Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A2A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors

Gibae Kim, Dnyandev B. Jarhad, Grim Lee, Gyudong Kim, Xiyan Hou, Jinha Yu, Chang Soo Lee, Eugene Warnick, Zhan Guo Gao, Sang Yeop Ahn, Dongik Kwak, Kichul Park, Summer Dabin Lee, Tae Uk Park, So Young Jung, Jong Hyun Lee, Jong Ryoul Choi, Myeongjoong Kim, Donghyun Kim, Bongtae KimKenneth A. Jacobson, Lak Shin Jeong

Research output: Contribution to journalArticlepeer-review

Abstract

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.

Original languageEnglish
Pages (from-to)10490-10507
Number of pages18
JournalJournal of Medicinal Chemistry
Volume67
Issue number12
DOIs
StatePublished - 27 Jun 2024

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© 2024 American Chemical Society

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