Prodrugs of Pyrazolo[3,4-d]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model
| Autor: | Francesca Musumeci, Pierpaolo Calandro, Anna Lucia Fallacara, Giulia Vignaroli, David Colecchia, Andrea Sartucci, Alessio Molinari, Mario Chiariello, Adriano Angelucci, Silvia Schenone, Maurizio Botta, Giulia Iovenitti, Claudio Zamperini, Massimo Valoti, Elena Dreassi, Andrea Mancini, Federica Coniglio, Claudio Festuccia, Alessia Calgani |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Animals Antineoplastic Agents Blood-Brain Barrier Brain Neoplasms Cell Line Tumor Drug Screening Assays Antitumor Glioblastoma Humans Membranes Artificial Mice Inbred C57BL Mice Nude Microsomes Liver Prodrugs Protein Kinase Inhibitors Pyrazoles Pyrimidines Small Molecule Libraries Solubility Structure-Activity Relationship Molecular Medicine Drug Discovery Pharmaceutical Science Nude Pharmaceutical Science Pharmacology Drug Screening Assays Inbred C57BL Mice 0302 clinical medicine Drug Discovery U87 media_common ADME Tumor Chemistry Prodrug Liver 030220 oncology & carcinogenesis Artificial Drug media_common.quotation_subject Cell Line 03 medical and health sciences Pharmacokinetics In vivo Microsomes Structure–activity relationship Membranes Antitumor 030104 developmental biology |
| Zdroj: | Journal of medicinal chemistry. 60(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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