Exploring C2 and N6 Substituent Effects on Truncated 4′-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands

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dc.contributor.authorNaik, Siddhi D.
dc.contributor.authorKim, Minjae
dc.contributor.authorChoi, Jiyoung
dc.contributor.authorKim, Gibae
dc.contributor.authorWoo Kim, Seung
dc.contributor.authorAswar, Vikas R.
dc.contributor.authorTripathi, Sushil K.
dc.contributor.authorGaikwad, Vidyasagar
dc.contributor.authorYu, Jinha
dc.contributor.authorShin Jeong, Lak
dc.date.accessioned2024-12-05T04:54:02Z
dc.date.available2024-12-05T04:54:02Z
dc.date.issued2024
dc.description.abstractBased 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.
dc.identifier.citationChemMedChem. Nov; 2024; e202400575 pp.
dc.identifier.issn1860-7179
dc.identifier.urihttps://doi.org/10.1002/cmdc.202400575
dc.identifier.urihttp://khandolacollege.ndl.gov.in/handle/123456789/98
dc.language.isoen
dc.publisherJohn Wiley & Sons
dc.subjectNATURAL SCIENCES::Chemistry
dc.titleExploring C2 and N6 Substituent Effects on Truncated 4′-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands
dc.typeArticle
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