Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A 2A /A 3 Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity.

Autor:	Kim G; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, 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., Byun WS; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., 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., 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., Hyun YE; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., 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, South Korea., Lee CS; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Qu S; 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., Kim JY; Future Medicine Company Limited, Seoul 06665, Republic of Korea., Ji S; HK Inno.N Corporation, Seoul 04551, Republic of Korea., Shin H; HK Inno.N Corporation, Seoul 04551, Republic of Korea., Choi JR; HK Inno.N Corporation, 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., Lee HW; Future Medicine Company Limited, Seoul 06665, Republic of Korea., Lee SK; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Jeong LS; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.; Future Medicine Company Limited, Seoul 06665, Republic of Korea.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Sep 14; Vol. 66 (17), pp. 12249-12265. Date of Electronic Publication: 2023 Aug 21.
DOI:	10.1021/acs.jmedchem.3c00806
Abstrakt:	Based on hA 2A AR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA 2A AR agonists into antagonists while maintaining affinity toward hA 3 AR. The final compounds of 2,8-disubstituted- N 6 -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 2A AR, including 5d with the highest affinity ( K i,A 2A = 7.7 ± 0.5 nM). The hA 2A AR- 5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA 3 AR. Structural SAR features and docking studies supported different binding modes at A 2A AR and A 3 AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which 5d displayed high oral absorption, moderate half-life, and bioavailability. Also, 5d significantly improved the antitumor effect of anti-PD-L1 in vivo . Overall, this study suggests that the novel dual A 2A AR/A 3 AR nucleoside antagonists would be promising drug candidates for immune-oncology.
Databáze:	MEDLINE
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