N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (1a, IB-MECA) exhibited polypharmacological characteristics targeting A3 adenosine receptor (AR), peroxisome proliferator-activated receptor (PPAR) γ, and PPARδ, simultaneously. The bioisosteric replacement of oxygen in 4'-oxoadenosines with selenium significantly increased the PPARδ-binding activity. 2-Chloro-N6-(3-iodobenzyl)-4'-selenoadenosine-5'-N-methyluronamide (3e) and related 4'-selenoadenosine derivatives significantly enhanced adiponectin biosynthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). The PPARδ-binding affinity, but not the A3 AR binding affinity, of 4'-selenoadenosine derivatives correlated with their adiponectin secretion stimulation. Compared with the sugar ring of 4'-oxoadenosine, that of 4'-selenoadenosine was more favorable in forming the South sugar conformation. In the molecular docking simulation, the South sugar conformation of compound 3e formed additional hydrogen bonds inside the PPARδ ligand-binding pocket compared with the North conformation. Therefore, the sugar conformation of 4'-selenoadenosine PPAR modulators affects the ligand binding affinity against PPARδ.

中文翻译：

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硒促进腺苷脂分泌的生物立体置换可增加对过氧化物酶体增殖物激活受体δ的结合亲和力。

N6-（3-碘苄基）腺苷-5'-N-甲基脲酰胺（1a，IB-MECA）同时具有针对A3腺苷受体（AR），过氧化物酶体增殖物激活受体（PPAR）γ和PPARδ的多药理学特性。用硒对4'-氧代腺苷中的氧进行生物等位置换可显着提高PPARδ的结合活性。2-氯-N6-（3-碘苄基）-4'-硒腺苷-5'-N-甲基脲酰胺（3e）和相关的4'-硒腺苷衍生物在人骨髓间充质干细胞（hBM-MSCs）脂肪形成过程中显着增强脂联素的生物合成）。4'-硒腺苷衍生物的PPARδ-结合亲和力而不是A3 AR结合亲和力与其脂联素分泌刺激有关。与4'-氧代腺苷的糖环相比，4'-氧代腺苷的糖环 -硒腺苷更有利于形成南糖构象。在分子对接模拟中，与North构象相比，化合物3e的South糖构象在PPARδ配体结合口袋内形成了额外的氢键。因此，4'-硒腺苷PPAR调节剂的糖构象影响对PPARδ的配体结合亲和力。