Exploring C2 and N6 Substituent Effects on Truncated 4′-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands
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Date
2024
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John Wiley & Sons
Abstract
Based on high binding affinity of truncated 2-hexynyl-4′-thioadenosine (3 a) at both A2A adenosine receptor (AR) and A3 AR, we explored structure-activity relationship (SAR) of the C2-substitution by altering chain length of the 2-hexynyl moiety, thereby evaluating the hydrophobic pocket size. A series of truncated N6-substituted 4′-thioadenosine derivatives with C2-alkynyl substitution were successfully synthesized from D-mannose, using a palladium-catalyzed Sonogashira coupling reaction as the key step, whose structures were confirmed by the X-ray crystal structure of 4 h. As the size of the alkynyl group at the C2-position increased, the binding affinity improved; however, when the substituted group was larger than hexynyl, the binding affinity decreased. The introduction of a bulky hydrophobic group such as 3-halobenzyl group at the free N6-amino group decreased the binding affinity at hA2AAR. These results confirm our previous findings that a free amino group at N6-position and longer hydrophobic chain at C2-position are essential for hA2A AR binding affinity. The introduction of a bulky hydrophobic group at free N6-amino group maintained the binding affinity at hA3 AR. The binding mode of truncated 2-substituted-4′-thioadenosine derivatives to hA2A and hA3 AR were predicted by a molecular docking study.
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NATURAL SCIENCES::Chemistry
Citation
ChemMedChem. Nov; 2024; e202400575 pp.