Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 7;146(5):2895-2900.
doi: 10.1021/jacs.3c13647. Epub 2024 Jan 26.

Intracellular Synthesis of Indoles Enabled by Visible-Light Photocatalysis

Cinzia D'Avino  1 , Sara Gutiérrez  1 , Max J Feldhaus  1 , María Tomás-Gamasa  1 , José Luis Mascareñas  1
Affiliations

Intracellular Synthesis of Indoles Enabled by Visible-Light Photocatalysis

Cinzia D'Avino et al. J Am Chem Soc. .

Abstract

Performing abiotic synthetic transformations in live cell environments represents a new, promising approach to interrogate and manipulate biology and to uncover new types of biomedical tools. We now found that photocatalytic bond-forming reactions can be added to the toolbox of bioorthogonal synthetic chemistry. Specifically, we demonstrate that exogenous styryl aryl azides can be converted into indoles inside living mammalian cells under photocatalytic conditions.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) Outline of direct photocatalytic activation mechanisms. (B and C) Schematic representation of photobiological applications of aryl azides. (D) This work: Photocatalytic synthesis of indoles in cells and schematic outline of a putative mechanism.
Figure 2
Figure 2
Reaction in HeLa cell cultures. (A) Experimental protocol. (B) Detection and quantification of 2a (acetonitrile extract) for the experiment with [Ru] = 50 μM (chromatogram and inset with the mass peak of 2a. (C) Quantification of the intracellular product 2a (gray, blue and green bars) and Ru(bpy)3 (dashed blue bars). Control = Cells treated with 50 μM of 1a, no irradiation, and no Ru(bpy)3. Error bars: standard deviation of three experiments. Blue LEDs: 45 min of irradiation, λmax = 456 nm; Green LEDs: 15 min of irradiation, λmax = 525 nm (20 mW cm–2). * = Coumarin as internal standard; [Ru] = Ru(bpy)3; and Eosin = Eosin Y.
Figure 3
Figure 3
Generation of 2b in HeLa cell cultures. (A) Photocatalytic reaction and micrographies of cells after incubation with the substrate (1b, a) or the product (2b, b). Scale bar: 20 μm. λexc = 405 nm, λem = 420–480 nm. (B) Fluorescence micrographies in reactions with increasing concentrations of Eosin Y (c–f, from 0 to 20 μM). C) Bar graphic based on CTFC measurements. The intracellular concentration of Eosin Y is also shown (gray bars). Error bars: standard deviation of three experiments. Green LEDs: 20 mW cm–2 (40 W lamp), λmax = 525 nm, 15 min of irradiation. PC = photocatalyst.
Figure 4
Figure 4
Selective cellular targeting using Eosin-CRGD as photocatalyst (Section S7). (A) Structure of the synthetic RGD derivative containing Eosin Y. (B) Fluorescence micrographies of HeLa (a,b) and MCF7 cells (c,d) (blue channel and brightfield) after incubation with 1b, and Eosin Y (a,c) or Eosin-CRGD (b,d), and irradiation. (C) Bar graphic showing the CTFC. Reaction conditions: Cells were pretreated with 50 μM of 1b and Eosin Y (5 μM, a), (15 μM, c) or Eosin-CRGD (5 μM, b), (15 μM, d), in DMEM for 15 min, washed with PBS (2×), and irradiated with green light in HEPES-DMEM for 15 min. The error bars indicated the standard deviation of three experiments. Scale bar: 20 μm. λexc = 405 nm, λem = 420–480 nm.
See this image and copyright information in PMC

References

    1. Johnston M. P.; Smith R. T.; MacMillan D. W. C. Visible Light Photocatalysis in Organic Synthesis. Angew. Chem., Int. Ed. 2016, 55, 15060–15078.
    2. Ravelli M.; Monti D.; Albini A. Photocatalysis in Organic Chemistry. Angew. Chem., Int. Ed. 2016, 55, 11902–11921.
    3. Marzo L.; Pagire S. K.; Reiser O.; König B. Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis?. Angew. Chem., Int. Ed. 2018, 57, 10034–10072. 10.1002/anie.201709766. - DOI - PubMed
    4. Romero N. A.; Nicewicz D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075–10166. 10.1021/acs.chemrev.6b00057. - DOI - PubMed
    1. Stephenson C. R. J.; Yoon T. P.; MacMillan D. W. C.. Visible Light Photocatalysis in Organic Chemistry; Wiley-VCH: Germany, 2018.
    2. Bonfield H. E.; Knauber T.; Lévesque F.; Moschetta E. G.; Susanne F.; Edwards L. J. Photons as a 21st century reagent. Nat. Commun. 2020, 11, 804.10.1038/s41467-019-13988-4. - DOI - PMC - PubMed
    3. Buzzetti L.; Crisenza G. E. M.; Melchiorre P. Mechanistic Studies in Photocatalysis. Angew. Chem., Int. Ed. 2019, 58, 3730–3747. 10.1002/anie.201809984. - DOI - PubMed
    4. Wang H.; Tian Y. M.; König B. Energy- and atom-efficient chemical synthesis with endergonic photocatalysis. Nat. Rev. Chem. 2022, 6, 745–755. 10.1038/s41570-022-00421-6. - DOI - PubMed
    5. Strieth-Kalthoff F.; Glorius F. Triplet Energy Transfer Photocatalysis: Unlocking the Next Level. Chem. 2020, 6, 1888.10.1016/j.chempr.2020.07.010. - DOI
    1. Correia J. H.; Rodrigues J. A.; Pimenta S.; Dong T.; Yang Z. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics. 2021, 13, 1332.10.3390/pharmaceutics13091332. - DOI - PMC - PubMed
    1. Wang H.; Li W.-G.; Zeng K.; Wu Y.-J.; Zhang Y.; Xu T.-L.; Chen Y. Photocatalysis Enables Visible-Light Uncaging of Bioactive Molecules in Live Cells. Angew. Chem., Int. Ed. 2019, 58, 561–656. 10.1002/anie.201811261. - DOI - PubMed
    2. Li M.; Gebremedhin K. H.; Ma D.; Pu Z.; Xiong T.; Xu Y.; Kim J. S.; Peng X. Conditionally Activatable Photoredox catalysis in Living Systems. J. Am. Chem. Soc. 2022, 144, 163–173. 10.1021/jacs.1c07372. - DOI - PubMed
    3. Zeng K.; Han L.; Chen Y. Endogenous Proteins Modulation in Live Cells with Small Molecules and Light. ChemBioChem. 2022, 23, e20220024410.1002/cbic.202200244. - DOI - PubMed
    4. Alonso-de Castro S.; Ruggiero E.; Ruiz-de-Angulo A.; Rezabal E.; Mareque-Rivas J. C.; Lopez X.; Lopez-Gallego F.; Salassa L. Riboflavin as bioorthogonal photocatalyst for the activation of a PtIV prodrug. Chem. Sci. 2017, 8, 4619–4625. 10.1039/C7SC01109A. - DOI - PMC - PubMed
    1. Liu W.; Watson E. E.; Winssinger N. Photocatalysis in Chemical Biology: Extending the Scope of Optochemical Control and Towards New Frontiers in Semisynthetic Bioconjugates and Biocatalysis. Helv. Chim. Acta 2021, 104, e20210017910.1002/hlca.202100179. - DOI
    2. Angerani S.; Winssinger N. Visible Light Photoredox Catalysis Using Ruthenium Complexes in Chemical Biology. Chem.—Eur. J. 2019, 25, 6661–6672. 10.1002/chem.201806024. - DOI - PubMed
    3. Meggers E. Photocatalysis in organic and medicinal chemistry. Topics in Current Chemistry 2018, 376, 3. - PubMed
    4. Madec H.; Figueiredo F.; Cariou K.; Roland S.; Sollogoub M.; Gasser G. Metal complexes for catalytic and photocatalytic reactions in living cells and organisms. Chem. Sci. 2023, 14, 409–442. 10.1039/D2SC05672K. - DOI - PMC - PubMed
    5. Interrogating Biological Systems Using Visible-Light-Powered Catalysis. Nat. Rev. Chem. 2021, 5, 322–337.10.1038/s41570-021-00265-6 - DOI - PubMed
    6. Li P.; Terrett J. A.; Zbieg J. R. Visible-Light Photocatalysis as an Enabling Technology for Drug Discovery: A Paradigm Shift for Chemical Reactivity. ACS Med. Chem. Lett. 2020, 11, 2120–2130. 10.1021/acsmedchemlett.0c00436. - DOI - PMC - PubMed
    7. Fang Y.; Zou P. Photocatalytic Proximity Labeling for Profiling the Subcellular Organization of Biomolecules. ChemBioChem. 2023, 24, e20220074510.1002/cbic.202200745. - DOI - PubMed
    8. Seath C. P.; Trowbridge A. D.; Muir T. W.; MacMillan D. W. Reactive intermediates for interactome mapping. Chem. Soc. Rev. 2021, 50, 2911–2926. 10.1039/D0CS01366H. - DOI - PubMed