Novel linked butanolide dimer compounds increase adiponectin production during adipogenesis in human mesenchymal stem cells through peroxisome proliferator-activated receptor gamma modulation

초록

Compounds inducing adiponectin production have therapeutic potential for metabolic diseases. During screening, heme oxygenase-1-inducing marliolide derivatives were identified as adiponectin-inducing compounds. Although some marliolide derivatives were directly bound to peroxisome proliferator-activated receptor gamma (PPAR gamma), the adiponectin-inducing activity did not correlate with the PPAR gamma binding affinity. The most potent adiponectin inducing compound, (E,4S,5S)-3-butylidene-dihydro-4-hydroxy-5-methylfuran-2(3H)-one (1a), exhibited the weakest PPAR gamma binding activity. A docking simulation suggested that two to molecules can be present in two different sites within the PPA gamma-ligand-binding pocket (LBP). Based on the docking model, novel linked butanolide dimer compounds were synthesized. A linked butanolide dimer compound, (3E,3'E,4S,4'S,5S,5'S)-3,3'-(decane-1,10-diylidene)bis(4-hydroxy-5-methyldihydrofuran-2(3H)-one) (3a), promoted adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs) as a novel PPARy full agonist (EC50, 4.34 mu M). This linked butanolide dimer study provides novel insight into PPARy biology, suggesting that small molecules can form multiple ligand interactions within the PPARy-LBP and thereby affect the functional outcomes of PPAR gamma activation. (C) 2019 Elsevier Masson SAS. All rights reserved.

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