Novel N(2)-Substituted Pyrazolo[3,4-d]pyrimidine Adenosine A(3) Receptor Antagonists: Inhibition of A(3)-Mediated Human Glioblastoma Cell Proliferation (dagger)
| Autor: | Luciana Marinelli, Concettina La Motta, Claudia Martini, Giovanni Greco, Sandro Cosconati, Federico Da Settimo, L. Mugnaini, Simona Daniele, Barbara Cosimelli, Anna Maria Marini, Silvia Salerno, Osele Ciampi, Francesca Simorini, Maria Letizia Trincavelli, Sabrina Taliani, Vittorio Limongelli, Ettore Novellino |
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| Přispěvatelé: | Taliani, S., La Motta, C., Mugnaini, L., Simorini, F., Salerno, S., Marini, A. M., Da Settimo, F., Cosconati, S., Cosimelli, Barbara, Greco, Giovanni, Limongelli, Vittorio, Marinelli, Luciana, Novellino, Ettore, Ciampi, O., Daniele, S., Trincavelli, M. L., Martini, C., Taliani, S, La Motta, C, Mugnaini, L, Simorini, F, Salerno, S, Marini, Am, Da Settimo, F, Cosconati, Sandro, Cosimelli, B, Greco, G, Limongelli, V, Marinelli, L, Novellino, E, Ciampi, O, Daniele, S, Trincavelli, Ml |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Agonist
MAPK/ERK pathway Models Molecular Pyrimidine medicine.drug_class Adenosine A3 Receptor Antagonists Antineoplastic Agents CHO Cells Binding Competitive chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Cricetulus Adenosine A3 Receptor Agonists Cell Line Tumor Cricetinae Drug Discovery medicine Cyclic AMP Animals Humans Phosphorylation Cell Proliferation Mitogen-Activated Protein Kinase 1 Glioblastoma cell Mitogen-Activated Protein Kinase 3 Kinase Chemistry Molecular biology Adenosine Enzyme Activation Pyrimidines Biochemistry Chemotherapy Adjuvant Molecular Medicine Pyrazoles Glioblastoma Intracellular medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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