2. Academic Validation
  3. 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

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

  • J Med Chem. 2024 Jun 27;67(12):10490-10507. doi: 10.1021/acs.jmedchem.4c01003.
Gibae Kim 1,  Dnyandev B Jarhad 1,  Grim Lee 1,  Gyudong Kim 1 2,  Xiyan Hou 1 3,  Jinha Yu 1 4,  Chang Soo Lee 1,  Eugene Warnick 5,  Zhan-Guo Gao 5,  Sang Yeop Ahn 6,  Dongik Kwak 6,  Kichul Park 7,  Summer Dabin Lee 7,  Tae-Uk Park 8,  So-Young Jung 8,  Jong Hyun Lee 9,  Jong-Ryoul Choi 9,  Myeongjoong Kim 9,  Donghyun Kim 9,  Bongtae Kim 9,  Kenneth A Jacobson 5,  Lak Shin Jeong 1 6
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 3 College of Life Science, Dalian Minzu University, Dalian 116600, People's Republic of China.
  • 4 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 5 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 6 Future Medicine Co., Ltd., 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea.
  • 7 LNPsolution, R&D Laboratory, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Republic of Korea.
  • 8 Preclincial Research Center (PRC), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea.
  • 9 HK inno.N Corp., Seoul 04551, Republic of Korea.
PMID: 38845345 DOI: 10.1021/acs.jmedchem.4c01003
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.

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