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Cyclodextrin

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Chemical structure of the three main types of cyclodextrins.

Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. They are used in food, pharmaceutical, drug delivery, and chemical industries, as well as agriculture and environmental engineering.[1]

Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape:

The largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units. Poorly-characterized mixtures, containing at least 150-membered cyclic oligosaccharides are also known.

Applications

β-Cyclodextrin

Drug delivery

Cyclodextrins are ingredients in more than 30 different approved medicines.[2] 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.[3][4] 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.[1] 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.[5] 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.[6]

Chromatography

β-cyclodextrins are used to produce stationary phase media for HPLC separations.[7]

Other

Cyclodextrins bind fragrances. Such devices are capable of releasing fragrances during ironing or when heated by human body. Such a device commonly used is a typical 'dryer sheet'. The heat from a clothes dryer releases the fragrance into the clothing. They are the main ingredient in Febreze which claims that the β-cyclodextrins "trap" odor-causing compounds, thereby reducing the odor.[1]

Cyclodextrins are also used to produce alcohol powder by encapsulating ethanol. The powder produces an alcoholic beverage when mixed with water.

Mouse studies indicated that subcutaneous administration of oligosaccharide 2-hydroxypropyl-β-cyclodextrin (2HPβCD) can solubilize cholesterol, removing it from the atheromatous plaque that causes atherosclerosis.[8] However, later work concluded that "treatment with 2HPβCD is ineffective in inducing atherosclerosis regression".[9]

Structure

γ-CD toroid structure showing spatial arrangement.

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 not hydrophobic, but considerably less hydrophilic than the aqueous environment and thus able to host other 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.

Synthesis

Cyclodextrins are prepared by enzymatic treatment of starch.[10][11] 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.[12] 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 mg/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.

Crystal structure of a rotaxane with an α-cyclodextrin macrocycle.[13]

Derivatives

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.[1] The primary alcohols can be tosylated. The degree of derivatization is an adjustable, i.e. full methylation vs partial.[14]

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.[15]

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.[16][17] 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.[18]

Research

In 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]-).[19]

β-Cyclodextrin complexes with certain carotenoid food colorants have been shown to intensify color, increase water solubility and improve light stability.[20][21]

Complexes formed between β-cyclodextrin and adamantane derivatives have been used to make self-healing materials, such as hydrogels[22] and low-friction surfaces.[23]

History

Space filling model of β-cyclodextrin.

Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891.[24] Soon after, F. Schardinger identified the three naturally occurring cyclodextrins: α, β, and γ. These compounds were therefore referred to as "Schardinger sugars". For 25 years, between 1911 and 1935, Hans Pringsheim in Germany was the leading researcher in this area,[25] 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.[26] Among the processes used for complexation, the kneading process seems to be one of the best.[27]

Safety

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.[1] Nevertheless, attempts to use β-Cyclodextrin for the prevention of atherosclerosis,[28] age-related lipofuscin accumulation[29] and obesity encounter an obstacle in the form of damage to the auditory nerve[30] and nephrotoxic effect.[31]

References

  1. ^ a b c d e Wimmer, Thomas (2012). "Cyclodextrins". Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH. doi:10.1002/14356007.e08_e02. ISBN 978-3527306732.
  2. ^ Gu, Alice; Wheate, Nial (2021). "Macrocycles as drug-enhancing excipients in pharmaceutical formulations". Journal of Inclusion Phenomena and Macrocyclic Chemistry. 100 (1–2): 55–69. doi:10.1007/s10847-021-01055-9. S2CID 233139034.
  3. ^ GRAS Notice No. GRN 000155, alpha-cyclodextrin;GRAS Notice No. GRN 000074, beta-cyclodextrin;GRAS Notice No. GRN 000046, gamma-cyclodextrin
  4. ^ Uekama, Kaneto; Hirayama, Fumitoshi; Irie, Tetsumi (1998). "Cyclodextrin Drug Carrier Systems". Chemical Reviews. 98 (5): 2045–2076. doi:10.1021/CR970025P. PMID 11848959.
  5. ^ Becket, Gordon; Schep, Leo J.; Tan, Mun Yee (1999). "Improvement of the in vitro dissolution of praziquantel by complexation with α-, β- and γ-cyclodextrins". International Journal of Pharmaceutics. 179 (1): 65–71. doi:10.1016/S0378-5173(98)00382-2. PMID 10053203.
  6. ^ Morrison, Peter W. J.; Connon, Che J.; Khutoryanskiy, Vitaliy V. (2013-01-18). "Cyclodextrin-Mediated Enhancement of Riboflavin Solubility and Corneal Permeability" (PDF). Molecular Pharmaceutics. 10 (2): 756–762. doi:10.1021/mp3005963. PMID 23294178.
  7. ^ Motoyama, Akira; Suzuki, Ayako; Shirota, Osamu; Namba, Ryujiro (2002). "Direct determination of pindolol enantiomers in human serum by column-switching LC-MS/MS using a phenylcarbamate-β-cyclodextrin chiral column". Journal of Pharmaceutical and Biomedical Analysis. 28 (1): 97–106. doi:10.1016/S0731-7085(01)00631-8. PMID 11861113.
  8. ^ Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S.; Bode, Niklas; Halvorsen, Bente; Ulas, Thomas; Skjelland, Mona; De Nardo, Dominic; Labzin, Larisa I.; Kerksiek, Anja; Hempel, Chris; Heneka, Michael T.; Hawxhurst, Victoria; Fitzgerald, Michael L.; Trebicka, Jonel; Björkhem, Ingemar; Gustafsson, Jan-Åke; Westerterp, Marit; Tall, Alan R.; Wright, Samuel D.; Espevik, Terje; Schultze, Joachim L.; Nickenig, Georg; Lütjohann, Dieter; Latz, Eicke (6 April 2016). "Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming". Science Translational Medicine. 8 (333): 333ra50. doi:10.1126/scitranslmed.aad6100. PMC 4878149. PMID 27053774.
  9. ^ Snip, Olga S.C.; Hoekstra, Menno; Zhang, Yiheng; Geerling, Janine J.; Van Eck, Miranda (2022). "2-Hydroxypropyl-beta-cyclodextrin Treatment Does Not Induce Atherosclerotic Lesion Regression in Western-Type Diet-Fed Apolipoprotein E Knockout Mice". Biomolecules. 12 (9). MDPI AG: 1205. doi:10.3390/biom12091205. PMC 9496214. PMID 36139044.
  10. ^ Szejtli, József (1998). "Introduction and General Overview of Cyclodextrin Chemistry". Chem. Rev. 98 (5): 1743–1754. doi:10.1021/cr970022c. PMID 11848947.
  11. ^ Biwer, A.; Antranikian, G.; Heinzle, E. (2002). "Enzymatic production of cyclodextrins". Applied Microbiology and Biotechnology. 59 (6): 609–17. doi:10.1007/s00253-002-1057-x. PMID 12226716. S2CID 12163906.
  12. ^ Farahat, Mohamed (2020-03-28). "Enhancement of β-cyclodextrin Production and Fabrication of Edible Antimicrobial Films Incorporated with Clove Essential Oil/β-cyclodextrin Inclusion Complex". Microbiology and Biotechnology Letters. 48 (1): 12–23. doi:10.4014/mbl.1909.09016. S2CID 216203179.
  13. ^ Stanier, Carol A.; O'Connell, Michael J.; Anderson, Harry L.; Clegg, William (2001). "Synthesis of fluorescent stilbene and tolan rotaxanes by Suzuki coupling". Chemical Communications (5): 493–494. doi:10.1039/b010015n.
  14. ^ Brady, Bernadette; Lynam, Nuala; O'Sullivan, Thomas; Ahern, Cormac; Darcy, Raphael (2000). "6A-O-p-Toluenesulfonyl-β-Cyclodextrin". Org. Synth. 77: 220. doi:10.15227/orgsyn.077.0220.
  15. ^ Rodal, Siv Kjersti; Skretting, Grethe; Garred, Øystein; Vilhardt, Frederik; van Deurs, Bo; Sandvig, Kirsten (1999). "Extraction of Cholesterol with Methyl-β-Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles". Molecular Biology of the Cell. 10 (4): 961–74. doi:10.1091/mbc.10.4.961. PMC 25220. PMID 10198050.
  16. ^ Kali, G; Haddadzadegan, S; Laffleur, F; Bernkop-Schnürch, A (2023). "Per-thiolated cyclodextrins: Nanosized drug carriers providing a prolonged gastrointestinal residence time". Carbohydrate Polymers. 300: 120275. doi:10.1016/j.carbpol.2022.120275. PMID 36372469.
  17. ^ Grassiri, B; Knoll, P; Fabiano, A; Piras, AM; Zambito, Y; Bernkop-Schnürch, A (2022). "Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery". International Journal of Molecular Sciences. 23 (5): 2612. doi:10.3390/ijms23052612. PMC 8910138. PMID 35269753.
  18. ^ Kaplan, Ö; Truszkowska, M; Kali, G; Knoll, P; Blanco Massani, M; Braun, DE; Bernkop-Schnürch, A (2023). "Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape". Carbohydrate Polymers. 316: 121070. doi:10.1016/j.carbpol.2023.121070. PMID 37321712.
  19. ^ Liu, Zhichang; Frasconi, Marco; Lei, Juying; Brown, Zachary J.; Zhu, Zhixue; Cao, Dennis; Iehl, Julien; Liu, Guoliang; Fahrenbach, Albert C.; Botros, Youssry Y.; Farha, Omar K.; Hupp, Joseph T.; Mirkin, Chad A.; Stoddart, J. Fraser (2013). "Selective isolation of gold facilitated by second-sphere coordination with α-cyclodextrin". Nature Communications. 4: 1855. Bibcode:2013NatCo...4.1855L. doi:10.1038/ncomms2891. PMC 3674257. PMID 23673640.
  20. ^ Marcolino, Vanessa Aparecida; Zanin, Gisella Maria; Durrant, Lucia Regina; Benassi, Marta De Toledo; Matioli, Graciette (2011). "Interaction of Curcumin and Bixin with β-Cyclodextrin: Complexation Methods, Stability, and Applications in Food". Journal of Agricultural and Food Chemistry. 59 (7): 3348–57. doi:10.1021/jf104223k. PMID 21381747.
  21. ^ De Oliveira, Vanessa E.; Almeida, Eduardo W. C.; Castro, Harlem V.; Edwards, Howell G. M.; Dos Santos, Hélio F.; De Oliveira, Luiz Fernando C. (2011). "Carotenoids and β-Cyclodextrin Inclusion Complexes: Raman Spectroscopy and Theoretical Investigation". The Journal of Physical Chemistry A. 115 (30): 8511–9. Bibcode:2011JPCA..115.8511D. doi:10.1021/jp2028142. PMID 21728366.
  22. ^ Harada, Akira; Takashima, Yoshinori; Nakahata, Masaki (2014-07-15). "Supramolecular Polymeric Materials via Cyclodextrin–Guest Interactions". Accounts of Chemical Research. 47 (7): 2128–2140. doi:10.1021/ar500109h. PMID 24911321.
  23. ^ Wang, Yixin; Sun, Yulong; Avestro, Alyssa-Jennifer; McGonigal, Paul R.; Zhang, Hongyu (November 2021). "Supramolecular repair of hydration lubrication surfaces". Chem. 8 (2): 480–493. doi:10.1016/j.chempr.2021.11.001.
  24. ^ Villiers, A. "Sur la transformation de la fécule en dextrine par le ferment butyrique". Compt. Rend. Acad. Sci. 1891: 536–8.
  25. ^ Crini, Grégorio (26 July 2020). "Twenty years of dextrin research: a tribute to Professor Hans Pringsheim (1876–1940)". Journal of Inclusion Phenomena and Macrocyclic Chemistry. 98 (1–2). Springer Science and Business Media LLC: 11–27. doi:10.1007/s10847-020-01013-x. S2CID 220774604.
  26. ^ Szejtli J. (1988). "Cyclodextrin Technology" vol 1. Springer, New York" ISBN 978-90-277-2314-7[page needed]
  27. ^ Gil, A.; Chamayou, A.; Leverd, E.; Bougaret, J.; Baron, M.; Couarraze, G. (2004). "Evolution of the interaction of a new chemical entity, eflucimibe, with γ-cyclodextrin during kneading process" (PDF). European Journal of Pharmaceutical Sciences. 23 (2): 123–9. doi:10.1016/j.ejps.2004.06.002. PMID 15451000. S2CID 31860374.
  28. ^ Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S.; Bode, Niklas; Halvorsen, Bente; Ulas, Thomas; Skjelland, Mona; De Nardo, Dominic; Labzin, Larisa I.; Kerksiek, Anja; Hempel, Chris; Heneka, Michael T.; Hawxhurst, Victoria; Fitzgerald, Michael L.; Trebicka, Jonel; Björkhem, Ingemar; Gustafsson, Jan-Åke; Westerterp, Marit; Tall, Alan R.; Wright, Samuel D.; Espevik, Terje; Schultze, Joachim L.; Nickenig, Georg; Lütjohann, Dieter; Latz, Eicke (2016). "Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming". Science Translational Medicine. 8 (333): 333ra50. doi:10.1126/scitranslmed.aad6100. PMC 4878149. PMID 27053774.
  29. ^ Gaspar, J., Mathieu, J., & Alvarez, P. (2017). 2-Hydroxypropyl-beta-cyclodextrin (HPβCD) reduces age-related lipofuscin accumulation through a cholesterol-associated pathway. Scientific reports, 7(1), 2197. PMC 5438378
  30. ^ Crumling MA, Liu L, Thomas PV, Benson J, Kanicki A, Kabara L, et al. (2012) Hearing Loss and Hair Cell Death in Mice Given the Cholesterol-Chelating Agent Hydroxypropyl-β-Cyclodextrin. PLoS ONE 7(12): e53280. doi:10.1371/journal.pone.0053280
  31. ^ Scantlebery, Angelique M. L.; Ochodnicky, Peter; Kors, Lotte; Rampanelli, Elena; Butter, Loes M.; El Boumashouli, Chaima; Claessen, Nike; Teske, Gwen J.; Van Den Bergh Weerman, Marius A.; Leemans, Jaklien C.; Roelofs, Joris J. T. H.; Florquin, Sandrine (2019). "β-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect". Scientific Reports. 9 (1): 17633. doi:10.1038/s41598-019-53890-z. PMC 6881402. PMID 31776357.
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