2-Formyl-komarovicine promotes adiponectin production in human mesenchymal stem cells through PPARγ partial agonism. Issue 5 (1st March 2018)

• Record Type: Journal Article
• Authors: Ahn, Sungjin; Lee, Moonyoung; An, Seungchan; Hyun, Sooyeol; Hwang, Jiho; Lee, Jongkook; Noh, Minsoo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 5(2018)
• Page Start: 1069
• Page End: 1075
• Publication Date: 2018-03-01
• Subjects: hBM-MSCs human bone marrow-derived mesenchymal stem cells -- IBMX isobutylmethylxanthine -- IDX insulin, dexamethasone, IBMX -- FABP4 fatty acid binding protein 4 -- PPAR peroxisome proliferator-activated receptor -- qRT-PCR quantitative real-time reverse transcription-polymerase chain reaction -- TR-FRET time-resolved fluorescence resonance energy transfer; 2-Formyl-komarovicine -- PPARγ partial agonist -- Adiponectin -- Adipogenesis -- Human mesenchymal stem cells; 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.2018.01.019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Adiponectin is a major adipocytokine secreted from mammalian adipocytes. Relatively low expression of adiponectin is associated with various human metabolic diseases and some cancers. Adiponectin-secreting compounds have therapeutic potential for these diseases. Adipogenesis of human bone marrow-mesenchymal stem cells (hBM-MSCs) has been used as a phenotypic assay to find adiponectin secreting compounds. In a phytochemical library screen, 2-formyl-komarovicine, 1-(quinolin-8-yl)-1, 3, 4, 9-tetrahydro-2 H -pyrido[3, 4- b ]indole-2-carbaldehyde, isolated from Nitraria komarovii was identified as a potential adiponectin-secreting compound. To validate the results of the impure phytochemical, we synthesized 2-formyl-komarovicine. The synthetic 2-formyl-komarovicine significantly promoted adiponectin production during adipogenesis in hBM-MSCs. In a target identification experiment, 2-formyl-komarovicine bound to peroxisome proliferator-activated receptor γ (PPARγ) in a concentration-dependent manner. Notably, 2-formyl-komarovicine competitively inhibited the adiponectin-promoting activity of a full PPARγ agonist, troglitazone, in hBM-MSCs, which is a pharmacological feature of a partial agonist. The ligand-docking model showed that 2-formyl-komarovicine interacted with the hydrophobic pocket of the PPARγ ligand-binding domain, but lacked an interaction to stabilize helix H12, which is one of the major binding themes of PPARγ partial agonists. We concluded that 2-formyl-komarovicine provides a novel pharmacophore for PPARγ partial agonists to increase adiponectin production.