Chiral inversion

Essentially there are two types of chiral inversion, unidirectional and bidirectional.{{cite journal | vauthors = Nguyen LA, He H, Pham-Huy C | title = Chiral drugs: an overview | journal = International Journal of Biomedical Science | volume = 2 | issue = 2 | pages = 85–100 | date = June 2006 | doi = 10.59566/IJBS.2006.2085 | pmid = 23674971 | pmc = 3614593 }} 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.{{cite journal | vauthors = Caldwell J, Hutt AJ, Fournel-Gigleux S | title = The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences | journal = Biochemical Pharmacology | volume = 37 | issue = 1 | pages = 105–114 | date = January 1988 | pmid = 3276314 | doi = 10.1016/0006-2952(88)90762-9 }} 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.{{cite journal | vauthors = Day RO, Graham GG, Williams KM, Champion GD, de Jager J | title = Clinical pharmacology of non-steroidal anti-inflammatory drugs | journal = Pharmacology & Therapeutics | volume = 33 | issue = 2–3 | pages = 383–433 | date = 1987 | pmid = 3310039 | doi = 10.1016/0163-7258(87)90072-6 }} In certain situations, carbenicillin, ethiazide, etoposide, zopiclone, pantoprazole, clopidogrel, ketorolac, albendazole-sulfoxide, lifibrol, and 5-aryl-thiazolidinedione also go through unidirectional chiral inversion.{{cite journal | vauthors = Wsól V, Skálová L, Szotáková B | title = Chiral inversion of drugs: coincidence or principle? | journal = Current Drug Metabolism | volume = 5 | issue = 6 | pages = 517–533 | date = December 2004 | pmid = 15578945 | doi = 10.2174/1389200043335360 }}   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.{{cite journal | vauthors = Wang YX, Gong N, Xin YF, Hao B, Zhou XJ, Pang CC | title = Biological implications of oxidation and unidirectional chiral inversion of D-amino acids | journal = Current Drug Metabolism | volume = 13 | issue = 3 | pages = 321–331 | date = March 2012 | pmid = 22304623 | doi = 10.2174/138920012799320392 }}{{cite journal | vauthors = Lehmann WD, Theobald N, Fischer R, Heinrich HC | title = Stereospecificity of phenylalanine plasma kinetics and hydroxylation in man following oral application of a stable isotope-labelled pseudo-racemic mixture of L- and D-phenylalanine | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 128 | issue = 2–3 | pages = 181–198 | date = March 1983 | pmid = 6851137 | doi = 10.1016/0009-8981(83)90319-4 }}

;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. A brief list of select pharmaceutical drugs that go through chiral inversion are presented in Table below..

File:Metabolic chiral inversion.png

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.{{Cite book |vauthors = Smith HJ, Williams H |url=https://www.worldcat.org/oclc/1100515958 |title=Smith and Williams' Introduction to the Principles of Drug Design and Action |publisher=CRC Press |year=1998 |isbn=978-1-315-27379-2 |edition=3rd |location=Boca Raton, FL |pages=117–183 |oclc=1100515958}}

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.

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) chiral inversion of organic compounds is caused by highly chiral endogenous molecules found in receptors, enzymes, and other structures. 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.{{cite journal | vauthors = Reichel C, Brugger R, Bang H, Geisslinger G, Brune K | title = Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen | journal = Mol Pharmacol | volume = 51 | issue = 4 | pages = 576–82 | date = April 1997 | pmid = 9106621 | doi = 10.1124/mol.51.4.576 }} 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.

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.{{Cite journal |last1=Berry |first1=B. W. |last2=Jamali |first2=F. |date=1991 |title=Presystemic and systemic chiral inversion of R-(-)-fenoprofen in the rat |url=https://pubmed.ncbi.nlm.nih.gov/1865366 |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=258 |issue=2 |pages=695–701 |doi=10.1016/S0022-3565(25)20451-7 |issn=0022-3565 |pmid=1865366}} 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. 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.

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.{{cite journal | vauthors = Wolf C | title = Stereolabile chiral compounds: analysis by dynamic chromatography and stopped-flow methods | journal = Chemical Society Reviews | volume = 34 | issue = 7 | pages = 595–608 | date = July 2005 | pmid = 15965541 | doi = 10.1039/b502508g }} 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.{{cite journal | vauthors = Krupcik J, Oswald P, Májek P, Sandra P, Armstrong W | title = Determination of the interconversion energy barrier of enantiomers by separation methods | journal = Journal of Chromatography A | volume = 1000 | issue = 1–2 | pages = 779–800 | date = June 2003 | pmid = 12877200 | doi = 10.1016/S0021-9673(03)00238-3 }} 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.

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).

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.{{cite journal | vauthors = Sanganyado E, Lu Z, Fu Q, Schlenk D, Gan J | title = Chiral pharmaceuticals: A review on their environmental occurrence and fate processes | journal = Water Research | volume = 124 | pages = 527–542 | date = November 2017 | pmid = 28806704 | doi = 10.1016/j.watres.2017.08.003 | bibcode = 2017WatRe.124..527S | url = https://www.dora.lib4ri.ch/eawag/islandora/object/eawag%3A15611 }} 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.{{Cite journal | vauthors = Chen L, Dean B, La H, Chen Y, Liang X |date=2019 |title=Stereoselective supercritical fluidic chromatography –mass spectrometry (SFC-MS) as a fast bioanalytical tool to assess chiral inversion in vivo and in vitro |journal=International Journal of Mass Spectrometry |language=en |volume=444 |pages=116172 |doi=10.1016/j.ijms.2019.06.008|bibcode=2019IJMSp.44416172C |s2cid=199078783 }}

File:Easson-Stedman Model.png

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){{cite journal | vauthors = Easson LH, Stedman E | title = Studies on the relationship between chemical constitution and physiological action: Molecular dissymmetry and physiological activity | journal = The Biochemical Journal | volume = 27 | issue = 4 | pages = 1257–1266 | date = 1933-01-01 | pmid = 16745220 | pmc = 1253018 | doi = 10.1042/bj0271257 }} 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.{{cite journal | vauthors = Ariëns EJ | title = Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology | journal = European Journal of Clinical Pharmacology | volume = 26 | issue = 6 | pages = 663–668 | date = 1984 | pmid = 6092093 | doi = 10.1007/BF00541922 | s2cid = 30916093 }}{{cite journal | vauthors = Ariëns EJ, Wuis EW, Veringa EJ | title = Stereoselectivity of bioactive xenobiotics. A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology | journal = Biochemical Pharmacology | volume = 37 | issue = 1 | pages = 9–18 | date = January 1988 | pmid = 3276322 | doi = 10.1016/0006-2952(88)90749-6 }} 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{{cite journal | vauthors = Ali I, Gupta VK, Aboul-Enein HY, Singh P, Sharma B | title = Role of racemization in optically active drugs development | journal = Chirality | volume = 19 | issue = 6 | pages = 453–463 | date = June 2007 | pmid = 17393472 | doi = 10.1002/chir.20397 }} 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.

• Ibuprofen
• Dexibuprofen
• Ketoprofen
• Thalidomide
• Fenoprofen
• Chiral drugs
• Chiral switch

{{Reflist}}

• {{Commons category-inline|Chiral inversion}}

Category:Chirality

Category:Enantiopure drugs

Category:Stereochemistry