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

Anna Fantinati, Giampaolo Morciano, Giulia Turrin, Gaia Pedriali, Salvatore Pacifico, Delia Preti, Valentina Albanese, Davide Illuminati, Virginia Cristofori, Carlotta Giorgi, Elena Tremoli, Paolo Pinton, Claudio Trapella

Journal: Bioorganic & medicinal chemistry letters 2022;72():128822

PMID: 35636649

Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Department of Enviromental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy.; Maria Cecilia Hospital, GVM Care&Research, 48033, Cotignola, RA; Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.; Maria Cecilia Hospital, GVM Care&Research, 48033, Cotignola, RA.; Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.; Maria Cecilia Hospital, GVM Care&Research, 48033, Cotignola, RA; Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: [email protected].; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: [email protected].

DOI: 10.1016/j.bmcl.2022.128822

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MeSH Terms: Adenosine Triphosphate, Azirines, Mitochondria, Mitochondrial Membrane Transport Proteins, Phosphatidylcholines, Urea