Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect

Abstract

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure–activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9′ were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.

Phytochemicals from Polyalthia Species: Potential and Implication on Anti-Oxidant, Anti-Inflammatory, Anti-Cancer, and Chemoprevention Activities

“…Scientific reports on leaves, bark, stem bark, root, twigs, and seeds of Polyalthia have revealed dozens of types of alkaloids and terpenes with numerous biological and pharmacological activities with chemopreventive potentials, such as anti-bacterial [18][19][20], anti-fungal [21], anti-viral [22,23], anti-plasmodial [24][25][26], anti-inflammatory [27][28][29], anti-ulcer [30], antitumor [31][32][33], and anti-cancer [34][35][36] effects.…”

“…The crude extracts of Polyalthia plants have been evaluated upon the anti-inflammation effects using in vitro and/or in vivo models. In Figure 3, several compounds from Polyalthia plants, including polycerasoidol (16) from P. cerasoides [28], 36-38, 43, 45, and 48 from P. longifolia [27,64], and 6S-styryllactones (71-73) from P. parviflora leaves [65], have revealed the anti-inflammation activities. Oyeyemi et al (2020) demonstrated that P. longifolia aqueous and methanolic leaf extracts present the prophylactic and the curative activities against cadmium (a major environmental pollutant)-induced hepatotoxicity by relieving the oxidative stress in rats [59].…”

“…The crude extracts of Polyalthia plants have been evaluated upon the anti-inflammation effects using in vitro and/or in vivo models. In Figure 3, several compounds from Polyalthia plants, including polycerasoidol (16) from P. cerasoides [28], 36-38, 43, 45, and 48 from P. longifolia [27,64], and 6S-styryllactones (71-73) from P. parviflora leaves [65], have revealed the anti-inflammation activities. Study has also shown that polycerasoidol (16) could decrease tumor necrosis factor alpha (TNFα-induced mononuclear cell adhesion to human umbilical endothelial cells at a concentration of 4.9 μM [28].…”

“…In Figure 3, several compounds from Polyalthia plants, including polycerasoidol (16) from P. cerasoides [28], 36-38, 43, 45, and 48 from P. longifolia [27,64], and 6S-styryllactones (71-73) from P. parviflora leaves [65], have revealed the anti-inflammation activities. Study has also shown that polycerasoidol (16) could decrease tumor necrosis factor alpha (TNFα-induced mononuclear cell adhesion to human umbilical endothelial cells at a concentration of 4.9 μM [28]. In addition, this prenylated benzopyran compound (16) was reported to be a dual peroxisome proliferator-activated receptor (PPAR)-agonists using in vitro activity assay plus prediction by molecular docking simulation, preventing cardiovascular events associated with metabolic disorders [28].…”

“…In fact, studies have demonstrated different effects of phytochemicals in the Polyalthia genus, such as that anti-inflammatory effects of 36 and 41 [64] have been authenticated on lipopolysaccharide (LPS)-treated RAW264.7 macrophages; 16-oxocleroda-3,13(14)E-dien-15-oic acid methyl ester (43) could inhibit formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fLMP/CB)-induced superoxide anion generation in human neutrophils [27]; 36 could ameliorate LPS-induced nitric oxide (NO) production in RAW264.7 macrophages [64] as well as inhibit LPS-induced neurotoxicity through the down-regulation of COX-2 and NF-κB (p65) [60]; and the production of NO and inflammatory cytokines (PGE2, and TNFα) were all reversed by the 36 treatment [60]. Study has also shown that polycerasoidol (16) could decrease tumor necrosis factor alpha (TNFα-induced mononuclear cell adhesion to human umbilical endothelial cells at a concentration of 4.9 µM [28]. In addition, this prenylated benzopyran compound (16) was reported to be a dual peroxisome proliferator-activated receptor (PPAR)-agonists using in vitro activity assay plus prediction by molecular docking simulation, preventing cardiovascular events associated with metabolic disorders [28].…”