Exploring C2 and N 6 Substituent Effects on Truncated 4'-Thioadenosine Derivatives as Dual A 2A and A 3 Adenosine Receptor Ligands
Based on high binding affinity of truncated 2-hexynyl-4'-thioadenosine (3 a) at both A adenosine receptor (AR) and A 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 s...
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Veröffentlicht in: | ChemMedChem 2024-10, p.e202400575 |
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Hauptverfasser: | , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Based on high binding affinity of truncated 2-hexynyl-4'-thioadenosine (3 a) at both A
adenosine receptor (AR) and A
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 N
-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 N
-amino group decreased the binding affinity at hA
AR. These results confirm our previous findings that a free amino group at N
-position and longer hydrophobic chain at C2-position are essential for hA
AR binding affinity. The introduction of a bulky hydrophobic group at free N
-amino group maintained the binding affinity at hA
AR. The binding mode of truncated 2-substituted-4'-thioadenosine derivatives to hA
and hA
AR were predicted by a molecular docking study. |
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ISSN: | 1860-7187 |