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

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• 作者：Sabrina Taliani ; Concettina La Motta ; Laura Mugnaini ; Francesca Simorini ; Silvia Salerno ; Anna Maria Marini ; Federico Da Settimo ; Sandro Cosconati ; Barbara Cosimelli ; Giovanni Greco ; Vittorio Limongel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：3954-3963
• 全文大小：1026K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

Adenosine induces glioma cell proliferation by means of an antiapoptotic effect, which is blocked by cotreatment with selective A₃ AR antagonists. In this study, a novel series of N²-substituted pyrazolo[3,4-d]pyrimidines 2a−u was developed as highly potent and selective A₃ AR antagonists. The most performing compounds were derivatives 2a (R₁ = CH₃ and R₂ = COC₆H₅; K_i 334, 728, and 0.60 nM at the human A₁, A_2A, and A₃ ARs, respectively) and 2b (R₁ = CH₃ and R₂ = COC₆H₄-4-OCH₃; K_i 1037, 3179, and 0.18 nM at the human A₁, A_2A, and A₃ ARs, respectively), which counteracted the effect of the A₃ AR agonists Cl-IB-MECA and IB-MECA on human glioma U87MG cell proliferation. This effect was concentration-dependent, with IC₅₀ values comparable to A₃ 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 A₃ AR agonist activation of intracellular kinases ERK 1/2.