Identification of small-molecule urea derivatives as PTPC modulators targeting the c subunit of F1/Fo-ATP synthase

[Display omitted] •Synthesis of urea derivatives.•Proposed mechanism of action.•Modulation of PTPC opening channel.•Mitochondrial permeability transition-driven regulated cell death.•Maintaining living and functional cells in cardiovascular diseases. Maintaining a high percentage of living and funct...

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Published in:Bioorganic & medicinal chemistry letters 2022-09, Vol.72, p.128822-128822, Article 128822
Main Authors: Fantinati, Anna, Morciano, Giampaolo, Turrin, Giulia, Pedriali, Gaia, Pacifico, Salvatore, Preti, Delia, Albanese, Valentina, Illuminati, Davide, Cristofori, Virginia, Giorgi, Carlotta, Tremoli, Elena, Pinton, Paolo, Trapella, Claudio
Format: Article
Language:English
Subjects:
Cardiovascular diseases
Mitochondria
PTPC
Urea derivatives
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Summary:[Display omitted] •Synthesis of urea derivatives.•Proposed mechanism of action.•Modulation of PTPC opening channel.•Mitochondrial permeability transition-driven regulated cell death.•Maintaining living and functional cells in cardiovascular diseases. Maintaining a high percentage of living and functional cells in those pathologies in which excessive cell death occurs, such as neurodegenerative disorders and cardiovascular diseases, is one of the most intriguing challenges in the field of biochemical research for drug discovery. Here, mitochondrial permeability transition-driven regulated cell death is the main mechanism of mitochondrial impairment and cell fate; this pathway is still lacking of satisfying pharmacological treatments to counteract its becoming; for this reason, it needs continuous and intense research to find new compounds as modulator of the permeability transition pore complex (PTPC) activity. In this study, we report the identification of small-molecule urea derivatives able to inhibit PTPC opening following calcium overload and selected for future use in cytoprotection.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128822