Natural phenolics and nuclear receptors (ER & PPAR): Isolation, structure determination and biological evaluation

Abstract

Plants originated mainly from Mediterranean region as well as from other higly deverse hot-spots all over the world have been phytochemically explored in the context of our continuing study towards the discovery of novel, active natural products presenting high affinity to nuclear reseptors. In particular estrogen receptor (ER) and peroxisome proliferator-activated receptor (PPAR) were the target-reseptors under investigation. Our study is mainly focused to the identification of secondary metabolites which present the capability to activate both isoforms of estrogen receptor (ERα& ERβ) [1] as well as the two isoforms of the peroxisome proliferator-activated receptor (PPARγ& PPARδ) [2]. Numerous of secondary metabolites belonging mostly to simple phenolics, to flavonoids and specifically to flavones, flavonols and methylether derivatives thereof and isoflavonoids mainly isoflavones, prenylated isoflavones and 2-arylbenzofurans have been identified using a bioguided approach or LC-MS-based methodologies. The structure elucidation of the isolated compounds was performed via HRMSn and 1 & 2D NMR [3], [4], [5], [6]. The biological evaluation was focused on the determination of the relative binding activity (RBA values) of the purified compounds to ERα and ERβ and/or PPARγ and PPARδ as well as on the exploration of the biological michanism of action using e-screen, reporter gene and analysis of gene expression assays. Determination of their proliferative and/or cytotoxic properties was also performed. A series of novel natural compounds belonging mostly to 2-arylbenzofurans and prenylated isoflavones were identified whereas a numerous thereof found to present significant estrogenic, antiestrogenic, SERM and/or antidiabetic activity [7], [8], [9].