Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15

Autor: Maria Giulia Nizi, Mirko M. Maksimainen, Sudarshan Murthy, Serena Massari, Juho Alaviuhkola, Barbara E. Lippok, Sven T. Sowa, Albert Galera-Prat, Renata Prunskaite-Hyyryläinen, Bernhard Lüscher, Patricia Korn, Lari Lehtiö, Oriana Tabarrini
Rok vydání: 2021
Předmět:
Zdroj: European journal of medicinal chemistry. 237
ISSN: 1768-3254
Popis: While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC
Databáze: OpenAIRE
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