Person:
Martín Cámara, Olmo

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First Name
Olmo
Last Name
Martín Cámara
URI
https://hdl.handle.net/20.500.14352/86252
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Química en Ciencias Farmacéuticas
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2021 - 20222
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Author: Cores Esperón, Ángel × Subject: 615.31 ×

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Now showing 1 - 2 of 2
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    Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
    (European Journal of Medicinal Chemistry, 2022) Staderini, Matteo; Vanni, Silvia; Colini Baldeschi, Arianna; Zattoni, Marco; Celauro, Luigi; Ferracin, Chiara; Bistaffa, Edoardo; Moda, Fabio; Pérez, Daniel I.; Martínez, Ana; Martín Carmona, María Antonia; Martín Cámara, Olmo; Cores Esperón, Ángel; Bianchini, Giulia; Kammerer, Robert; Menéndez Ramos, José Carlos; Legname, Giuseppe; Bolognesi, Maria Laura
    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.
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    Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation
    (Antioxidants, 2021) Cores Esperón, Ángel; Carmona Zafra, Noelia; Martín Cámara, Olmo; Sánchez Cebrián, Juan Domingo; Duarte, Pablo; Villacampa Sanz, Mercedes; Bermejo Bescos, María De La Paloma; Martín-Aragón Álvarez, Sagrario; León Martínez, Rafael; Menéndez Ramos, José Carlos
    Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.