If we use the lock-and-key theory of enzyme action, we say that S -ibuprofen is the key that fits the lock the receptor site of the enzyme.
From www. The production of PGH2 ceases along with the pain and fever caused by the body's inflammatory response. Why is only one of the enantiomers of Ibuprofen effective? Ernest Z. Sep 11, How ibuprofen does it Ibuprofen is 2- 4-isobutylphenyl propanoic acid. Its structure is From scienceline. Why only the S isomer works The S -ibuprofen has the same shape as the molecules that activate the COX enzymes to produce prostaglandins.
Ibuprofen functions by strongly inhibiting the conversion of arachidonic acid into prostaglandin E2, which serves as a chemical signal for vasodilatation inflammation and pain perception. It has been shown for the aryl-substituted proprionic acid NSAIDS, compounds such as ibuprofen, naproxen and related compounds, that of the two enantiomers only one has the desired biological activity.
With ibuprofen the R - - —enantiomer has been shown to be non-harmful so currently most commercial ibuprofen is sold in a racemic form 2,3. It has been found that humans have an enzyme which isomerizes the Inactive R- form to the active S- isomer in vivo. As such, there are two possible enantiomers of ibuprofen, with the potential for different biological effects and metabolism for each enantiomer. It was logical, then, that there was the potential for improving the selectivity and potency of ibuprofen formulations by marketing ibuprofen as a single-enantiomer product as occurs with naproxen, another NSAID.
Further in vivo testing, however, revealed the existence of an isomerase 2-arylpropionyl-CoA epimerase which converted R -ibuprofen to the active S -enantiomer. Biochim Biophys Acta 3 : —7. Epimerization and hydrolysis of ibuprofenyl-coenzyme A".
Drug Metab Dispos 20 2 : —7. Mol Pharmacol 51 4 : — There are several different types of enantiomeric resolutions. The first type of resolution discovered was the direct crystallization method. In this method, the compound in question, forms half the crystals containing predominantly the R enantiomer and the other half containing predominantly the S enantiomer 2. The different crystals, if carefully examined can be physically separated by differences in their appearances.
Alternately, if you have an enantiomerically pure crystal this can be used as a seed crystal to precipitate the crystals of one enantiomer preferentially. This process was first used by Louis Pasteur in his groundbreaking resolution of tartaric acid. This first resolution greatly aided the development of our understanding of the stereochemistry of organic compounds and led to the discovery that many organic molecules have isomers that are non-superimposable mirror images 2,6.
This type of resolution, however, only works with 5 to 10 percent of organic compounds. The remaining organic compounds tend to form racemic crystals containing equal amounts of both enantiomers, thereby precluding resolution using the direct crystallization method.
Easson-Stedman hypothetical interaction between the two enantiomers of a racemic drug with a receptor at the drug binding sites. The three substituents A, B, C of the active enantiomer left can interact with three binding sites a, b, c of a receptor by forming three contacts Aa, Bb and Cc, whereas the inactive enantiomer right cannot because the contact is insufficient. Note: This figure is in the publication of McConalthy and Owens Chiral separation, also called chiral resolution, is a procedure used to separe the two isomers of a racemic compound in pharmaceutical industry as well as in clinical analysis.
Various methodologies used for chiral separation on both analytical and preparative scales will be described below. During chemical synthesis, many drugs obtained can be racemized in situ by a variety of chemical reactions, even the procedure used has started with pure enantiomeric reagents.
In industry, two main categories of techniques are often applied for chiral resolution: the classical methods and the modern technologies 60 , For the classical approach, the most widely used technique is the resolution by diastereomeric salt formation.
In this strategy, an acid-base reaction is involved between a racemic drug and a pure single enantiomer called resolving agent. This reaction leads to the formation of two diastereomeric salts that now have different physical and chemical properties. These two diastereomers obtained can be easily separated either by crystallization or by filtration if one is soluble and the other is insoluble. Finally, the salt is decomposed by treatment with either acid or base, then the pure enantiomer is obtained 44 , The two diastereomers formed can also be separated by classical achiral liquid chromatography.
This method has been used in the resolution of -methyl-L-dopa, asparagine and glutamic acid Another classical approach is the enzymatic or kinetic resolution. In this methodology, resolution is achieved by means of biochemical process that destroys one enantiomeric form.
Certain microorganisms such as yeasts, molds, bacteria can only degrade one of two isomers of a racemate by enzymatic assimilation, the other which is not digested remains in solution, then it is isolated 60 , Enzymatic resolution has been used in the preparation of lotrafiban benzodiazepine , levofoxacin antibacterial drug , and S-naproxen antiinflammatory drug For the modern technologies, preparative high-performance liquid chromatography HPLC is the method of choice for the enantiomer separation.
Chiral HPLC has proven to be one of the best methods for the direct separation and analysis of enantiomers. In chromatographic methods, two techniques are used: indirect and direct.
The indirect HPLC involves derivatization of samples with a chiral derivatization reagent i. This indirect HPLC method is rarely used in industry, but frequently performed in biological analysis because of its high sensitivity. The last technique is rarely used in industry because of its high cost and low efficiency.
Direct chiral separations using CSPs are more widely used and are more predictable, in mechanistic terms, than those using chiral additives in the mobile phase. Among a hundred HPLC CSPs commercially available, only some types of chiral sorbents following are presently the most widely used for preparative HPLC in industry: carbohydrate cellulose, amylose , polyacrilamide, diallyltartardiamide, Pirkle phases, chirobiotic phases vancomycin, teicoplanin However, there is no single CSP that can be considered universal, i.
Choosing the right column for the enantioseparation of a racemic compound is difficult. The decision relies mostly on empirical data and experience However, the understanding of the recogntion mechanisms of chiral selectors with enantiomers can help the chromatographists to resolve some problems of resolution and to economize time-consuming.
According to Aboun-Enein and Ali 60 all chiral selectors provide a chiral surface to enantiomers, which form with the selectors temporary complexes, having different bonding energies. The enantiomers differ in their binding energies because they fit differently into the chiral selector structures.
Consequently, the two enantiomers can be eluted at different times by the mobile phase and then separately collected. Brieftly, in general, the recognition mechanism on a chiral selector is based on a key-and-lock arrangement However, many other factors such as mobile phase composition pH, electrolytes, solvent nature , size and length of column, temperature etc also play a key role for chiral resolution.
As reported by Burke and Henderson 44 the basic concept of SMB technology is the continuous countercurrent movement of stationary and mobile phases in which the movement of a stationary phase is simulated. The small particles in this component are packed into single columns and connected to form a circle.
Four external valves allow the addition and subtraction of feed and effluent. The mobile phase is pumped through the circle and when it passes the stationary phase a slight separation occurs, the less absorbable compound running in front and the more absorbable compound staying behind.
When steady state is reached, the system can be operated continuously. If all flow rates and the shift time are determined correctly, raffinate and extract fractions can be withdrawn in high purity 44 , An example of a pharmaceutical compound separated by SMB chromatography is tramadol The scheme of the SMB chromatography is described in the article of Johannsen et al The SMB procedure allows to reduce solvent consumption, and consequently may lower the production cost. To avoid the racemization in situ during chiral drug preparation, an asymmetry synthesis using chiral catalysts has been developed by W.
Knowles, R. Noyori and K. Sharpless, the Nobel Prize in chemistry 6 , Most of the available asymmetric chemical catalysts are organometal types including transition metals such as titanium, and noble metals such as osmium, palladium, and rhodium. Chiral catalysts are like enzymes in that both have a high degree of specificity. They allow stereospecific reactions to take place and therefore avoid the formation of racemates.
Chiral chemical catalysts are hardier than enzymes, and tolerate higher temperatures. However, the use of chiral chemical catalysts is usually costly.
L-Dopa anti-Parkinson agent , naproxen anti-inflammatory drug are some examples of single enantiomer drugs produced by this catalytic asymmetric synthesis 24 , 66 , The analyses of chiral drugs in biological fluids are much more difficult than their quantifications and separations in industry although they can use the same physical techniques. The extraction of drugs and toxics in biological matrices for physical chemical analysis HPLC, GC, MS , a key step of bioanalysis, is used to clean the samples by removing proteins and other interfering biological compounds before analysis.
For the extraction of a pair of enantiomer drug from biological samples, two techniques are used: liquid-liquid extraction and solid-phase extraction SPE. For the first technique, the choice of extraction solvent depends on the polarity of the chiral drug. In most cases, a buffer with pH is usually added into the sample before solvent extraction in order to liberate drug from protein.
As the two enantiomers have the same chemical and physical properties, in general, the recoveries of two enantiomers are the same for the control samples. The classical liquid extraction is in general time-consuming, but it is cheaper and sometimes it can give high recovery and clean extract. However, some new liquid-phase microextraction techniques recently cited in the literature seem simple and rapid For the solid-phase extraction technique, two kind of sorbents are used: classical reversed-phase silica-bonded with C18 and recent polymeric sorbent.
The last extraction technique with polymeric sorbent showed a great advantage about recovery and universal use in comparison with classical reversed-phase cartridge as He et al 69 have recently published. For the bioanalysis of racemic drugs, two kinds of analytical methods have been developed: the physical methods and the enantioselective immunoassays. Chiral analysis by physical methods. In the first group, chiral chromatography including high performance liquid chromatography HPLC , gas chromatography GC , supercritical fluid chromatography SFC and capillary electrophoresis CE is most readily accomplished for the enantiomer resolution.
HPLC is the most widely used of the four methods. As in industry, two HPLC techniques are used: indirect and direct. In contrast to industry, the indirect HPLC using chiral derivatization reagent with the formation of two diastereomers is frequently performed in bioanalysis because of its high sensitivity. However, this indirect technique requires a functional group in the analyte drug e. A chiral derivating reagent a pure single enantiomer added in the sample will react with these functions to form two diastereomers that can be separated by a classical reversed-phase column C18 or C8 Because of the limitation of the indirect HPLC, direct chiral separations using chiral stationary phases CSPs are the most used because of its simplicity and its rapidity.
Today, nearly a hundred CSPs have been developed and are recently marketed, but some types of chiral HPLC columns following are the most used in bioanalysis: cyclodextrine and its derivatives, carbohydrate cellulose, amylose , Pirkle phases, chirobiotic phases.
Antibiotics or chirobiotic phases such as vancomycin-CSP or eremomycin-CSP can also separate thalidomide and amino acids, respectively 76 , Liquid chromatography-mass spectrometry LC-MS , gas chromatography-mass spectrometry GC-MS and capillary electrophoresis CE are other physical methods for the separation of numerous chiral pharmaceuticals 79 - Unfortunately, until today, there is no single CSP that can resolve all classes of racemic compounds in bioanalysis, contrary to achiral reversed- phase C18 or C8.
The choice of a chiral column is in general examined on the interaction mechanism between CSP and chiral analyte Enantioselective immunoassays. In contrast to physical methods, immunoassays do not require a preliminary extraction of biosample before analysis. Some techniques such as radioimmunoassays or enzymo-immunoassays ELISA used for the determination of some enantiomer drugs propranolol, methadone, amphetamine, warfarin, atropine, pentobarbital were developed, but still on experimental scale 55 - In recent years, as patent on a successful drug nears expiration, pharmaceutical manufacturers have sometimes marketed a single stereoisomer of the old racemic drug as a new drug chiral switch , often with claims of greater activity, less toxicity or both.
Many currently marketed drugs are racemic mixtures of stereoisomers. They may be enantiomers, which are non-superimposable mirror images, or geometric isomers, which are not mirror images, but in either case stereoisomers can differ markedly from each other in bioactivity and pharmacokinetics.
The FDA now requires manufacturers to identify and characterize each individual isomer of a new racemic mixture. However, the differences between stereoisomers may not be clinically significant. The levofloxacin, S - isomer of ofloxacin, has an important clinical advantage over racemic ofloxacin, but for some other stereoisomers marketed recently as the patent was expiring on the original racemic mixture such as esomeprazole, levalbuterol, dexmethylphenidate and escitalopram , no such advantage has been clinically demonstrated.
Accounting for the growing development of chiral drugs as racemate and single enantiomer worldwide, it is primordial to promote the chiral separation and its development because this operation plays a key role not only in pharmaceutical industry but also in clinical therapeutics. Nowadays, many drugs are still used as racemates with their side-effects, this problem is probably due not only to the difficulty in chiral separation technique but also to the production costs.
If a new separation method for chiral drugs will be developed with its large application scale and low cost, the number of racemic drugs could diminish significantly. The direct production of a single drug enantiomer by asymmetric synthesis is useful when its other antipode is found toxic or entirely inactive. However, for the drug discovery process, the obtention of a racemate could give triple informations about the drug to be explored i.
Theoretically, the use of a single isomer is ideal, but practically, the decision must be taken after long clinical observation between racemate and single enantiomer actions. In some therapeutic cases, the use of a racemate is more helpful than that of each single isomer because of the complementary effects of each other.
Therefore, preparative and analytical HPLC are very useful at the experimental step of drug discovery and also are an invaluable tool for the searcher. The ultimate choice of the separation technique either physical or chemical depends on the nature of each drug to be produced and also on the quantity, the time and the cost of the production. Our body is a great factory of chiral selectors, and could well distinguish the stereoform of a chiral drug, we can ask if it is interesting to transform some old achiral drug into its chiral derivative in order to discover some unexpected pharmacological effect.
Thalidomide is a chiral drug with a multitude of pharmacological activities, maybe some of them could be given by one or more of its numerous chiral metabolites. In clinical therapeutics, the use of a chiral assay is still not universally performed. Use of a non-stereoselective determination for a drug administered as a racemate may result in erroneous therapeutic interpretation.
For example, for the same dosage of a racemic drug administered to two patients, a non-chiral assay can give the same racemate concentrations for both patients. But, the ratio of the active form and the inactive one can differ in two patients and thanks to the last results, the physician can correctly interpret the difference in clinical observation between them.
Therefore, it is important to promote the automatization of some chiral techniques used in clinic such as chiral HPLC and enantioselective immunoassays. It is also helpful to inform their utility to doctors and pharmacists. Besides, drug dictionary and pharmacopeia have to mention the chiral form of a drug i. These informations will be a precious guide for all healthcare professionals. The chiral separation of racemic drugs is a necessary operation in pharmaceutical industry as well as in clinical therapeutics.
Therefore, the development of new chiral separation techniques is and will be a topic subject in academic research as well as in industrial advance. However, the use of a single isomer must be seriously taken after long clinical assessments between racemate and single enantiomer actions because in some cases, racemates have more therapeutic advantages than single isomers. It is also important to give more informations about chiral drugs especially racemic form to healthcare professionals in order to help them for finding an optimal treatment and a right therapeutic control.
National Center for Biotechnology Information , U. Int J Biomed Sci. Author information Copyright and License information Disclaimer. Fax: 33 1 ; E-mails: rf. Licensee Master Publishing Group.
This article has been cited by other articles in PMC. Keywords: analysis, chiral drugs, chiral separation, chiral terms, enantioselective antibodies, metabolism, pharmacokinetics, pharmacology, toxicology. Open in a separate window. Figure 1. Group 1. Racemic drugs with one major bioactive enantiomer In this group, there are a number of cardiovascular drugs, agents widely used for the treatment of hypertension, heart failure, arrhythmias, and other diseases.
Group 2. Racemic drugs with equally bioactive enantiomers There are only some racemic drugs that could belong to this group such as cyclophosphamide antineoplastic , flecainide antiarrhythmic , fluoxetine antidepressant Group 3. Racemic drugs with chiral inversion There are two kinds of drug chiral inversion: unidirectional and bidirectional inversion Figure 2. In pharmaceutical industry During chemical synthesis, many drugs obtained can be racemized in situ by a variety of chemical reactions, even the procedure used has started with pure enantiomeric reagents.
In clinical analysis The analyses of chiral drugs in biological fluids are much more difficult than their quantifications and separations in industry although they can use the same physical techniques. Analytical methods For the bioanalysis of racemic drugs, two kinds of analytical methods have been developed: the physical methods and the enantioselective immunoassays.
Challener CA. In: Chiral drugs. Aldershot England : Ashgate Publisher; Overview of chirality; pp. Drayer DE. The early history of stereochemistry. In: Wainer IW, editor. Drug stereochemistry. Analytical methods and pharmacology. New York: Marcel Dekker Publisher; Rentsch KM. The importance of stereoselective determination of drugs in the clinical laboratory.
Journal of Biochemical and Biophysical Methods. Walther W, Netscher T. Design and development of chiral reagents for the chromatographic determination of chiral alcohols. Katzung BG. In: Basic and clinical pharmacology. The nature of drugs; pp.
Borman S. Asymmetric catalysis wins. Chemistry Nobel honors Knowles, Noyori, Sharpless for chiral syntheses.
0コメント