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, Andrea
Primo
;
Buccioni, Michela
Secondo
;
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.
File in questo prodotto:
File Dimensione Formato  
Pharmaceuticals 2023 vol. 16(2) art. n. 167.pdf

accesso aperto

Licenza: PUBBLICO - Creative Commons
Dimensione 3.93 MB
Formato Adobe PDF
3.93 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/479586
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 5
social impact