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
- 주제(기타) Chemistry, Medicinal
- 설명문(일반) [Kim, Gibae; Hou, Xiyan; Byun, Woong Sub; Kim, Gyudong; Jarhad, Dnyandev B.; Lee, Grim; Hyun, Young Eum; Yu, Jinha; Lee, Chang Soo; Qu, Shuhao; Lee, Sang Kook; Jeong, Lak Shin] Seoul Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Seoul 08826, South Korea; [Hou, Xiyan] Dalian Minzu Univ, Coll Life Sci, Dalian 116600, Peoples R China; [Byun, Woong Sub] Stanford Univ, Stanford Sch Med, Dept Chem & Syst Biol, Chem H, Stanford, CA 94305 USA; [Byun, Woong Sub] Stanford Univ, Stanford Canc Inst, Stanford Sch Med, Stanford, CA 94305 USA; [Kim, Gyudong] Chonnam Natl Univ, Coll Pharm, Gwangju 61186, South Korea; [Kim, Gyudong] Chonnam Natl Univ, Res Inst Drug Dev, Gwangju 61186, South Korea; [Yu, Jinha] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Yu, Jinha] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Warnick, Eugene; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA; [Kim, Ji Yong; Lee, Hyuk Woo; Jeong, Lak Shin] Future Med Co Ltd, Seoul 06665, South Korea; [Ji, Seunghee; Shin, Hyunwoo; Choi, Jong-Ryoul] HK Inno N Corp, Seoul 04551, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000211596
- 본문언어 영어
- Published As https://doi.org/10.1021/acs.jmedchem.3c00806
- PubMed 37603705
초록/요약
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.
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