Chiral inversion

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Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule. [1] [2] [3] [4]

Contents

Chiral inversion happens depending on various factors (viz. biological-, solvent-, light-, temperature- induced, etc.) and the energy barrier associated with the stereogenic element present in the chiral molecule. 2-Arylpropionic acid nonsteroidal anti-inflammatory drugs (NSAIDs) provide one of the best pharmaceutical examples of chiral inversion. Chirality is attributed to a molecule due to the presence of a stereogenic element (viz. center, planar, helical, or axis). Many pharmaceutical drugs are chiral and have a labile (configurationally unstable) stereogenic element. Chiral compounds with stereogenic center are found to have high energy barriers for inversion and generally undergo biologically mediated chiral inversion.  While compounds with helical or planar chirality have low energy barriers and chiral inversions are often caused by solvent, light, temperature. [5] When this happens, the configuration of the chiral molecule may rapidly change reversibly or irreversibly depending on the conditions. The chiral inversion has been intensively studied in the context of the pharmacological and toxicological consequences. [6] Other than NSAIDs, chiral drugs with different chemical structures can also show this effect.

Chiral drugs have different effects on the body depending on whether one enantiomer or both enantiomers act on different biological targets. As a result, chiral inversion can change how a pharmaceutical drug works in the body. From a pharmacological and toxicological point of view, it is very important to learn more about chiral inversion, the things that make it happen, and the tools used to figure out chiral inversion.

Types

Essentially there are two types of chiral inversion, unidirectional and bidirectional. [7] Inversion process is dependent on species and substrate.

Unidirectional
chiral inversion (enzyme mediated) was described only with 2-arylpropionate nonsteroidal anti-inflammatory drugs (NSAIDs), namely ibuprofen, ketoprofen, fenoprofen, benoxaprophen, etc. [8] For this group, only S-enantiomer (eutomer) is active i.e. has  analgesic and anti-inflammatory effect. In the body, only inactive R-enantiomer can undergo chiral inversion by hepatic enzymes into the active S-enantiomer and not vice versa. The “inactive” R-isomer (distomer) may be responsible for the gastrointestinal irritation and related side-effects associated with NSAIDs. [9] In certain situations, carbenicillin, ethiazide, etoposide, zopiclone, pantoprazole, clopidogrel, ketorolac, albendazole-sulfoxide, lifibrol, and 5-aryl-thiazolidinedione also go through unidirectional chiral inversion. [10]   Chiral inversions were found to happen in a group of important compounds called α-amino acids. Amino acids exist in two mirror-image versions (D- and L- configurations). Several D-amino acids, like D-methionine, D-proline, D-serine, D-alanine, D-aspartate, D-leucine, and D-phenylalanine, have been shown to go through unidirectional chiral inversion in mammals. [11] [12]
Bidirectional
chiral inversion or racemization type of inversion is shown by pharmaceutical drugs including 3-hydroxy-benzodiazapine class of drugs (oxazepam, lorazepam, temazepam), thalidomide, and tiaprofenic acid. [7] A brief list of select pharmaceutical drugs that go through chiral inversion are presented in Table below..
List (select) of pharmaceutical drugs that undergo chiral inversion
Pharmaceutical drugTherapeutic categorySpeciesModel systemReferences
Ibuprofen NSAIDMan, rat, mouse, guinea pigIn vivoAso, Yoshioka, & Yasushi, 1990 [13] [14]
Ketoprofen NSAIDRabbit, rat, humanIn vivoJamali, Mehvar, & Psutto, 1989 [15]
Benoxaprophen NSAIDHumanIn vivoCaldwell, Hutt, & Fournel-Gifleu, 1988 [8]
Fenoprofen NSAIDHuman, rabbitIn vivoJamali, Mehvar, & Psutto, 1989 [15]
Ketorolac NSAIDMan/RatIn vitroVakily, Corrigan, & Jamali, 1995 [16]
Carbenicillin AntimicrobialManIn vitroAso, Yoshioka, & Yasushi, 1990 [13]
Thalidomide Immunomodulatory agentManIn vitroEriksson, Björkman, & Höglund, 2001 [17]
Ketamine General anaestheticRatIn vivoEdwards, & Mather, 2001 [18]
Ethiazide DiureticManIn vitroAso, Yoshioka, & Yasushi, 1990 [13]
Zopiclone Hypnotics and sedativesRatIn vitroFernandez, et al.., 2002 [19]
Clopidogrel Antiplatlet medicationRatIn vitroReist, et al., 2000 [20]
Albendazol-sulfoxide Anthelmintic agentSheep/CattleIn vitroVirkel, Lifschitz, Pis, & Lanusee, 2002 [21]
Lifibrol Lipid lowering  agentDogIn vitroWalter, & Hsu, 1994 [22]
5-Aryl-Thiazolidinedione Antidiabetic agentMan/DogIn vitroWelch, Kress, Beconi, &  Mathre, 2003 [23]
Pantoprazole Proton-pump inhibitorRatIn vitroMasubuchi, Yamazaki, & Tanaka, 1998 [24]
Etoposide Antineoplastic agentRatIn vivoAso, Yoshioka, & Yasushi, 1990 [13]

Mechanism

Metabolic inversion - Ibuprofen enantiomers Metabolic chiral inversion.png
Metabolic inversion - Ibuprofen enantiomers

It is well documented that (R)-enantiomers of profens in the presence of coenzyme A (CoA), adenosine triphosphate (ATP) and Mg+2 are converted to active (S)-forms. The pathways of chiral inversion is illustrated taking ibuprofen as the prototype, in the scheme below. [14] [25]

The pathway consists mainly of three steps:

  1. Stereoselective activation: Stereoselective activation of (R)-profen by the formation of the thioester, in the presence of CoA, ATP and Mg+2. (S)-profen does not form the thioester.
  2. Epimerization (Racemization): The enzyme epimerase 2-arylpropionic-CoA changes the (R)-thioester to the (S)-thioester. This process is called "racemization" or "epimerization."
  3. Hydrolysis: With the help of hydrolase/thioesterase, thioesters are broken down into their (R)- and (S)-forms

Because the acyl-CoA thioester (profenyl-CoA) changes the structure of triglycerides and phospholipids, metabolic chiral inversion may cause toxic effects. [10]

Factors influencing inversion

Chiral drugs with stereo-labile configuration are likely to undergo interconversion of the enantiomers that may be enzymatic (biological) or non-enzymatic. Enzyme-mediated conversion is the process of chiral inversion that happens in a living organism. Non-enzymatic inversion of drugs is important and relevant in the pharmaceutical manufacturing process. This may have impact on the shelf-life of a drug and the economic feasibility of the resolution. Inversion can also happen without enzymes when precolumn derivatization is used in enantioselective chromatographic separation techniques. Racemization can also happen in the acidic environment of the stomach and other bodily fluids.

Enzyme-mediated (biological)

Enzyme-mediated (biological) chiral inversion of organic compounds is caused by highly chiral endogenous molecules found in receptors, enzymes, and other structures. [8] While enzyme inhibitors suppress enzyme activity, enzyme inducers boost enzyme concentration and activity. The primary determinants of inter-individual variability in drug metabolism in humans are thought to include genetic polymorphism and a variety of other variables, including age, gender, biological conditions, pregnancy, illnesses, stress, nutrition, and drugs. For instance, Reichel et al. [26] reported that a 2-arylpropionyl-coenzyme-A epimerase was molecularly cloned and expressed as a crucial enzyme in the inversion metabolism of ibuprofen. Ibuprofen's chiral inversion by enzymes has been documented in humans. [27]

Species differences

Tissue variations

The liver, gastrointestinal tract (GIT), lungs, kidney, and brain are among the tissues that participate in the chiral inversion of medicines. The liver has been shown to be the most crucial organ in the development of this mechanism. [28] Although some studies contend that rat liver homogenates lack the enzymatic mechanisms necessary to invert the R-enantiomers of flurbiprofen, naproxen, suprofen, and ibuprofen, the liver may also be involved in the inversion of R-ibuprofen in rats. [15] On the other hand, it was noted that certain medicines underwent chiral inversion without the involvement of the liver (hepatocytes). Although liver did not play a substantial role in the inversion of benoxaprofen, studies using benoxaprofen and ketoprofen show that one of the primary sites of inversion in rats is the GI tract. [15]

Route of administration

Inter-individual variability

Non-enzymatic

Sample handling and manufacturing process

Temperature and pH

Analytical methods

Chiral inversion is a very important part of designing and making drugs. Because this process can change how chiral drugs work in the body and can cause side effects that can be serious or even fatal. Traditionally, chiral inversions have been studied with NMR spectroscopy at different temperatures and chiroptical methods like polarimetry. But strong, complementary methods based on dynamic chromatography (GC, HPLC, SFC, CEC, and MEKC) and electrophoresis have been made and used to figure out how the enantiomeric composition of stereo-labile chiral compounds changes over time. [29] Most of the time, liquid chromatographic methods are used to do enantioselective analysis of chiral drugs. When an analyte with one stereogenic center or axis is separated well, the chromatogram will show two peaks. But if the analyte is stereo-labile, the peaks tend to merge. [30] How much coalescence there is will depend on how fast chiral inversion and enantioresolution happen. Over time, the peaks will merge into a flat area. Dynamic chromatography shows how the elution profile changes over time. This makes it useful for figuring out how pH, temperature, and solvents affect chiral inversion, which can happen on the stationary phase, in the injector, or in the detector. [29]

Multidimensional approaches have been used to improve separation and detection. Table below shows a list of common methods and experiments used to figure out chiral inversion. Any of these methods can then be used to determine chiral inversion. Which instrument is used to analyze a chiral compound depends on its physical and chemical properties (i.e., the solubility, vapor pressure, thermal and solvent stability, and detection). [29]

Instruments and experimental approaches used for investigating stereo-labile compounds [30]
InstrumentExperimental operational approaches
Dynamic NMRCombining classical kinetic studies with chiral separation
Dynamic  gas chromatographyContinuous flow models
Dynamic supercritical fluid chromatographyPeak form analysis - involves comparison of real chromatograms with simulated peaks
Dynamic liquid chromatographyStopped-flow method
Dynamic capillary electrophoresisStochastic methods
Dynamic micellar electrokinetic chromatographyDeconvolution methods
Dynamic capillary electrochromatographyApproximation function methods

For example, capillary electrophoresis or liquid chromatography could be used if the analyte can be ionized and has a high vapor pressure, but it is also soluble in polar solvents. [31] On the other hand, gas chromatography is the best way to test a substance that is stable at high temperatures but has a low vapor pressure. When compared to gas or liquid chromatography, supercritical fluid chromatography is a better way to measure chiral inversion because it uses mass spectrometers and a green method. [32]

Significance in drug development

Three-point attachment model Easson-Stedman Model.png
Three-point attachment model

Enantiomers of a chiral drug often interact in an enantioselective way in a chiral environment. This may be offered by different biotic substances (viz. proteins, nucleic acids, phospholipids and oligosaccharides). They are made up of chiral building blocks that are put together in space in handed conformations. These biological targets function as receptors for the drug enantiomers. So, at the binding sites of these receptors, enantiomers will be seen as different chemical species. The three point attachment model (Easson & Stedman model) [33] can be used to see how chiral discrimination works. Figure depicts how the enantiomers of a drug interact with receptors in a way that depends on the drug's shape. This model was made for chiral drugs with a single stereogenic center. It says that there are three binding sites in the receptor (B', C' and D') that match the drug's pharmacophoric groups (B, C, D). A three-point fit (good fit) is possible for the eutomer at BB', CC' and DD'(Fig. A). Even though the distomer is the wrong enantiomer, it can fit either a one-point interaction (bad fit), or a two-point attachment (CC' and DD') with the same receptor site as shown in (Fig. B).

Eutomer is the version that works the way you want it to, and distomer is the version that doesn't work or works in a way you don't want it to. [34] [35] Most of the time, the mirror-image versions have different binding affinities. In the eutomer, the ligands or moiety around a stereogenic element have more binding energy than in the distomer. When the eutomer goes through chiral inversion, it loses its ability to bind to a biological receptor. Because of these enantiospecific interactions, therapeutic and toxicological properties are enantioselective [27] [6] So, the stereo-stability of chiral drugs may have big effects on the process of making new drugs, especially when it comes to how pharmaceutical, pharmacokinetic, and pharmacodynamic information is read and understood. At every stage of designing, making, and testing a drug for safety, chiral inversion must be taken into account.

See also

Related Research Articles

<span class="mw-page-title-main">Ketoprofen</span> NSAID analgesic medication

Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin.

In chemistry, a racemic mixture or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates.

<span class="mw-page-title-main">Ibuprofen</span> Medication used for treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Enantiomer</span> Stereoisomers which are non-superposable mirror images of each other

In chemistry, an enantiomer – also called optical isomer, antipode, or optical antipode – is one of two stereoisomers that are non-superposable onto their own mirror image. Enantiomers are much like one's right and left hands; without mirroring one of them, hands cannot be superposed onto each other. No amount of reorientation in three spatial dimensions will allow the four unique groups on the chiral carbon to line up exactly. The number of stereoisomers a molecule has can be determined by the number of chiral carbons it has. Stereoisomers include both enantiomers and diastereomers.

In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic form. This creates a 1:1 molar ratio of enantiomers and is referred to as a racemic mixture. Plus and minus forms are called Dextrorotation and levorotation. The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.

<span class="mw-page-title-main">Chirality (chemistry)</span> Geometric property of some molecules and ions

In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality. The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

<span class="mw-page-title-main">Enantioselective synthesis</span> Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts."

<span class="mw-page-title-main">Biocatalysis</span> Use of natural catalysts to perform chemical transformations

Biocatalysis refers to the use of living (biological) systems or their parts to speed up (catalyze) chemical reactions. In biocatalytic processes, natural catalysts, such as enzymes, perform chemical transformations on organic compounds. Both enzymes that have been more or less isolated and enzymes still residing inside living cells are employed for this task. Modern biotechnology, specifically directed evolution, has made the production of modified or non-natural enzymes possible. This has enabled the development of enzymes that can catalyze novel small molecule transformations that may be difficult or impossible using classical synthetic organic chemistry. Utilizing natural or modified enzymes to perform organic synthesis is termed chemoenzymatic synthesis; the reactions performed by the enzyme are classified as chemoenzymatic reactions.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.

<span class="mw-page-title-main">Flunoxaprofen</span> Chemical compound

Flunoxaprofen, also known as Priaxim, is a chiral nonsteroidal anti-inflammatory drug (NSAID). It is closely related to naproxen, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis and rheumatoid arthritis. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity.

<span class="mw-page-title-main">Dexibuprofen</span> Chemical compound

Dexibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). It is the active dextrorotatory enantiomer of ibuprofen. Most ibuprofen formulations contain a racemic mixture of both isomers.

<span class="mw-page-title-main">Fenoprofen</span> NSAID analgesic and anti-inflammatory drug

Fenoprofen, sold under the brand name Nalfon among others, is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. It is available as a generic medication.

Chiral Lewis acids (CLAs) are a type of Lewis acid catalyst. These acids affect the chirality of the substrate as they react with it. In such reactions, synthesis favors the formation of a specific enantiomer or diastereomer. The method is an enantioselective asymmetric synthesis reaction. Since they affect chirality, they produce optically active products from optically inactive or mixed starting materials. This type of preferential formation of one enantiomer or diastereomer over the other is formally known as asymmetric induction. In this kind of Lewis acid, the electron-accepting atom is typically a metal, such as indium, zinc, lithium, aluminium, titanium, or boron. The chiral-altering ligands employed for synthesizing these acids often have multiple Lewis basic sites that allow the formation of a ring structure involving the metal atom.

An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind differently to target receptors. Chirality can be observed when the geometric properties of an object is not superimposable with its mirror image. Two forms of a molecule are formed from a chiral carbon, these two forms are called enantiomers. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects. The desired enantiomer is known as an eutomer while the undesired enantiomer is known as the distomer. When equal amounts of both enantiomers are found in a mixture, the mixture is known as a racemic mixture. If a mixture for a drug does not have a 1:1 ratio of its enantiomers it is a candidate for an enantiopure drug. Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by resolving a racemic mixture. On a case-by-case basis, the U.S. Food and Drug Administration (FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture. Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval and for patenting is independent, and differs country by country.

The eudysmic ratio represents the difference in pharmacologic activity between the two enantiomers of a drug. In most cases where a chiral compound is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio significantly differing from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. For example, (S)-propranolol meaning that (S)-propranolol is 130 times more active as its (R)-enantiomer.

<span class="mw-page-title-main">Indacrinone</span> Chemical compound

Indacrinone is a loop diuretic. It can be used in patients of gout with hypertension as an antihypertensive because it decreases reabsorption of uric acid, while other diuretics increase it.

A chiral switch is a chiral drug that has already approved as racemate but has been re-developed as a single enantiomer. The term chiral switching was introduced by Agranat and Caner in 1999 to describe the development of single enantiomers from racemate drugs. For example, levofloxacin is a chiral switch of racemic ofloxacin. The essential principle of a chiral switch is that there is a change in the status of chirality. In general, the term chiral switch is preferred over racemic switch because the switch is usually happening from a racemic drug to the corresponding single enantiomer(s). It is important to understand that chiral switches are treated as a selection invention. A selection invention is an invention that selects a group of new members from a previously known class on the basis of superior properties. To express the pharmacological activities of each of the chiral twins of a racemic drug two technical terms have been coined eutomer and distomer. The member of the chiral twin that has greater physiological activity is referred to as the eutomer and the other one with lesser activity is referred to as distomer. The eutomer/distomer ratio is called the eudisimic ratio and reflects the degree of enantioselectivity of the biological activity.

Chemical compounds that come as mirror-image pairs are referred to by chemists as chiral or handed molecules. Each twin is called an enantiomer. Drugs that exhibit handedness are referred to as chiral drugs. Chiral drugs that are equimolar (1:1) mixture of enantiomers are called racemic drugs and these are obviously devoid of optical rotation. The most commonly encountered stereogenic unit, that confers chirality to drug molecules are stereogenic center. Stereogenic center can be due to the presence of tetrahedral tetra coordinate atoms (C,N,P) and pyramidal tricoordinate atoms (N,S). The word chiral describes the three-dimensional architecture of the molecule and does not reveal the stereochemical composition. Hence "chiral drug" does not say whether the drug is racemic, single enantiomer or some other combination of stereoisomers. To resolve this issue Joseph Gal introduced a new term called unichiral. Unichiral indicates that the stereochemical composition of a chiral drug is homogenous consisting of a single enantiomer.

Chiral analysis refers to the quantification of component enantiomers of racemic drug substances or pharmaceutical compounds. Other synonyms commonly used include enantiomer analysis, enantiomeric analysis, and enantioselective analysis. Chiral analysis includes all analytical procedures focused on the characterization of the properties of chiral drugs. Chiral analysis is usually performed with chiral separation methods where the enantiomers are separated on an analytical scale and simultaneously assayed for each enantiomer.

<span class="mw-page-title-main">Profen (drug class)</span>

The profens are a class of nonsteroidal anti-inflammatory drugs. Profens are also known as 2-arylpropionic acids to reflect their chemical structure. The most common example of a profen is ibuprofen, which has been sold under the brand name Profen among others.

References

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