Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A_2A/A₃ Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity.

ABSTRACT: Based on hA_2AAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA_2AAR agonists into antagonists while maintaining affinity toward hA₃AR. The final compounds of 2,8-disubstituted-N⁶-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA_2AAR, including 5d with the highest affinity (K_i,A2A = 7.7 ± 0.5 nM). The hA_2AAR-5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conforma

SUBMITTER: Kim G 

PROVIDER: S-EPMC10896643 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature