Synthesis and Biological Evaluation of 5'-Deoxy-adenosine Derivatives as A₃ Adenosine Receptor Ligands.

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-12-11 eCollection Date: 2025-01-09 DOI:10.1021/acsmedchemlett.4c00522

Minjae Kim, Siddhi D Naik, Hongseok Choi, Seung Woo Kim, Jung Hoon Park, Misuk Joung, Jiyoon Song, Vidyasagar B Gaikwad, Meehyein Kim, Lak Shin Jeong

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Abstract

The A₃ Adenosine Receptor (A₃AR) is an important therapeutic target due to its role in inflammation and immune response regulation. Herein, we synthesized and evaluated 5'-deoxy-adenosine derivatives with oxygen at the 4'-position, comparing them to previously studied 4'-thionucleosides. Compound 1h exhibited the highest binding affinity (K _i = 5.9 ± 1.1 nM), consistent with the trend observed in the 4'-thionucleosides. Notably, the 5'-deoxy-adenosine derivatives demonstrated enhanced agonistic activity. Docking studies with compound 1h revealed a shift in binding mode when oxygen replaced sulfur at the 4'-position. The compounds retained strong interactions with critical residues, such as Thr94, even without a hydrogen bond donor at the 5'-position. These results explain the increased agonistic effect observed when the ring heteroatom was changed from sulfur to oxygen.

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5'-脱氧腺苷衍生物作为A3腺苷受体配体的合成及生物学评价。

A3腺苷受体（A3AR）因其在炎症和免疫反应调节中的作用而成为重要的治疗靶点。在此，我们合成并评价了在4‘位置含氧的5’-脱氧腺苷衍生物，并将其与先前研究的4'-硫代核苷进行了比较。化合物1h表现出最高的结合亲和力（K i = 5.9±1.1 nM），与4′-硫代核苷中观察到的趋势一致。值得注意的是，5'-脱氧腺苷衍生物表现出增强的激动活性。与化合物1h的对接研究表明，当氧取代4'位置上的硫时，结合模式发生了变化。即使在5'位置没有氢键供体，该化合物仍与关键残基（如Thr94）保持强相互作用。这些结果解释了当环杂原子由硫变为氧时所观察到的激动效应增加。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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