Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines

  • J Med Chem. 2008 Mar 13;51(5):1252-9. doi: 10.1021/jm701240c.
Fabrizio Manetti  1 ,  Chiara Brullo ,  Matteo Magnani ,  Francesca Mosci ,  Beatrice Chelli ,  Emmanuele Crespan ,  Silvia Schenone ,  Antonella Naldini ,  Olga Bruno ,  Maria Letizia Trincavelli ,  Giovanni Maga ,  Fabio Carraro ,  Claudia Martini ,  Francesco Bondavalli ,  Maurizio Botta
Affiliations
  • 1. Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.
PMID: 18257513 DOI: 10.1021/jm701240c
Abstract

Results from molecular docking calculations and Grid mapping laid the foundations for a structure-based optimization approach to improve the biological properties of pyrazolo-pyrimidine derivatives in terms of inhibition of Abl enzymatic activity and antiproliferative properties toward human leukemia cells. Insertion of halogen substituents with various substitution patterns, suggested by simulations, led to a significant improvement of leukemia cell growth inhibition and to an increase up to 1 order of magnitude of the affinity toward Abl.