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

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

  • J Med Chem. 2017 Jul 27;60(14):6305-6320. doi: 10.1021/acs.jmedchem.7b00637.
Giulia Vignaroli 1 2,  Giulia Iovenitti 1 2,  Claudio Zamperini 1 2,  Federica Coniglio 1 2,  Pierpaolo Calandro 1,  Alessio Molinari 1,  Anna Lucia Fallacara 1,  Andrea Sartucci 1,  Alessia Calgani 3,  David Colecchia 4,  Andrea Mancini 3,  Claudio Festuccia 3,  Elena Dreassi 1,  Massimo Valoti 5,  Francesca Musumeci 6,  Mario Chiariello 4,  Adriano Angelucci 3,  Maurizio Botta 1 2 7,  Silvia Schenone 4
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
  • 2 Lead Discovery Siena S.r.l. , via Vittorio Alfieri 31, Castelnuovo Berardenga, 53019 Siena, Italy.
  • 3 Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila , Via Vetoio, 67100 Coppito, L'Aquila, Italy.
  • 4 Consiglio Nazionale delle Ricerche, Istituto di Fisiologia Clinica and Istituto Toscano Tumori, Core Research Laboratory , Via Fiorentina 1, 53100 Siena, Italy.
  • 5 Dipartimento di Scienze della Vita, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
  • 6 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova , Viale Benedetto XV 3, 16132 Genova, Italy.
  • 7 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University , BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, Pennsylvania 19122, United States.
PMID: 28650650 DOI: 10.1021/acs.jmedchem.7b00637
Abstract

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.

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