Symmetry and Asymmetry in Medicinal Chemistry

…“I’ll tell you all my ideas about Looking-glass House. First, there’s the room you can see through the glass—that’s just the same as our drawing room, only the things go the other way. Well then, the books are something like our books, only the words go the wrong way; I know that, because I’ve held up one of our books to the glass, and then they hold up one in the other room. How would you like to live in Looking-glass House, Kitty? I wonder if they’d give you milk in there? Perhaps Looking-glass milk isn’t good to drink”…

Lewis Caroll: Through the Looking-Glass (Chapter I: Looking-Glass House)

Let us leave aside the questions of how to read books behind a mirror and what milk tastes like, and instead take a closer look at the fascinating phenomenon of chirality from a scientific point of view. Asymmetry (chirality) is one of the most important phenomena in nature, and in the entire universe in general, as it causes the uniqueness of life and life processes [1,2,3,4,5] (see Figure 1).

Chirality is caused by the so-called chiral element in the structure of a molecule, which can be a center (chiral atom—each of its bonds binds a different group, most often carbon, but it can also be sulfur, nitrogen, phosphorus, etc.), an axis (with limited rotation around a single bond, e.g., 1,3-disubstituted allenes or biphenyls), or a plane (e.g., helicenes). Enantiomers (optical antipodes) are two chemical substances that have the same molecular and structural formula, but the spatial arrangement of their molecules forms mirror images (right and left hands). They are most easily distinguished by their ability to rotate the plane of polarized light (using the polarimetry method). They usually contain one or more chiral atoms. Enantiomers have opposite configurations at all chiral centers; if they differ at only some, they are diastereomers (two diastereomers are not mirror images of each other). A racemate is an optically inactive equimolar mixture of a pair of enantiomers. Optical isomers are described in terms of nomenclature either by the older Fischer projection (still used in the nomenclature of amino acids and carbohydrates), or by the universal Cahn–Ingold–Prelog system, which describes the configuration at each chiral atom separately [7,8,9,10].

Chirality appears in many fields of science, from particle physics to astronomy and to the chemistry of life. Life here on Earth is a chemical system capable of self-reproduction and evolution, and is based on chiral molecules [3]. The question of why life is built on homochiral (having the same sense of chirality) biomolecules (l-amino acids and d-saccharides [11,12,13]) and why it was not built on their opposite mirror images is still one of the greatest mysteries of the origin of life [14,15,16,17,18]. Although recent research has shown that d-amino acids in plants, prokaryotes, eukaryotes, and even human tissues [19,20,21,22,23,24,25] are more widespread than previously thought, the fact remains that there are about 500 α-amino acids in nature, and of these, only 20(+2) l-amino acids are proteogenic [26]. On the other hand, bacteria and animals use d-amino acids mainly as components of antibiotics or poisons/toxins [20,22,27,28,29,30]. Compared to the occurrence of d-amino acids, the occurrence of l-saccharides in nature is rare [3,31], with the exception of arabinose, fucose, and rhamnose, which paradoxically occur more often in the l-configuration than in the d-form [31,32,33]. It is therefore necessary to accept the phenomenon of homochirality and also the fact that Earth’s entire biosystem and all living beings are chiral [12,34,35]. One of the basic principles of life is recognition. Recognition/discrimination at the level of sophistication required for life must be asymmetric. In addition, life must be energetically profitable (fulfill the second law of thermodynamics); therefore, one enantiomer is preferentially formed [3,36,37,38,39].

The three-dimensional (3D) arrangement of organic molecules significantly affects not only their physical, physicochemical, and chemical properties, but also their biological effects [40,41,42,43]. The biochemistry of life requires the ability to recognize/distinguish between specific molecular structures and subsequently initiate specific biochemical reactions. Biodiscrimination is a direct consequence of the spatial arrangement of molecules. Chirality is the basis of enantiomeric discrimination. In many cases, a minimal change (with respect to the internal energy of the molecule, such as changes in optical activity) is sufficient to make the biological effect of one form different from that of the other enantiomer. However, it should be noted that in addition to chirality, conformational (free rotation around a single bond) and/or geometric (rigidity of double/triple bonds and cyclic structures described as cis/trans) stereoisomerism must also be taken into account. However, chiral recognition of organic molecules is considered one of the most important criteria for biological activity [5,40,44,45,46].

Biodiscrimination of chiral systems is studied on enzymes and receptors because they most often show a stereochemical preference for one of the two enantiomers—that is, only one enantiomer can assume the appropriate spatial arrangement for interaction with the active site of the enzyme/receptor. Therefore, different enantiomers will interact with different biomolecules within the organism, which can lead to different biological effects. This mutual recognition in the highest possible perfection of external molecules and their internal biopartners is essential for life [40,41,47,48,49,50]. The mechanisms of biodiscrimination (in terms of drug–enzyme–receptor– active site interaction) are described by two models. The first of these, the so-called three-point model, was published by Easson and Stedman in 1933. The principle is that the more potent enantiomer binds to the catalytically active site through three interactions, while the less potent enantiomer can interact at only one or two points [51,52]. Thus, it will not interact fully or induce the desired biological reaction. However, this model has encountered a number of limitations [53,54,55], and, over time, a four-point model has emerged that better reflects the 3D biodiscrimination of substrates in receptor cavities [56,57,58], with minor subsequent modifications/additions [59,60,61] (see Figure 2).

The consequences of enantiomer biodiscrimination are also reflected in their terminology. The more potent or the one with the desired pharmacological activity is called the eutomer, whereas the less potent one (or the one with undesirable effects) is the distomer. The eutomer-to-distomer activity ratio (eudismic ratio) is a measure of the stereoselectivity of a particular system [40,62,63]. This 3D recognition (enantiomeric discrimination) is based on weak intermolecular interactions [40], which are realized mainly by electrostatic interactions and are also observable in the gas phase [64] as well as in the liquid phase [65,66].

Based on all the facts given above (including biodiscrimination and therefore possible defense against pathogens), the artificial preparation of mirror organisms (and especially bacteria) is a hypothetically dangerous opening of Pandora’s box. Although, from a scientific point of view, this problem is extremely interesting, in the interests of preserving life on Earth as we know it, it is highly controversial to prepare “artificial” organisms against which terrestrial life cannot protect itself. However, this contribution does not aim to discuss this difficult topic; it was only mentioned in context [67,68,69].

Probably the most popular cases of 3D recognition are examples of smells, tastes, and communication using various chemicals, namely semiochemicals (pheromones or allelochemicals [70,71,72,73]) that are successfully used in insect control (bait to attract males to traps, or in very high concentrations to disorient insects and prevent mating [74]).

If we focus on fragrant essences (essential oils), (S)-(−)-limonene smells like lemon, while (R)-(+)-limonene has an orange scent [75], (S)-(+)-carvone smells like cumin, and (R)-(−)-carvone has a mint scent [75]. Menthol contains three chiral centers, and thus eight stereoisomers, but only one of them has a menthol aroma, with the configuration 1R,2S,5R [76]. Not surprisingly, olfactory receptors are composed of l-amino acids, so they are very sensitive to the chirality of molecules. Furthermore, differences in olfactory receptors for aromas not only lead to changes in the perception of the smell of individual enantiomers, but also to sensitivity and changes in the intensity of its perception [77,78]. Tangentially, aromas are a billion-dollar business [79].

The role of chirality in taste perception is illustrated by the well-known example of asparagine; the (R)-enantiomer is sweet, while (S)-asparagine is bitter [80]. Only the (6S,1’S)-isomer of hernandulcine is 1000-fold sweeter than sucrose, while the others are bitter or tasteless [81]. Both d-saccharides and l-saccharides taste mostly sweet [82]; however, the replacement of d-saccharides with l-saccharides, which are not metabolized in the human body, is associated with the economically unprofitable production of l-saccharides [82,83]. The d-/l-stereoisomers of amino acids differ only slightly in taste—depending on the structure, they have a sweet, bitter, or umami taste—but significantly in intensity, with the d-forms being approximately 1.2-fold stronger [84,85,86].

Chirality in the field of pharmaceuticals began to be studied in detail after the Contergan affair caused by the drug thalidomide in the early 1960s [87]. It was found that the effects caused by the chirality of drugs could be observed in pharmacodynamics, pharmacokinetics, and also in drug–drug interactions and toxicity [40,41,50,62,63,88,89]. However, sometimes enantiomers can have the same effect (or the activity of both is not significantly different) [40,41,62,63,90,91]; however, in most cases, one isomer is more active, e.g., levocetirizine, escitalopram [63]. Sometimes enantiomers can have completely different or even opposite effects. Textbook examples of enantiomers of drugs with different pharmacodynamic properties are all β-adrenolytics (effective only in the form of (S)-isomers) [62,63], and the antitussive (2R,3S)-levopropoxyphene, while its isomer (2S,3R)-dextropropoxyphene is an analgesic [40]. d-(−)-threo-Chloramphenicol is the only stereoisomer with antibacterial activity (the other forms are inactive and toxic) or related to the antituberculosis drug (S,S)-ethambutol, the other isomers of which are also inactive and highly toxic [40,41]. Enantiomers of drugs, such as selegiline, mianserin, fluoxetine, and ketamine, are metabolized differently and form toxic products [40,41]. Some drugs undergo so-called chiral inversion in the body under the influence of enzymes, when the body prepares the second (and itself toxic) isomer [40,41,62,63]. Examples of such chiral inversion include non-steroidal anti-inflammatory drugs from the profen class (e.g., ibuprofen, naproxen), where the body creates the active (S)-enantiomer from the inactive (R)—form [40,41,62,63], or the already-mentioned thalidomide, where the body spontaneously produces a second teratogenic enantiomer from the administered pure enantiomer [87]. Differences in the interactions of individual enantiomers and chiral biomacromolecules involved in pharmacokinetic processes can be found, for example, when active transport in the human body is used (absorption from the gastrointestinal system, interaction with blood plasma proteins, influx/efflux transporters in the cell wall, excretory proteins during tubular elimination in the kidneys), or when interacting with enzymes involved in biotransformation [40,41,50,62,63,92,93]. Individual enantiomers may therefore exhibit different levels of toxicity, which may be caused directly by the isomer’s own biological activity or indirectly by metabolic transformation in the organism [40,41,50,94].

Given all this, it is not surprising that chirality is an essential and practical topic in the study of bioactive compounds. This Special Issue is therefore focused on recent research activities in the field of bioactive compounds across all areas of medicinal chemistry.