Cyclodextrins An Overview

1. Gent 2001 CyclodextrinsAn Overview Matthias Arenskötter Florence Folmer Chris Llewellyn Aurélie Pardo Frank Reinecke Grazia Trebbi

2. Cyclodextrins - An Overview • . Introduction • . Microbial Production • . Purification And Fractionation • . Properties • . Applications

3. Introduction • Cyclodextrins (CDs) are torus shaped cyclic oligomers consisting of 6 (),7 (b) or 8 (g-CD) glucose units with a-1,4-linkages with a hydrophobic cavity and a hydrophilic exterior

4. Introduction History: • 1891 Discovery, Villiers • 1903 Descriptions of properties, Shardinger • 1939 Tilden and Hudson were able to show that the conversion of starch to CD was due to the action of an enzyme, CD Glycosyl-Transferase (CGTase), which was secreted into the culture medium.

5. Introduction • 1957 Complexation ability of CDs widely accepted; Cramer, French • 1981 First International Symposium on CDs, Szejtli • 1987 Total synthesis, Ogawa • 1994 Total synthesis of cyclo[D-Glcp(1->4)]5

6. Introduction • Today CDs are only synthesized either by fermentation or enzymatically. • Many CGTases from different microorganisms are known, cloned, sequenced, characterized and used for production of CDs.

7. Introduction Applications: • Because of their unique properties CDs allow „packaging on a molecular level“ of various molecules which is applied in pharmaceutics, food and flavours etc... • Used in chromatographic columns CDs can separate stereoisomers. • Derivatives of CDs can even be used to mimic enzymes.

8. Cyclodextrins - An Overview • . Introduction • . Microbial Production • . Purification And Fractionation • . Properties • . Applications

9. Microbial Production • CGTases are produced by many different bacterial species of the genus Bacillus but also by Flavobacterium sp., Klebsiella pneumoniae and Micrococcus sp. • Genes have been cloned and recombinantly expressed in Escherichia coli and other organisms, including for example Solanum tuberosum (Potato).

10. G H G H E F E F D A D A CGTase C B C B a-CD starch Microbial Production • The CGTase acts on linear starch and transfers a part of the chain (F) to its own non-reducing end (A) as indicated in this model:

11. Cyclodextrins - An Overview • . Introduction • . Microbial Production • . Purification And Fractionation • . Properties • . Applications

12. Purification and Fractionation • Enzymatic synthesized CDs are selectively precipitated by organic solvents.

13. Cyclodextrins - An Overview • . Introduction • . Microbial Production • . Purification And Fractionation • . Properties • . Applications

14. Properties Important Properties: • CDs have hydrophobic cavities of different sizes enabling the complexation of hydrophic guest molecules. • These complexes represent a solution for insolubility. • They have neither a reducing nor a non-reducing end-group.

15. Properties Stability: • CDs are not decomposed by hot aqueous alkali and rather resistant to acid hydrolysis. • CDs are resistant to a-amylases (except microbial enzymes) and they are completely resistant to yeast-fermentation and b-amylases.

16. Properties

17. Properties

18. Cyclodextrins - An Overview • . Introduction • . Microbial Production • . Purification And Fractionation • . Properties • . Applications

19. Applications Pharmaceutical industry: • Treatment of inflammation or throat infection (with iodine) • Coronary dilatation (with nitroglycerin) • Anti-ulcerate (with benexate) • Vectors for vitamins or hormones • Reduction of side-effects and increase in efficiency of anti-cancer drugs

20. Solid Complex Cyclodextrin Competing Agent Dissolution (kd) (kc) (ki) Adsorption (ka) Dissolved Complex Drug Competing Agent-Cycloddextrin Complex Biomembrane Systemic Circulation Drug Applications Pharmaceutical industry:

21. Applications Cosmetics & Hygiene: • Long-lasting perfume release • Deodoriser (with peppermint oil, i.e.) • Removal of dryness wrinkles (with seaweed compounds, Vitamin A & E) • Anti-cellulitis compound • Shampoo industry • Teeth cleaning, anti-plaque compound • Antibacterial in refrigerators

22. Applications Food industry: • Emulsion stabiliser • Taste-masking • Long-lasting flavouring • Removal of cholesterol from milk, butter, eggs, a.o.

23. Applications Paint industry: • Increase in compatibility of paint ingredients • Increase in stability of the paint • Increase in the range of colours and in the quality of dyes

24. Applications Environmental protection: • Reduction in oxidiser requirements in paper production • Environmentally friendly oil-spill clean-up • Treatment of tree-wounds (with auxin) • Mobilisation of toxins without leaving toxic residues behind (innovative technique)

25. Applications Environmental protection: • Removal or detoxification of waste material, esp. aromatic pollutants • Use in agriculture to increase the stability and the efficiency of herbicides, insecticides, repellents,…

26. Applications Chemical and biochemical applications: • Reaction catalyst in adhesives • Use in chromatography (separation of stereoisomers) • Increase in speed of diagnostic test reaction

27. Applications Chemical and biochemical applications: • Enzyme mimicry Dimer of b-cyclodextrin linked on primary side by a metal-binding-group as catalyst of hydrolysis of a phosphate diester

28. Summary • When Cyclodextrins were discovered they were just a chemical curiosity but today a lot of applications are known. • Due to intensive studies and advances in production procedures prices continue to decrease making CDs attractive for many applications. • To date more than 3300 European Patents are registered indicating great industrial interest.

29. Group Members • Matthias Arenskötter, Westfälische Wilhelms-Universität Münster, Germany • Florence Folmer, University of Wales Bangor, UK • Chris Llewellyn, University of Wales Swansea, UK • Aurélie Pardo, Institue Nationale Polytechnique de Toulouse, France • Frank Reinecke , Westfälische Wilhelms-Universität Münster, Germany • Grazia Trebbi, Universita´ di Bologna, Italy