1283727-49-0Relevant articles and documents
Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4- d ]pyrimidines active in hypoxic human leukemia Cells: A lead optimization study
Radi, Marco,Dreassi, Elena,Brullo, Chiara,Crespan, Emmanuele,Tintori, Cristina,Bernardo, Vincenzo,Valoti, Massimo,Zamperini, Claudio,Daigl, Henry,Musumeci, Francesca,Carraro, Fabio,Naldini, Antonella,Filippi, Irene,Maga, Giovanni,Schenone, Silvia,Botta, Maurizio
experimental part, p. 2610 - 2626 (2011/06/21)
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.
