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基于结构的吡唑并[3,4-d]嘧啶类化合物作为Abl抑制剂及对人白血病细胞系的抗增殖剂的优化

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

作者信息

Manetti Fabrizio, Brullo Chiara, Magnani Matteo, Mosci Francesca, Chelli Beatrice, Crespan Emmanuele, Schenone Silvia, Naldini Antonella, Bruno Olga, Trincavelli Maria Letizia, Maga Giovanni, Carraro Fabio, Martini Claudia, Bondavalli Francesco, Botta Maurizio

机构信息

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.

出版信息

J Med Chem. 2008 Mar 13;51(5):1252-9. doi: 10.1021/jm701240c. Epub 2008 Feb 8.

DOI:10.1021/jm701240c
PMID:18257513
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.

摘要

分子对接计算和网格映射的结果为基于结构的优化方法奠定了基础，该方法旨在从抑制Abl酶活性和对人白血病细胞的抗增殖特性方面改善吡唑并嘧啶衍生物的生物学性质。模拟结果表明，插入具有不同取代模式的卤素取代基可显著提高白血病细胞生长抑制率，并使对Abl的亲和力提高多达1个数量级。

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