Novel N2-substituted pyrazolo[3,4-d]pyrimidine adenosine A3 receptor antagonists: inhibition of A3-mediated human glioblastoma cell proliferation.

Abstract

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) = CH(3) and R(2) = COC(6)H(5); K(i) 334, 728, and 0.60 nM at the human A(1), A(2A), and A(3) ARs, respectively) and 2b (R(1) = CH(3) and R(2) = COC(6)H(4)-4-OCH(3); 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 IC(50) 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.

• Authors: Sabrina Taliani, Concettina La Motta, Laura Mugnaini, Francesca Simorini, Silvia Salerno, Anna Maria Marini, Federico Da Settimo, Sandro Cosconati, Barbara Cosimelli, Giovanni Greco, Vittorio Limongelli, Luciana Marinelli, Ettore Novellino, Osele Ciampi, Simona Daniele, Maria Letizia Trincavelli, Claudia Martini
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 10 Pg. 3954-63 (May 27 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20408530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine A3 Receptor Agonists
• Adenosine A3 Receptor Antagonists
• Antineoplastic Agents
• Pyrazoles
• Pyrimidines
• Cyclic AMP
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Adenosine A3 Receptor Agonists
• Adenosine A3 Receptor Antagonists
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding, Competitive
• CHO Cells
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemotherapy, Adjuvant
• Cricetinae
• Cricetulus
• Cyclic AMP (metabolism)
• Enzyme Activation
• Glioblastoma
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Models, Molecular
• Phosphorylation
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Structure-Activity Relationship