cyclodextrin

File:B-cyclodextrin.jpg]]

Cyclodextrins are ingredients in more than 30 different approved medicines.{{cite journal | doi = 10.1007/s10847-021-01055-9 | title = Macrocycles as drug-enhancing excipients in pharmaceutical formulations | year = 2021 | vauthors = Gu A, Wheate N | journal = Journal of Inclusion Phenomena and Macrocyclic Chemistry| volume = 100 | issue = 1–2 | pages = 55–69 | s2cid = 233139034 }} With a hydrophobic interior and hydrophilic exterior, cyclodextrins form complexes with hydrophobic compounds. Alpha-, beta-, and gamma-cyclodextrin are all generally recognized as safe by the U.S. FDA.{{cite web | url = http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASListings/ucm154385.htm | id = GRAS Notice No. GRN 000155 | title = Alpha-cyclodextrin | publisher = U.S Food and Drug Administration }}; {{cite web | url = http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASListings/ucm154182.htm | id = GRAS Notice No. GRN 000074 | title = Beta-cyclodextrin | publisher = U.S Food and Drug Administration }}; {{cite web | url = http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASListings/ucm153769.htm | id = GRAS Notice No. GRN 000046 | title = Gamma-cyclodextrin | publisher = U.S Food and Drug Administration }}{{cite journal | vauthors = Uekama K, Hirayama F, Irie T | title = Cyclodextrin Drug Carrier Systems | journal = Chemical Reviews | volume = 98 | issue = 5 | pages = 2045–2076 | date = July 1998 | pmid = 11848959 | doi = 10.1021/CR970025P }} They have been applied for delivery of a variety of drugs, including hydrocortisone, prostaglandin, nitroglycerin, itraconazole, chloramphenicol. The cyclodextrin confers solubility and stability to these drugs. The inclusion compounds of cyclodextrins with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions.{{cite journal | vauthors = Becket G, Schep LJ, Tan MY | title = Improvement of the in vitro dissolution of praziquantel by complexation with alpha-, beta- and gamma-cyclodextrins | journal = International Journal of Pharmaceutics | volume = 179 | issue = 1 | pages = 65–71 | date = March 1999 | pmid = 10053203 | doi = 10.1016/S0378-5173(98)00382-2 }} In most cases the mechanism of controlled degradation of such complexes is based on pH change of water solutions, leading to the loss of hydrogen or ionic bonds between the host and the guest molecules. Alternative means for the disruption of the complexes take advantage of heating or action of enzymes able to cleave α-1,4 linkages between glucose monomers. Cyclodextrins were also shown to enhance mucosal penetration of drugs.{{cite journal | vauthors = Morrison PW, Connon CJ, Khutoryanskiy VV | title = Cyclodextrin-mediated enhancement of riboflavin solubility and corneal permeability | journal = Molecular Pharmaceutics | volume = 10 | issue = 2 | pages = 756–762 | date = February 2013 | pmid = 23294178 | doi = 10.1021/mp3005963 | url = https://orca.cardiff.ac.uk/id/eprint/101359/ }}

β-cyclodextrins are used to produce stationary phase media for HPLC separations.{{cite journal | vauthors = Motoyama A, Suzuki A, Shirota O, Namba R | title = Direct determination of pindolol enantiomers in human serum by column-switching LC-MS/MS using a phenylcarbamate-beta-cyclodextrin chiral column | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 28 | issue = 1 | pages = 97–106 | date = April 2002 | pmid = 11861113 | doi = 10.1016/S0731-7085(01)00631-8 }}

Cyclodextrins bind fragrances. Such devices are capable of releasing fragrances when heated, such as by ironing, body heat, or a dryer. A common application is a typical 'dryer sheet'. They are also the main ingredient in Febreze, which claims that the β-cyclodextrins "trap" odor-causing compounds, thereby reducing the odor.

Cyclodextrins are also used to produce alcohol powder by encapsulating ethanol. The powder produces an alcoholic beverage when mixed with water, or can also be taken in a pill.{{Cite web |title=Powdered Alcohol: An Encapsulation | work = National Alcohol Beverage Control Association |url=https://www.nabca.org/powdered-alcohol-encapsulation |access-date=2024-01-22 }} The approval of powdered alcohol by the FDA in 2014 was met with wide-spread bans and backlash in the United States.{{Cite web |title=Powdered Alcohol |url=https://alcohol.org/guides/powdered-alcohol/ |access-date=2024-01-22 |website=Alcohol.org |language=en}}

Image:Gamma CD cone shape.jpg

Typical cyclodextrins are constituted by 6-8 glucopyranoside units. These subunits are linked by 1,4 glycosidic bonds. The cyclodextrins have toroidal shapes, with the larger and the smaller openings of the toroid exposing to the solvent secondary and primary hydroxyl groups respectively. Because of this arrangement, the interior of the toroids is considerably less hydrophilic than the aqueous environment and thus able to host hydrophobic molecules. In contrast, the exterior is sufficiently hydrophilic to impart cyclodextrins (or their complexes) water solubility. They are not soluble in typical organic solvents.

Cyclodextrins are prepared by enzymatic treatment of starch.{{cite journal | vauthors = Szejtli J | title = Introduction and General Overview of Cyclodextrin Chemistry | journal = Chemical Reviews | volume = 98 | issue = 5 | pages = 1743–1754 | date = July 1998 | pmid = 11848947 | doi = 10.1021/cr970022c }}{{cite journal | vauthors = Biwer A, Antranikian G, Heinzle E | title = Enzymatic production of cyclodextrins | journal = Applied Microbiology and Biotechnology | volume = 59 | issue = 6 | pages = 609–617 | date = September 2002 | pmid = 12226716 | doi = 10.1007/s00253-002-1057-x | s2cid = 12163906 }} Commonly cyclodextrin glycosyltransferase (CGTase) is employed along with α-amylase. First starch is liquified either by heat treatment or using α-amylase, then CGTase is added for the enzymatic conversion. CGTases produce mixtures of cyclodextrins, thus the product of the conversion results in a mixture of the three main types of cyclic molecules, in ratios that are strictly dependent on the enzyme used: each CGTase has its own characteristic α:β:γ synthesis ratio.{{Cite journal| vauthors = Farahat M |date=2020-03-28|title=Enhancement of β-cyclodextrin Production and Fabrication of Edible Antimicrobial Films Incorporated with Clove Essential Oil/β-cyclodextrin Inclusion Complex|journal=Microbiology and Biotechnology Letters|volume=48|issue=1|pages=12–23|doi=10.4014/mbl.1909.09016|s2cid=216203179|url=https://zenodo.org/record/4458882|doi-access=free}} Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is poorly water-soluble (18.5 g/L or 16.3 mM at 25 °C) can be easily retrieved through crystallization while the more soluble α- and γ-CDs (145 and 232 g/L respectively) are usually purified by means of expensive and time consuming chromatography techniques. As an alternative a "complexing agent" can be added during the enzymatic conversion step: such agents (usually organic solvents like toluene, acetone or ethanol) form a complex with the desired cyclodextrin which subsequently precipitates. The complex formation drives the conversion of starch towards the synthesis of the precipitated cyclodextrin, thus enriching its content in the final mixture of products. Wacker Chemie AG uses dedicated enzymes, that can produce alpha-, beta- or gamma-cyclodextrin specifically. This is very valuable especially for the food industry, as only alpha- and gamma-cyclodextrin can be consumed without a daily intake limit.

Image:Rotaxane Crystal Structure ChemComm page493 2001 commons.jpg with an α-cyclodextrin macrocycle.{{cite journal |doi=10.1039/b010015n |title=Synthesis of fluorescent stilbene and tolan rotaxanes by Suzuki coupling |year=2001 | vauthors = Stanier CA, O'Connell MJ, Clegg W, Anderson HL |journal=Chemical Communications |issue=5 |pages=493–494}}]]

Interest in cyclodextrins is enhanced because their host–guest behavior can be manipulated by chemical modification of the hydroxyl groups. O-Methylation and acetylation are typical conversions. Propylene oxide gives hydroxypropylated derivatives. The primary alcohols can be tosylated. The degree of derivatization is an adjustable, i.e. full methylation vs partial.{{cite journal|title=6A-O-p-Toluenesulfonyl-β-Cyclodextrin| vauthors = Brady B, Lynam N, O'Sullivan T, Ahern C, Darcy R |journal=Organic Syntheses |year=2000|volume=77|page=220|doi=10.15227/orgsyn.077.0220}}

Both β-cyclodextrin and methyl-β-cyclodextrin (MβCD) remove cholesterol from cultured cells. The methylated form MβCD was found to be more efficient than β-cyclodextrin. The water-soluble MβCD is known to form soluble inclusion complexes with cholesterol, thereby enhancing its solubility in aqueous solution. MβCD is employed for the preparation of cholesterol-free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes.{{cite journal | vauthors = Rodal SK, Skretting G, Garred O, Vilhardt F, van Deurs B, Sandvig K | title = Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles | journal = Molecular Biology of the Cell | volume = 10 | issue = 4 | pages = 961–974 | date = April 1999 | pmid = 10198050 | pmc = 25220 | doi = 10.1091/mbc.10.4.961 }}

Due to the covalent attachment of thiol groups to cyclodextrins high mucoadhesive properties can be introduced as these thiolated oligomers (thiomers) are capable of forming disulfide bonds with cysteine-rich subdomains of mucus glycoproteins. The gastrointestinal and ocular residence time of thiolated cyclodextrins is therefore substantially prolonged.{{cite journal | vauthors = Kali G, Haddadzadegan S, Laffleur F, Bernkop-Schnürch A | title = Per-thiolated cyclodextrins: Nanosized drug carriers providing a prolonged gastrointestinal residence time | journal = Carbohydrate Polymers | volume = 300 | pages = 120275 | date = January 2023 | pmid = 36372469 | doi = 10.1016/j.carbpol.2022.120275 | doi-access = free }}{{cite journal | vauthors = Grassiri B, Knoll P, Fabiano A, Piras AM, Zambito Y, Bernkop-Schnürch A | title = Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery | journal = International Journal of Molecular Sciences | volume = 23 | issue = 5 | pages = 2612 | date = February 2022 | pmid = 35269753 | pmc = 8910138 | doi = 10.3390/ijms23052612 | doi-access = free }} Furthermore, thiolated cyclodextrins are actively taken up by target cells releasing their payload into the cytoplasma. The cellular uptake of various model drugs, for instance, was up to 20-fold improved by using thiolated α-cyclodextrin as carrier system.{{cite journal | vauthors = Kaplan Ö, Truszkowska M, Kali G, Knoll P, Blanco Massani M, Braun DE, Bernkop-Schnürch A | title = Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape | journal = Carbohydrate Polymers | volume = 316 | pages = 121070 | date = September 2023 | pmid = 37321712 | doi = 10.1016/j.carbpol.2023.121070 | doi-access = free }}

File:Synthesis of US active cyclodextrin nanoparticles.gifIn supramolecular chemistry, cyclodextrins are precursors to mechanically interlocked molecular architectures, such as rotaxanes and catenanes. Illustrative, α-cyclodextrin form second-sphere coordination complex with tetrabromoaurate anion ([AuBr4]-).{{cite journal | vauthors = Liu Z, Frasconi M, Lei J, Brown ZJ, Zhu Z, Cao D, Iehl J, Liu G, Fahrenbach AC, Botros YY, Farha OK, Hupp JT, Mirkin CA, Fraser Stoddart J | title = Selective isolation of gold facilitated by second-sphere coordination with α-cyclodextrin | journal = Nature Communications | volume = 4 | pages = 1855 | year = 2013 | pmid = 23673640 | pmc = 3674257 | doi = 10.1038/ncomms2891 | bibcode = 2013NatCo...4.1855L }}

β-Cyclodextrin complexes with certain carotenoid food colorants have been shown to intensify color, increase water solubility and improve light stability.{{cite journal | vauthors = Marcolino VA, Zanin GM, Durrant LR, Benassi M, Matioli G | title = Interaction of curcumin and bixin with β-cyclodextrin: complexation methods, stability, and applications in food | journal = Journal of Agricultural and Food Chemistry | volume = 59 | issue = 7 | pages = 3348–3357 | date = April 2011 | pmid = 21381747 | doi = 10.1021/jf104223k }}{{cite journal | vauthors = de Oliveira VE, Almeida EW, Castro HV, Edwards HG, Dos Santos HF, de Oliveira LF | title = Carotenoids and β-cyclodextrin inclusion complexes: Raman spectroscopy and theoretical investigation | journal = The Journal of Physical Chemistry A | volume = 115 | issue = 30 | pages = 8511–8519 | date = August 2011 | pmid = 21728366 | doi = 10.1021/jp2028142 | bibcode = 2011JPCA..115.8511D }}

Complexes formed between β-cyclodextrin and adamantane derivatives have been used to make self-healing materials, such as hydrogels{{cite journal | vauthors = Harada A, Takashima Y, Nakahata M | title = Supramolecular polymeric materials via cyclodextrin-guest interactions | journal = Accounts of Chemical Research | volume = 47 | issue = 7 | pages = 2128–2140 | date = July 2014 | pmid = 24911321 | doi = 10.1021/ar500109h }} and low-friction surfaces.{{Cite journal| vauthors = Wang Y, Sun Y, Avestro AJ, McGonigal PR, Zhang H |date=November 2021|title=Supramolecular repair of hydration lubrication surfaces|journal=Chem|volume=8 |issue=2 |pages=480–493|doi=10.1016/j.chempr.2021.11.001|doi-access=free}}

Using the host-guest interaction between β-Cyclodextrin and Perfluorohexane, acoustically active nanoparticles were created.{{cite journal | vauthors = Khirallah J, Schmieley R, Demirel E, Rehman TU, Howell J, Durmaz YY, Vlaisavljevich E | title = Nanoparticle-mediated histotripsy (NMH) using perfluorohexane 'nanocones' | journal = Physics in Medicine and Biology | volume = 64 | issue = 12 | pages = 125018 | date = June 2019 | pmid = 31071701 | doi = 10.1088/1361-6560/ab207e | bibcode = 2019PMB....64l5018K }} These nanoparticles were combined with histotripsy, leading to the development of Nanoparticle-Mediated Histotripsy (NMH). NMH addresses limitations of traditional histotripsy, such as non-selectivity and the requirement for high pressure.{{cite journal | vauthors = Rehman TU, Khirallah J, Demirel E, Howell J, Vlaisavljevich E, Yuksel Durmaz Y | title = Development of Acoustically Active Nanocones Using the Host-Guest Interaction as a New Histotripsy Agent | journal = ACS Omega | volume = 4 | issue = 2 | pages = 4176–4184 | date = February 2019 | pmid = 31459627 | pmc = 6649115 | doi = 10.1021/acsomega.8b02922 }} This promising new method has potential applications in cell ablation for various purposes, including cancer treatment.{{cite journal | vauthors = Toydemir C, Hall S, Demirel E, Elmaci DN, Gol D, Vlaisavljevich E, Yuksel Durmaz Y | title = Bioconjugated β-Cyclodextrin-Perfluorohexane Nanocone Clusters as Functional Nanoparticles for Nanoparticle-Mediated Histotripsy | journal = Biomacromolecules | volume = 23 | issue = 12 | pages = 5297–5311 | date = December 2022 | pmid = 36418020 | doi = 10.1021/acs.biomac.2c01110 }}

Image:beta-cyclodextrin3D.png

Cyclodextrins were called "cellulosine" when first described by A. Villiers in 1891.{{cite journal | vauthors = Villiers A | title = Sur la transformation de la fécule en dextrine par le ferment butyrique | journal = Compt. Rend. Acad. Sci. | volume = 1891 | pages = 536–8 }} Soon after, F. Schardinger identified the three naturally occurring cyclodextrins: α, β, and γ, referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Hans Pringsheim in Germany was the leading researcher in this area,{{cite journal | vauthors = Crini G | title=Twenty years of dextrin research: a tribute to Professor Hans Pringsheim (1876–1940) | journal=Journal of Inclusion Phenomena and Macrocyclic Chemistry | publisher=Springer Science and Business Media LLC | volume=98 | issue=1–2 | date=26 July 2020 | doi=10.1007/s10847-020-01013-x| pages=11–27| s2cid=220774604 }} demonstrating that cyclodextrins formed stable aqueous complexes with many other chemicals. By the mid-1970s, each of the natural cyclodextrins had been structurally and chemically characterized and many more complexes had been studied. Since the 1970s, extensive work has been conducted by Szejtli and others exploring encapsulation by cyclodextrins and their derivatives for industrial and pharmacologic applications.{{cite book | vauthors = Szejtli J |title=Cyclodextrin Technology | volume = 1 |date=1988 |publisher=Kluwer Academic Publishers |location=Dordrecht; Boston |isbn=978-90-277-2314-7}} {{page needed|date=April 2013}} Among the processes used for complexation, the kneading process seems to be one of the best.{{cite journal | vauthors = Gil A, Chamayou A, Leverd E, Bougaret J, Baron M, Couarraze G | title = Evolution of the interaction of a new chemical entity, eflucimibe, with gamma-cyclodextrin during kneading process | journal = European Journal of Pharmaceutical Sciences | volume = 23 | issue = 2 | pages = 123–129 | date = October 2004 | pmid = 15451000 | doi = 10.1016/j.ejps.2004.06.002 | s2cid = 31860374 | url = https://hal.archives-ouvertes.fr/hal-01632796/file/Evolution_of_the_interaction_of_a_new_chemical_entity.pdf }}

Cyclodextrins are of wide interest in part because they appear nontoxic in animal studies. The LD50 (oral, rats) is on the order of grams per kilogram. Nevertheless, attempts to use β-cyclodextrin for the prevention of atherosclerosis,{{cite journal | vauthors = Zimmer S, Grebe A, Bakke SS, Bode N, Halvorsen B, Ulas T, Skjelland M, De Nardo D, Labzin LI, Kerksiek A, Hempel C, Heneka MT, Hawxhurst V, Fitzgerald ML, Trebicka J, Björkhem I, Gustafsson JÅ, Westerterp M, Tall AR, Wright SD, Espevik T, Schultze JL, Nickenig G, Lütjohann D, Latz E | title = Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming | journal = Science Translational Medicine | volume = 8 | issue = 333 | pages = 333ra50 | date = April 2016 | pmid = 27053774 | pmc = 4878149 | doi = 10.1126/scitranslmed.aad6100 }} age-related lipofuscin accumulation{{cite journal | vauthors = Gaspar J, Mathieu J, Alvarez P | title = 2-Hydroxypropyl-beta-cyclodextrin (HPβCD) reduces age-related lipofuscin accumulation through a cholesterol-associated pathway | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 2197 | date = May 2017 | pmid = 28526856 | pmc = 5438378 | doi = 10.1038/s41598-017-02387-8 | bibcode = 2017NatSR...7.2197G }} and obesity encounter an obstacle in the form of damage to the auditory nerve{{cite journal | vauthors = Crumling MA, Liu L, Thomas PV, Benson J, Kanicki A, Kabara L, Hälsey K, Dolan D, Duncan RK | title = Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e53280 | date = 2012 | pmid = 23285273 | pmc = 3532434 | doi = 10.1371/journal.pone.0053280 | doi-access = free | bibcode = 2012PLoSO...753280C }} and nephrotoxic effect.{{cite journal | vauthors = Scantlebery AM, Ochodnicky P, Kors L, Rampanelli E, Butter LM, El Boumashouli C, Claessen N, Teske GJ, van den Bergh Weerman MA, Leemans JC, Roelofs JJ, Florquin S | title = β-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 17633 | date = November 2019 | pmid = 31776357 | pmc = 6881402 | doi = 10.1038/s41598-019-53890-z | bibcode = 2019NatSR...917633S }}

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Category:Oligosaccharides

Category:Starch

Category:Macrocycles

Category:Chelating agents

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