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Photobiological properties of 3-psoralenacetic acids

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Abstract

Some 4,8-dimethyl-3-psoralenacetic acids were synthesized and studied. All the designed psoralenacetic acids bear alkyl or cycloalkyl substituents at the furan ring. These psoralenacetic acids were shown to be a novel class of psoralen derivatives characterized by an interesting photobiological profile. The carboxylic group at the 3 position, useful to confer hydrophilic properties, appears to be detrimental to the classical intercalation into DNA, likely because of repulsive interactions with the negative surface of the macromolecule. Nevertheless, the new derivatives possess a notable photoantiproliferative activity, due to a peculiar mechanism of action consisting of a decarboxylation step before exerting their photobiological activity. The most active compound 2 is able to induce a noteworthy photocytotoxic effect, with GI50 values being submicromolar on human tumor cell lines and no effect in the dark. The involvement of DNA photoaddition after UVA light-mediated decarboxylation and ROS formation is responsible for its biological activity, as demonstrated comparing the activity profile of the decarboxylated analogue. However, other biological targets seem to be involved in the photooxidative damage, such as proteins. Compound 2 could thus be considered as a prodrug, inactive without UVA light but activated upon specific irradiation, thus preventing unselective side effects and opening new perspectives on agents useful in photochemotherapy.

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Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, Padova, 35131, Italy

    Lisa Dalla Via, Giovanni Marzaro, Adriana Chilin & Giorgia Miolo

  2. Department of Chemistry, University of Perugia, via Elce di Sotto 8, Perugia, 06123, Italy

    Alessandra Mazzoli

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  1. Lisa Dalla Via
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  2. Giovanni Marzaro
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  3. Alessandra Mazzoli
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  4. Adriana Chilin
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  5. Giorgia Miolo
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Correspondence to Giorgia Miolo.

Additional information

Electronic supplementary information (ESI) available: Synthesis of compound 7, table of log?D, mass spectra of photoadducts, and mass spectra of photolysis products. See DOI: 10.1039/c5pp00210a

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Dalla Via, L., Marzaro, G., Mazzoli, A. et al. Photobiological properties of 3-psoralenacetic acids. Photochem Photobiol Sci 14, 2074–2086 (2015). https://doi.org/10.1039/c5pp00210a

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