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

Autor:	Kim G; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Jarhad DB; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Lee G; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Kim G; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea., Hou X; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; College of Life Science, Dalian Minzu University, Dalian 116600, People's Republic of China., Yu J; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Lee CS; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Warnick E; 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., Gao ZG; 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., Ahn SY; Future Medicine Co., Ltd., 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea., Kwak D; Future Medicine Co., Ltd., 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea., Park K; LNPsolution, R&D Laboratory, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Republic of Korea., Lee SD; LNPsolution, R&D Laboratory, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Republic of Korea., Park TU; Preclincial Research Center (PRC), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea., Jung SY; Preclincial Research Center (PRC), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea., Lee JH; HK inno.N Corp., Seoul 04551, Republic of Korea., Choi JR; HK inno.N Corp., Seoul 04551, Republic of Korea., Kim M; HK inno.N Corp., Seoul 04551, Republic of Korea., Kim D; HK inno.N Corp., Seoul 04551, Republic of Korea., Kim B; HK inno.N Corp., Seoul 04551, Republic of Korea., Jacobson KA; 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., Jeong LS; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; Future Medicine Co., Ltd., 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jun 27; Vol. 67 (12), pp. 10490-10507. Date of Electronic Publication: 2024 Jun 06.
DOI:	10.1021/acs.jmedchem.4c01003
Abstrakt:	Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA 2A AR 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 hA 3 AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA 2A AR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA 2A AR ( K i ,hA2A = 5.0 ± 0.5 nM, K i ,hA3 / K i ,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.
Databáze:	MEDLINE
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