SECTION I. Analysis, Fate, and Toxicity of Chiral Pollutantsin the Environment

Overview of Chiral Pollutants in the Environment and Food

INTRODUCTION

Chirality was defined early in 1997 by the IUPAC (International Union of Pure and Applied Chemistry) as “the geometric property of a rigid object (or spatial arrangement of points or atoms) of being non-superposable on its mirror image.” This definition is derived from the absence of any symmetry elements in the molecule, including a mirror plane, a center of inversion, or a rotation- reflection axis. Conversely, an achiral molecule is that which is superposable on its mirror image (IUPAC, 1997).

The most usual type of chirality is that originated by a center of asymmetry given by a stereo- genic unit, i.e., an atom that is bonded to a set of ligands in a three-dimensional disposition not superposable to its mirror copy (Ribeiro et al., 2012b). Generally, the stereogenic element is generated by a tetrahedron carbon holding four different substituents, but other atoms as sulfur, phosphorous, and silicon may also generate a stereogenic unit (Testa et al., 2014). This stereogenic element will result in the so-called enantiomers that are two molecules with non-superposable left-handed and right-handed mirror images (Ribeiro et al., 2012b). Any exchange of two of the ligands in a molecule with a stereogenic center originates its enantiomer, being the resulting pair of molecules non-superposable and mirror images of each other (IUPAC, 1997). The molecule is chiral when only one unique chiral center is present, but the presence of more than one stereogenic center may lead to chiral or achiral molecules (Solomons, 2011). Moreover, axial, planar, and helical chirality are also possible (Allenmark, 1991; Allenmark and Gawronski, 2008). In an achiral context, enantiomers behave equally due to their identical thermodynamic properties, namely solubility, pA'a. melting and boiling points, partition coefficient, etc. (Ribeiro et al., 2017). They only differ on their chiroptics by rotating the plane of polarized light in the opposite direction and thus circular dichroism (CD) (Siligardi and Hussain. 2017), optical rotatory dispersion (ORD), and polarimetry

Chemical and three-dimensional structures of the pharmaceutical beta-blocker propranolol (l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol)

FIGURE 1.1 Chemical and three-dimensional structures of the pharmaceutical beta-blocker propranolol (l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol): (a) chemical structure of (S)-(-)-propranolol; (b) three- dimensional structure of (S)-(-)-propranolol; (c) chemical structure of (R)-(+)-propranolol; (d) three-dimensional structure of (R)-(+)-propranolol.

(Brittain. 2017) are the available tools to distinguish them. Polarimetry is the traditional methodology to distinguish enantiomers which rotate differently the polarized light: to the right or clockwise (dextrorotatory, (d) or (+)-enantiomers) or to the left or counterclockwise (levorotatory, (/) or (-)-enantiomers) (Ribeiro et al., 2017). Depending on the three-dimensional arrangement of the substituents in relation to the stereogenic unit, enantiomers can be named as (R)- or (S)- from the Latin rectus and sinister, respectively (example in Figure 1.1).

Various proportions of enantiomers can occur leading to: (i) a racemate or racemic mixture, which corresponds to an equimolar mixture of enantiomers, thus resulting in the absence of rotation of the polarized light; (ii) an enantiomerically pure substance corresponding to a single enantiomer with consequent rotation of the polarized light; or (iii) a mixture of enantiomers in proportions different from 1:1, also resulting in the rotation of the polarized light (Eliel and Wilen, 1994). The similar physical and chemical properties of enantiomers are observed under achiral circumstances, w'hereas they can behave differently under chiral conditions that are usually found in biological media or alternatively when they react with other chiral compounds (Ribeiro et al., 2017). In fact, biological structures owe their frequent “intrinsic chirality” to their correspondent chiral units, namely proteins, glycoproteins, DNA. and RNA that are vital molecules consisting of important chiral molecules in their structure, respectively, amino acids, carbohydrates, deoxyri- bose, and ribose (Huhnerfuss and Shah, 2009; Muller and Kohler, 2004; Tiritan et al., 2016). This “intrinsic chirality” of biological entities (enzymes, receptors, membrane proteins, or other binding molecules) provides an enantioselective mechanism called chiral recognition, which originates dissimilar interactions between the enantiomers and the receptor and consequently different biological effects of enantiomers of a chiral compound, including different toxicity (Ribeiro et al., 2012b). As an example, the beta-blocker propranolol has one unique chiral center and thus two enantiomers (Figure 1.2), with the (S)-(-)-l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol) having a pharmacological activity 100 times higher than the (R)-(+)-l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol) (Pavlinov et al. 1990).

A lower activity or even any effect on a certain receptor is expected when the enantiomer binds to the receptor less intensively or does not bind, respectively. However, this “ineffective” enantiomer for the target receptor may be a ligand for another receptor responsible for other effects, which include unwanted toxic effects (Ribeiro et al., 2012b,c). Although chiral compounds naturally occurring in the environment (e.g., epinephrine, hyoscine, levodopa, levothyroxine,

Illustrative interactions of the enantiomers of a chiral compound with its target receptor representing

FIGURE 1.2 Illustrative interactions of the enantiomers of a chiral compound with its target receptor representing: (a) the interaction with the more potent enantiomer (S)-(-)-propranolol: and (b) the interaction with the less active (R)-(+)-propranolol.

morphine, etc.) (Gal, 2006; Tiritan et al„ 2016) are typically pure enantiomers, anthropogenic chiral compounds (e.g., pharmaceuticals, illicit drugs, pesticides, etc.) are used either as enan- tiomerically pure or racemic mixtures, despite the desired biological effect is usually due to one enantiomer.

 
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