Cyclodextrin

Cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides).

Cyclodextrins are produced from starch by means of enzymatic conversion. They are used in food, pharmaceutical,^[1] and chemical industries, as well as agriculture and environmental engineering. Hydroxypropyl Beta Cyclodextrin (HPßCD) is the chief active compound found in Procter and Gamble's deodorizing product "Febreze" under the brand name "Clenzaire".

Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The 5-membered macrocycle is not natural. Recently, the largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, even at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. thus denoting:

• α -cyclodextrin: six membered sugar ring molecule
• β -cyclodextrin: seven sugar ring molecule
• γ -cyclodextrin: eight sugar ring molecule

Chemical structure of the three main types of cyclodextrins.

History of cyclodextrins

Space filling model of β-cyclodextrin.

Cyclodextrins, as they are known today, were called "cellulosine" when first described by A. Villiers in 1891.^[2] 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, Pringsheim in Germany was the leading researcher in this area, 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.^[3] Among the processes used for complexation, the kneading process seems to be one of the best.^[4]

In 2009, research from the lab of Drs. Michael S. Brown and Joseph L. Goldstein, Nobel Prize winning scientists who pioneered the study of cholesterol metabolism, was published showing how cyclodextrin assists in moving cholesterol out of lysosomes in Niemann-Pick Type C disease. Niemann Pick Type C disease is a lysosomal storage disease causing progressive deterioration of the nervous system and dementia. It usually affects young children by interfering with their ability to metabolize cholesterol at the cellular level. Numerous research studies have followed showing that Hydroxypropyl Beta Cyclodextrin (HPßCD) is not simply an agent to solubilize drugs but has powerful pharmacological properties. In April 2009, Investigational New Drug (IND) applications were approved by the U.S. Food and Drug Administration (FDA) in a one time clinical trial to treat identical twin girls suffering from Niemann-Pick Type C disease with intravenous infusions of Hydroxypropyl Beta Cyclodextrin (HPßCD).[14] On May 17, 2010, the FDA approved an orphan drug application for Hydroxypropyl Beta Cyclodextrin (Trappsol brand). On July 14, 2010, Children's Hospital & Research Center Oakland filed a second IND application with the FDA to deliver Hydroxypropyl Beta Cyclodextrin directly into the central nervous system of the twins to bypass the blood brain barrier. On September 23, 2010, the hospital announced that the FDA granted clearance of the intrathecal application and will begin the world’s first HPßCD administration into the brain.

Structure

γ-CD toroid structure showing spatial arrangement.

Typical cyclodextrins are constituted by 6-8 glucopyranoside units, can be topologically represented as toroids 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.

The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. This is the reason why cyclodextrins have attracted much interest in many fields, especially pharmaceutical applications: because 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 cleavage 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.

Synthesis

The production of cyclodextrins is relatively simple and involves treatment of ordinary starch with a set of easily available enzymes.^[6] 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 can synthesize all forms 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. Purification of the three types of cyclodextrins takes advantage of the different water solubility of the molecules: β-CD which is very poorly water soluble (18.5 g/l or 16.3mM) (at 25C???) 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.

Uses

Crystal structure of a rotaxane with an α-cyclodextrin macrocycle.^[7]

Cyclodextrins are able to form host-guest complexes with hydrophobic molecules given the unique nature imparted by their structure. As a result, these molecules have found a number of applications in a wide range of fields. Other than the above mentioned pharmaceutical applications for drug release, cyclodextrins can be employed in environmental protection: these molecules can effectively immobilise inside their rings toxic compounds, like trichloroethane or heavy metals, or can form complexes with stable substances, like trichlorfon (an organophosphorus insecticide) or sewage sludge, enhancing their decomposition.

In the food industry cyclodextrins are employed for the preparation of cholesterol free products: the bulky and hydrophobic cholesterol molecule is easily lodged inside cyclodextrin rings that are then removed. Alpha-, beta-, and gamma-cyclodextrin are all generally recognized as safe by the FDA.^[8][9][10]

Weight loss supplements are marketed from alpha-cyclodextrin which claim to bind to fat and be an alternative to other anti-obesity medications.^[11][12]

Other food applications further include the ability to stabilize volatile or unstable compounds and the reduction of unwanted tastes and odour. Alpha-cyclodextrin is used as emulsifier in food and cosmetic applications. Reportedly cyclodextrins are used in alcohol powder, a powder for mixing alcoholic drinks.

The strong ability of complexing fragrances can also be used for another purpose: first dry, solid cyclodextrin microparticles are exposed to a controlled contact with fumes of active compounds, then they are added to fabric or paper products. 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.

The ability of cyclodextrins to form complexes with hydrophobic molecules^[13] has led to their usage in supramolecular chemistry. In particular they have been used to synthesize certain mechanically-interlocked molecular architectures, such as rotaxanes and catenanes, by reacting the ends of the threaded guest.

The application of cyclodextrin as supramolecular carrier is also possible in organometallic reactions. The mechanism of action probably takes place in the interfacial region.^[14] Wipff also demonstrated by computational study that the reaction occurs in the interfacial layer. The application of cyclodextrins as supramolecular carrier is possible in various organometallic catalysis.

β-cyclodextrins are used to produce HPLC columns allowing chiral enantiomers separation.^[15]

Derivatives

Methyl-beta-cyclodextrin

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 that are then removed. MβCD is also employed in research to disrupt lipid rafts by removing cholesterol from membranes.^[16]

References

1. ^ Menuel, S.; Joly, J.-P.; Courcot, B.; Elysée, J.; Ghermani, N.-E.; Marsua, A. "Synthesis and inclusion ability of a bis-β-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent" Tetrahedron, 67, 7, 1706-1714 doi:10.1016/j.tet.2006.10.070
2. ^ Villiers A., Sur la transformation de la fécule en dextrine par le ferment butyrique, Compt. Rend. Fr. Acad. Sci. 1891:435-8
3. ^ Szejtli J. (1988). "Cyclodextrin Technology" vol 1. Springer, New York" ISBN 978-90-277-2314-7
4. ^ Gil A., Chamayou A, Leverd E., Bougaret J., Baron M., Couarraze G. (2004). "Evolution of the interaction of a new chemical entity, eflucimibe, with gamma cyclodextrin during kneading process". Eur. J. Pharm Sciences 23: 123–129. doi:10.1016/j.ejps.2004.06.002. 
5. ^ Becket G, Schep LJ, Tan MY (March 1999). "Improvement of the in vitro dissolution of praziquantel by complexation with alpha-, beta- and gamma-cyclodextrins.". Int J Pharm 179 (1): 65–71. doi:10.1016/S0378-5173(98)00382-2. PMID 10053203. 
6. ^ Biwer A, Antranikian G, Heinzle E. (2002). "Enzymatic production of cyclodextrins". Appl Microbiol Biotechnol 59 (6): 609–17. doi:10.1007/s00253-002-1057-x. PMID 12226716. 
7. ^ C. A. Stanier, M. J. O Connell, H. L. Anderson and W. Clegg (2001). "Synthesis of fluorescent stilbene and tolan rotaxanes by Suzuki coupling". Chem. Commun. (5): 493–494. doi:10.1039/b010015n. 
8. ^ GRAS Notice No. GRN 000155, alpha-cyclodextrin
9. ^ GRAS Notice No. GRN 000074, beta-cyclodextrin
10. ^ GRAS Notice No. GRN 000046, gamma-cyclodextrin
11. ^ Artiss, J.D.; Brogan, K.; Brucal, M.; Moghaddam, M.; Jen, K.L.C. (2006). "The effects of a new soluble dietary fiber on weight gain and selected blood parameters in rats". Metabolism 55 (2): 195–202. doi:10.1016/j.metabol.2005.08.012. PMID 16423626. http://linkinghub.elsevier.com/retrieve/pii/S0026049505003355 
12. ^ Grunberger, G.; Artiss, J.D.; Jen, K.L.C. (2007). "The benefits of early intervention in obese diabetic patients with FBCx TM-a new dietary fibre". Diabetes Metab Res Rev 23 (1): 56–62. doi:10.1002/dmrr.687. PMID 17013969. http://www3.interscience.wiley.com/journal/113385490/abstract 
13. ^ Brocos P., Banquy X., Díaz-Vergara N., Pérez-Casas S., Costas M., Piñeiro Á. (2010). "Similarities and differences between Cyclodextrin-Sodium Dodecyl Sulfate Host-Guest Complexes of Different Stoichiometries: Molecular Dynamics Simulations at Several Temperatures". J. Phys. Chem. B 114: 12455–67. doi:10.1021/jp103223u. http://pubs.acs.org/doi/abs/10.1021/jp103223u. 
14. ^ Leclercq L., Bricout H., Tilloy S., Monflier E. (2007). "Biphasic aqueous organometallic catalysis promoted by cyclodextrins: Can surface tension measurements explain the efficiency of chemically modified cyclodextrins?". J. Colloid Interface Sci. 307 (2): 481–7. doi:10.1016/j.jcis.2006.12.001. PMID 17188284. 
15. ^ 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. 
16. ^ Rodal, "Extraction of Cholesterol with Methyl--Cyclodextrin Perturbs Formation of Clathrin-coated Endocytic Vesicles"

External links

• Cyclodextrin Database
• Addi and Cassi Hempel, identical twins with Niemann Pick Type C being treated with HPßCD cyclodextrin
• Information on Cyclodextrin, HIV/AIDS and Niemann Pick Type C
• OpenCDLig: a free Web application for host/guest complexes
• The European Cyclodextrin Society
• Cyclodextrin Technologies Development, Inc.