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γ- and δ-lactones as fumarate esters analogues and their neuroprotective effects

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Abstract

The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.

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Acknowledgements

We are grateful to Università degli Studi di Trieste ‘Finanziamento di Ateneo per progetti di ricerca scientifica FRA 2016 e FRA 2020’ for financial support.

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  1. Department of Chemical and Pharmaceutical Sciences, University of Trieste, P.zle Europa 1, 34128, Trieste, Italy

    Francesca Cateni, Patrizia Nitti, Sara Drioli & Giuseppe Procida

  2. Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127, Trieste, Italy

    Renzo Menegazzi & Maurizio Romano

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  1. Francesca Cateni
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Cateni, F., Nitti, P., Drioli, S. et al. γ- and δ-lactones as fumarate esters analogues and their neuroprotective effects. Med Chem Res 30, 913–924 (2021). https://doi.org/10.1007/s00044-020-02698-y

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