Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models



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Staderini, Matteo and Vanni, Silvia and Colini Baldeschi, Arianna and Zattoni, Marco and Celauro, Luigi and Ferracin, Chiara and Bistaffa, Edoardo and Moda, Fabio and Pérez, Daniel I. and Martínez, Ana and Martín Carmona, María Antonia and Martín Cámara, Olmo and Cores Esperón, Ángel and Bianchini, Giulia and Kammerer, Robert and Menéndez Ramos, José Carlos and Legname, Giuseppe and Bolognesi, Maria Laura (2022) Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models. European Journal of Medicinal Chemistry, 245 . p. 114923. ISSN 0223-5234

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Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four- step route, and a representative member was confirmed to have native fluorescence, including a band in the near- infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cellClines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrP levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain- independent anti-prion compounds.

Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2022)

Uncontrolled Keywords:Prions; Prion protein; GN8; Theranostics; Carbazoles
Subjects:Medical sciences > Pharmacy > Pharmaceutical chemistry
Medical sciences > Pharmacy > Organic chemistry
ID Code:75696
Deposited On:22 Nov 2022 08:16
Last Modified:22 Nov 2022 10:20

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