Utilisation of Tetraphenylethene-Derived Probes with Aggregation-Induced Emission Properties in Fluorescence Detection of Biothiols

  • Mengjie Liu
  • Yuning HongEmail author


Thiol-containing biomolecules (biothiols), including cysteine (Cys), homocysteine (Hcy), glutathione (GSH) and hydrogen sulphide (H2S), have crucial implications in human physiology and pathophysiology. They can be qualitatively and quantitatively analysed in the tissues of interest using sensitive and specific fluorescent probes, which may in turn reflect alternations in cellular activities and disease manifestations. In this regard, probes with aggregation-induced emission (AIE) properties are preferential owing to their enhanced emission in the aqueous environment present in biological systems. In this chapter, we review the recent progress in biothiol-specific probes that are derived from the well-documented tetraphenylethene (TPE) scaffold. In particular, we highlight their underlying reaction mechanisms with the target biothiol(s) and their applications in cell imaging where available.


Biothiol Cysteine Homocysteine Glutathione H2Fluorescence Aggregation-induced emission TPE Turn-on probe 


  1. 1.
    Ueland PM et al (1993) Total homocysteine in plasma or serum: methods and clinical applications. Clin Chem 39:1764–1779Google Scholar
  2. 2.
    Brigham MP, Stein WH, Moore S (1960) The concentrations of cysteine and cystine in human blood plasma. J Clin Invest 39:1633–1638CrossRefGoogle Scholar
  3. 3.
    Tsogas GZ, Kappi FA, Vlessidis AG, Giokas DL (2018) Recent advances in nanomaterial probes for optical biothiol sensing: a review. Anal Lett 51:443–468CrossRefGoogle Scholar
  4. 4.
    Mansoor MA, Svardal AM, Ueland PM (1992) Determination of the in vivo redox status of cysteine, cysteinylglycine, homocysteine, and glutathione in human plasma. Anal Biochem 200:218–229CrossRefGoogle Scholar
  5. 5.
    Suzuki K, Sagara M, Aoki C, Tanaka S, Aso Y (2017) Clinical implication of plasma hydrogen sulfide levels in Japanese patients with Type 2 diabetes. Intern Med 56:17–21CrossRefGoogle Scholar
  6. 6.
    Jiang J et al (2016) Hydrogen sulfide - mechanisms of toxicity and development of an antidote. Sci Rep 6:20831CrossRefGoogle Scholar
  7. 7.
    Maulik VT, Jennifer SL, Teruna JS (2009) The role of thiols and disulfides on protein stability. Curr Protein Pept Sci 10:614–625CrossRefGoogle Scholar
  8. 8.
    Jensen KP, Ryde U (2003) Conversion of homocysteine to methionine by methionine synthase: a density functional study. J Am Chem Soc 125:13970–13971CrossRefGoogle Scholar
  9. 9.
    Medina MÁ, Urdiales JL, Amores-Sánchez MI (2001) Roles of homocysteine in cell metabolism. Eur J Biochem 268:3871–3882CrossRefGoogle Scholar
  10. 10.
    Townsend DM, Tew KD, Tapiero H (2003) The importance of glutathione in human disease. Biomed Pharmacother 57:145–155CrossRefGoogle Scholar
  11. 11.
    Nakagawa I, Suzuki M, Yanagiya T, Imura N, Naganuma A (1995) Effect of glutathione depletion on metallothionein synthesis induced by paraquat in mice. Tohoku J Exp Med 177:249–262CrossRefGoogle Scholar
  12. 12.
    Moskaug JØ, Carlsen H, Myhrstad MC, Blomhoff R (2005) Polyphenols and glutathione synthesis regulation. Am J Clin Nutr 81:277S–283SCrossRefGoogle Scholar
  13. 13.
    Li L, Moore PK (2007) An overview of the biological significance of endogenous gases: new roles for old molecules. Biochem Soc Trans 35:1138–1141CrossRefGoogle Scholar
  14. 14.
    Bhatia M (2015) In: Moore PK, Whiteman M (eds) Chemistry, biochemistry and pharmacology of hydrogen sulfide. Springer, Berlin, pp 165–180CrossRefGoogle Scholar
  15. 15.
    Papapetropoulos A et al (2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci 106:21972–21977CrossRefGoogle Scholar
  16. 16.
    Bhatia M (2005) Hydrogen sulfide as a vasodilator. IUBMB Life 57:603–606CrossRefGoogle Scholar
  17. 17.
    Kimura Y, Goto Y-I, Kimura Y-I (2009) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria Antioxid. Redox Signal 12:1–13Google Scholar
  18. 18.
    Whiteman M et al (2004) The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’? J Neurochem 90:765–768CrossRefGoogle Scholar
  19. 19.
    Lieberman MW et al (1996) Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice. Proc Natl Acad Sci U S A 93:7923–7926CrossRefGoogle Scholar
  20. 20.
    Alena F, Dixon W, Thomas P, Jimbow K (1995) Glutathione plays a key role in the depigmenting and melanocytotoxic action of N-acetyl-4-S-cysteaminylphenol in black and yellow hair follicles. J Invest Dermatol 104:792–797CrossRefGoogle Scholar
  21. 21.
    Khoshbaten M et al (2010) N-Acetylcysteine improves liver function in patients with non-alcoholic fatty liver disease. Hepat Mon 10:12–16Google Scholar
  22. 22.
    Nakai K et al (2015) Effects of topical N-acetylcysteine on skin hydration/transepidermal water loss in healthy volunteers and atopic dermatitis patients. Ann Dermatol 27:450–451CrossRefGoogle Scholar
  23. 23.
    Zhang SM et al (2003) A prospective study of plasma total cysteine and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 12:1188–1193Google Scholar
  24. 24.
    Bostom AG, Culleton BF (1999) Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 10:891–900Google Scholar
  25. 25.
    Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14:6CrossRefGoogle Scholar
  26. 26.
    Sachdev P (2004) Homocisteína e transtornos psiquiátricos. Rev Bras Psiquiatr 26:50–56CrossRefGoogle Scholar
  27. 27.
    Uys JD, Mulholland PJ, Townsend DM (2014) Glutathione and redox signaling in substance abuse. Biomed Pharmacother 68:799–807CrossRefGoogle Scholar
  28. 28.
    Prussick R, Prussick L, Gutman J (2013) Psoriasis improvement in patients using glutathione-enhancing, nondenatured whey protein isolate: a pilot study. J Clin Aesthet Dermatol 6:23–26Google Scholar
  29. 29.
    Yuan L, Kaplowitz N (2009) Glutathione in liver diseases and hepatotoxicity. Mol Aspects Med 30:29–41CrossRefGoogle Scholar
  30. 30.
    Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 22:343–352CrossRefGoogle Scholar
  31. 31.
    Conklin KA (2004) Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 3:294–300CrossRefGoogle Scholar
  32. 32.
    Eto K, Kimura H (2002) The production of hydrogen sulfide is regulated by testosterone and S-adenosyl-l-methionine in mouse brain. J Neurochem 83:80–86CrossRefGoogle Scholar
  33. 33.
    Cao X, Cao L, Ding L, Bian J-S (2018) A new hope for a devastating disease: hydrogen sulfide in Parkinson’s disease. Mol Neurobiol 55:3789–3799Google Scholar
  34. 34.
    Zhang L-M, Jiang C-X, Liu D-W (2009) Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochem Res 34:1984–1992CrossRefGoogle Scholar
  35. 35.
    Yin C-X, Xiong K-M, Huo F-J, Salamanca JC, Strongin RM (2017) Fluorescent probes with multiple binding sites for the discrimination of Cys, Hcy, and GSH. Angew Chem Int Ed 56:13188–13198CrossRefGoogle Scholar
  36. 36.
    Chen X, Zhou Y, Peng X, Yoon J (2010) Fluorescent and colorimetric probes for detection of thiols. Chem Soc Rev 39:2120–2135. Scholar
  37. 37.
    de Silva AP et al (1997) Signaling recognition events with fluorescent sensors and switches. Chem Rev 97:1515–1566CrossRefGoogle Scholar
  38. 38.
    Martínez-Máñez R, Sancenón F (2003) Fluorogenic and chromogenic chemosensors and reagents for anions. Chem Rev 103:4419–4476CrossRefGoogle Scholar
  39. 39.
    Kim SA, Schwille P (2003) Intracellular applications of fluorescence correlation spectroscopy: prospects for neuroscience. Curr Opin Neurobiol 13:583–590CrossRefGoogle Scholar
  40. 40.
    Zhang H, Zhang C, Liu R, Yi L, Sun H (2015) A highly selective and sensitive fluorescent thiol probe through dual-reactive and dual-quenching groups. Chem Commun 51:2029–2032CrossRefGoogle Scholar
  41. 41.
    Rusin O et al (2004) Visual detection of cysteine and homocysteine. J Am Chem Soc 126:438–439CrossRefGoogle Scholar
  42. 42.
    Matsumoto T, Urano Y, Shoda T, Kojima H, Nagano T (2007) A thiol-reactive fluorescence probe based on donor-excited photoinduced electron transfer: key role of ortho substitution. Org Lett 9:3375–3377CrossRefGoogle Scholar
  43. 43.
    Wang S-P et al (2009) A colorimetric and fluorescent merocyanine-based probe for biological thiols. Org Biomol Chem 7:4017–4020CrossRefGoogle Scholar
  44. 44.
    Luo J et al (2001) Aggregation-induced emission of 1-methyl-1,2,3,4,5-pentaphenylsilole. Chem Commun 0:1740–1741.!divAbstract
  45. 45.
    Tang BZ et al (2001) Efficient blue emission from siloles. J Mater Chem 11:2974–2978CrossRefGoogle Scholar
  46. 46.
    Liu M et al (2017) 9-Vinylanthracene based fluorogens: synthesis, structure-property relationships and applications. Molecules 22:2148CrossRefGoogle Scholar
  47. 47.
    Dong Y et al (2012) Supramolecular interactions induced fluorescent organic nanowires with high quantum yield based on 9,10-distyrylanthracene. CrstEngComm 14:6593–6598CrossRefGoogle Scholar
  48. 48.
    Peng L et al (2014) A fluorescent probe for thiols based on aggregation-induced emission and its application in live-cell imaging. Dyes Pigm 108:24–31CrossRefGoogle Scholar
  49. 49.
    Chen S et al (2013) Full-range intracellular pH sensing by an aggregation-induced emission-active two-channel ratiometric fluorogen. J Am Chem Soc 135:4926–4929CrossRefGoogle Scholar
  50. 50.
    Chen M et al (2015) Tetraphenylpyrazine-based AIEgens: facile preparation and tunable light emission. Chem Sci 6:1932–1937CrossRefGoogle Scholar
  51. 51.
    Mei J, Leung NLC, Kwok RTK, Lam JWY, Tang BZ (2015) Aggregation-induced emission: together we shine, united we soar! Chem Rev 115:11718–11940CrossRefGoogle Scholar
  52. 52.
    Leung CWT et al (2014) Superior fluorescent probe for detection of cardiolipin. Anal Chem 86:1263–1268CrossRefGoogle Scholar
  53. 53.
    Huang Y et al (2014) Tetraphenylethylene conjugated with a specific peptide as a fluorescence turn-on bioprobe for the highly specific detection and tracing of tumor markers in live cancer cells. Chem A Eur J 20:158–164CrossRefGoogle Scholar
  54. 54.
    Hong Y, Chen S, Leung CWT, Lam JWY, Tang BZ (2013) Water-soluble tetraphenylethene derivatives as fluorescent “light-up” probes for nucleic acid detection and their applications in cell imaging. Chem Asian J 8:1806–1812CrossRefGoogle Scholar
  55. 55.
    Michael A (1887) On the addition of sodium acetacetic ether and analogous sodium compounds to unsaturated organic ethers. Am Chem J 9:115Google Scholar
  56. 56.
    Vernon B, Tirelli N, Bächi T, Haldimann D, Hubbell JA (2003) Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. J Biomed Mater Res A 64A:447–456CrossRefGoogle Scholar
  57. 57.
    Mather BD, Viswanathan K, Miller KM, Long TE (2006) Michael addition reactions in macromolecular design for emerging technologies. Prog Polym Sci 31:487–531CrossRefGoogle Scholar
  58. 58.
    Li X et al (2012) Simple fluorescent probe derived from tetraphenylethylene and benzoquinone for instantaneous biothiol detection. Anal Methods 4:3338–3443CrossRefGoogle Scholar
  59. 59.
    Zhang R et al (2014) Fluorogen-peptide conjugates with tunable aggregation-induced emission characteristics for bioprobe design. ACS Appl Mater Interfaces 6:14302–14310CrossRefGoogle Scholar
  60. 60.
    Yuan Y et al (2014) Rational design of fluorescent light-up probes based on an AIE luminogen for targeted intracellular thiol imaging. Chem Commun 50:295–297CrossRefGoogle Scholar
  61. 61.
    Yu Y et al (2013) Thiol-reactive molecule with dual-emission-enhancement property for specific prestaining of cysteine containing proteins in SDS-PAGE. ACS Appl Mater Interfaces 5:4613–4616CrossRefGoogle Scholar
  62. 62.
    Liu Y et al (2010) Simple biosensor with high selectivity and sensitivity: thiol-specific biomolecular probing and intracellular imaging by AIE fluorogen on a TLC plate through a thiol–ene click mechanism. Chem A Eur J 16:8433–8438CrossRefGoogle Scholar
  63. 63.
    Chen MZ et al (2017) A thiol probe for measuring unfolded protein load and proteostasis in cells. Nat Commun 8:474CrossRefGoogle Scholar
  64. 64.
    Lou X et al (2014) A selective glutathione probe based on AIE fluorogen and its application in enzymatic activity assay. Sci Rep 4:4272CrossRefGoogle Scholar
  65. 65.
    Zhao N et al (2015) A fluorescent probe with aggregation-induced emission characteristics for distinguishing homocysteine over cysteine and glutathione. J Mater Chem C 3:8397–8402CrossRefGoogle Scholar
  66. 66.
    Chen S et al (2014) Discrimination of homocysteine, cysteine and glutathione using an aggregation-induced-emission-active hemicyanine dye. J Mater Chem B 2:3919–3923CrossRefGoogle Scholar
  67. 67.
    Lou X et al (2014) A new turn-on chemosensor for bio-thiols based on the nanoaggregates of a tetraphenylethene-coumarin fluorophore. Nanoscale 6:14691–14696CrossRefGoogle Scholar
  68. 68.
    Cai Y et al (2014) A sensitivity tuneable tetraphenylethene-based fluorescent probe for directly indicating the concentration of hydrogen sulfide. Chem Commun 50:8892–8895CrossRefGoogle Scholar
  69. 69.
    Zhang W, Kang J, Li P, Wang H, Tang B (2015) Dual signaling molecule sensor for rapid detection of hydrogen sulfide based on modified tetraphenylethylene. Anal Chem 87:8964–8969CrossRefGoogle Scholar
  70. 70.
    Zhang Y et al (2016) Organic nanoparticles formed by aggregation-induced fluorescent molecules for detection of hydrogen sulfide in living cells. Sci China Chem 59:106–113CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Chemistry and PhysicsLa Trobe Institute for Molecular Science, La Trobe UniversityMelbourneAustralia

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