Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ

  • Bioorg Med Chem. 2020 Jan 1;28(1):115226. doi: 10.1016/j.bmc.2019.115226.
Seungchan An  1 ,  Jinha Yu  2 ,  Hongseok Choi  2 ,  Hyejin Ko  1 ,  Sungjin Ahn  1 ,  Jeayoung C Shin  1 ,  Jeong Joo Pyo  1 ,  Lak Shin Jeong  3 ,  Minsoo Noh  4
Affiliations
  • 1. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
  • 2. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Pharmaceutical Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
  • 3. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Pharmaceutical Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: [email protected].
  • 4. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: [email protected].
PMID: 31806266 DOI: 10.1016/j.bmc.2019.115226
Abstract

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.

Keywords
Adeonsine A(3) receptor; Adiponectin; PPARγ; PPARδ; Polypharmacology; Selenoadenosine.
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