Resveratrol and pterostilbene: A comparative overview of their chemistry, biosynthesis, plant sources and pharmacological properties

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INTRODUCTION

Stilbenes are phenolic compounds having two aromatic rings with −OH groups and are linked by a double-bonded ethylene bridge (Akinwumi et al., 2018; El Khawand et al., 2018). Found in higher plants, stilbenes exist as monomeric, dimeric, trimeric, oligomeric, and polymeric forms, or as glycosides. Stilbenes possess biological activities, such as anti-diabetic, anti-obesity, cardioprotective, neuroprotective, anti-inflammatory, anti-atherosclerosis, and anti-cancer properties (Akinwumi et al., 2018). Resveratrol and pterostilbene represent two of the monomeric stilbenes with well-studied biological activities and molecular effects (Tsai et al., 2017).

It was reported that the consumption of red wine in France has cardioprotective effects and reduces the risk of cardiovascular diseases (Renaud and de Lorgeril, 1992). The low occurrence of coronary heart diseases among the French people, despite their high-fat diet, is popularly known as the French paradox (Sun et al., 2002). These health benefits of red wine have been attributed to resveratrol (Siemann and Creasy, 1992). Since then, much research was conducted on the cardioprotective and other medicinal properties of resveratrol, a major compound of red grapes and red wine (Catalgol et al., 2012). Pharmacological activities of resveratrol include cardioprotective (Hsieh and Wu, 2018), antioxidant (Cavallini et al., 2016), anti-inflammatory (de Sẚ Coutinho et al., 2018), anti-atherosclerosis (Bonnefont-Rousselot, 2016), anti-aging (Bhullar and Hubbard, 2015; Li et al., 2018), anti-diabetic (Szkudelski and Szkudelska, 2011), anti-osteoporosis (Tou et al., 2015), and anti-obesity (de Ligt et al., 2015; Pan et al., 2018) properties.

Among the many pharmacological activities of resveratrol (Baur and Sinclair, 2006; Berman et al., 2017), its anti-cancer properties are most well-known. Since its first report by Jang et al. (1997), there are many reviews on the subject (Rauf et al., 2018; Varoni et al., 2016). Displaying various molecular mechanisms, resveratrol has shown to be a promising and multi-target agent for cancer prevention and treatment.

In recent years, the neuroprotective effects of resveratrol have also gained much research interest. The overall health benefits of resveratrol toward age-related diseases have become a topic of intense investigations (Timmers et al., 2012). Reviews on the neuroprotective properties of resveratrol are mostly age-related neurodegenerative disorders related to Alzheimer’s disease and Parkinson’s disease (Tellone et al., 2015), brain degeneration (Poulose et al., 2015), and neurological disorders, such as stroke and CNS injury (Lopez et al., 2015). Currently, there is one comprehensive review by Bastianetto et al. (2015) that summarized recent findings on the molecular mechanisms of action and discussed possible roles of resveratrol in the prevention of various neurological disorders.

Pterostilbene was reported by Remsberg et al. (2008) to have anti-cancer, anti-inflammatory, antioxidant, and analgesic effects on rats. These findings generated much research excitement in pterostilbene and subsequently, properties, such as anti-cancer (McCormack and Mc Fadden, 2012; Nutakul et al., 2011), anti-inflammatory (Dvorakova and Landa, 2017), neuroprotective (Poulose et al., 2015; Wang et al., 2016), anti-obesity (Aguirre et al., 2016; Pan et al., 2018), anti-diabetic (Tastekin et al., 2018), antioxidant (McCormack and McFadden, 2013; Rimando et al., 2002), anxiolytic (Al Rahim et al., 2013), and anti-aging (Li et al., 2018) activities have been documented. Recently, the promising therapeutic potential of pterostilbene and its mechanistic insight based on recent preclinical evidence was reviewed by Kosuru et al. (2016).

This comparative overview on the pharmacological properties of resveratrol and pterostilbene is appropriate and timely as the surge in the number of research studies in recent years has generated a wealth of new knowledge. Such useful information will set the platform for scientists to conduct further research on resveratrol, pterostilbene, and other derivatives. References cited in this overview were procured from databases downloaded from Science Direct, Google Scholar, and PubMed.

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CHEMISTRY

Resveratrol or trans-3,4′,5-trihydroxystilbene is a monomer stilbene with a molecular formula of C₁₄H₁₂O₃ and a molecular weight of 228.25 g/mol. The molecule has two aromatic rings, linked by an ethylene bridge with an ethene double bond (Fig. 1). Ring A has two hydroxyl (−OH) groups at C3 and C5, and ring B has one −OH group at C4′ (Tsai et al., 2017). Resveratrol has a 6−2−6 carbon skeleton with m-hydroquinone and 4′-hydroxystyryl moieties involving rings A and B, respectively (Niesen et al., 2013).

In food products, resveratrol commonly occurs in the trans form rather than in the cis form (Anisimova et al., 2011). When resveratrol is exposed to ultraviolet and visible light, trans to cis isomerization occurs (Silva et al., 2013). The rarer cis-resveratrol is less stable and is not commercially available (Cottart et al., 2010). Red wine is rich in trans-resveratrol, and its moderate consumption has health benefits of lower rates of prostate cancer (Schoonen et al., 2005). Against PC-3 prostate cancer cells, trans-resveratrol was reported to be a more effective anti-cancer agent than cis-resveratrol and dihydro-resveratrol (Anisimova et al., 2011). Earlier, trans-resveratrol has been reported to be 10 times more potent in inducing apoptosis of HL60 leukemia cells as compared to cis-resveratrol (Roberti et al., 2003).

Pterostilbene or trans-3,5-dimethoxy-4′-hydroxystilbene has a molecular formula of C₁₆H₁₆O₃, molecular weight of 256.30 g/mol (Kosuru et al., 2016; McCormack and Mc Fadden, 2012; Tsai et al., 2017). Its other names are dimethoxy resveratrol, 3,5′-dimethoxy-4-stilbenol and 4-[2-(3,5-dimethoxyphenyl) ethenyl] phenol. Being a dimethylated analog of resveratrol, pterostilbene is structurally similar to resveratrol by having one hydroxyl group at C4′ of ring B but differs by having two −OCH₃ groups at C3 and C5 of ring A (Fig. 2). Like resveratrol, the trans form of pterostilbene is more abundant than the cis form (Kosuru et al., 2016).

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BIOSYNTHESIS AND PLANT SOURCES

In plants, the biosynthesis of resveratrol and pterostilbene shares similar substrates and biosynthetic pathway as flavonoids (Jeandet et al., 2010; Poulose et al., 2015). Unlike flavonoids which are produced by most plants, only a few plant species synthesize these stilbenes. The biosynthetic pathway of resveratrol begins with phenylalanine of the shikimate pathway, which undergoes various enzymatic reactions to produce p-coumaroyl-CoA. In the presence of malonyl-CoA and stilbene synthase, trans-resveratrol is produced via an aldol reaction. Trans-resveratrol is then converted to pterostilbene by O-methyl transferase.

Figure 1. The molecular structures of trans-resveratrol with cis-resveratrol as inset. [Click here to view]

Resveratrol was first isolated from the roots of Veratrum grandiflorum and later from the roots of Polygonum cuspidatum (Nonomura et al., 1963). From P. cuspidatum, an important traditional medicine in China, the content of resveratrol has been reported to be 1.8 mg/g (Zhao et al., 2005). The compound has been isolated from more 70 plant species, including grapes and red wine (Rege et al., 2014). Red grapes and red wine, as shown in Figure 3, are the main dietary sources of resveratrol. Red grapes contain mainly of piceid (1.5−7.3 μg/g), while red wine is rich in resveratrol (1.0−18 μg/ml) (Burns et al., 2002). From the skin of grapes, the content of resveratrol ranged from 2.48 to 6.47 μg/g (Rimando et al., 2004). The concentration of trans-resveratrol in red wine is six times higher than in white wine, which contains high levels of cis-resveratrol (Rege et al., 2014). A possible explanation is that red wine is produced without removing the skin of grapes, whereas white wine is fermented after the removal of the skin.

Pterostilbene was first isolated from Pterocarpus santalinus (sandalwood) in 1940 (Seshadri, 1972), and later identified in Vitis vinifera (grape vine) (Adrian et al., 2000; Langcake et al., 1979), Pterocarpus marsupium (Indian kino) (Manickam et al., 1997; Maurya et al., 1984), Vaccinium berries (Rimando et al., 2004), and Arachis hypogaea (peanut) (Sobolev et al., 2011).

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PHARMACOLOGICAL PROPERTIES

Resveratrol and pterostilbene exhibit many similarities in pharmacological properties (Akinwumi et al., 2018; Tsai et al., 2017; Wang and Sang, 2018). They include antioxidant, neuroprotective anti-cancer, cardioprotective, analgesic, anti-atherosclerosis, anti-aging, anti-diabetic, anti-inflammatory, and anti-obesity activities.

Studies have shown that both resveratrol and pterostilbene are able to cross the blood–brain barrier and influence brain activity (Lange and Lee, 2017). The blood–brain barrier is a diffusion barrier essential for the normal functioning of the central nervous system. Located at the capillaries between the blood and cerebral tissue, the blood–brain barrier has endothelial cells with tight junctions that impede the influx of most blood-borne compounds from entering the brain (Ballabh et al., 2004; Kanwar et al., 2012). Small lipophilic molecules, such as oxygen (O₂) and carbon dioxide (CO₂), can diffuse through plasma membranes while nutrients, such as glucose and amino acids, and larger molecules, including insulin, leptin, and iron transferrin, enter the brain via transporters and receptor-mediated endocytosis, respectively. The blood–brain barrier has been reported to prevent 98% of small molecules and 100% of large molecules from reaching the brain (Kanwar et al., 2012).

A study by Wang et al. (2002) demonstrated that the resveratrol can cross the blood–brain barrier and protects against cerebral ischemic injury in gerbils. The study noted that after injection into these animals, resveratrol rapidly enters the bloodstream as glucuronide conjugate, crosses the blood–brain barrier, and is subsequently enters the brain tissue. Resveratrol was retained in the brain for up to 4 hours.

Figure 2. The molecular structures of trans-pterostilbene with cis-pterostilbene as inset. [Click here to view]

Although there are structural and bioactivity similarities between resveratrol and pterostilbene, pharmacological properties of pterostilbene are often stronger than those of resveratrol (Table 1).

The stronger pharmacological properties in pterostilbene than resveratrol have been attributed to the dimethoxy groups at C3 and C5 of ring A (Fig. 2). With these structural characteristics, pterostilbene is more lipophilic, enhancing its membrane permeability, bioavailability, and bioactivity (Kapetanovic et al., 2011; McCormack and Mc Fadden, 2012; Wang and Sang, 2018). Overall, pterostilbene performs better in membrane permeability and metabolic stability than resveratrol. This increases the bioavailability, and enhances the pharmacokinetic profile and pharmacological activities of pterostilbene.

Studies have shown that both resveratrol and pterostilbene are safe for human consumption. In a clinical trial conducted on 40 healthy volunteers, resveratrol was found to be safe after daily doses of 0.5, 1.0, 2.5, and 5.0 g for 29 days, with the exception of 2.5 and 5.0 g doses which caused some gastrointestinal discomfort (Brown et al., 2010). In two studies, 28 daily doses of 50, 150, or 500 mg/kg body weight, and 90 daily dose of 700 mg/kg body weight of Resvida™ (high-purity resveratrol) did not have any adverse effects on rats (Williams et al., 2009). For pterostilbene, a clinical trial (randomized, double-blind, and placebo-controlled) conducted in 80 healthy volunteers for 6–8 weeks, demonstrated that the pterostilbene is generally safe for consumption at doses of up to 250 mg/day (Riche et al., 2013). Biochemical analysis showed that the pterostilbene had no adverse reactions on liver, kidney, and glucose markers.

Figure 3. Red grapes (left) and red wine (right). [Click here to view]

Kapetanovic et al. (2011) reported that there was greater oral absorption and cellular uptake of pterostilene in rats than resveratrol. One of the studies indicated that the pterostilbene (orally administered) displayed 95% bioavailability, as compared to resveratrol with only 20% bioavailability. In addition, the half-life of resveratrol in the blood was found to be 14 minutes (Asensi et al., 2002), whereas pterostilbene with two –OCH₃ groups had a half-life of 105 minutes or seven times longer than resveratrol (Remsberg et al., 2008).

Table 1. Comparative pharmacological properties of pterostilbene (PS) and resveratrol (RV). [Click here to view]

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