A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported and proved to be active against several tumor cell lines. Among these compds., a promising antileukemia lead (I) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead I is described in the present work. A series of more sol. pyrazolo[3,4-d]pyrimidine derivs. were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compds. 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 soly., microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogs of lead I as promising antileukemia agents.

Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study.

BRULLO, CHIARA;MUSUMECI, FRANCESCA;SCHENONE, SILVIA;
2011-01-01

Abstract

A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported and proved to be active against several tumor cell lines. Among these compds., a promising antileukemia lead (I) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead I is described in the present work. A series of more sol. pyrazolo[3,4-d]pyrimidine derivs. were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compds. 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 soly., microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogs of lead I as promising antileukemia agents.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/293355
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