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Indole-5,6-quinones display hallmark properties of eumelanin

Nature Chemistry volume 15, pages 787–793 (2023)Cite this article

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Abstract

Melanins are ubiquitous biopolymers produced from phenols and catechols by oxidation. They provide photoprotection, pigmentation and redox activity to most life forms, and inspire synthetic materials with desirable optical, electronic and mechanical properties. The chemical structures of melanins remain elusive, however, creating uncertainty about their roles, and preventing the design of synthetic mimics with tailored properties. Indole-5,6-quinone (IQ) has been implicated as a biosynthetic intermediate and structural subunit of mammalian eumelanin pigments, but its instability has prevented its isolation and unambiguous characterization. Here we use steric shielding to stabilize IQ and show that ‘blocked’ derivatives exhibit eumelanin’s characteristic ultrafast nonradiative decay and its ability to absorb light from the ultraviolet to the near-infrared. These new compounds are also redox-active and a source of paramagnetism, emulating eumelanin’s unique electronic properties, which include persistent radicals. Blocked IQs are atomistically precise and tailorable molecules that can offer a bottom–up understanding of emergent properties in eumelanin and have the potential to advance the rational design of melanin-inspired materials.

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Fig. 1: The biosynthesis of eumelanin, decoupling oxidation from polymerization, and emergence of optical and electronic properties.
Fig. 2: Synthesis of IQ and characterization of redox properties.
Fig. 3: Long-wavelength absorption in IQ-Me.
Fig. 4: Ultrafast excited-state decay to the electronic ground state by the stabilized IQ compounds and the effects of β-ring fusion.

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Data availability

The data supporting the main findings of this study are available in the article, Supplementary Information and source data. Source data are available for download, free of charge, from the Open Science Framework (OSF) data repository at https://osf.io/f253n/. The supplementary crystallographic information file has been deposited with the Cambridge Crystallographic Data Centre (CCDC) under deposition no. CCDC 2191886. It can be obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif. Cartesian coordinates of all structures reported in the paper are provided in the source data for the Supplementary Information. All structures of sterically blocked compounds are also deposited in the ioChem-BD repository and can be accessed via https://doi.org/10.19061/iochem-bd-4-49. Source data are provided with this paper.

References

  1. D’Ischia, M. et al. Melanins and melanogenesis: methods, standards, protocols. Pigment Cell Melanoma Res. 26, 616–633 (2013).

    Article  PubMed  Google Scholar 

  2. Liu, Y., Ai, K. & Lu, L. Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental and biomedical fields. Chem. Rev. 114, 5057–5115 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Cao, W. et al. Unraveling the structure and function of melanin through synthesis. J. Am. Chem. Soc. 143, 2622–2637 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Huang, L. et al. Recent advances and progress on melanin-like materials and their biomedical applications. Biomacromolecules 19, 1858–1868 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Meredith, P. & Sarna, T. The physical and chemical properties of eumelanin. Pigment Cell Res. 19, 572–594 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Meyer Zum Gottesberge, A. M. Physiology and pathophysiology of inner ear melanin. Pigment Cell Res. 1, 238–249 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. D’Ischia, M., Napolitano, A., Pezzella, A., Meredith, P. & Buehler, M. Melanin biopolymers: tailoring chemical complexity for materials design. Angew. Chem. Int. Ed. 59, 11196–11205 (2020).

    Article  Google Scholar 

  8. D’Ischia, M., Napolitano, A. & Pezzella, A. 5,6‐Dihydroxyindole chemistry: unexplored opportunities beyond eumelanin. Eur. J. Org. Chem. 2011, 5501–5516 (2011).

    Article  Google Scholar 

  9. Ryu, J. H., Messersmith, P. B. & Lee, H. Polydopamine surface chemistry: a decade of discovery. ACS Appl. Mater. Interfaces 10, 7523–7540 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nofsinger, J. B., Forest, S. E., Eibest, L. M., Gold, K. A. & Simon, J. D. Probing the building blocks of eumelanins using scanning electron microscopy. Pigment Cell Res. 13, 179–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Meredith, P. et al. Towards structure-property-function relationships for eumelanin. Soft Matter 2, 37–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Luisi, P. L. Emergence in chemistry: chemistry as the embodiment of emergence. Found. Chem. 4, 183–200 (2002).

    Article  CAS  Google Scholar 

  13. Tran, M. L., Powell, B. J. & Meredith, P. Chemical and structural disorder in eumelanins: a possible explanation for broadband absorbance. Biophys. J. 90, 743–752 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Micillo, R. et al. Eumelanin broadband absorption develops from aggregation-modulated chromophore interactions under structural and redox control. Sci. Rep. 7, 41532 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pezzella, A. et al. Disentangling eumelanin ‘black chromophore’: visible absorption changes as signatures of oxidation state- and aggregation-dependent dynamic interactions in a model water-soluble 5,6-dihydroxyindole polymer. J. Am. Chem. Soc. 131, 15270–15275 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Raper, H. S. The tyrosinase-tyrosine reaction: production from tyrosine of 5, 6-dihydroxyindole and 5, 6-dihydroxyindole-2-carboxylic acid—the precursors of melanin. Biochem. J. 21, 89–96 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Corradini, M. G., Napolicano, A. & Prota, G. A biosynthetic approach to the structure of eumelanins. The isolation of oligomers from 5,6-dihydroxy-1-methylindole. Tetrahedron 42, 2083–2088 (1986).

    Article  CAS  Google Scholar 

  18. Wang, J. & Blancafort, L. Stability and optical absorption of a comprehensive virtual library of minimal eumelanin oligomer models. Angew. Chem. Int. Ed. 60, 18800–18809 (2021).

    Article  CAS  Google Scholar 

  19. D’Ischia, M. et al. 5,6-Dihydroxyindoles and indole-5,6-diones. Adv. Heterocycl. Chem. 89, 1–63 (2005).

    Article  Google Scholar 

  20. Napolitano, A., Pezzella, A., d’lschia, M. & Prota, G. The first characterisation of a transient 5,6-indolequinone. Tetrahedron Lett. 37, 4241–4242 (1996).

    Article  CAS  Google Scholar 

  21. Il’Ichev, Y. V. & Simon, J. D. Building blocks of eumelanin: relative stability and excitation energies of tautomers of 5,6-dihydroxyindole and 5,6-indolequinone. J. Phys. Chem. B 107, 7162–7171 (2003).

    Article  Google Scholar 

  22. Macdonald, A. L. & Trotter, J. Crystal and molecular structure of o-benzoquinone. J. Chem. Soc. Perkin Trans. 2, 476–480 (1973).

    Article  Google Scholar 

  23. René, A. & Evans, D. H. Electrochemical reduction of some o-quinone anion radicals: why is the current intensity so small? J. Phys. Chem. C 116, 14454–14460 (2012).

    Article  Google Scholar 

  24. Huynh, M. T., Anson, C. W., Cavell, A. C., Stahl, S. S. & Hammes-Schiffer, S. Quinone 1e− and 2e−/2H+ reduction potentials: identification and analysis of deviations from systematic scaling relationships. J. Am. Chem. Soc. 138, 15903–15910 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Namazian, M. & Coote, M. L. Accurate calculation of absolute one-electron redox potentials of some para-quinone derivatives in acetonitrile. J. Phys. Chem. A 111, 7227–7232 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Bernardus Mostert, A., Powell, B. J., Gentle, I. R. & Meredith, P. On the origin of electrical conductivity in the bio-electronic material melanin. Appl. Phys. Lett. 100, 093701 (2012).

    Article  Google Scholar 

  27. Bedran, Z. V. et al. Water-activated semiquinone formation and carboxylic acid dissociation in melanin revealed by infrared spectroscopy. Polymers 13, 4403 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mostert, A. B. On the free radical redox chemistry of 5,6-dihydroxyindole. Chem. Phys. 546, 111158 (2021).

    Article  CAS  Google Scholar 

  29. Paulin, J. V., Batagin-Neto, A., Meredith, P., Graeff, C. F. O. & Mostert, A. B. Shedding light on the free radical nature of sulfonated melanins. J. Phys. Chem. B 124, 10365–10373 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Rienecker, S. B., Mostert, A. B., Schenk, G., Hanson, G. R. & Meredith, P. Heavy water as a probe of the free radical nature and electrical conductivity of melanin. J. Phys. Chem. B 119, 14994–15000 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Felix, C. C. & Sealy, R. C. Photolysis of melanin precursors: formation of semiquinone radicals and their complexation with diamagnetic metal ions. Photochem. Photobiol. 34, 423–429 (1981).

    Article  CAS  Google Scholar 

  32. Felix, C. C., Hyde, J. S. & Sealy, R. C. Photoreactions of melanin: a new transient species and evidence for triplet state involvement. Biochem. Biophys. Res. Commun. 88, 456–461 (1979).

    Article  CAS  PubMed  Google Scholar 

  33. Pezzella, A. et al. Free radical coupling of o-semiquinones uncovered. J. Am. Chem. Soc. 135, 12142–12149 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Ulas, G., Lemmin, T., Wu, Y., Gassner, G. T. & Degrado, W. F. Designed metalloprotein stabilizes a semiquinone radical. Nat. Chem. 8, 354–359 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Blois, M. S., Zahlan, A. B. & Maling, J. E. Electron spin resonance studies on melanin. Biophys. J. 4, 471–490 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mostert, A. B., Rienecker, S. B., Noble, C., Hanson, G. R. & Meredith, P. The photoreactive free radical in eumelanin. Sci. Adv. 4, eaaq1293 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Prabhananda, B. S. Spin density distributions and g values in semiquinones. J. Chem. Phys. 79, 5752–5757 (1983).

    Article  CAS  Google Scholar 

  38. Lahti, P. M. Advances in Physical Organic Chemistry Vol. 45 (Elsevier, 2011).

  39. Xie, C., Lahti, P. M. & George, C. Modulating spin delocalization in phenoxyl radicals conjugated with heterocycles. Org. Lett. 2, 3417–3420 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Middleton, C. T. et al. DNA excited-state dynamics: from single bases to the double helix. Annu. Rev. Phys. Chem. 60, 217–239 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Abiola, T. T., Whittock, A. L. & Stavros, V. G. Unravelling the photoprotective mechanisms of nature-inspired ultraviolet filters using ultrafast spectroscopy. Molecules 25, 3945 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Baker, L. A., Greenough, S. E. & Stavros, V. G. A perspective on the ultrafast photochemistry of solution-phase sunscreen molecules. J. Phys. Chem. Lett. 7, 4655–4665 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Grieco, C., Kohl, F. R., Hanes, A. T. & Kohler, B. Probing the heterogeneous structure of eumelanin using ultrafast vibrational fingerprinting. Nat. Commun. 11, 4569 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. El‐Sayed, M. A. Spin–orbit coupling and the radiationless processes in nitrogen heterocyclics. J. Chem. Phys. 38, 2834–2838 (1963).

    Article  Google Scholar 

  45. Ghosh, P. & Ghosh, D. Elucidating the photoprotection mechanism of eumelanin monomers. J. Phys. Chem. B 121, 5988–5994 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Corani, A. et al. Bottom-up approach to eumelanin photoprotection: emission dynamics in parallel sets of water-soluble 5,6-dihydroxyindole-based model systems. J. Phys. Chem. B 116, 13151–13158 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Nogueira, J. J. et al. Sequential proton-coupled electron transfer mediates excited-state deactivation of a eumelanin building block. J. Phys. Chem. Lett. 8, 1004–1008 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Wendlandt, A. E. & Stahl, S. S. Quinone‐catalyzed selective oxidation of organic molecules. Angew. Chem. Int. Ed. 54, 14638–14658 (2015).

    Article  CAS  Google Scholar 

  49. Huang, Z. & Lumb, J.-P. A catalyst-controlled aerobic coupling of ortho-quinones and phenols applied to the synthesis of aryl ethers. Angew. Chem. Int. Ed. 55, 11543–11547 (2016).

    Article  CAS  Google Scholar 

  50. Cao, Y. et al. Highly efficient NIR-II photothermal conversion based on an organic conjugated polymer. Chem. Mater. 29, 718–725 (2017).

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support for synthetic and analytical work at McGill University was provided by the Natural Sciences and Engineering Research Council of Canada (Discovery Grant to J.-P.L). Spectroscopic work at The Ohio State University was supported in part by Ohio Eminent Scholar funds. L.B. acknowledges project PID2019-104654GB-I00 of the Ministerio de Ciencia e Innovación for funding. We are grateful to R. Stein for assistance with EPR spectroscopy, D. Chhin on electrochemistry and H. Titi on X-ray crystallography (McGill University). X.W. acknowledges the Natural Sciences and Engineering Research Council of Canada for a postgraduate scholarship (PGS-D). A.M. acknowledges Secretaria d’Universitats de Recerca and the European Social Fund (fellowship2021FI_B00690) for financial support. L.K. thanks C. Grieco for useful discussions.

Author information

Author notes

  1. These authors contributed equally: Xueqing Wang, Lilia Kinziabulatova, Marco Bortoli.

Authors and Affiliations

  1. Department of Chemistry, McGill University, Montreal, Quebec, Canada

    Xueqing Wang, Haiyan Huang & Jean-Philip Lumb

  2. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA

    Lilia Kinziabulatova, Marisa A. Barilla & Bern Kohler

  3. Institut de Química Computacional i Catàlisi, Facultat de Ciències, Universitat de Girona, Girona, Spain

    Marco Bortoli, Anju Manickoth & Lluís Blancafort

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Contributions

X.W. carried out the synthetic work and H.H. contributed to the synthetic planning. X.W. carried out the structural characterization, EPR studies and CV measurements. L.K. performed spectroscopic measurements, and M.A.B. contributed to fluorescence measurements and quantum yield calculations. M.B. and A.M. conducted computational work and theoretical analysis. J.-P.L., B.K., L.B., X.W., L.K. and M.B. wrote the paper. All authors contributed to revisions. Collaboration of this work was managed by B.K., L.B. and J.-P.L.

Corresponding authors

Correspondence to Lluís Blancafort, Bern Kohler or Jean-Philip Lumb.

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Nature Chemistry thanks Tolga Karsili, Alessandro Pezzella, Natercia Das Neves Rodrigues and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Tables 1–10, Figs. 1–14 and Discussion.

Supplementary Data 1

Source data for supplementary figures and tables.

Supplementary Data 2

Cartesian coordinates for all computed structures.

Supplementary Data 3

Cif file for X-ray structure of IQ-MeO.

Source data

Source Data Fig. 2

Source data for CV and EPR.

Source Data Fig. 2

Cif file for X-ray structure.

Source Data Fig. 3

Source data for absorbance spectra.

Source Data Fig. 4

Source data for the transient absorption spectra.

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Wang, X., Kinziabulatova, L., Bortoli, M. et al. Indole-5,6-quinones display hallmark properties of eumelanin. Nat. Chem. 15, 787–793 (2023). https://doi.org/10.1038/s41557-023-01175-4

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