Prodrugs of Pyrazolo[3,4‑d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model

Pyrazolo­[3,4-d]­pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo­[3,4-d]­pyrimidine prodrugs (1a−...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of medicinal chemistry 2017-07, Vol.60 (14), p.6305-6320
Hauptverfasser: Vignaroli, Giulia, Iovenitti, Giulia, Zamperini, Claudio, Coniglio, Federica, Calandro, Pierpaolo, Molinari, Alessio, Fallacara, Anna Lucia, Sartucci, Andrea, Calgani, Alessia, Colecchia, David, Mancini, Andrea, Festuccia, Claudio, Dreassi, Elena, Valoti, Massimo, Musumeci, Francesca, Chiariello, Mario, Angelucci, Adriano, Botta, Maurizio, Schenone, Silvia
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Pyrazolo­[3,4-d]­pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo­[3,4-d]­pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4–4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b00637