Cyanidin Synthesis Essay

A correct understanding of Cy3G’s bioactivity requires knowing its structural features and physicochemical behavior. For example, its binding potential and radical scavenging capacity (RSC) depend on its REDOX behavior while its absorption and metabolic fate within the gastrointestinal (GI) tract relies on the presence of glucose and/or other glycoside moieties. Pure Cy3G is susceptible to degradation by many physicochemical factors including pH, light, oxygen, solvents, temperature and metal ions [11,18,19]. From a technological perspective, this justifies why ACNs-based products are not widely used as pigments [20] since they are unstable during storage [21]. Also, Cy3G is exposed to many factors along the GI tract (pH, ionic strength), which affect its bioaccessibility, bioavailability and further bioactivity [22,23]. In the following section, some of these features are reviewed.

2.1. Chemical Structure

ACNs are anthocyanidin glycosides. Their backbone consists of a benzopyran core [benzoyl ring (A), pyran ring (C)], a phenolic ring (ring B) attached to its (2-position and a sugar moiety mainly at its 3-position in the C-ring (Figure 1). 31 anthocyanidin (aglycones) and more than 600 ACNs have been identified to date [16]. However, 90% of all naturally occurring ACNs are based on six aglycones differing in their B-ring substitution pattern: cyanidin (Cy) about 50%, delphinidin (Dp), pelargodin (Pg) and peonidin (Pn) about 12% each and petunidin (Pt), malvidin (Mv) about 7% each. These aglycons are further classified by the nature and number of bonded sugars and the presence of aliphatic or aromatic carboxylates (attached to their sugar moieties) [10,24], with 3-monosides (mainly glucosides), 3-biosides, 3,5- and 3,7-diglucosides from the 3 non-methylated aglycones (Cy, Dp and Pg) the most common.

From an analytical standpoint, the structural diversity of ACNs represents a challenge for their isolation and identification [10,21]. However, the mass spectral fingerprint of Cy and many of its naturally occurring glycosides have been established so far [14,16,17,25], some included in Table 1.

The pattern of glycosylation and methylation influences Cy’s hydrophobic (octanol)/hydrophilic (water) partition coefficient (LogP), its polar surface area (Å2) and its molecular weight (MW), all having important implications in the metabolic fate of Cy-derivates (ADME: Absorption, Distribution, Metabolism and Excretion) [26]: Cy has a lower MW (287.24 g/mol) and Å2 (114.3) and is less hydrophilic (LogP = 3.05) than Cy3G (449.4 g/mol, Å2 = 191, LogP = 0.39; Table 1). A second glycosylation (Cy-3,5-O-diglucoside, Cy3,5GG) increases its hydrophilic nature but that compromises its absorption capacity [27] while an extra malonyl group (Cy3MG) does the opposite [28]. Other structural features in Cy3G also have important implications on its chemical reactivity in vitro. Fernandes et al. [9] used STD-NMR spectroscopy and molecular dynamics simulations to show that the absence of an extra hydroxyl at R5’ in Cy3G (Figure 1) affects its binding capacity toward citrus pectins when compared to Dp3G. Also, Phan et al. [29] demonstrated that Cy3G (as flavylium cation, pH 3.4) binds spontaneously within 1 min to bacterial (Gluconacetobacter xylinus ATCC 53524)-derived cellulose, steadily increasing up to 2 h. They reported that this binding behavior is not limited by the available interacting sites in cellulose but to the amount of free Cy3G molecules, proposing a Langmuir binding isotherm model (Equation (1)):

Q = Qmax × [(KL·C) × (1 + KL × C)−1]

where Q is the amount of absorbed Cy3G per unit mass of cellulose (µg·mg−1), Qmax is the apparent maximum adsorption capacity (1109 µg·mg−1 of cellulose), KL is the apparent binding affinity constant and C is the free Cy3G concentration at equilibrium (mM).

By applying this equation, a “Cy3G saturation effect” can be observed at about 200 mM. Also, Oliveira and Pintado [30] using an in vitro model to simulate GI conditions demonstrated a “bind-release” behavior between Cy3G and pectin/chitosan at each digestion step (oral, gastric, and intestinal), suggesting a protective mechanism of this polymeric mixture over Gy3G degradation since Cy3G is progressively released from protein and polysaccharide bonds, which are available for its potential absorption by GI epithelial cells.

It is noteworthy that Cy3G also binds to proteins in vitro. In the same experiment reported by Oliveira and Pintado [30], an even stronger binding capacity of Cy3G toward P/C+β-lactoglobulin was observed. Tang et al. [31] reported the differential binding capacity of three ACNs to human serum albumin (HSA; Dp3G> Cy3G> Pg3G) but their capability to induce structural changes in this protein was different (Pg3G> Cy3G> Dp3G). Tang et al. [32], by using multi-spectral techniques and molecular modeling, suggested that Cy3G–protein interactions are established by hydrogen bonding and van der Waals forces and, as a consequence, the secondary structure of bovine serum albumin (BSA), hemoglobin (Hb), and myoglobin (Mb) is partially destroyed (less% α-helixes). These molecular interactions have important implications in Cy3G transport in the bloodstream (HSA) but could also affect the correct functionality of heme-containing proteins (Hb, Mb). Cy3G is commonly represented as a cation (Figure 1), which is only possible under acidic conditions such as in gastric juice, and in silico assays have revealed that cationic Cy3G cannot be absorbed through passive diffusion [33]. However, a simple substitution at R3′ [–H (Pg3G) by –OH (Cy3G)] modifies Cy3G bioaccessibility, absorptivity, and metabolism within enterocytes [34].

Lastly, rare anthocyanidins such as 3-deoxy-anthocyanidins, hydroxylated at the 6th position, 5, 7, 3′, 5′-O-glycosilated, C-glycosylated, or aliphatic (mainly malonic and pyruvic acids)- or PC-acylated ACNs, which are also currently studied [9,10,28,35] because they seem to be more bioactive than conventional counterparts. For instance, Cy-malonyl-glucoside (Cy-Mal-3G) possesses a stronger anti-cancer (colon, liver, prostate, and breast) activity than Cy3G [36]. Also, Cy3G acylated with lauric acid improves its stability because an ester group is more stable than a hydroxyl group [37]. However, the formation of Cy3G adducts with pyruvic acid during wine ageing or fruit juice processing reduces (about 10 times) its radical RSC toward the superoxide anion [38].

2.2. Color

The color of ACNs-rich fruits is a matter of quantity (biosynthesis), molecular inter-play and physicochemical stability. In particular, production and stability of red Cy3G in plants has been extensively studied in horticultural sciences, an aspect that will be further discussed in this article. Many structural features, such as the number of hydroxyl groups, their degree of methylation and the nature and number of sugar moieties bound to the molecule, are related to the color of ACNs. In nature, ACNs show great color diversity from yellow (480 nm) to red (730 nm), and, particularly, Cy3G confers a red hue to fruits [27]. However, the maximum absorption [λmax (εmol) nm] of its flavylium (2-phenyl-1-benzopyrilium) nucleus [10] is more restricted to the six most common aglycones and is related to their B-ring hydroxylation pattern: Cy and Pn (516 nm), Pg (520 nm), and Dp, Pt, Mv (546 nm).

The color stability of ACNs depends on their structure, pH, temperature, light and the presence of complexing agents such as PC and metals [21]. The simple attack by water or sulfites converts the flavylium ion into a colorless pseudobase (nucleophilic addition). However, the color of ACNs also depends on their interactions with other molecules via hydrogen bonds or via “hydrophobic vertical stacking” which is a combination of van der Waals and hydrophobic forces between the planar flavylium and another planar molecule to form a π-π complex. Color enhancement [hyperchromic effect (ΔA) + bathochromic shift (Δλ)] and a stabilization phenomenon called co-pigmentation, results from several inter-molecular associations: (i) between two identical ACNs (self-association); (ii) between one of its aromatic substituents (intra-molecular co-pigmentation) with another non-colored molecule (intermolecular co-pigmentation) or; (iii) with a metal ion, forming π-π and other complexes in solution [10]. For example, Bakowska et al. [39] reported a Δλ = 21.4 nm and ΔA = 0.48 with complexes of Cy3G and flavones isolated from Scutellaria baicalensis Georgi, a Chinese herb used to treat bacterial infections of the respiratory system and GI tract. Pacheco-Palencia [21], when evaluating the influence of the external addition (ratio 1:10 w/w) of rooibos tea (rich in flavone-C-glycosides) to commercial rosemary extracts on the stability of two açai-derived ACNs [40% Cy3G (40%) + 60% Cy-3-O-rutinoside (Cy3R)] model solutions (500 mg/L), found an ΔA

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