichao; Li, Haidong; Xian, Liman; Xu, Feng; Xia, Jing; Fan, Jiangli; Du, Jianjun; Wang, Jingyun; Peng, Xiaojun
      Biomaterials (2018), 177 (), 78-87CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      Although excellent fluorescent probes have been developed for DNA, good probes for RNA remain lacking. The shortage of reported and com. RNA probes is attributable to their severe interference from DNA. As DNA and RNA have similar structures but different functions, it has been an imperative challenge to develop RNA probes that differentiate from DNA. In this study, an NIR fluorescent probe, NBE, is described, which contains a bulky julolidine group that can fit in a spacious RNA pocket and emit intense fluorescence. However, NBE has no response to DNA, as it cannot intercalate into the double strands or even in the DNA minor groove. The sensing mechanism is similar to the effect of a door-bolt. NBE shows excellent performance in RNA sensing (outstanding photostability, high selectivity and fast response), whether in aq. buffers, fixed cells or living cells. These findings might provide not only a potential imaging tool but also a new design strategy for the recognition of RNA while avoiding interference from DNA.
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      (c) Guo, L.; Chan, M. S.; Xu, D.; Tam, D. Y.; Bolze, F.; Lo, P. K.; Wong, M. S. Indole-based cyanine as a nuclear RNA-selective two-photon fluorescent probe for live cell imaging. ACS Chem. Biol. 2015, 10, 1171– 1175,  DOI: 10.1021/cb500927r
      9c
      Indole-based Cyanine as a Nuclear RNA-Selective Two-Photon Fluorescent Probe for Live Cell Imaging
      Guo, Lei; Chan, Miu Shan; Xu, Di; Tam, Dick Yan; Bolze, Frederic; Lo, Pik Kwan; Wong, Man Shing
      ACS Chemical Biology (2015), 10 (5), 1171-1175CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      The subcellular targeting properties of the indole-based cyanines can be tuned by the functional substituent attached onto the indole moiety in which the first example of a highly RNA-selective and two-photon active fluorescent light-up probe for high contrast and brightness TPEF images of rRNA in the nucleolus of live cells has been developed. It is important to find that this cyanine binds much stronger toward RNA than DNA in a buffer soln. as well as selectively stains and targets to rRNA in the nucleolus. Remarkably, the TPEF brightness (Φσmax) is dramatically increased with 11-fold enhancement in the presence of rRNA, leading to the record high Φσmax of 228 GM for RNA. This probe not only shows good biocompatibility and superior photostability but also offers general applicability to various live cell lines including HeLa, HepG2, MCF-7, and KB cells and excellent counterstaining compatibility with com. available DNA or protein trackers.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisl2nsLY%253D&md5=922e4cd12a8af5a501fccac108662170
    10. 10
      Wang, C.; Lu, Y.-J.; Cai, S.-Y.; Long, W.; Zheng, Y.-Y.; Lin, J.-W.; Yan, Y.; Huang, X.-H.; Wong, W.-L.; Zhang, K.; Chow, C. F. Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach. Sens. Actuators B 2018, 262, 386– 394,  DOI: 10.1016/j.snb.2018.02.004
      10
      Advancing small ligands targeting RNA for better binding affinity and specificity: A study of structural influence through molecular design approach
      Wang, Cong; Lu, Yu-Jing; Cai, Sen-Yuan; Long, Wei; Zheng, Yuan-Yuan; Lin, Jing-Wen; Yan, Yan; Huang, Xuan-He; Wong, Wing-Leung; Zhang, Kun; Chow, Cheuk-Fai
      Sensors and Actuators, B: Chemical (2018), 262 (), 386-394CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
      The cell permeable small fluorescent org. mols. possessing RNA-specific binding property were synthesized for the study of structural influence on two detg. factors of binding affinity and specificity. The newly developed and structurally simple ligands show much higher RNA-binding affinity (equil. binding const.: PI1, K = 4.50 × 105 M-1; PI2, K = 4.48 × 105 M-1) than that of a well-studied RNA-selective dye E36 (K = 0.89 × 105 M-1) by the introduction of an aminoethylpiperidine group on the quinolinium scaffold. In addn., the in vivo study of live cell imaging (human prostate cancer cells) indicated that these small mols. are able to provide strong interaction signals when binding with RNA in the region of nucleolus and cytoplasm. The interaction specificity of the mol. towards RNA is found much higher than other types of nucleic acids, which was further supported by the digest tests with RNase (RNase). The exptl. results of the present study not only provide important cues on the fluorescent signaling, binding affinity, and specificity advancement with the small RNA-specific binding ligands through structurally refinement of mol. scaffolds, but also give complementary information in searching lead ligands for targeting RNA sequence using high-throughput compd. screening techniques and mol. modeling studies.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFKmsbo%253D&md5=a76a456d28f0f3151bdfb9e61ee23e22
    11. 11
      (a) Yoshino, Y.; Sato, Y.; Nishizawa, S. Deep-red light-up signaling of benzo[c,d]indole-quinoline monomethine cyanine for imaging of nucleolar RNA in living cells and for sequence-selective RNA analysis. Anal. Chem. 2019, 91, 14254– 14260,  DOI: 10.1021/acs.analchem.9b01997
      11a
      Deep-Red Light-up Signaling of Benzo[c,d]indole-Quinoline Monomethine Cyanine for Imaging of Nucleolar RNA in Living Cells and for Sequence-Selective RNA Analysis
      Yoshino, Yukina; Sato, Yusuke; Nishizawa, Seiichi
      Analytical Chemistry (Washington, DC, United States) (2019), 91 (22), 14254-14260CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      RNA-binding small probes with deep-red emission are promising for RNA anal. in biol. media without suffering from background fluorescence. Here benzo[c,d]indole-quinoline (BIQ), an asym. monomethine cyanine analog, was newly developed as a novel RNA-selective probe with light-up signaling ability in the deep-red spectral range. BIQ features a significant light-up response (105-fold) with an emission max. at 657 nm as well as improved photostability over the com. available RNA-selective probe, SYTO RNA select. BIQ was successfully applied to the fluorescence imaging of nucleolar RNAs in living cells with negligible cytotoxicity. Furthermore, we found the useful ability of BIQ as a base surrogate integrated in peptide nucleic acid (PNA) oligonucleotides for RNA sequence anal. BIQ base surrogate functioned as a deep-red light-up base surrogate in forced intercalation (FIT) and triplex-forming FIT (tFIT) systems for the sequence-selective detection of single-stranded and double-stranded RNAs, resp.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFektr7O&md5=86fe5d3e467d2c4c4039f47b1c103221
      (b) Sato, Y.; Igarashi, Y.; Suzuki, M.; Higuchi, K.; Nishizawa, S. Deep-red fluorogenic cyanine dyes carrying an amino-group-terminated side chain for improved RNA detection and nucleolar RNA imaging. RSC Adv. 2021, 11, 35436– 35439,  DOI: 10.1039/D1RA05872J
      11b
      Deep-red fluorogenic cyanine dyes carrying an amino group-terminated side chain for improved RNA detection and nucleolar RNA imaging
      Sato, Yusuke; Igarashi, Yugo; Suzuki, Michiyuki; Higuchi, Kei; Nishizawa, Seiichi
      RSC Advances (2021), 11 (56), 35436-35439CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      The introduction of an amino-group-terminated side chain into deep-red emissive benzo[c,d]indole-quinoline monomethine cyanine dye has led to the improved detection of RNAs as well as the imaging of nucleolar RNAs in cells.
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    12. 12
      (a) Kovalska, V. B.; Tokar, V. P.; Losytskyy, M. Y.; Deligeorgiev, T.; Vassilev, A.; Gadjev, N.; Drexhage, K. H.; Yarmoluk, S. M. Studies of monomeric and homodimeric oxazolo[4,5-b]pyridinium cyanine dyes as fluorescent probes for nucleic acids visualization. J. Biochem. Biophys. Methods 2006, 68, 155– 165,  DOI: 10.1016/j.jbbm.2006.04.006
      12a
      Studies of monomeric and homodimeric oxazolo[4,5-b]pyridinium cyanine dyes as fluorescent probes for nucleic acids visualization
      Kovalska, V. B.; Tokar, V. P.; Losytskyy, M. Yu.; Deligeorgiev, T.; Vassilev, A.; Gadjev, N.; Drexhage, K.-H.; Yarmoluk, S. M.
      Journal of Biochemical and Biophysical Methods (2006), 68 (3), 155-165CODEN: JBBMDG; ISSN:0165-022X. (Elsevier Ltd.)
      The series of recently synthesized monomeric and homodimeric cyanine dyes based on monomethine cyanine chromophore with oxazolo[4,5-b]pyridinium and quinoline end groups were studied as possible fluorescent probes for nucleic acids detection. Significant fluorescence enhancement and intensity level (quantum yield up to 0.75) was obsd. for all the dyes in the presence of DNA. The oxazolo[4,5-b]pyridinium cyanines demonstrated high sensitivity as fluorescent stains for post-electrophoretic visualization of nucleic acids in agarose gels upon both VIS and UV transillumination, and the visualized band contained 0.8 ng of dsDNA.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVGntbg%253D&md5=2fed135ad3d60eece47001ca3a08049e
      (b) Hövelmann, F.; Gaspar, I.; Ephrussi, A.; Seitz, O. Brightness enhanced DNA FIT-probes for wash-free RNA imaging in tissues. J. Am. Chem. Soc. 2013, 135, 19025– 19032,  DOI: 10.1021/ja410674h
      12b
      Brightness enhanced DNA FIT-probes for wash-free RNA imaging in tissue
      Hovelmann Felix; Gaspar Imre; Ephrussi Anne; Seitz Oliver
      Journal of the American Chemical Society (2013), 135 (50), 19025-32 ISSN:.
      Fluorogenic oligonucleotides enable RNA imaging in cells and tissues. A high responsiveness of fluorescence is required when unbound probes cannot be washed away. Furthermore, emission should be bright in order to enable detection against autofluorescent background. The development of fluorescence-quenched hybridization probes has led to remarkable improvement of fluorescence responsiveness. Yet, comparably little attention has been paid to the brightness of smart probes. We describe hybridization probes that combine responsiveness with a high brightness of the measured signal. The method relies upon quencher-free DNA forced intercalation (FIT)-probes, in which two (or more) intercalator dyes of the thiazole orange (TO) family serve as nucleobase surrogates. Initial experiments on multi-TO-labeled probes led to improvements of responsiveness, but self-quenching limited their brightness. To enhance both brightness and responsiveness the highly responsive TO nucleoside was combined with the highly emissive oxazolopyridine analogue JO. Single-stranded TO/JO FIT-probes are dark. In the probe-target duplex, quenching caused by torsional twisting and dye-dye contact is prevented. The TO nucleoside appears to serve as a light collector that increases the extinction coefficient and transfers excitation energy to the JO emitter. This leads to very bright JO emission upon hybridization (F/F0 = 23, brightness = 43 mL mol(-1) cm(-1) at λex = 516 nm). TO/JO FIT-probes allowed the direct fluorescence microscopic imaging of oskar mRNA within a complex tissue. Of note, RNA imaging was feasible under wide-field excitation conditions. The described protocol enables rapid RNA imaging in tissue without the need for cutting-edge equipment, time-consuming washing, or signal amplification.
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    13. 13
      Walczynski, K.; Zuiderveld, O. P.; Timmerman, H. Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists. Eur. J. Med. Chem. 2005, 40, 15– 23,  DOI: 10.1016/j.ejmech.2004.09.010
      13
      Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists
      Walczynski, Krzysztof; Zuiderveld, Obbe P.; Timmerman, Henk
      European Journal of Medicinal Chemistry (2005), 40 (1), 15-23CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Ltd.)
      Propylpiperazinyl benzoxazoles, benzothiazoles, oxazolopyridines, and thiazolopyridines I [X = O, S; Y, Z, A, B = CH, N (either none or one of the variable groups is N)] and their hydrobromide salts are prepd. as selective histamine H3 receptor antagonists; their histamine H3 antagonist activities and the relationship between their structures and activities are discussed. Propylpiperazinyl-substituted thiazolopyridines and a propylpiperazinyl-substituted benzothiazole are better histamine H3 antagonists than propylpiperazinyl-substituted oxazolopyridines and a propylpiperazinyl-substituted benzooxazole. I (X = S; Y = A = B = CH; Z = N) is the most potent histamine H3 antagonist of the series, with a pA2 value of 7.25, while the corresponding oxazolopyridine I (X = O; Y = A = B = CH; Z = N) has a pA2 value of 6.9.
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    14. 14
      Zhang, S.; Fan, J.; Li, Z.; Hao, N.; Cao, J.; Wu, T.; Wang, J.; Peng, X. A bright red fluorescent cyanine dye for live-cell nucleic acid imaging, with high photostability and a large Stokes shift. J. Mater. Chem. B 2014, 2, 2688– 2693,  DOI: 10.1039/C3TB21844A
      14
      A bright red fluorescent cyanine dye for live-cell nucleic acid imaging, with high photostability and a large Stokes shift
      Zhang, Si; Fan, Jiangli; Li, Zhiyong; Hao, Naijia; Cao, Jianfang; Wu, Tong; Wang, Jingyun; Peng, Xiaojun
      Journal of Materials Chemistry B: Materials for Biology and Medicine (2014), 2 (18), 2688-2693CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)
      Many probes for nucleic acids are available, but few of them satisfy multiple criteria, particularly high photostability to endure laser scanning. The authors report a cyanine dye TO3-CN (I) for the first time, synthesized by introducing a CN group to the trimethine chain of the classical red emitting TO-3 dye to improve its photostability, as well as their spectral properties and interaction with nucleic acids. TO3-CN shows excellent light fastness and a large fluorescence Stokes shift (more than 40 nm). Because of its sensitive fluorescence response to nucleic acids with a large fluorescence quantum yield (more than 0.7) and low cytotoxicity, this dye may be a potential candidate for nucleic acid detection in vitro and intracellular fluorescence imaging.
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    15. 15
      Deligeorgiev, T. G.; Gadjev, N. I.; Drexhage, K. H. Styryl dyes containing the benz[c,d]indolium hetrocycles. Dyes Pigm 1991, 15, 215– 223,  DOI: 10.1016/0143-7208(91)80006-U
      15
      Styryl dyes containing the benz[c,d]indolium heterocycle
      Deligeorgiev, T.; Gadzhiev, N.; Drexhage, K. H.
      Dyes and Pigments (1991), 15 (3), 215-23CODEN: DYPIDX; ISSN:0143-7208.
      The synthesis of I was described where R = Et, CH2CH:CH2; R1 = H or R1R2 = (CH2)3; R2 = Et or R2R3 = (CH2)4 or (CH2)2O(CH2)2; R3 = Et, CH2CH2CN or R3R4 = (CH2)3; R4 = H; R5 = EtO, MeO, OH, or H. The dyes adsorb in the region 636-686 nm. The structure of the compds. was confirmed by elemental anal., electronic adsorption spectra, IR, and, in some cases, 1H-NMR spectroscopy.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXktFSrtr4%253D&md5=9ba96b199b94bbe930a259c9f7a1e8b6
    16. 16
      Nygren, J.; Svanvik, N.; Kubista, M. The interactions between the fluorescent dye thiazole orange and DNA. Biopolymers 1998, 46, 39– 51,  DOI: 10.1002/(SICI)1097-0282(199807)46:1<39::AID-BIP4>3.0.CO;2-Z
      16
      The interactions between the fluorescent dye thiazole orange and DNA
      Nygren, Jan; Svanvik, Nicke; Kubista, Mikael
      Biopolymers (1998), 46 (1), 39-51CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
      The interaction of the fluorescent dye thiazole orange (TO) with nucleic acids is characterized. It is found that TO binds with highest affinity to double-stranded (ds) DNA [log(K) ≈ 5.5 at 100 mM salt], about 5-10 times weaker to single-stranded polypurines, and further 10-1000 times weaker to single-stranded polypyrimidines. TO binds as a monomer to dsDNAs and poly(dA), both as a monomer and as a dimer to poly(dG) and mainly as a dimer to poly(dC) and poly(dT). The fluorescence quantum yield of TO free in soln. is about 2·10-4, and it increases to about 0.1 when bound to dsDNA or to poly(dA), and to about 0.4 when bound to poly(dG). Estd. quantum yields of TO bound to poly(dC) and poly(dT) are about 0.06 and 0.01, resp. The quantum yield of bound TO depends on temp. and decreases about threefold between 5 and 50°C.
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    17. 17
      Yarmoluk, S. M.; Lukashov, S. S.; Losytskyy, M. Y.; Akerman, B.; Kornyushyna, O. S. Interactions of cyanine dyes with nucleic acids: XXVI. Intercalation of the trimethine cyanine dye cyan 2 into double-stranded DNA: study by spectral luminescence methods. Spectrochim. Acta, Part A 2002, 58, 3223– 3232,  DOI: 10.1016/S1386-1425(02)00100-2
      17
      Interaction of cyanine dyes with nucleic acids. XXVI. Intercalation of the trimethine cyanine dye Cyan 2 into double-stranded DNA: study by spectral luminescence methods
      Yarmoluk, S. M.; Lukashov, S. S.; Losytskyy, M. Yu.; Akerman, B.; Kornyushyna, O. S.
      Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2002), 58A (14), 3223-3232CODEN: SAMCAS; ISSN:1386-1425. (Elsevier Science B.V.)
      The interaction between double-stranded (ds) DNA and the cyanine dye Cyan 2 has been studied with spectral luminescence methods. Binding const. values have been detd. by fluorescence titrn. and dye distribution in the two-phase system Et acetate-water (3.6×104 and 1.5×104 M-1, resp.). Cyan 2 exhibits a small specificity for guanine-cytosine (GC) sequences in total DNA and synthetic polydeoxynucleotides poly(dA/dT) and poly(dGdC/dGdC). The DNA complexes with Cyan 2 are stable at high-ionic strength soln. when NaCl is added. The dye mol. complexed with DNA is apparently shielded from the anionic quencher-iodide ion. The neg. linear dichroism of the visible absorption band of aligned Cyan 2-DNA complexes indicates that the bound dye lies almost perpendicularly to the DNA helix axis. The linear dichroism of the absorption band at 260 nm suggests a considerable change in the DNA B-form. The results are consistent with an intercalative binding interaction between Cyan 2 and ds DNA.
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    18. 18
      Lubitz, I.; Zikich, D.; Kotlyar, A. Specific high-affinity binding of thiazole orange to triplex and G-quadruplex DNA. Biochemistry 2010, 49, 3567– 3574,  DOI: 10.1021/bi1000849
      18
      Specific High-Affinity Binding of Thiazole Orange to Triplex and G-Quadruplex DNA
      Lubitz, Irit; Zikich, Dragoslav; Kotlyar, Alexander
      Biochemistry (2010), 49 (17), 3567-3574CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      Interaction of Thiazole Orange (TO) with double-, triple-, and quadruple-stranded forms of DNA was studied. The authors have demonstrated by UV-vis absorption, CD, and fluorescence spectroscopy that TO binds with much higher affinity to triplex and G-quadruplex DNA structures compared to double-stranded (ds) DNA. Complexes of the dye with DNA triplexes and G-quadruplexes are very stable and do not dissoc. during chromatog. and gel electrophoresis. TO binding to either triple- or quadruple-stranded DNA structures results in a >1000-fold increase in dye fluorescence. The fluorescence titrn. data showed that TO to triad and tetrad ratios, in tight complexes with the triplex and the G-quadruplex, are equal to 0.5 and 1, resp. Preferential binding of TO to triplexes and G-quadruplexes enables selective detection of only these DNA forms in gels in the absence of free TO in electrophoresis running buffer. The authors have also demonstrated that incubation of U2OS cells with submicromolar concns. of TO results in preferential staining of certain areas in the nucleus in contrast to DAPI which binds to dsDNA and efficiently stains regions that are unstained with TO. The authors suggest that TO staining may be useful for the detection of noncanonical structural motifs in genomic DNA.
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    19. 19
      (a) Carreon, J. R.; Stewart, K. M.; Mahon, K. P., Jr.; Shin, S.; Kelley, S. O. Cyanine dye conjugates as probes for live cell imaging. Bioorg. Med. Chem. Lett. 2007, 17, 5182– 5185,  DOI: 10.1016/j.bmcl.2007.06.097
      19a
      Cyanine dye conjugates as probes for live cell imaging
      Carreon, Jay R.; Stewart, Kelly M.; Mahon, Kerry P.; Shin, Stephanie; Kelley, Shana O.
      Bioorganic & Medicinal Chemistry Letters (2007), 17 (18), 5182-5185CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
      A series of fluorescent compds. suitable for live cell imaging is described. Functionalized forms of four different asym. cyanine dyes are reported that are amenable to peptide conjugation. The photophys. properties of the modified dyes and conjugates and the use of the compds. as cellular imaging agents are described. The results obtained indicate that these spectrally versatile compds., which have absorption and emission profiles spanning the visible spectrum, are useful probes for cellular imaging.
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      (b) Kurutos, A.; Orehovec, I.; Saftic, D.; Horvat, L.; Crnolatac, I.; Piantanida, I.; Deligeorgiev, T. Cell penetrating, mitochondria targeting multiply charged DABCO-cyanine dyes. Dyes Pigm 2018, 158, 517– 525,  DOI: 10.1016/j.dyepig.2018.05.035
      19b
      Cell penetrating, mitochondria targeting multiply charged DABCO-cyanine dyes
      Kurutos, Atanas; Orehovec, Iva; Saftic, Dijana; Horvat, Lucija; Crnolatac, Ivo; Piantanida, Ivo; Deligeorgiev, Todor
      Dyes and Pigments (2018), 158 (), 517-525CODEN: DYPIDX; ISSN:0143-7208. (Elsevier Ltd.)
      The authors prepd. new series of lipophilic cyanine dyes equipped with several cationic quaternary ammonium moieties. This was achieved by introducing DABCO within the structures. Furthermore, to study the influence of the addnl. cationic charges on the cellular uptake, DABCO was quaternized with Me group or alkyl piperidine cation. Spectroscopic and isothermal titrn. calorimetry studies as well as MTT assay and subcellular localization using confocal laser scanning microscopy revealed that some of the presented dyes combine low anti-proliferative effect with efficient cellular uptake, high affinity towards ds-DNA/RNA and remarkable fluorescent marking of mitochondria.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVCgtL%252FL&md5=9f074fef3329833a6f014b825074ffd5
    20. 20
      (a) Shen, Y.; Shao, T.; Fang, B.; Du, W.; Zhang, M.; Liu, J.; Liu, T.; Tian, X.; Zhang, Q.; Wang, A.; Yang, J.; Wu, J.; Tian, Y. Visualization of mitochondrial DNA in living cells with super-resolution microscopy using thiophene-based terpyridine Zn (II) complexes. Chem. Commun. 2018, 54, 11288– 11291,  DOI: 10.1039/C8CC06276E
      20a
      Visualization of mitochondrial DNA in living cells with super-resolution microscopy using thiophene-based terpyridine Zn(II) complexes
      Shen, Yu; Shao, Tao; Fang, Bin; Du, Wei; Zhang, Mingzhu; Liu, Jiejie; Liu, Tianyan; Tian, Xiaohe; Zhang, Qiong; Wang, Aidong; Yang, Jiaxiang; Wu, Jieying; Tian, Yupeng
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (80), 11288-11291CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      We present a thiophene-based terpyridine Zn(II) complex (namely LC) which could specifically target live cell mitochondria via binding with mitochondrial DNA (mtDNA). Due to its high biocompatibility, red emission and photo-stability, mtDNA distribution within mitochondrial cristae and inner matrix in living cells was successfully visualized using stimulated emission depletion (STED) nanoscopy with unprecedented resoln.
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      (b) Chen, Y.; Wei, X.-R.; Sun, R.; Xu, Y.-J.; Ge, J.-F. The application of azonia-cyanine dyes for nucleic acids imaging in mitochondria. Sens. Actuators B 2019, 281, 499– 506,  DOI: 10.1016/j.snb.2018.10.146
      20b
      The application of azonia-cyanine dyes for nucleic acids imaging in mitochondria
      Chen, Yuan; Wei, Xue-Rui; Sun, Ru; Xu, Yu-Jie; Ge, Jian-Feng
      Sensors and Actuators, B: Chemical (2019), 281 (), 499-506CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
      Five cyanine dyes with azonia unit have been prepd. by the reaction of pyrido[1,2-a]pyrimidinium ions and suitable aldehydes. Before further research, their photo and thermal stabilities were detd. in the first place. At least 88% absorption remained after 5 h irradiating illustrated all of these dyes had excellent photo stability. Meanwhile, the decompn. temp. of dyes was around 200 °C which demonstrated they had good thermal stability. Therefore, the good photo and thermal stability made them possible to be probes. Subsequently, the optical properties of probes toward nucleic acids had been measured. TheirOFF-ON fluorescent responses towards nucleic acids were investigated. In addn., confocal microscopy imaging of probe 1a in live HeLa cells indicated that probe 1a could image mitochondrial nucleic acid.
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    21. 21
      (a) Du, W.; Wang, H.; Zhu, Y.; Tian, X.; Zhang, M.; Zhang, Q.; De Souza, S. C.; Wang, A.; Zhou, H.; Zhang, Z.; Wu, J.; Tian, Y. Highly hydrophilic, two-photon fluorescent terpyridine derivatives containing quaternary ammonium for specific recognizing ribosome RNA in living cells. ACS Appl. Mater. Interfaces 2017, 9, 31424– 31432,  DOI: 10.1021/acsami.7b08068
      21a
      Highly Hydrophilic, Two-photon Fluorescent Terpyridine Derivatives Containing Quaternary Ammonium for Specific Recognizing Ribosome RNA in Living Cells
      Du, Wei; Wang, Hui; Zhu, Yingzhong; Tian, Xiaohe; Zhang, Mingzhu; Zhang, Qiong; De Souza, Senio Campos; Wang, Aidong; Zhou, Hongping; Zhang, Zhongping; Wu, Jieying; Tian, Yupeng
      ACS Applied Materials & Interfaces (2017), 9 (37), 31424-31432CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      A two-photon fluorescent probe (J1, I) that selectively stains intracellular nucleolar RNA was screened from three water-sol. terpyridine derivs. (J1, J2, J3) with quaternary ammonium groups. The photophys. properties of J1-J3 were systemically studied both exptl. and theor., revealing that J1-J3 possess large Stokes shifts, and the two-photon absorption action cross sections range from 38 GM to 97 GM in the near IR region. J1 could specifically stain nucleoli by targeting nucleolar rRNA from the recognition expts. in vitro, two-photon imaging expts. and stimulated emission depletion (STED) in vivo. The mechanism of action in which J1 binds to nucleolar rRNA was researched via both expts. and mol. modeling. The high binding selectivity of J1 to nucleolar RNA over cytosolic RNA, makes this probe a potential candidate to visualize rRNA probe in living cells.
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      (b) Wang, L.; Xia, Q.; Liu, R.; Qu, J. A red fluorescent probe for ribonucleic acid (RNA) detection, cancer cell tracing and tumor growth monitoring. Sens. Actuators B 2018, 273, 935– 943,  DOI: 10.1016/j.snb.2018.07.018
      21b
      A red fluorescent probe for ribonucleic acid (RNA) detection, cancer cell tracing and tumor growth monitoring
      Wang, Lei; Xia, Qi; Liu, Ruiyuan; Qu, Jinqing
      Sensors and Actuators, B: Chemical (2018), 273 (), 935-943CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
      A red fluorescent probe, PFB, is designed and synthesized, which presents several remarkable features including a large Stokes shift (85nm), long emission wavelength, high photostability and good biocompatibility. PFB also displays the solvent-dependent effect, which is verified by the d. functional theory (DFT) calcns. Addnl., PFB can act as a fluorescent probe for cellular imaging with high uptake efficiency and highly sensitive detection toward RNA under low optimum concn. (1μM), which enables it to achieve cancer cell tracing in vitro and tumor growth monitoring in vivo. The results of real-time tracking expt. reveal that PFB can be traced in stained HepG-2 cells for 11 generations and monitor tumor growth for 18 days. This work highlights the potential application of PFB as a promising alternative to the com. RNA fluorescent probes.
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    22. 22
      Sun, W.; Fan, J.; Hu, C.; Cao, J.; Zhang, H.; Xiong, X.; Wang, J.; Cui, S.; Sun, S.; Peng, X. A two-photon fluorescent probe with near-infrared emission for hydrogen sulfide imaging in biosystems. Chem. Commun. 2013, 49, 3890– 3892,  DOI: 10.1039/c3cc41244j
      22
      A two-photon fluorescent probe with near-infrared emission for hydrogen sulfide imaging in biosystems
      Sun, Wen; Fan, Jiangli; Hu, Chong; Cao, Jianfang; Zhang, Hua; Xiong, Xiaoqing; Wang, Jingyun; Cui, Shuang; Sun, Shiguo; Peng, Xiaojun
      Chemical Communications (Cambridge, United Kingdom) (2013), 49 (37), 3890-3892CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Hydrogen sulfide (H2S) is emerging as an important gasotransmitter but remains difficult to study. Here we report a novel two-photon fluorescent probe with NIR emission for H2S detection. It was successfully used to realize H2S imaging in bovine serum, living cells, tissues as well as in living mice.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c02408.

    • Experimental details, absorption spectra, fluorescence response, photostability, live-cell imaging, cytotoxicity of BIOP (PDF)


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