The discovery of novel isoflavone pan peroxisome proliferator-activated receptor agonists Azadeh Matin a , Munikumar Reddy Doddareddy a , Navnath Gavande a , Srinivas Nammi b,  , Paul W. Groundwater a , Rebecca H. Roubin a , David E. Hibbs a,⇑ a Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia b School of Science and Health, University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia article info Article history: Received 29 August 2012 Revised 11 November 2012 Accepted 17 November 2012 Available online 3 December 2012 Keywords: PPARa PPARc PPARd Pan PPAR agonist Type II diabetes mellitus Metabolic syndrome Peroxisome proliferator-activated receptor abstract Twenty three dual PPARa and c molecules of natural product origin, previously reported by our group, were further investigated for pan PPAR transactivation against PPARd. The in vitro cell toxicity profile, as well as, in silico study of the most active molecules within this new class of pan PPAR agonists are also described. 3 0 ,5 0 Dimethoxy-7 hydroxyisoflavone 6, W-baptigenin 7,4 0 fluoro-7 hydroxyisoflavone 8, and 3 0 methoxy-7 hydroxyisoflavone 9 were identified as the most potent molecules studied within the set compared to the commercially available pan PPAR agonist, bezafibrate 1. These novel active molecules may thus be useful as future leads in PPAR-related disorders, including type II diabetes mellitus and met- abolic syndrome. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The PPAR family consists of three subtypes, namely PPAR alpha, PPAR gamma and PPAR delta/beta that are encoded by three distinct genes. 1–5 Each isotype exhibits different patterns of tissue distribution, has specific pharmacological activators, ligand speci- ficity, and physiological roles. 1,2,4,6 PPAR alpha is mainly found in tissues with a high rate of fatty acid metabolism, including: brown adipose tissue, liver, kidney, heart and muscle. 1,3,5 It plays an important role in the inflamma- tory response, uptake and oxidation of fatty acids and lipoprotein metabolism, as well as glucose homeostasis. 1,4 Unsaturated fatty acids, leukotriene B4, and 8 hydroxyeicosatetraenoic acid are endogenous ligands of PPAR alpha. 5,7 PPAR gamma is principally expressed in adipose tissue, intesti- nal cells, and macrophages, in addition to being localized at lower concentrations in other tissues including skeletal muscle and endothelium. 1 This receptor is involved in the regulation of adipocyte proliferation and differentiation, as well as glucose homeostasis and insulin sensitization. 1 Unsaturated fatty acids, 15-hydroxyeicosatetraenoic acid, 9- and 13-hydroxyocta-decadie- noic acid and 15-deoxyD12, 1 prostaglandin J2 have been reported as PPAR gamma endogenous ligands. 7,5 However, they have shown to bind PPAR gamma at micromolar levels, therefore indicating that it may not be the case. 8 PPAR delta is localized more ubiquitously and is found in most cell types. 1 Numerous studies have highlighted the physiological importance of PPAR delta in the regulation of fatty acid catabolism, energy homeostasis, wound healing, blastocyst implantation, as well as lipid trafficking in macrophages and trophoblasts. 9,10 PPAR delta endogenous ligands are unsaturated fatty acids, carbaprosta- cyclin and components of very low density lipoproteins. 7 It has been suggested that pan peroxisome proliferator-acti- vated receptor (PPAR) agonists which have the ability to activate all three PPAR isoforms (a, c, and d) 11,12 may have advantages over PPARc and dual PPARa and c agonists in the treatment of meta- bolic disorders such as type 2 diabetes mellitus (T2DM) and cardio- vascular disease. Such pan PPAR agonists might overcome some of the limitations associated with current PPAR drugs, which include weight gain and cardiovascular risks. 11–22 Recent studies have highlighted the cardioprotective role of PPARd, as well as its poten- tial in targeting dyslipidemia and the alleviation of weight gain. 15,23–26 The stimulation of PPARd complements the role of PPARa in treating lipid abnormalities, in addition to helping to pre- vent the weight gain that is a typical adverse effect of PPARc agents. 15,23,27–29 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.11.040 ⇑ Corresponding author. Tel.: +61 2 93516005; fax: +61 2 93514391. E-mail address: david.hibbs@sydney.edu.au (D.E. Hibbs).   Current address. Bioorganic & Medicinal Chemistry 21 (2013) 766–778 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc