Based on a screening of a chemical library of A(2A) adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1 delta) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors ", demonstrated good CK1 delta inhibitory activity combined with a high binding affinity, especially for the A(2A)AR. The N-6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 mu M and KiA(2A) = 0.076 mu M) showed the best balance of A(2A)AR affinity and CK1 delta inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein-ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.
“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies
Spinaci, AndreaPrimo
;Buccioni, MichelaSecondo
;Cui, Chang;Dal Ben, Diego;Francucci, Beatrice;Lambertucci, Catia;Marucci, Gabriella;Volpini, Rosaria
Ultimo
2023-01-01
Abstract
Based on a screening of a chemical library of A(2A) adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1 delta) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors ", demonstrated good CK1 delta inhibitory activity combined with a high binding affinity, especially for the A(2A)AR. The N-6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 mu M and KiA(2A) = 0.076 mu M) showed the best balance of A(2A)AR affinity and CK1 delta inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein-ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.