Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ. Issue 1 (1st January 2020)

• Record Type: Journal Article
• Authors: An, Seungchan; Yu, Jinha; Choi, Hongseok; Ko, Hyejin; Ahn, Sungjin; Shin, Jeayoung C.; Pyo, Jeong Joo; Jeong, Lak Shin; Noh, Minsoo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 1(2020)
• Publication Date: 2020-01-01
• Subjects: Selenoadenosine -- Adeonsine A3 receptor -- PPARγ -- PPARδ -- Polypharmacology -- Adiponectin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115226
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: N 6 -(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- N 6 -(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.