Novel N2-Substituted Pyrazolo[3,4-d]pyrimidine Adenosine A3 Receptor Antagonists: Inhibition of A3-Mediated Human Glioblastoma Cell Proliferation

被引：46

作者：

Taliani, Sabrina ^{[1
]}

La Motta, Concettina ^{[1
]}

Mugnaini, Laura ^{[1
]}

Simorini, Francesca ^{[1
]}

Salerno, Silvia ^{[1
]}

Marini, Anna Maria ^{[1
]}

Da Settimo, Federico ^{[1
]}

Cosconati, Sandro ^{[2
]}

Cosimelli, Barbara ^{[2
]}

Greco, Giovanni ^{[2
]}

Limongelli, Vittorio ^{[2
]}

Marinelli, Luciana ^{[2
]}

Novellino, Ettore ^{[2
]}

Ciampi, Osele ^{[3
]}

Daniele, Simona ^{[3
]}

Trincavelli, Maria Letizia ^{[3
]}

Martini, Claudia ^{[3
]}

机构：

[1] Univ Pisa, Dipartimento Sci Farmaceut, I-56126 Pisa, Italy

[2] Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy

[3] Univ Pisa, Dipartimento Psichiatria Neurobiol Farmacol & Bio, I-56126 Pisa, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 10期

关键词：

SITE-DIRECTED MUTAGENESIS; LIGAND RECOGNITION; A(1); DERIVATIVES; POTENT; PHARMACOLOGY; EXPRESSION; PROFILE; ACTIVATION; SYSTEM;

D O I：

10.1021/jm901785w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A(3) AR antagonists. In this study, a novel series of N-2-substituted pyrazolo[3,4-d]pyrimidines 2a-u was developed as highly potent and selective A(3) AR antagonists. The most performing compounds were derivatives 2a (R-1 = CH3 and R-2 = COC6H5; K-i 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R-1 = CH3 and R-2 = COC6H4-4-OCH3; K-i 1037, 3179, and 0.18 nM at the human A(1), A(2A), and A(3) ARs, respectively), which counteracted the effect of the A(3) AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC50 values comparable to A(3) AR binding affinity values of 2a and 2b, thereby suggesting that their effects were receptor-mediated. Furthermore, the antiproliferative activity of the new compounds was demonstrated to be mediated by the block of A(3) AR agonist activation of intracellular kinases ERK 1/2.

引用

页码：3954 / 3963

页数：10

共 54 条

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