Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors

被引：91

作者：

Gupta, Sanjay ^{[1
]}

Rodrigues, Ligia M. ^{[1
]}

Esteves, Ana P. ^{[1
]}

Oliveira-Campos, Ana M. F. ^{[1
]}

Jose Nascimento, M. Sao ^{[2
]}

Nazareth, N. ^{[2
]}

Cidade, Honorina ^{[2
]}

Neves, Marta P. ^{[2
]}

Fernandes, Eduarda ^{[3
]}

Pinto, Madalena ^{[2
]}

Cerqueira, Nuno M. F. S. A. ^{[4
]}

Bras, Natercia ^{[4
]}

机构：

[1] Univ Minho, Ctr Quim, P-4710057 Braga, Portugal

[2] Univ Porto CEQOFFUP, Ctr Estudos Quim Organ Fitoquim & Farmacol, Lab Microbiol & Quim Organ, Fac Farm, P-4050047 Oporto, Portugal

[3] Univ Porto, REQUIMTE, Dept Quim Fis, Fac Farm, P-4050047 Oporto, Portugal

[4] Univ Porto, REQUIMTE, Dept Quim, Fac Ciencias, P-4169007 Oporto, Portugal

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 43卷 / 04期

关键词：

nitrogen heterocycles; aminocyanopyrazole derivatives; pyrazolo[3,4-d]pyrimidines; xanthine oxidase; antitumour agents; cytotoxic; docking; computational studies;

D O I：

10.1016/j.ejmech.2007.06.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC50 values below 1 mu M. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors. (c) 2007 Elsevier Masson SAS. All rights reserved.

引用

页码：771 / 780

页数：10

共 33 条

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