title: Pyrazolo[3,4-d]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors.
abstract: Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble antitumor prodrugs (7 and 8). In vitro studies confirmed a significant improvement of aqueous solubility and, for compound 8, good plasma stability, suggesting superior in vivo bioavailability. As expected, the uncleaved water-soluble prodrugs 7 and 8 showed no activity toward the enzymatic targets (c-Src and c-Abl) but revealed promising antiproliferative activity in myeloid cell lines, as a consequence of the in vitro hydrolysis of the selected solubilizing moiety, followed by the release of the active compounds (1 and 2).
authors.affiliation: Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.affiliation: Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.affiliation: Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Dreassi
authors.affiliation: Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy ; Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila , Via Vetoio, 67100 Coppito, L'Aquila, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila , Via Vetoio, 67100 Coppito, L'Aquila, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sanità
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR , Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR , Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kissova
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR , Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: Dipartimento di Scienza Farmaceutiche, Università degli Studi di Genova , Viale benedetto XV 3, 16132 Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Dipartimento di Scienza Farmaceutiche, Università degli Studi di Genova , Viale benedetto XV 3, 16132 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
authors.affiliation: Dipartimentodi Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy ; 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.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
keywords: Prodrug; aqueous solubility; dual c-Src and c-Abl inhibitor; pyrazolo[3,4-d]pyrimidine