Homochirality of biological systems and racemates of synthetic compounds
As mentioned earlier, while stereoisomers are widely distributed in nature, biological systems tend to exclusively prefer a specific form of enantiomer; for example, amino acids exist in the L-form and sugars in the D-form, demonstrating homochirality. This preference is related to interactions with molecules such as enzymes and receptors. For instance, enzymes can selectively react only with substrates that have a specific stereostructure, meaning that only certain isomers can interact with them to function.
When artificially synthesizing drugs that need to function within biological systems, compounds with chiral centers will typically produce both enantiomers. This can pose challenges to the selectivity of these enzymes. Depending on their stereostructure, enantiomers may react with biomolecules and exhibit activity, or they may have no activity or even lead to unintended side effects, resulting in potentially harmful outcomes.
Left-handed or right-handed, we usually extend our right hand for a handshake. Even left-handed individuals become accustomed to using scissors designed for right-handed people. When extending an unchosen hand for a handshake to show goodwill, the intended message can be lost, and unintended signals may be sent, similar to how two sets of enantiomers can convey unintentional signals to one another, potentially causing confusion. However, biomolecules have already established homochirality internally, allowing them to function seamlessly without causing such confusion.
The problem arises not within living organisms, where molecular synthesis occurs, but outside of them, specifically in artificial synthesis. While living organisms possess enzymes that provide high selectivity and efficiency for specific forms, no such enzymes exist in artificial molecular synthesis. Thus, in laboratories, compounds are typically produced as racemic mixtures, containing both enantiomers. This phenomenon leads some to argue that the very existence of homochirality is evidence of life.
Racemic mixtures are rare in nature. So, what significance do artificial synthesis and racemic mixtures hold for ordinary people? Most people, including myself, rarely find themselves in situations where they need to be concerned about synthesizing molecules with both enantiomers in a laboratory setting. However, we often purchase and take medications from pharmacies. In many cases, it is not merely a choice but a necessity to take these medications. A significant number of drugs contain chiral molecules, and these chiral drugs are almost always produced as racemates. The two enantiomers that make up a racemic mixture can exhibit very different behaviors in terms of pharmacokinetics—such as absorption, distribution, biological transformation, and excretion—as well as pharmacological effects when they encounter biological systems.
Thalidomide tragedy
So, what does it mean that artificial molecular synthesis, such as pharmaceuticals, always results in the presence of both enantiomer forms as racemic mixtures? The weight of this issue can be understood by examining one of the most tragic and horrifying events in pharmaceutical history: the case of thalidomide. This incident caused countless victims and left an invaluable lesson for humanity.
In the early 1960s, a drug developed by a German company, thalidomide, was prescribed as a sedative and soon became widely used to alleviate morning sickness such as nausea and vomiting in pregnant women. It was deemed safe after animal testing, primarily conducted on rats, and was released to the market. However, it led to the birth of newborns with severe congenital deformities among mothers who had taken the drug. Approximately ten thousand newborns were born with little or no limbs, having either failed to grow arms and legs or been born without them at all.
The background of the tragedy is as follows. Among the two enantiomers of this drug, the R-enantiomer exhibits sedative effects, while the S-enantiomer inhibits angiogenesis. When taken by pregnant women, the S-enantiomer prevents the growth of blood vessels that supply the nutrients necessary for the growth and differentiation of fetal cells, ultimately hindering the normal development of limbs. During drug manufacturing, these two enantiomers are synthesized simultaneously and exist in a mixed state, and the concept that they can have different physiological effects was not widely understood at that time. Even if it had been technically possible to separate the two enantiomers, the cost would likely have been very high. Furthermore, it was later revealed that even if the two enantiomers were completely separated and only the R-enantiomer was manufactured, they could still undergo bioinversion in the body, resulting in the synthesis of both forms.
This incident left many lessons regarding pharmaceutical manufacturing. The limitations of animal testing became significantly highlighted, emphasizing that metabolic pathways differ between animals and humans, leading to potentially different physiological responses. It also raised awareness of the critical importance of thorough analysis and safety assurance for the individual physiological actions of each enantiomer. Consequently, this led to major changes and strengthened regulations in clinical trials, including the stability, toxicity, pharmacokinetics, and metabolism of new chemical entities in drug development, as well as the drug approval process and monitoring. The impact on a more systematic and cautious approach to chiral drugs goes without saying
Chiral Drugs
Many pharmaceuticals produced artificially in pharmaceutical company laboratories are chiral drugs, and it is an unavoidable fact that they are synthesized as racemic mixtures of R- and S-enantiomers in a 1:1 ratio. These two forms, resembling twins, can have entirely different physiological properties. Of course, among chiral drugs, some are known to be sufficiently safe even in their racemic mixture state, and inactive enantiomers can be naturally converted into active enantiomers through enzymatic action in the body. Additionally, there are cases where inactive enantiomers are non-harmful and are prescribed as racemic mixtures without additional considerations (such as ibuprofen). In some cases, both formulations of the racemic mixture and the single enantiomer, which is more costly due to the separation process, are manufactured and sold. This allows patients to choose based on their economic circumstances, giving them the option to select the formulation that best fits their financial situation (e.g., esomeprazole, which is the S-enantiomer, and omeprazole, which is the racemic mixture). There are also cases where the differences between the enantiomers are not substantial enough to require separate consideration.
For reference, the state in which a drug binds to its target (such as enzymes or receptors) and exerts pharmacological action, producing immediate therapeutic effects, is called the active form. In contrast, the inactive form refers to the state of the drug that has no pharmacological action and must be metabolized in the liver or other organs to be converted into the active form. For example, T4 preparations, such as Synthroid for patients with hypothyroidism, are inactive drugs that must be converted into T3 by enzymes through metabolism in the liver and kidneys to exert physiological effects.
Pharmacokinetics and pharmacodynamics in drug development
The process of new drug development includes both pharmacokinetics and pharmacodynamics. Pharmacokinetics is the field that studies how drugs are absorbed, distributed, metabolized, and excreted in the body. In the case of chiral drugs, although the two enantiomers are the same substance, they can exhibit differences in solubility and barrier permeability, leading to varying absorption rates. Additionally, the distribution ratios of each enantiomer within body tissues may differ, and metabolic rates can change based on selective enzyme action, resulting in different durations of active states in the body. Differences can also arise in the excretion pathways, such as the kidneys, where one enantiomer may be reabsorbed.
Pharmacodynamics, on the other hand, is the study of how drugs act on targets like receptors or enzymes in the body to produce physiological effects. It is important to note that chiral drugs can exhibit differences in pharmacological activity, efficacy, and side effects. Receptors and enzymes are protein molecules, and as mentioned earlier, most proteins in the body are composed of L-amino acids, which possess chirality themselves. Therefore, they exhibit greater affinity for chiral drugs that have complementary structures.
As a result, enantiomers may only show activity when binding to specific receptors, and one enantiomer may act as a full agonist, demonstrating efficacy, while the other may function as an antagonist, blocking effects. The two enantiomers can yield a wide range of outcomes. However, the most critical point is that one of the enantiomers may provide therapeutic effects, while the other could potentially induce toxicity or adverse side effects. When developing chiral drugs, it is essential to evaluate these various aspects to make informed decisions regarding drug formulation.
Chiral Pharmacology: eutomer and distomer
With the increasing interest in racemic drugs and advancements in chiral-related technologies, a new field known as stereochemistry has emerged. This field considers the two chiral enantiomers as separate entities and studies their individual pharmacological activities. Among the two enantiomers, the one with stronger physiological and pharmacological activity is referred to as the eutomer, while the one with relatively weaker activity is called the distomer.
When the two mirror-image enantiomers of chiral drugs can be clearly distinguished as eutomer and distomer, the drug development process can focus on maximizing efficacy by utilizing only the active enantiomer, the eutomer. If the distomer poses risks of toxicity or side effects, a strategy known as "chiral switching" can be employed to convert it into the eutomer, ensuring both stability and efficacy.
Of course, if the distomer has the potential to cause severe toxicity, it may be possible to separate and remove it entirely from the final product after drug synthesis. However, this approach would require highly precise chiral separation techniques, which could lead to additional costs.
The two faces of chiral drugs
Let’s examine specific examples of the two faces of chiral drugs. In previous discussions, we explored various methods of naming mirror-image isomers, and in this context, we will distinguish the two enantiomers using the most common and internationally accepted R/S nomenclature.
The S-enantiomer of penicillamine, which has one chiral center, is used as a heavy metal chelator and for the treatment of rheumatoid arthritis, particularly in cases of Wilson's disease, where it helps manage excessive copper accumulation in the body. In contrast, the R-enantiomer is highly toxic and has a greater potential for side effects, which is why only the active form (the eutomer) is typically used to design safer medications.
Another widely used anesthetic, ketamine, has its S-enantiomer, S-ketamine, known for its excellent sedative and antidepressant effects. However, the R-enantiomer, R-ketamine, can cause side effects such as hallucinations and symptoms of schizophrenia. In various articles related to drug use involving certain celebrities, ketamine is often mentioned, and it is likely referring to R-ketamine. Given the title "suspected ketamine use," it is clear that R-ketamine is a dangerous psychoactive drug and can be considered a distinct distomer. Esketamine, a formulation consisting solely of S-ketamine rather than a racemic mixture, is commercially available and is used as a general anesthetic and for the treatment of depression.
Parkinson's disease and L-dopa
L-Dopa (dopa, levodopa, S-enantiomer) is a well-known treatment for Parkinson's disease and serves as a dopamine precursor drug to replenish the insufficient dopamine levels in the brain. Parkinson's disease occurs due to the destruction of dopaminergic neurons, which leads to a reduction in dopamine signaling that regulates movement and emotional control. L-Dopa was the first drug approved for the treatment of this condition and continues to be the most widely used.
Since dopamine cannot cross the blood-brain barrier (BBB), L-Dopa, its precursor, is administered instead. This allows it to be converted into dopamine within the brain. The sequential synthesis pathway of catecholamines (which are neurotransmitters or hormones) in the body follows this order: L-tyrosine → L-Dopa → dopamine → norepinephrine → epinephrine. Naturally, due to the homochirality of biomolecules, only L-Dopa is produced in the human body.
However, when synthesized artificially as a drug, both L- and D-forms (S/R-enantiomers) are produced. The D-enantiomer is not only ineffective because the body's enzymes have difficulty recognizing it, but it has also been shown to have very negative effects on the immune system, such as causing granulocytopenia in white blood cells. Therefore, only the L-Dopa single enantiomer has been approved and is used as a medication.
Methamphetamine: illegal drug vs. nasal decongestant
The S-enantiomer of methamphetamine has a potent effect on inhibiting the reuptake of dopamine and norepinephrine while promoting their release. This makes it highly effective for treating central nervous system disorders such as ADHD. However, the central nervous system stimulation effect of the S-enantiomer is 4 to 10 times stronger than that of the R-enantiomer, which raises concerns about misuse and abuse. It has a high potential to be used as an illegal drug, such as a stimulant, which is why it is strictly regulated in many countries.
In contrast, the R-enantiomer has much milder central effects and primarily acts peripherally. It has been legally sold as a component in some cold medications for relieving nasal congestion. However, due to the negative image associated with the S-enantiomer, the R-enantiomer has largely been replaced by other ingredients that also provide decongestant effects. This serves as a clear example of how the two mirror-image forms exhibit very different physiological properties.
Ethambutol and Naproxen
The (S,S)-enantiomer of ethambutol, which has two chiral centers, is used as a potent treatment for pulmonary tuberculosis by inhibiting bacterial cell wall synthesis. In contrast, the (R,R)-enantiomer has been shown to cause optic neuropathy, potentially leading to color blindness or permanent vision loss. Initially, it was produced as a racemic mixture, but current drug information indicates that the IUPAC name is specified as ‘(2S,2'S)-2,2'-(ethane-1,2-diyldiimino)dibutan-1-ol,’ suggesting that it is now manufactured in an enantiopure, single enantiomer, drug form.[1]
On the other hand, the S-enantiomer of naproxen is a non-steroidal anti-inflammatory drug (NSAID) used to treat conditions like rheumatoid arthritis and gout. However, concerns have been raised about the potential toxicity of its distomer, the R-enantiomer, which has minimal physiological activity but could cause liver damage. As a result, naproxen is manufactured and used solely as the S-enantiomer.[2]
There are chiral drugs that are more familiar to us, where the pharmacological differences between the two enantiomers do not appear to be significant enough to warrant attention, leading to the use of racemic mixtures. The decision on the manufacturing form likely involved a comparison between the stability that can be achieved by separating the two forms and the high costs associated with producing a specific enantiomer.
Anticoagulant Warfarin
Warfarin, commonly known by the name Coumadin, is a representative chiral drug that inhibits the reduction of inactive vitamin K to its active form. By doing so, it suppresses and decreases the activity of vitamin K-dependent coagulation factors, slowing down the coagulation process and providing an anticoagulant effect to prevent thrombus formation. For this reason, it is also referred to as a vitamin K antagonist.
Experimental results indicate that the S-enantiomer of warfarin is approximately 3 to 5 times more potent than the R-enantiomer and is metabolized more quickly in the body. However, due to the relatively small difference in their effects, warfarin has typically been manufactured as a racemic mixture.[3]
Ibuprofen
Ibuprofen (C₁₃H₁₈O₂), a well-known analgesic, antipyretic, and anti-inflammatory drug, is commonly used as a racemic mixture. The S-enantiomer is the active form, while the R-enantiomer is inactive and is converted to the S-form in the body. In practice, the S-enantiomer can be isolated to create dexibuprofen, which is reported to have stronger efficacy and fewer side effects, such as gastritis and dyspepsia, compared to ibuprofen. Dexibuprofen serves as an example of a chiral switch.
Chiral Inversion
One of the characteristics that can occur in chiral drugs is chiral inversion. At the beginning of this discussion, the tragedy of thalidomide was mentioned, highlighting that even if the two enantiomers are administered separately, they can interconvert in the body.
Chiral inversion, or bioinversion, refers to the process where one enantiomer is converted into another through enzymatic or chemical metabolism within the body. A representative example of chiral inversion can be found in the propene series of drugs, which are widely used as anti-inflammatory agents, analgesics, and antipyretics. This group includes well-known non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, which are structurally derived from 2-arylpropionic acid. Typically, the S-enantiomer exhibits pharmacological effects, while the R-enantiomer has little to no activity or can be converted into the S-enantiomer by enzymes in the kidneys or liver. Since the role of enzymes is crucial in this inversion process, it is often referred to as metabolic chiral inversion.
If our body is injured, it responds by initiating an immediate inflammatory reaction. One of the key responses is the secretion of inflammatory mediators like prostaglandins, which induce fever and pain to facilitate rapid recovery. Analgesics work by blocking or inhibiting the synthesis of prostaglandins, thereby alleviating inflammation and providing antipyretic and analgesic effects.
In the case of ibuprofen, it has been proven in laboratory studies that the S-enantiomer has a prostaglandin inhibitory effect that is an impressive 160 times stronger than that of the R-enantiomer. When S-enantiomer is administered alone, it shows a more rapid and potent analgesic effect, with reduced side effects. While individual metabolic capacities may vary, it is reported that up to 70% of the R-enantiomer can be converted to the S-enantiomer in the body.[4] Currently, both the racemic form of ibuprofen and the enantiopure S-enantiomer, dexibuprofen, are available on the market.
Some prominent researchers in chiral studies have remarked in their lectures that distinguishing between the two enantiomers is “not a big deal,” implying that there is no particular necessity to differentiate them. However, using enantiopure drugs wouldn’t be more effective, assuming cost is not a limiting factor?
The most significant case related to chiral inversion is thalidomide. As previously explained, the two enantiomers of thalidomide exhibit vastly different effects in the body. Even if manufactured as an enantiopure drug, the interconversion between the two enantiomers in the body means that the risk of teratogenic effects cannot be completely eliminated, thus safety cannot be guaranteed. Therefore, it is essential to thoroughly evaluate and analyze these pharmacological properties during drug development.
Chiral switch
Chiral switching refers to the process of developing a new drug by isolating the more effective and less side-effect-prone active enantiomer from a racemic mixture originally marketed. The resulting drug is also termed a chiral switch. For example, omeprazole, a proton pump inhibitor, exists as a racemic mixture with R- and S-enantiomers in a 1:1 ratio. Among these, the S-enantiomer has a significantly stronger effect in inhibiting gastric acid secretion, leading to the development of esomeprazole, which utilizes only the S-enantiomer.
While the efficacy of omeprazole can vary significantly due to individual metabolic capabilities and variations in the metabolic enzyme CYP2C19, esomeprazole offers more uniform absorption and less variability in metabolism, resulting in much higher bioavailability and stronger, longer-lasting gastric acid suppression. However, the manufacturing cost of esomeprazole is higher due to the chiral switching process. Therefore, unless the patient is severely affected by high metabolic variability or requires significant gastric acid suppression, omeprazole, the racemic form, may be prescribed considering the patient's economic situation.
Beyond the medical intention of enhancing drug efficacy and reducing side effects, chiral switching is also known as a strategic marketing practice. When the patent for an existing racemic drug expires, it becomes generic, allowing other pharmaceutical companies to manufacture and sell the same drug. This leads to increased competition and reduced prices, ultimately resulting in a significant decrease in profits for the original patent holder.
In the case of blockbuster drugs, pharmaceutical companies may employ an "evergreening strategy" to extend patent protection by isolating the more effective enantiomer and developing it as an enantiopure drug. By applying for a new patent on this single enantiomer, they can create a new market and secure benefits such as several years of patent exclusivity and data exclusivity, which can substantially increase the company's profits. However, this strategy may be less appealing if there isn't a significant difference in efficacy between the racemic mixture and the enantiopure drug due to price considerations.
Recently, there seems to be a shift in the chiral switch strategy, with many drug development efforts now targeting enantiopure products from the early stages. This trend will be further discussed in the following article on current chiral drug trends.
Drug repurposing/repositioning
Thalidomide re-emerges in the context of drug repositioning. As previously discussed, the S-enantiomer of thalidomide caused fatal side effects by inhibiting the formation of blood vessels necessary for delivering nutrients for fetal growth, leading to teratogenic effects. However, for the same reason, thalidomide has begun to gain attention as an effective anti-cancer treatment. Tumors need to generate blood vessels to grow, and thalidomide can inhibit this process.
The anti-angiogenic effect of thalidomide is particularly useful in the treatment of cancers like multiple myeloma, a type of blood cancer, where it is being reevaluated as a valuable drug. Additionally, thalidomide promotes the production of the cytokine interleukin-2 (IL-2), enhances T-cell generation, inhibits tumor necrosis factor-alpha (TNF-α), and stimulates natural killer (NK) cells, thereby reducing inflammation and modulating the immune system.[5] This ability suggests its potential effectiveness in treating autoimmune and inflammatory diseases.
This transformation of the infamous thalidomide highlights that the drug itself is not inherently toxic or harmful; rather, the key lies in who uses it and how it is applied. Depending on its application, it can either pose risks or serve as a solution.
In this discussion, we have explored various characteristics of chiral drugs and how enantiomers are utilized during the drug development process. In the following article, we will delve deeper into the recent trends and directions related to chiral drugs.
[References]
[1] https://www.ebi.ac.uk/chebi/searchId.do?chebiId=4877
[2] Naproxen-induced liver injury
https://pubmed.ncbi.nlm.nih.gov/21947732/
[3] Enantiomers of warfarin and vitamin K1 metabolism.
https://doi.org/10.1111/j.1365-2125.1986.tb02966.x
[4] Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)
https://journals.viamedica.pl/medical_research_journal/article/download/MRJ.2017.0001/41638
[5] How Thalidomide Works Against Cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4084783/
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