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
  • 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.