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4-Amino-1,8-naphthalimide based fluorescent photoinduced electron transfer (PET) pH sensors as liposomal cellular imaging agents: The effect of substituent patterns on PET directional quenching

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Abstract

Four new fluorescent sensors (1–4) based on the 4-amino-1,8-naphthalimide fluorophores (Naps) have been synthesized based on the classical fluorophorespacer-receptor model. These four compounds all gave rise to emission bands centred at ca. 535 nm, which were found to be highly pH dependent, the emission being ‘switched on’ in acidic media, while being quenched due to PET from the amino moieties to the excited state of the Nap at more alkaline pH. The luminescent pH dependence for these probes was found to be highly dependent on the substitution on the imide site, as well as the polyamine chain attached to the position 4-amino moiety. In the case of sensor 2 the presence of the 4-amino-aniline dominated the pH dependent quenching. Nevertheless, at higher pH, PET quenching was also found to occur from the polyamine site. Hence, 2 is better described as a receptor1-spacer1-fluorophore-spacer2-receptor2 system, where the dominant PET process is due to (normally less favourable) ‘directional’ PET quenching from the 4-amino-aniline unit to the Nap site. Similar trends and pH fluorescence dependences were also seen for 3 and 4. These compounds were also tested for their imaging potential and toxicity against HeLa cells (using DRAQ5 as nuclear stain which does now show pH dependent changes in acidic and neutral pH) and the results demonstrated that these compounds have reduced cellular viability at moderately high concentrations (with IC50 values between ca. 8–30 µmol·L−1), but were found to be suitable for intracellular pH determination at 1 µmol ·L−1concentrations, where no real toxicity was observed. This allowed us to employ these as lysosomal probes at sub-toxic concentrations, where the Nap based emission was found to be pH depended, mirroring that seen in aqueous solution for 1–4, with the main fluorescence changes occurring within acidic to neutral pH.

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Acknowledgements

We thank Science Foundation Ireland (SFI PI Award 13/IA/1865 to TG) and TCD for financial support. We also thank the Ministerio of Economía y Competitividad of Spain and The Irish Research Council (IRC) for the funding of postdoctoral fellowships to MMC and AFH (GOIPD/2018/162), respectively. We thank Dr J. E. O’Brien, M. Reuther and G. Hessman (School of Chemistry, TCD) for assisting with NMR and MS.

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Authors and Affiliations

  1. School of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland

    Miguel Martínez-Calvo, Sandra A. Bright, Emma B. Veale, Adam F. Henwood & Thorfinnur Gunnlaugsson

  2. School of Biochemistry and Immunology and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland

    Sandra A. Bright & D. Clive Williams

  3. Departamento de Química Orgánica Universidade de Santiago de Compostela, Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), Rúa Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain

    Miguel Martínez-Calvo

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  1. Miguel Martínez-Calvo
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Correspondence to Miguel Martínez-Calvo or Thorfinnur Gunnlaugsson.

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Martínez-Calvo, M., Bright, S.A., Veale, E.B. et al. 4-Amino-1,8-naphthalimide based fluorescent photoinduced electron transfer (PET) pH sensors as liposomal cellular imaging agents: The effect of substituent patterns on PET directional quenching. Front. Chem. Sci. Eng. 14, 61–75 (2020). https://doi.org/10.1007/s11705-019-1862-8

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