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Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A<sub>2A</sub>/A<sub>3</sub> Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity
- Title
- Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A<sub>2A</sub>/A<sub>3</sub> Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity
- Authors
- Kim, Gibae; Hou, Xiyan; Byun, Woong Sub; Kim, Gyudong; Jarhad, Dnyandev B.; Lee, Grim; Hyun, Young Eum; Yu, Jinha; Lee, Chang Soo; Qu, Shuhao; Warnick, Eugene; Gao, Zhan-Guo; Kim, Ji Yong; Ji, Seunghee; Shin, Hyunwoo; Choi, Jong-Ryoul; Jacobson, Kenneth A.; Lee, Hyuk Woo; Lee, Sang Kook; Jeong, Lak Shin
- Ewha Authors
- 유진하
- SCOPUS Author ID
- 유진하
- Issue Date
- 2023
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 66, no. 17, pp. 12249 - 12265
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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 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(2A)AR, including 5d with the highest affinity (Ki, A d(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 hA3AR. Structural SAR features and docking studies supported different binding modes at A(2A)AR and A3AR, 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/A3AR nucleoside antagonists would be promising drug candidates for immune-oncology.
- DOI
- 10.1021/acs.jmedchem.3c00806
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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