title: Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study.
abstract: A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.
authors: Dipartimento Farmaco Chimico Tecnologico, University of Siena, Siena, Italy.
authors: Marco
authors: M
authors: Radi
authors: Elena
authors: E
authors: Dreassi
authors: Chiara
authors: C
authors: Brullo
authors: Emmanuele
authors: E
authors: Crespan
authors: Cristina
authors: C
authors: Tintori
authors: Vincenzo
authors: V
authors: Bernardo
authors: Massimo
authors: M
authors: Valoti
authors: Claudio
authors: C
authors: Zamperini
authors: Henry
authors: H
authors: Daigl
authors: Francesca
authors: F
authors: Musumeci
authors: Fabio
authors: F
authors: Carraro
authors: Antonella
authors: A
authors: Naldini
authors: Irene
authors: I
authors: Filippi
authors: Giovanni
authors: G
authors: Maga
authors: Silvia
authors: S
authors: Schenone
authors: Maurizio
authors: M
authors: Botta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine