Review: A History of Cyclodextrins - Chemical Reviews (ACS

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Review: A History of Cyclodextrins Grégorio Crini* Faculté Sciences & Techniques, UMR Chrono-environnement 6249, Université de Franche-Comté, 16 Route de Gray, 25030, Besançon Cedex, France 7.8. Controlled Release of Fragrances and Aromas 7.9. Textiles and Cosmetotextiles 7.10. Cyclodextrin-Based Supramolecular Architectures 7.11. Cyclodextrins and Click Chemistry 7.12. Cyclodextrins and Sugar-Based Surfactants 7.13. Cyclodextrins and Membranes 7.14. Cyclodextrins and Remediation 7.15. The Cyclodextrin Scientific Community 8. Conclusions Author Information Corresponding Author Notes Biography Acknowledgments References

CONTENTS 1. Introduction 2. Discovery: 1891−1911 2.1. Antoine Villiers (1854−1932) 2.2. Franz Schardinger (1853−1920) 3. The Period of Doubt: 1911−1935 3.1. Hans Pringsheim (1876−1940) 3.2. Paul Karrer (1889−1971) 3.3. Other Studies during the Period of Doubt 4. Reaching Maturity: 1935−1950 4.1. Karl Johann Freudenberg (1886−1983) 4.2. Dexter French (1918−1981) 4.3. Other Works during the Period of Reaching Maturity 5. Exploration: 1950−1970 5.1. Dexter French during the Exploration Period 5.2. Friedrich Cramer (1923−2003) 5.3. Benito Casu 5.4. Myron Lee Bender (1924−1988) 5.5. Other Works during the Exploration Period 6. The Period of Application: From 1970 until Now 6.1. Wolfram Saenger 6.2. The Works of Myron Lee Bender during the Period of Application 6.3. József Szejtli (1933−2004) 6.4. Cyclodextrins: From 1970 until Now 7. Cyclodextrins − Present Situation, Trends, and Outlook: Personal Remarks 7.1. Cyclodextrins and Their Capacity To Form Inclusion Complexes 7.2. Cyclodextrins and Their Tendency To Form Aggregates 7.3. Cyclodextrins and Pharmacy 7.4. Cyclodextrins and Nanotechnology 7.5. Biomedical Applications and Biomedicine 7.6. Cyclodextrins and Food 7.7. Cyclodextrins and Chromatography © 2014 American Chemical Society

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1. INTRODUCTION Cyclodextrins (CDs) are synthetic substances obtained from the enzymatic degradation of one of the most essential polysaccharides, starch. CDs belong to the family of cage molecules; that is, the core of their structure is composed of a dimensionally stable hydrophobic cavity that can trap or encapsulate other molecules. The remarkable encapsulation properties lead to a “host−guest” type relationship that can modify and/or improve the physical, chemical, and/or biological characteristics of the guest molecule. Applications are found in practically all sectors of industry but especially pharmacy, food, chemistry, chromatography, catalysis, biotechnology, agriculture, cosmetics, hygiene, medicine, textiles, and the environment. Although they have been known for 120 years, CDs only really took off in the 1980s with the first applications in the pharmaceutical and food industries. This expansion was made possible by the production on an industrial scale of the three CDs known as “native”, that is, α-, β-, and γCDs. They were produced in a highly pure form as early as 1984, lowering prices considerably, which made an enormous contribution to their development, especially that of β-CD (Figure 1). Numerous patents have been filed since the 1980s, and an abundant scientific literature has built up. The main aim of this Review is to describe the 120 years of the development of CDs. I have roughly divided it into five periods: discovery from 1891 to 1911, a period of doubt from 1911 to 1935, exploration in 1935−1950, 1950−1970 when notions matured, and finally the period of application from 1970 to the present day. The different periods are illustrated by

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Received: February 10, 2014 Published: September 23, 2014 10940

dx.doi.org/10.1021/cr500081p | Chem. Rev. 2014, 114, 10940−10975

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Figure 1. β-Cyclodextrin: Top view of the Stuart molecular model (left) and structure (right).

Figure 2. Extract of the first proceedings of the French “Académie des Sciences” of February 1891.

amylobacter (Clostridium butyricum) on potato starch. A student of the well-known Professor Berthelot, Antoine Villiers was born in Carcassonne in the south of France. He qualified in toxicology and occupied the newly created chair of analytical chemistry at the School of Pharmacy in Paris. As professor of analytical chemistry in the same school, where he remained from 1886 to 1924, Villiers was particularly drawn to various aspects of the chemistry of natural substances including carbohydrates and alkaloids. His scientific work is reported in two doctoral memoirs (1880) and 29 other multidisciplinary papers dealing with chemistry (extractive, organic, inorganic, and physical chemistry), pharmacy, and microbiology, as was the rule at the time. In the early 1890s, during experiments on the degradation and reduction of carbohydrates under the action of ferments, Villiers noted the formation of unwanted crystals with particular properties; he had discovered CD molecules. In the Proceedings of the Académie des Sciences of February 1891 (Figure 2) published by the Bulletin of the Paris Chemical Society, Villiers described that, under certain conditions (50 g of potato starch in 1 L of water at 100 °C subsequently seeded with Bacillus amylobacter and incubated for several days in an oven at 40 °C), potato starch can ferment to mainly yield dextrins.1,2 The term dextrins had already been used at the time to describe the degradation products and/or the intermediate decomposition products of starch (note that the production of dextrins by the degradation of starch through heating was discovered in 18213). Villiers showed how easy it was to

considering examples of studies that appeared in the literature and in particular those of several great scientists who have left their mark on the history of these molecules, that is, Villiers from France, Schardinger from Austria, Karrer from Switzerland, Pringsheim, Freudenberg, Cramer, and Saenger from Germany, French and Bender from the U.S., Casu from Italy, and Szejtli from Hungary. Although this historic review cannot hope to be exhaustive, it does highlight the work of those researchers who have contributed to the development of our knowledge of CDs throughout the 120 years of their history. To do this, an extensive list of data from about 510 publications has been compiled. However, because of the extremely large number of papers, proceedings, conference abstracts, patents, book chapters, monographs, books, series, and lectures, in this Review, the discussion will be limited to CD-related relevant publications. Readers interested in a detailed description and applications on CDs and CDs derivatives should refer to the excellent library database “Cyclodextrin News” from CYCLOLAB, Ltd. (Hungary), which is a periodical collecting all of the CD papers, patents, and conferences.

2. DISCOVERY: 1891−1911 2.1. Antoine Villiers (1854−1932)

The history of cyclodextrins began in France in the late 19th century with the work of the pharmacist and chemist Antoine Villiers on the action of enzymes on various carbohydrates, particularly studies using the butyric ferment Bacillus 10941


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Figure 3. Extract of the second proceedings of the French “Académie des Sciences” of June 1891.

butyric ferment. Solubility in water at room temperature is low but rises with temperature. By manipulating the experimental conditions, Villiers obtained two distinct crystallized cellulosines, most probably α-dextrin (α-cyclodextrin) and β-dextrin (β-cyclodextrin). It was only in 1972 that Manor and Saenger6 demonstrated that the formula [(C6H10O5)6 − H2O] was that of α-CD-hexahydrate, the same formula as that proposed in 1891 to describe one of Villiers’s cellulosines. Villiers considered these novel substances as isomers of starch, almost insoluble in water, soluble in alcohol, nonfermentable, acid resistant, and which can be converted into ethers under the action of acid chlorides. Villiers concluded that the properties of these particular dextrins were very clearly different from those of the various saccharides known at the time. Nevertheless, he did not pursue research into CDs, preferring to focus on alkaloids. It would appear that Villiers used a culture of Bacillus amylobacter that was probably not pure but actually a coculture with another bacillus (Bacillus macerans); this was suggested by Robert Koch as long ago as 1891 and supported by Franz Schardinger in the early 20th century.7 Indeed, the strain of bacteria that was responsible for the CD formation was only isolated 20 years later by Schardinger. It was the famous German school of chemistry and biochemistry working on starch and cellulose at the start of the 20th century that, during studies of the structure, chemical modification, and degradation of these two polysaccharides, was to rediscover these dextrins, which certain researchers, including Hans Pringsheim at the same period, classed as “polyamyloses” (polyamylosen in German).

transform starch to yield the novel carbohydrate under the action of the bacillus. When the amylaceous paste was inoculated with the bacillus, it became transformed into a slightly acidic liquid, giving off the very characteristic smell of butyric acid. Subsequently, when studying the physical and chemical properties of the dextrins in more detail, he noted that a large proportion of the substances present could no longer be digested by the bacillus and that the crystals were resistant to the action of water and acid. He found that, when purified by fractional precipitation, the dextrins presented very different optical rotation properties and were difficult to hydrolyze any further. Iodine stains red those dextrins that have a high optical activity, and the intensity of the stain decreases with the optical activity. Dextrins with the lowest optical activity are no longer stained by iodine at all. In addition, their reducing power increases as their optical activity decreases. Finally, in this pioneering article, Villiers concluded that the absence of maltose and glucose indicated that the butyric ferment caused the transformation of the starch directly into dextrin without the involvement of intermediates such as diastases secreted by the ferment. During this bacterial transformation of the starch, Villiers also obtained other byproducts in small quantities after several weeks of incubation, in particular a highly crystalline substance with a composition intermediate between that of starch and that of dextrin. Three grams of this carbohydrate was obtained as crystals after bacterial digestion of 1000 g of starch. The crystals were found in the alcohol that was used for the precipitation of dextrin. Out of scientific curiosity, Villiers then focused on the characterization of these byproducts. In June 1891, in a second collection of proceedings (Figure 3), Villiers described the chemical composition of this novel crystalline carbohydrate.4,5 It was represented by a multiple of the formula [(C6H10O5)2 + 3H2O], and he proposed the name “cellulosine” due to the similarities with cellulose, which is also resistant to acid hydrolysis and which lacks reducing sugars.4,5 Villiers noted that the “white crystals with a very slight sweetness” showed extremely high optical activity, much higher than those of certain dextrins formed under the action of the

2.2. Franz Schardinger (1853−1920)

At the beginning of the last century in Vienna, the Austrian chemist and bacteriologist Franz Schardinger, Chief Inspector of the Untersuchungsanstalt f ür Lebensmittel, studied heatresistant micro-organisms that can lead to food poisoning. Among his numerous research themes, he aimed to improve understanding of the chemistry and degradation of starch. In 1903, he discovered that a type of extremely heat resistant 10942


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Figure 4. First page of the article by Professor Franz Schardinger on dextrins in 1903.

the works of Robert Koch (1843−1910), a German doctor and bacteriologist specializing in microorganisms (Professor Koch is considered to be the founder of modern bacteriology), who had put forward the idea that, in the conditions of sterilization described by Villiers, the bacillus used was not pure.12 Between 1905 and 1911, Schardinger gave the first detailed description of the preparation, separation, and purification of the two cellulosines first described by Villiers.11−15 He also studied their chemistry reporting their behavior in the presence of alcohols, chloroform, ether, and iodine solution. He showed that dextrins were nonreducing to copper reagents and nonfermentable by yeast. Schardinger also discovered that the dextrins could be synthesized from several sources of starch (potatoes, rice, wheat) and bacteria (the formation of dextrins depended on the type of bacteria digesting starch). He concluded that about 25−30% of the starch was converted to crystalline dextrins depending on these parameters. He also based his method of separation on the ease of crystallization of the β-dextrin from water and its low solubility at room temperature followed by precipitation of the α-dextrin from the mother liquor by the addition of alcohol. The distinction between the two forms was always made through their ability to form complexes of different colors with iodine (this reaction was to be studied again by other researchers including Euler and Myrbäck16 in 1922 and Dube17 in 1947). The colors were gray-green for dry α-dextrin (the color changing to blue in the presence of water) and reddish purple (brownish) for β-dextrin (whether wet or dry). In 1911, Schardinger considered that the

microorganism was able to dissolve starch and form crystalline byproducts remarkably similar to the cellulosine reported by Villiers.8,9 He published his results in the journal Zeitschrif t f ür Untersuchung der Nahrungs- and Genuβmittel (Figure 4). Schardinger observed that cellulosine was often formed in starch-based media containing putrefying microorganisms.8 He managed to isolate the strain of bacteria responsible for the degradation of starch and the formation of the crystalline products; he called it strain II.9 Using the iodine reaction, a simple colorimetric test, he distinguished two types of polysaccharide, which he called crystalline dextrin A and crystalline dextrin B (krystallisiertes dextrins in German). The B form resembled Villiers’ cellulosine. Schardinger found that it was possible to isolate pure fractions: he obtained a maximum yield of 30% crystalline dextrins from starch, the main form obtained being dextrin B. However, he noted that with time, the activity of the strain II microorganism decreased. In 1904, he isolated a new microorganism, which he first called rottebazillus I due to its action on potato starch, and then several months later he used the Latin name Bacillus macerans.10 Schardinger reported that the bacillus was able to give the same crystalline dextrins as before, which he designated as crystalline polysaccharides (“krystallisiertes polysaccharides”). Using the characteristic reaction that starch derivatives show with iodine, he proposed a distinction between a crystalline amylose and a crystalline amylodextrin.11 The yields obtained by Schardinger were 10-fold those reported by Villiers. To account for this result, he took inspiration from 10943


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subject for investigation not only for Pringsheim but also for numerous other researchers such as Karrer and Freudenberg.23 In the hands of Pringsheim, Schardinger’s observations on the formation of crystalline decomposition products of starch under the action of B. macerans mainly led to the elaboration of a possible interpretation of the chemical structure of amylose and of amylopectin.27−34 For Pringsheim, the Schardinger dextrins arose through the bacterial depolymerization of starch to the fundamental units: the amylose fraction being broken down into the α-series of dextrins (polyamyloses) and the amylopectin fraction being degraded to the β-series. For over 20 years, Pringsheim and his various collaborators (Alfred Langhans, Franz Eissler, Stefanie Lichtenstein, Walter Persch, Diamandi Dernikos, Kurt Goldstein, Arthur Beiser, Arnold Steingroever, Alfred Wiener, Alexander Weidinger, Eugen Schapiro, James Irvine, Paul Meyersohn) penned an abundant literature on their studies of dextrins,27−53 although the studies suffered from numerous errors due to the use of dextrins that were not pure and to problems arising from separation of the fractions and from the use of unsuitable analytical methods (e.g., determination of the masses by cryoscopy). It results that Pringsheim’s copious results are difficult to exploit. From 1910, Pringsheim repeated Schardinger’s experiments.27 He isolated pure α-dextrins and β-dextrins, and described their fundamental properties, confirming the conclusions previously reported by Schardinger. He also showed that the two dextrins were soluble in water but insoluble in alcohol, ether, and chloroform, and they did not reduce Fehling’s solution. Pringsheim reported that about 25− 30% of the starch could be converted to crystalline dextrins, with an additional larger amount of amorphous dextrins, confirming the results of Schardinger. In all experiments, the major crystalline product was also the so-called β-dextrin. The simplest means to distinguish between the α- and β-dextrins was the iodine reaction: a solution of α-dextrin gave a yellowish-green and of β-dextrin a reddish-brown color with iodine. Pringsheim also succeeded in depolymerizing the Schardinger dextrins into polyamyloses and studied the relationship between these polyamyloses and the amylose and amylopectin molecules.40,42 Indeed, in 1924, Pringsheim found that amylose could be converted into a diamylose (Schardinger’s α-dextrin), while a triamylose (Schardinger’s β-dextrin) could be converted from amylopectin either through acetylation or through heating the polysaccharides in glycerin at 200 °C, in accordance with the results published by Pictet and Jahn.54 On treating the polyamyloses formed by B. macerans with cold concentrated hydrochloric acid, Pringsheim obtained a disaccharide C 12 H 22 O 10 , which he termed amylobiose (it reduced Fehling’s solution), while amylopectin yielded a reducing trisaccharide (named amylotriose) under the same conditions. Both amylobiose and amylotriose, when acted upon by malt diastase, were converted quantitatively into maltose. Pringsheim summarized his works distinguishing two series: the α-series (alpha-series) of dextrins obtained from the amylose fraction of the starch molecule, which contained 2n Dglucose units per molecule, and the β-series (beta-series) from amylopectin fraction degradation containing 3n D-glucose units per molecule. In fact, he considered four and two distinct substances in the α-series (α-diamylose, α-tetraamylose, αhexaamylose, and α-octaamylose) and the β-series (triamylose and hexaamylose), respectively. Pringsheim concluded (i) that α-dextrin was composed of four groups of C6H10O5, a hypothetical polyamylose to which he applied the term “α-

nomenclature that he had proposed in 1904 was not in fact appropriate and decided to call Villiers’ cellulosines crystalline α-dextrin and crystalline β-dextrin.15 Schardinger was the first researcher to describe the fundamental properties of these dextrins, and he is also acknowledged as being the first to lay down the basis of their chemistry, including their ability to form complexes. Indeed, he became known as the “Founding Father” of cyclodextrin chemistry. He also hypothesized that the crystalline substances were cyclic “polysaccharides”; this was taken up again 30 years later by Freudenberg who came to the conclusion that they were cyclic oligosaccharides.18 Schardinger in fact never managed to elucidate their structure, and it was only in the late 1940s that the first X-ray analyses confirmed his hypothesis.19 The major discovery of Schardinger was to isolate the microorganism able to synthesize the enzyme that catalyzes the degradation of starch into cyclodextrins. This was identified a few years later as cyclodextrin glucosyltransferase, which more exactly attacked amylose, the linear component of starch. It can be noted that even today the most frequently used source of enzyme for the production of CDs is Bacillus macerans. The terms crystalline α-dextrin and crystalline βdextrin were indeed used for the first time by Schardinger, which is why for many years cyclodextrins were called Schardinger dextrins in his honor (almost up to the 1970s) even though their discovery is still attributed to Professor Antoine Villiers. Professor Franz Schardinger decided to stop his research into dextrins in 1911, and as a conclusion15 he wrote: “I realize that still very many questions remain unsolved; the answer to these I must leave to another, who, owing to more favorable external conditions, can deal with the subject more intensively.”

3. THE PERIOD OF DOUBT: 1911−1935 The span of time from 1911 to 1935 is known as “the period of doubt”. The two names that marked this period most were Hans Pringsheim (Chemischen Institut der Universität, Berlin, Germany) and Paul Karrer (University of Zurich, Switzerland). It should be noted that at that time the structure of the dextrins had not yet been established (it would be determined by Freudenberg in the mid-1930s), nor had those of starch or cellulose. For instance, it was not clearly established that starch was a macromolecule composed of several units of glucopyranose.3,20−26 During this period of doubt, numerous derivatives of starch, including Schardinger dextrins, were synthesized and studied. 3.1. Hans Pringsheim (1876−1940)

It was first the German chemist and biochemist Hans Pringsheim of the University of Berlin who, around 1910, played an important role in research into dextrins, or, as he preferred to call them, polyamyloses (“krystallisiertes polyamylosen”). Hans Pringsheim was born in 1876 in Silesia. Graduating from the university of Heidelberg (doctorate in 1901), he was recognized not only for his fundamental and applied research into the chemistry of monosaccharides (sugars), polysaccharides (e.g., polyoses, cellulose, inulin, starch, glycogen), and degradation products (dextrins), but also for his numerous collaborations with industry. Pringsheim was considered to be a world authority on these topics. At the beginning of the 1900s, the composition of starch, its depolymerization, its degradation, and its conversion through hydrolysis into simpler carbohydrates had long been a favorite 10944


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amylose”, and (ii) that Schardinger’s β-dextrin was found to contain six of the hypothetical “amylose” groups (hexaamylose). He also concluded that the crystalline dextrins formed characteristic iodine adducts upon the addition of iodine− iodide solution, and this test was simple, rapid, and very useful. Similar results and conclusions were previously reported by Karrer.55−57 However, Karrer regarded maltose as the fundamental unit of the whole of the starch molecule, while for Pringsheim the polyamyloses were the basic units of the starch molecule. Pringsheim also was convinced that the dextrins were composed solely of glucose units bonded by α1,4-glucosidic linkages as in starch, in accordance with the hypothesis previously reported by Karrer,57 and these dextrins were of much lower molecular weight than starch and completely nonreducing.41 However, Pringsheim failed to elucidate the cyclic structure of the dextrins. Pringsheim also conducted several tests to determine whether the dextrins were physiologically available either to plants or to animals, but he was not able to detect any starch formation with the dextrins, although maltose gave rise to starch. The Schardinger dextrins were not fermentable and hence not utilized by yeast. Using biological tests on animals (rabbits, pigs) for the treatment of diabetes,48,52 he concluded: “α-Dextrin directly utilized would be a suitable source of energy for diabetics since it only occasionally cause nausea and there is no noticeable increase in urine sugar.” The main achievement of his works was the discovery in 1930 that crystalline dextrins and their acetate derivatives tended to form complexes with various organic compounds.47,48,53 Indeed, he showed that dextrins are able to form insoluble crystalline complexes with many liquids, notably hydrocarbons and halogenated hydrocarbons. For example, he was the first to study the halogen complexes of dextrins.42 This property of the Schardinger dextrins, previously observed by Schardinger himself, was to be demonstrated a few years later by Freudenberg,58 Tilden and Hudson,59,60 and French.61 Pringsheim summarized the whole of his works and conclusions in a first book52 entitled Die Polysaccharide (Figure 5) published in German, and the works of Schardinger and his own conclusions on these dextrins in the very first mini-review53 in 1932 in his second book entitled The Chemistry of the Monosaccharides and of the Polysaccharides. Professor Hans Pringsheim gave numerous conferences around the world and in particular in the U.S. (as an instructor in chemistry at Harvard University, visiting scientist at Cornell University, etc.), and he is considered to be the first researcher to have published prolifically on the subject, although the majority of the data was unreliable.

Figure 5. Cover of Pringsheim’s book published in 1931 where Professor Hans Pringsheim described various characteristics of the “krystallisierte dextrin - polyamylosen” and summarized the works of Professor Schardinger. Reprinted with permission from ref 52. Copyright 2014 Springer-Verlag.

returned to Zurich. The next year, he accepted the position of professor of Organic Chemistry at the Chemisches Institut and succeeded Professor Werner as director of this institute. Karrer started studies on the chemistry of sugars and polysaccharides (starches, glycogen, inulin, cellulose, chitin, etc.). His studies on polysaccharides were compiled in an excellent monograph entitled Polymere Kohlenhydrate published at Leipzig in 1925.68 Karrer also started to take an interest in Schardinger dextrins. Like Schardinger and Pringsheim, Karrer studied these crystallized dextrins with the expectation that they would shed some light on the synthesis and degradation of starch. He studied their chemistry and their interactions with ions. For instance, he studied the interactions between dextrins and barium,62 sodium,65 and potassium.66 Karrer also showed that the dextrins were made up of several components and introduced the notion of series. Like Pringsheim, Karrer was convinced that the α-series of dextrins was composed of at least four distinct substances differing in molecular size. However, he disagreed with the subdivision of the β-series into triamylose and hexaamylose.62 For Karrer, these two products were identical. To argument his conclusions, he evoked that acetolysis of the dextrins gave essentially the same yield of maltose as starch or maltose itself gave, when treated similarly; this was strong evidence against the trisaccharide character of βdextrin. He was the first to propose that dextrins are composed

3.2. Paul Karrer (1889−1971)

In the early 1920s, the Swiss chemist Paul Karrer, Nobel Prize winner in 1937 for his work on vitamins, also published several studies on Schardinger dextrins.55−57,62−68 Paul Karrer, the son of Swiss parents, was born in Moscow on April 21, 1889. His family returned to Switzerland in 1892 where he studied chemistry at the University of Zurich. In 1911, Karrer presented his doctoral thesis entitled “Die nitrosopentammin-kobaltsalze” under the guidance of Professor Alfred Werner (Nobel Prize in chemistry in 1913). Karrer studied organic arsenic compounds. These studies were of fundamental interest at the time, and he accepted a position of researcher at the Georg-Speyer Haus Foundation in Frankfurt working with Professor Paul Ehrlich (Nobel Prize in medicine in 1908) on the therapeutic applications of these organic compounds. In 1918, Karrer 10945


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of maltose units only joined by α(1→4) glucosidic linkages,56,57 although Pringsheim remained unconvinced by Karrer’s conclusions. However, just like Schardinger and Pringsheim, Karrer failed to elucidate the cyclic structure of the dextrins. He then rapidly abandoned his research on dextrins to focus on different substances such as vitamins and carotenoids. Professor Paul Karrer published more than 1000 papers, most of them in the Helvetica Chimica Acta. He served as rector of Zürich University (1950−1952) and received many distinctions (Honoris causa Doctor from the University of Paris) and prizes (he was awarded the Marcel Benoist Prize, Switzerland and the Cannizzaro Prize, Italy).69−72

made on Schardinger dextrins suddenly accelerated due to the numerous contributions of these two researchers. 4.1. Karl Johann Freudenberg (1886−1983)

Karl Johann Freudenberg was born on January 29, 1886 in Weinheim, near Heidelberg, Germany.88 He studied chemistry at the University of Bonn from 1904 to 1907 and presented his Ph.D. under the direction of Professor Emil Fischer on the structure of Chinese gallotannin at the University of Berlin in 1910. Freudenberg worked with Fisher until July 1914, when he received an appointment as Assistant Professor at the University of Kiel. On returning to Kiel after the Great War, he was promoted to Associate Professor in 1919 and moved to Munich. In 1921, he became professor at Freiburg University and in 1922 at Heidelberg University. Freudenberg was already acknowledged in the 1920s for his work on the structures and stereochemistry of substances of plant origin (such as terpenes, sugars, and flavonoids) and polysaccharides such as cellulose (determination of the exact formula in 1928) and starch (determination of the structure in 1930 and demonstration of the branched structure of amylopectin in 1940). From 1920, Freudenberg was attracted by the synthesis and the chemistry of Schardinger dextrins.75 Yet, it was only in the early 1930s that he focused entirely on dextrins because he wanted to obtain information on the degradation products of starch to be able to elucidate its structure.58,76,89−92 In 1926, he accepted a position of professor at Karlsruhe University (from 1926 to 1956). Freudenberg originally considered the Schardinger dextrins to be chain molecules intermediate between maltose and starch, having a nonreducing chain termination such as D-gluconic acid type of unit.76 In 1935, he described a method for the synthesis of Schardinger dextrins with high purity and, using a cryoscopic method for the determination of molecular weights (Figure 6), reported (erroneously) the number of glucose units that the CDs contained: five for α-dextrin and six for β-dextrin.58 Freudenberg and Jacobi improved the separation of dextrins and produced a scheme based not only on solubility differences

3.3. Other Studies during the Period of Doubt

Other studies should be mentioned from this period of doubt. Around 1910, in addition to the groups of Pringsheim and Karrer, others were also studying these novel substances. We can mention the publications of Wilhelm Biltz73,74 and of Karl Freudenberg.58,75,76 Freudenberg was the first researcher, as far back as 1922, to focus on the chemical modification of dextrins, and in particular of tosylated residues.75 The first patent was filed in 1925 by the German Fritz Lange for IG Farbenindustrie.77 In the early 1930s, the German groups of Max Ulmann78−80 in the Kaiser Wilhelm Institute für Chemie in Berlin and of Arthur Miekeley81,82 of the Kaiser Wilhelm Institute für Lederforschung in Dresden confirmed the work of Schardinger on α-dextrin. Ulmann was also investigating the modification of the dextrins and observed that the α-dextrin ethanol complex had two different crystal modifications, which could be interconverted.80 This was the first observation that a same guest may form different crystal structures with the same dextrin. Miekeley came to the same conclusions as Karrer as to the existence of α(1→4) glycosidic linkages. He also published experimental data (optical activity, chemical composition), which complemented those of Pringsheim.81 However, in a paper entitled “On the questionable existence of the so-called alpha diamylose”, Miekeley disagreed with Pringsheim’s conclusions on the polymerization−depolymerization scheme.81,82 In the same period, Zacherov described the characteristics of Bacillus macerans.83 However, despite the significant progress that was made, this period of doubt (1911−1935) did nothing to stimulate the development of Schardinger dextrins−cyclodextrins. The work was even marred by frequently contradictory results and hot debate between the different laboratories, especially those of Pringsheim and of Karrer, due mainly to confusion arising from the terminology of the different compounds, the purity of the different dextrins used, and the lack of certainty concerning their structure.81,82,84−87 In 1935, Freudenberg wrote that one of the main sources of confusion during this period was due to the unresolved question of the purity of the dextrins used.58 Moreover, few researchers at that time believed in the potential that these new molecules had, considering them to be laboratory curiosities or unwanted byproducts of starch degradation.

4. REACHING MATURITY: 1935−1950 From 1935 to 1950, Schardinger dextrins entered the period when they reached maturity with two research groups distinguishing themselves: that of Karl Johann Freudenberg (1886−1983) at the University of Heidelberg, Germany, and the American group headed by the chemist Dexter French (1918−1981) at Iowa State College. The scientific progress

Figure 6. First page of the article of Professor Freudenberg published in 1935 in the journal Justus Liebigs Annalen der Chemie where, with his student Richard Jacobi, he described a method for the synthesis of Schardinger dextrins with high purity. Reprinted with permission from ref 58. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA. 10946


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mechanism proposed that the dextrins were preformed within the starch macromolecules.93,99 Other researchers such as Tilden and Hudson also agreed with this mechanism. However, Freudenberg did not agree with the generally accepted point of view at that time concerning the nature of the bonding of the Dglucose units, and he abandoned this mechanism very quickly. He then took inspiration from the work of Charles Samuel Hanes (Botany School, Cambridge) and his helical model of the structure of starch and the α-D nature of the glucose units.106 The second mechanism that he proposed to interpret the formation of dextrins by Bacillus macerans was based on a transglucosylation reaction. He suggested that the enzyme involved was able to degrade the helical structure of the starch, that is, the amylose fraction, and that there ensued a rearrangement of the glucose units, which were then able to form a ring structure. However, he was unable to prove this mechanism. It would be confirmed a few years later by French107 using chromatography and by Takeo and Kuge108,109 using crystallography. In 1947, Freudenberg and his team described the first scheme for the isolation of pure fractions,110,111 a protocol modified from the initial procedure published in 1935.58 They were the first to prepare almost pure β-dextrins, using bromobenzene as precipitant (α-dextrin did not precipitate, while β-dextrin and γ-dextrin were readily precipitated). One year later, they discovered γ dextrin96 and elucidated its structure between 1948 and 1950.112 Freudenberg also proposed the possible existence of CDs with 9 or 10 units of glucose. Their existence was demonstrated a few years later by French. It should also be noted that the group of Akiya also claims this discovery for itself, along with that of a new strain of Bacillus macerans.113−116 Freudenberg published an impressive number of results (over a period of 60 years he published more than 450 papers), which are still used as references today (Table 1). Freudenberg’s work greatly advanced the understanding of the structure and chemistry of Schardinger dextrins and helped to pave the road for the development of their (forthcoming) applications.117−119 Freudenberg trained numerous students including Otto Westphal (future Nobel Prize winner) and Friedrich Cramer, whose work on (cyclo)dextrins was also acknowledged. He was an eminent scientist and visionary who left his researchers and students “free to pursue their research and their studies rather as their inspiration took them”. Like Professor Pringsheim, Professor Karl Johann Freudenberg gave numerous conferences throughout the world, and especially in the U.S., Japan, India, and Switzerland, and he received international recognition and numerous prizes (Emil Fisher Medal, Alexander Michterlich Medal, Doctor Honoris causa from the Universities of Basel and Berlin, Foreign Membership in the Royal Society in 1963, etc.). His talent also was applied in academic and civic affairs. He served as rector of Heidelberg University (1949−1950) and as a member of the City Council from 1951 to 1956, primarily engaging in city planning and adult education. He also devoted a considerable amount of time and energy to local and family history, as well as to the history of chemistry.120−124 His life and personality were portrayed in Heidelberger Jahrbücher by Friedrich Cramer.123 The journals Angewandte Chemie and Phytochemistry devoted a special issue to him in 1956121 and 1984,88 respectively.

of the dextrins themselves as initially proposed by Schardinger but also on the differences in solubilities and rates of crystallization of their acetates. The protocol was difficult because it involved many acetylation and saponification reactions but produced an α-dextrin completely free of impurities. A year later, in 1936, Freudenberg studied the nature of the glycosidic bonds using the changes in optical rotation and reducing power during methylation reactions of the dextrins and their ring conformation (“Konstellation”) using rigid Kekulé models.18,92 The dextrins gave rotation− time curves closely parallel to those given by starch, and the models did not allow free rotation about the individual bonds.18 The same year, Freudenberg also went over the structural studies of Schardinger, Karrer, Pringsheim, and Miekeley. He hypothesized that α- and β-dextrins have a cyclic structure, and he tried to prove it.18,92 He observed that enzymatic hydrolysis gave no trace of a sugar unit other than D-glucose, and methylation studies failed to reveal the presence of any Dglucose units. Freudenberg concluded that glucose was the only product of acid hydrolysis of dextrins.92,93 Two years later, he came to the same conclusion as Schardinger concerning the cyclic chemical structure of dextrins,94 although initially he considered them to be straight-chain molecules with nonreducing end-groups.76 A few years later, by studying the reactions of hydrolysis, enzymatic hydrolysis, and acetolysis of permethylated dextrins, Freudenberg and his co-workers experimentally demonstrated that the molecules had a cyclic structure composed of maltose units bound together by α-(1→ 4) glycosidic linkages.95,96 In 1948, Freudenberg and his doctoral student Cramer also demonstrated his conclusions using optical activity data.96 Moreover, it should be pointed out that during the same period, several other groups came to similar conclusions. We can mention Kratky and Schneidmesser97 and Borchert98 who confirmed the cyclic structure of dextrins by X-ray crystallography. It is Freudenberg who is acknowledged for determining the cyclic structure of α-dextrin and β-dextrin and their description, even though the molecular weight and the number of glucose units involved were not correct. In 1938, Freudenberg founded the Research Institute for the Chemistry of Wood and Polysaccharides, a research center devoted mainly to starch, cellulose, lignin, and their derivatives (including dextrins) and degradation products. He was director of this institute from 1938 to 1969. At the end of the 1930s, Freudenberg also suggested, for the first time, the hydrophobicity of the inner surface of the dextrin and noted how dextrins had the ability to accept molecular inclusions in their cavity.99−101 A few years later, to explain these inclusions, he was the first to show the involvement of hydrophobic forces in the formation of the complexes.96,102−105 Originally, however, Freudenberg was convinced that the dextrins and the amylose helix were lined with a hydrocarbon interior, and thus the cavity of the dextrins has been referred to as hydrocarbon in nature. In parallel, the enzymatic production of dextrins was investigated. Freudenberg was the first scientist to propose a mechanism of action for Bacillus macerans.93,99−101 In fact, he proposed two mechanisms because, at the time, the exact structure of the starch macromolecule and the nature of the bonding between the glucose units were still under debate. In 1939, in a comprehensive review99 on polysaccharides, Freudenberg wrote: “α-Dextrin is a cyclic pentaose containing five maltose bonds; such a system, which is probably preformed in starch, necessitates the assumption of side chains.” Indeed, the first 10947


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Dexter French (1918−1981). Dexter French was born in Des Moines, IA, on February 23, 1918. In 1935, he studied chemistry at the University of Dubuque, and in 1938, he entered Iowa State College, working under Professors R. S. Bear and R. E. Rundle. In 1942, French presented, at the Iowa State College, his doctoral thesis entitled “An investigation of the configuration of starch and its crystalline degradation products”. His work mainly concerned the study of starch and its various fractions using X-ray diffraction and a method developed to assay iodine for the determination of the amylose and amylopectin fractions of starch, the flagship research domain of the laboratory.125−130 After 2 years as a postdoctoral fellow in the Department of Physical Chemistry of Harvard Medical School (1944) and in the laboratories of the Corn Products Refining Co. in Illinois (1945), French returned to Iowa State College in 1946 as an Assistant Professor in Chemistry. Following in the steps of Professor Robert E. Rundle, Dexter French started to take an interest in Schardinger dextrins. Very quickly, French, like Freudenberg, became a pioneer in the preparation of the compounds in a very pure state, and in the understanding of their structure and their chemistry. Between 1942 and 1950, French and his co-workers published numerous studies.61,131−136 French’s first work concerned the molecular weights of the Schardinger dextrins. He went over the results published by Freudenberg and Jacobi in 1935, and he hypothesized that the cryoscopic method used by Freudenberg was inappropriate to determine the molecular weights because the dextrins were of comparatively high molecular weight and were very difficult to free from low molecular weight impurities. In 1942, French and Rundle, using the X-ray diffraction technique and crystal density measurements, determined the molecular weights of α- and β-dextrins and discovered the exact number of glucose units per dextrin, that is, six and seven, respectively (Figure 7).61 They demonstrated that molecular weights were integral multiples of the value 162.1 for a glucose residue. French and Rundle concluded that the X-ray diffraction

Table 1. Recap of the Main Results of Freudenberg on Schardinger Dextrins year

result

1922 1930

tosylated dextrins Schardinger dextrins: laboratory curiosities and/or unwanted byproducts of starch degradation Schardinger dextrins: chain molecules intermediate between maltose and starch the dextrins were lined with a hydrocarbon interior synthesis of Schardinger dextrins with high purity determination of molecular weights (five for α-dextrin and six for β-dextrin) solubility differences of the dextrins chemical modification of dextrins (acetylation, methylation, saponification reactions) studies on the nature of the glycosidic bonds hypothesis on the cyclic nature cyclic chemical structure of dextrins hydrophobicity of the inner surface of the dextrins ability to form inclusion complexes Foundation of the Research Institute for the Chemistry of Wood and Polysaccharides description of the mechanism of action for Bacillus macerans cyclic structure composed of maltose units bound together by α(1→ 4) glycosidic linkages the first scheme for the isolation of pure fractions discovery of γ-dextrin Freudenberg and Cramer demonstrated their conclusions on cyclic structure using optical activity data the first indication of the existence of dextrins comprising more than 8 glycosyl units structure of γ-dextrin involvement of hydrophobic forces in the formation of the complexes possible existence of dextrins with 9 or 10 units of glucose first patent concerning applications in pharmaceutical formulations

1935

1936 1938

1939 1943 1947 1948

1950

1953

4.2. Dexter French (1918−1981)

The list of prestigious researchers who have contributed to the development of cyclodextrin includes the American chemist

Figure 7. First page of the first article of Professor French published in 1942 in Journal of American Chemical Society. Reprinted with permission from ref 61. Copyright 2014 American Chemical Society. 10948


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Figure 8. Top: Functional structural scheme of α-CD (n = 6), β-CD (n = 7), and γ-CD (n = 8). Bottom: Geometric dimensions of cyclodextrins.

amylose.” Freudenberg claimed that the conclusions of French on the structure and composition of dextrins were ambiguous due to the use of products that were not pure, and thus the new nomenclature inappropriate.110−113 French was among the early researchers, along with Freudenberg and Cramer, to focus on improving the production of dextrins, which had always proved problematic. In 1948, he demonstrated that Bacillus macerans was capable of producing a glycosidic exchange reaction between maltose and cyclohexaamylose, which resulted in the formation of higher weight saccharides,131 confirming the concept of glycosidic exchange introduced by Cori. In 1949, he described the protocols he used to prepare the three cycloamyloses.132,133 Indeed, using the conclusions of Tilden and Hudson59,60,138,139 on the enzymolysis conditions, which affected the yield and proportion of the dextrins, and their own results on the solubilities of Schardinger dextrins, French proposed a new protocol for the separation and purification of dextrins that did not require the acetylation and saponification steps used by Freudenberg.58 His studies showed that treatment of starch with the amylase of B. macerans gave crude starch digests containing the three cycloamyloses (∼60% α-dextrin, ∼20% βdextrin, and ∼20% γ-dextrin) together with small amounts of higher cycloamyloses, confirming the results of Freudenberg.58 Moreover, the protocol permitted the facile separation of pure dextrins by differential precipitation using specific precipitants such as bromobenzene and propan-1-ol. It is important to note that the separation and the purification of the mixture were difficult, as reflected in their price at the end of the 1970s when industrial scale production really started. Later, in the mid1980s, advancements in biotechnology led to drastic improvements in the production and purification of CDs. Determining the chemical structure of the dextrins was also a goal for which French used crystallographic data and classical polysaccharide reactions. He showed that 2,3,6-trimethylglucose was the only product of methylation of cycloamyloses followed by hydrolysis.61,134 Solubility data of dextrins in water at room temperature according to French were as follows: αdextrin 14.5 g/100 mL, β-dextrin 1.8 g/100 mL, and 20% γdextrin 23.2 g/100 mL. In 1950, French determined the

technique was better suited to the determination of the molecular weights of high molecular weight crystalline substances because impurities (solvent of crystallization and inorganic ash) were of minor importance. French also showed that Schardinger dextrins were cyclic oligosaccharides (the model of “cycloamyloses” was constructed from glucopyranose units in the boat conformation), formed from starch polysaccharide, and were nonreducing D-glucopyranosyl polymers containing 6, 7, or 8 units linked by α-D-(1→4) bonds (Figure 8). Schardinger dextrins were found to be rather anomalous structures with interesting physicochemical properties when compared to the linear oligosaccharides. The cavity of dextrins was referred to as hydrocarbon in nature by French, although this theory was originally attributed to Freudenberg.101 This hypothesis originated before the advent of the modern conformational theory: in 1965, Thoma and Stewart pointed out that the cavity of cyclodextrins had definitively no hydrocarbon character.137 It was at this time that French proposed that dextrins be called cycloamyloses.61 Indeed, he introduced the cycloamylose-based nomenclature: cyclohexaamylose for α-dextrin, cycloheptaamylose for β-dextrin, and cyclooctaamylose for γdextrin. Two systems of nomenclature were in current use. The first of these indicated the number of residues in the cyclic polymer by prefixing a Greek letter to the series name. Because the smallest known dextrin was a hexamer, it was assigned the prefix α. The cyclic heptaose and octaose were referred to, respectively, as β- and γ-dextrins. Schardinger called the dextrins crystallized amylose and crystallized amylopectin, and Pringsheim used the name of polyamylose and referred to the individual compounds such as α-tetraamylose and β-hexaamylose, while Freudenberg referred to these compounds as αdextrin and β-dextrin, and later as pentaosan and hexaosan. In the alternate system proposed by French, the homologues were designated by the names cyclohexa-, cyclohepta-, and cyclooctaamylose, the Greek prefix corresponding to the degree of polymerization. This latter scheme was preferred because it was more descriptive of the structures.137 However, in 1947, Karl Freudenberg110 wrote: “It appears to be premature to rename the α-dextrin cyclohexa-amylose and the β-dextrin cyclohepta10949


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Table 2. Nomenclature of the Three Main (Cyclo)dextrins According to Villiers, Schardinger, Pringsheim, Karrer, Freudenberg, French, and Cramer author

α-D-G(1→4) 6 cyclo

Schardinger

crystalline amylose crystalline dextrin A dextrin crystallized amylose crystalline dextrin α α-diamylose α-tetramylose α-hexaamylose α-octaamylose α-amylosane α-diamylose α-isoamylosan α-dextrin pentaosan cyclohexaglucane α(1→4) cyclohexaamylose α-cyclodextrin

Pringsheim/Karrer

Freudenberg

Frencha Cramer a

α-dextrin

Villiers

β-dextrin

γ-dextrin

α-D-G(1→4) 7 cyclo cellulosine crystalline amylodextrin crystalline dextrin B dextrin crystallized amylopectin crystalline dextrin β β-triamylose β-hexaamylose β-amylosan β-isoamylosan

β-dextrin hexaosan cycloheptaglucane α(1→4) cycloheptaamylose β-cyclodextrin

γ-dextrin cyclooctaglucane α(1→4) cyclooctaamylose γ-cyclodextrin

French proposed the names cyclononaamylose for δ-dextrin and cyclodecaamylose for ε-dextrin.

molecular size and structure of the γ-dextrin, previously regarded by Freudenberg as a cyclic heptasaccharide. Using partial acid hydrolysis and enzyme digestion followed by X-ray measurements and paper chromatography, French showed that this dextrin was composed of eight glucose residues symmetrically arranged in a ring and linked together by α-1,4-glucosidic bonds.134 For this cyclic octasaccharide of the amylose series, French suggested the name cyclooctaamylose. In the late 1950s, French and co-workers had established the molecular weight, the exact chemical structure, the dimensions, and the types of bonding in the three cycloamyloses (α-, β-, and γ-dextrins).

in its action on starch but also in the conditions required for optimal activity. The same year, they described a simple protocol for purifying the amylase of B. macerans using both precipitation by acetone, adsorption, and dialysis steps. The enzyme purified had an activity 140 times that of the initial enzyme solution and was able to convert 1000 times its weight of starch in 30 min at 40 °C.60 From their studies, Tilden and Hudson also concluded that the resulting Schardinger dextrins were derived from some basic configuration pre-existing in the starch molecule. Since Tilden and Hudson’s discovery of Bacillus macerans cycloamylose glucanotransferase, effort was devoted to working out methods for cycloamylose production and the details of the mechanism. These two researchers also laid down the basis of the enzymology of dextrins, and their findings were validated and used for over 30 years. In the mid-1940s, the Swedish group of Myrbäck151 and the Americans working with Carl F. Cori154 (Department of Pharmacology, St. Louis, MO) described the action mechanism involved in the enzyme synthesis of Schardinger dextrins, in agreement with the results previously published by Freudenberg.93,99−101 Cori, then Myrbäck, was the first to point out that the rate of hydrolysis of Schardinger dextrin was much slower in its initial phase than later on. According to French,132,133 in the initial phase, the rate of hydrolysis of dextrins was 4−5-fold slower than in the final phases, and according to Myrbäck,149 it was 3-fold slower. An interesting observation was reported in several publications:151,155,156 after a few days, the Schardinger dextrins formed under the action of B. macerans gradually disappeared. In 1948, French demonstrated that this observation was due to the reversibility of the action of the enzyme.107,131,135 These investigations into B. macerans covered a period of over 40 years: in the 1940s with the works of Samec,157 of Blinc,152,153 and of Kerr,141,142 in the 1950s by Hale and Rawlings,153 and by Akiya’s group113−116 who claimed certain discoveries for themselves, in the 1960s158,159 and 1970s160 with a few lively debates as to the interpretation of results, then in the early 1980s161 with the appearance of the first commercially available cyclodextrins.

4.3. Other Works during the Period of Reaching Maturity

During this period when the Schardinger dextrins were reaching maturity (1935−1950), we should also mention the studies of Evelyn B. Tilden and Claude S. Hudson (National Institute of Health, Maryland),59,60,138−140 Ralph W. Kerr (Research Laboratories of the Corn Products Refining Co.),141−145 Karl Myrbäck (Institute of Organic Chemistry and Biochemistry, Stockholm),146−151 and Marta Blinc (Mikrobiologie der König Alexander Universität, Ljubljana)152,153 working on the bacteria that produce the dextrins. It is acknowledged that the enzyme in Bacillus macerans responsible for the conversion of starch into dextrin was discovered by the Americans Tilden and Hudson and given the name of cycloamylose glucanotransferase (CGTase or cyclodextrin glucanotransferase).59,60 Tilden and Hudson isolated a cell-free enzyme preparation from B. macerans (Acrobacillus macerans) that had the ability to convert starch into cycloamyloses with interesting yields (∼55%). They showed that the formation of crystalline dextrins was due to an enzyme separable from the bacteria. Prior to this discovery, cycloamyloses were made using live cultures of B. macerans. Tilden and Hudson noted that it was essential to determine the optimal conditions cultural for the production of the enzyme and the optimal pH and temperature for enzyme activity for effective use of the enzyme. They also reported that the type of bacteria was important; for example, the action of B. polymyxa on starch was quite different from that of B. macerans not only 10950


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Mention can also be made of the publications of Kerr141,142 and of Wilson140 who showed, for instance, that the dextrin yield was much higher for fractions rich in amylose than for amylopectin-rich starting materials. Ralph W. Kerr (The Research Laboratories of the Corn Products Refining Co.) also published several studies on the specific action of amylases on starch.143−145 Gruenhut et al. (Research Laboratory Stein Hall and Co., New York) proposed a simple method to form nitrates of the Schardinger dextrins using nitrogen pentoxide in chloroform in the presence of sodium fluoride.162 The structure of the derivatives was confirmed by their X-ray powder patterns. At the end of the 1940s, encouraged by the works of Freudenberg, Friedrich Cramer focused on the properties of Schardinger dextrins, or French cycloamyloses, especially on their inclusion properties. Cramer was the first to use the word cyclodextrins (abbreviated CDs) to define them.163,164 That was, in fact, the title of his doctoral thesis (Ph.D. in 1949 under the supervision of Freudenberg). From 1950 onward, this terminology was increasingly used,165,166 but the nomenclature of CDs remained a subject of debate until the 1990s.167−169 Table 2 gathers the different nomenclatures used up until the middle of the 20th century. Just like the “period of doubt”, the “period of reaching maturity” was nonetheless marked by several contradictory results,17,23,97,99,138,162 due, at least in part, to confusion in the nomenclature, dubious purity of the dextrin samples, and differences in the protocols used.85,86,170,171 In addition, in the late 1940s and early 1950s, researchers had not fully realized the potential of cycloamyloses and had little faith in their complexation properties. Moreover, although the methods for the laboratory-scale preparation were known, these molecules remained very expensive products, and were available only in small amounts as fine chemicals.

several units of D(+) glucopyranose in which the glucose units are bound together by α-(1→4) glycosidic linkages. The structure required special arrangements of functional groups in cycloamylose molecules, resulting in a variety of interesting features: (i) as a consequence of the C-1 conformation of the glucopyranose units, all of the secondary hydroxyl groups were located on one side of the torus, whereas all of the primary hydroxyl groups were located on the opposite side of the torus; (ii) the interior of the torus consisted only of a ring of C−H groups, a ring of glucosidic oxygens, and another ring of C−H groups; and (iii) the interior of the cavity was relatively apolar as compared to water. The C-2 and C-3 hydroxyl groups of the adjacent glucopyranose units form hydrogen bonds, which stabilize the shape of the molecule and at the same time significantly influence its solubility in water. Figure 8 shows a sketch of the characteristic structural features of CDs. In the 1970s, Corey−Pauling−Kultun molecular models of cycloamyloses−cyclodextrins were proposed to describe these features. In the mid-1950s, French who was named Professor of Chemistry (in 1955) and shortly afterward of Biochemistry (in 1960), continued to publish extensively his works on Schardinger dextrins−cycloamyloses. In 1954, he described the reaction occurring during the enzymatic degradation of amylose and, in particular, the mechanism of action of Bacillus macerans by chromatographic experiments,107,173−175 pursuing the work of Freudenberg.93,99−101 This description was also in agreement with the results of Tilden and Hudson,60 Myrbäck,151 and Cori.154 French reported that CGTase, which catalyzes the degradation of starch into cycloamylose, was mainly produced by Bacillus strains, in agreement with the conclusions previously reported by Tilden and Hudson.59,60 It also converts 1,4-linked α-glucans to cycloamyloses, the enzyme being a member of the α-amylase family of glycosyl hydrolases. This enzyme performs three transglycosylation reactions involving cyclization, coupling, and disproportionation (disproportionation activity toward glucose residues), and also a hydrolysis reaction. Cycling is a process of transferring the reducing end sugar to another sugar residue in the same oligosaccharide chain, resulting in the formation of a cyclic compound. CDs are formed by an intramolecular transglycosylation reaction where the terminal 4-OH group of the intermediate acts as an acceptor. This reaction is reversible, and the ring can be opened by the CGTase to undergo further reaction. The coupling reaction is when a CD molecule is combined with a linear oligosaccharide chain to produce longer linear oligosaccharides. Disproportionation is the major transferase reaction in which a linear maltooligosaccharide is cleaved and transferred to a linear acceptor substrate. Hydrolysis is the transfer of the newly formed reducing ends to water, resulting in the oligosaccharides being broken down into smaller units. This schematic representation of the CGTase-catalyzed transglycosylation reaction was finally demonstrated in the 2000s. French also reported that CGTases produced a mixture of α-, β-, and γ-CD in different proportions, and enzymes that were predominantly capable of producing CD could decrease subsequent purification costs.175 At that time, several other laboratories were also investigating the action of B. macerans on starch and published similar conclusions.113,143,156 Cycloamylose glucanotransferases have been detected in various microorganisms, and the glucanotransferase was purified by Hale and Rawlings.156 Several investigators published data on this topic in the 1970s,158−160 and the work before 1980 was

5. EXPLORATION: 1950−1970 Between 1950 and 1970, Schardinger dextrins or French cycloamyloses continued to be investigated, and the studies of Freudenberg and French were finally acknowledged. Freudenberg was thus accredited with the determination of the cyclic structure of dextrins α and β and with the discovery of γdextrin. French was recognized as having determined the structure of γ-dextrin and for having named the cycloamyloses.172 During this period of exploration, the groups working in the lab of the German chemist and philosopher Friedrich Cramer (1923−2003) of the Max Planck Institute für Experimentelle Medizin in Göttingen, the group of the Italian chemist and biochemist Benito Casu (born 1927) at the Istituto di Chimica e Biochimica G. Ronzoni in Milan, and the American group headed by the chemist Myron Lee Bender (1924−1988) of Northwestern University were remarkable, and French’s lab also continued to publish numerous articles on cycloamyloses. 5.1. Dexter French during the Exploration Period

Dexter French was appointed Associate Professor in Chemistry in 1951. At this period, he studied the periodate oxidation reactions that open the glucose units of the dextrins (he demonstrated that periodate oxidation produced neither formic acid nor formaldehyde)136 and the acid hydrolysis reactions,134 and this enabled him to formally demonstrate the cyclic structure proposed by Freudenberg. His main conclusion was that the cycloamyloses are macromolecules composed of 10951


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Table 3. Recap of the Main Results of French on Schardinger Dextrins year

result

1942

(exact) molecular weights of the Schardinger dextrins Schardinger dextrins are cyclic oligosaccharides formed from starch Schardinger dextrins are nonreducing D-glucopyranosyl polymers containing 6, 7, or 8 units linked by α-D-(1→4) bonds the cavity of dextrins is referred to as hydrocarbon in nature introduction of the cycloamylose-based nomenclature description of the mechanism of action for Bacillus macerans demonstration of the concept of glycosidic exchange description of new protocols for the preparation of Schardinger dextrins with high purity facile protocol for the separation and purification of dextrins chemical structure of cycloamyloses types of bonding in the three cycloamyloses and dimensions methylation of cycloamyloses solubility data and effect of temperature molecular size and structure of the γ-dextrin demonstration of the cyclic structure using oxidation reactions: cycloamyloses are macromolecules composed of several units of D(+)-glucopyranose cycloamylose is regarded rather as a truncated cone than a cylinder structure: the secondary hydroxyl groups are located on one side of the torus; the primary hydroxyl groups are located on the opposite side of the torus; the interior of cavity is apolar demonstration of the mechanism of action for Bacillus macerans three transglycosylation reactions are reported in the mechanism CGTase is mainly produced by Bacillus strains French write up an excellent state-of-the art on the Schardinger dextrins the toxicity of the cycloamyloses is reported studies on the formation of inclusion complexes using various techniques involvement of hydrophobic forces in the formation of the complexes possible existence of cycloamyloses with 9, 10, 11, and 12 units of glucose development of a fractionation method for isolation of larger homologues of cycloamyloses structure of ζ-dextrins and η-dextrins

1943 1948 1949 1950

1951

1954

1957 1959 1961 1965

summarized in Kainuma’s excellent review in 1984.161 In 1957, French discovered two other cycloamyloses: δ-dextrin (deltadextrin) and ε-dextrin (epsilon-dextrin) containing 9 and 10 units of glucose, respectively.174,177 French is often mistakenly said to have written the very first review of Schardinger dextrins in 1957.176 The dextrins were described in German by Pringsheim in 1931 in his first book51 and in English in 1932 in a mini-revue,52 and in German by Samec and Blinc in a review dated 1940.178,179 Nevertheless, French wrote up an excellent state-of-the-art of over 70 pages with 159 references, entitled “The Schardinger Dextrins”, on the subject where he described the history of Schardinger dextrins, which he divided into two general periods (the discovery, between 1891 and 1935, and maturity from 1935 to 1950), their characteristics, their chemistry and derivatives, and their biochemical properties. This review was the first “historical survey illustrating the metamorphosis of the Schardinger dextrins”. French’s review also covered the synthesis and production of cycloamylose by B. macerans amylase and summarized conclusions on complexation with small organic molecules, and iodine and iodide. While French’s review is still commonly cited, it contained a significant error. Indeed, the only result of French’s that posed a problem and that led to extensive debate was that of the toxicity of the cycloamyloses.176 The first studies carried out in the rat led to the conclusion that Schardinger dextrins presented a certain toxicity. French and his co-workers observed that the rats refused to eat food containing highly refined dextrins except in very small quantities. Despite the small doses, rat mortality was 100% within a week of introducing highly purified β-dextrin into the diet. Post-mortem examination did not reveal the cause

of death. In his studies, experimental conditions, such as the purity of dextrins, the number of rats treated, or the existence of a control group, were not mentioned. One of the hypotheses was traces of solvent remaining in the dextrins, which the rats could have smelled; they are known to have a highly developed sense of smell.180−182 This result published by French deterred many scientists from developing cycloamylose-containing products for human use. The observations and conclusions drawn by French were only refuted much later following studies with the same animal model.183−187 French concluded his review with (i) “It would appear that the Schardinger dextrins exhibit a toxic effect, possibly by virtue of their remarkable complexing ability, and in any case, the suggestion of Professor Pringsheim that they be used as an energy source by diabetics looks risky” and (ii) “The Schardinger dextrins will continue to serve, delight, teach, and intrigue the carbohydrate chemist for many years to come.” French also studied the formation of inclusion complexes. For example, he used spectrophotometry to study once more the interactions between the cycloamyloses and iodine.171,188−192 He showed that absorption spectroscopy was an interesting method to determine the dissociation constant (Kd) of the inclusion complex between cycloamylose and a substrate.188 The values of Kd can be easily obtained from the observed change in absorbance and the concentration of cycloamylose added according the Benesi−Hildebrand method.193 In 1959, X-ray diffraction studies showed that small molecules such as iodine are able to interact with the cavity of cycloamyloses,192 confirming the studies of Freudenberg and Cramer. French also showed that high temperature cellulose column chromatography was one of the most effective methods 10952


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Figure 9. Schematic illustrations of the association of free cyclodextrin (“host”) and substrate (“guest”) to form substrate−CD complexes.

for the quantitative analysis of mixtures of cycloamyloses.177,194 This method was required in connection with the production of cycloamyloses because these products were simultaneously produced from starch together with the higher series of cycloamyloses. In 1961, Pulley and French177 indicated the existence of cycloamyloses comprising more than 8 glycosyl units, in accordance with the hypothesis published by Freudenberg and Cramer96 in 1948. However, the results on the large cycloamyloses by Pulley and French have for many years been regarded as dubious because they were not able to experimentally distinguish the large cyclodextrins from branched derivatives. In the mid-1960s, French continued to study cycloamyloses with a larger ring. He developed a fractionation method for isolation of larger homologues of cycloamyloses after extensive β-amylase digestion to hydrolyze maltooligosaccharides.177 French reported the structure and the dimensions not only of δ- and ε-dextrins, but also of zetadextrins (ζ-dextrins) and eta-dextrins (η-dextrins) containing 11 and 12 glucose units (French et al., 1965). The discovery of ζ-dextrins and η-dextrins was however attributed to Thoma and Stewart.137 For French, the conclusions available at the end of the 1960s can be summarized into three important points: (i) cycloamyloses are very promising molecules but require further study; (ii) they are expensive when they are modified and thus only available in small quantities; and (iii) they appear to be toxic. This last point was only clarified in the 1970s. The numerous fundamental studies of French led to growth in the interest in these substances as model enzymes and aroma stabilizing agents for the food industry, even though at the time, industrial application of cycloamyloses was still not considered feasible. Professor Dexter French is distinguished not only for his contribution to chemistry, biochemistry, and enzymology of saccharides (and in particular starch) and dextrins (Table 3), but also for his qualities as a teacher and mentor. Among the students he taught, we can mention Harvey Dube, Melvin Levine, Robert McIntire, John H. Pazur, and John Robyt.

Dexter French also received many distinctions and prizes. In 1964, for instance, he received the Hudson Award of the Division of Carbohydrate Chemistry of the American Chemical Society for his contribution to the chemistry of dextrins. He also received the Award of Merit of the Japanese Society of Starch Science in 1971, the Alsberg-Schoch Award of the American Association of Cereal Chemists in 1974, and the Iowa Award of the Iowa Section of the American Chemical Society in 1977. He was an active member of the editorial boards of the Journal of Biological Chemistry, Carbohydrate Research, and Advances in Carbohydrate Chemistry and Biochemistry. The journals Carbohydrate Research and Advances in Carbohydrate Chemistry and Biochemistry devoted a special issue to him in 1978 to celebrate his 60th birthday,195 and then again in 1984.196 5.2. Friedrich Cramer (1923−2003)

Friedrich Cramer was born in Breslau, Poland, on September 20, 1923. He studied chemistry in 1942 in Breslau and a year later continued his studies in Heidelberg, Germany (Ph.D. in 1949), working under the supervision of Professor Freudenberg. The doctoral work done by Cramer on cyclodextrins was published in the early 1950s,197−205 adding to the results of Freudenberg and confirming those of French on the physical (cavity size) and chemical (reactivity) properties, the structure and chemistry of cyclodextrins (CDs). Like French, Cramer also investigated the enzymatic production of CDs, their separation and purification, and characterization.165,206 For instance, Cramer described an easy protocol to separate α-, β-, and γ-CDs from the digest by selective precipitation using appropriate organic compounds. The α-, β-, and γ-CDs could be precipitated by addition of a tetrachloroethylene−tetrachloroethane mixture, followed by the addition of p-cumene. αCD was isolated by selective precipitation with cyclohexane, βCD with fluorobenzene, and γ-CD with anthracene. Cramer showed that the enzyme from B. macerans was active in the pH range 4−8, the optimum being at pH 6. The temperature optimum was at 40 °C.205 Cramer concluded that the 10953


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Cramer determined the dissociation constants of CD complexes of several substrates by kinetic, spectroscopic, and competitive inhibition methods, and studied their chemistry. For instance, Cramer showed that α-CD complexes with phenol and benzoic acid guests in the head first position were more stable than in the tail first position, while β-CD complexes with the same guests preferred the tail first position (Figure 10). This would be confirmed a few years later by Saenger and Szejtli. Cramer also investigated the solubilities of inclusion complexes of 28 various aromatic and aliphatic compounds.212 He showed that guest compounds range from polar substances such as acids, amines, and halogens to highly apolar aliphatic and aromatic hydrocarbons, and even rare gases.211−213 He prepared, for example, crystalline gas complexes by exposing α-CD solutions to various gases at 7− 120 atm pressure for 5−8 days at 20 °C. He reported that by forming inclusion complexes with CD, the solubility and oxidative stability of certain compounds could be increased. Many studies of the formation of inclusion complexes were published and not only by Cramer. For instance, in 1953, Broser and Lautsch used spectrophotometric assay to determine that CD and stain molecules combined in a 1:1 ratio.214 In 1965, Hybl et al. were the first to determine the structure of the complex between α-CD and potassium acetate using three-dimensional X-ray diffraction data.215 They found that in the solid state the acetate anions were complexed by the CD, and this was known as the first direct evidence for molecular complexation. These results also demonstrated the particular structure of CDs: CD cavities were slightly “V” shaped with the secondary hydroxyl side more open than the primary hydroxyl side; the primary hydroxyl groups could rotate so as to partially block the cavity, while the secondary hydroxyl groups on relatively rigid chains could not. Hybl et al. also found that all of the glucose residues of CD are in the 4C1 chair conformation.215 Using these results, Bender and Komiyama reported, in 1978, a schematic diagram of two glucopyranose units of a cyclodextrin molecule illustrating details of the α-(1,4) glycosidic linkage and the numbering system employed to describe the glucopyranose rings.216 At the end of the 1960s, Takeo and Kuge also reported that X-ray crystallography was an interesting method to elucidate the structure of CDs and their complexes.108,109 The first patent concerning applications was called “Method for preparation of inclusion compounds of physiologically active organic compounds” and was filed in 1953 by Karl Freudenberg, Friedrich Cramer, and Hans Plieninger (1914− 1984) and covered the most important aspects of Schardinger dextrins in pharmaceutical formulations.217 In this patent, the authors demonstrated that complexation with dextrins afforded protection against oxidation for substances sensitive to the air and greatly increased the solubility in water of substances with a low solubility. The potential use of Schardinger dextrins in pharmaceuticals had been launched. It was not until the 1970s and 1980s though that the first industrial scale applications appeared (mainly due to the fact that French reported in 1957 the toxicity of cycloamyloses in animal studies). As early as 1953, Cramer gave the basis for supramolecular catalysis involving CDs.202 He showed the catalytic role that CDs could play in chemical reactions through a key−lock interaction similar to that of an enzyme−substrate complex. These results were of fundamental interest at the time, and Professor Alexander Todd invited Cramer for a 1-year visit to his laboratory in Cambdrige.164 Cramer returned to Heidelberg

superiority of his method over previous procedures resided in the technical ease and the completeness of precipitation. He explained his results by the difference in the sizes of cavities of α-, β-, and γ-CDs. Similar results were previously reported by French.132,177 However, Cramer was mainly recognized for his work on inclusion complexes in solution and in the solid state (Figure 9), although they were only fully acknowledged at the end of the 1970s.200,203,205,208 Cramer showed that the main value of CDs resided in their ring structure and their consequent ability to include guest molecules inside their internal cavity. As regards the inclusion complex formation (Figure 10), CD should be regarded rather

Figure 10. Two possible penetration pathways (left, head first; right, tail first) for benzoic acid, phenol, and methylated benzoic acids (X = COOH or OH; R1, R2, R3 = H or CH3).

as a truncated cone than a cylinder (Figure 9). This was at the origin of many (future) applications. Indeed between 1952 and 1954, Cramer discovered that the toroidal form of these molecules enabled them to accept various molecules inside their cavity, confirming the hypotheses Schardinger put forward at the beginning of the 19th century.201 Cramer then commenced the study of the complexation phenomena.208 For instance, he studied the effect of cyclodextrins on the optical spectra of dye molecules. Methylene Blue forms an inclusion complex resulting in the basochromic shift of its two absorption maxima by 5 and 10 nm, respectively. In 1956, he introduced the notion of “inclusion complex”.205−207 Note however that a very similar term in German, “einschlussverbindungen” (literally “inclusion compounds”), was coined by W. Schlenk in 1950.209,210 Cramer showed how CDs can act as refuge molecules, able to reversibly form complexes with molecules inserted into their internal cavity, giving rise to inclusion complexes.211,212 The interior of the cavity is considered as a lipophilic microenvironment into which a nonpolar hydrophobic molecule can slide. This raises two important points: (i) no covalent bonding occurs between the CD and the molecule it accepts; and (ii) the association− dissociation of the two parts is in equilibrium. The guest is maintained within the cavity by noncovalent forces (hydrogen bonding, hydrophobic interactions, and van der Waals forces), which are thus weak and enable the whole system to be reversible. In the nomenclature proposed by Cramer, if the guest is located within the CD cavity, then the two elements together are known as an inclusion complex. Thus, the formation of such complexes implies that the size of the guest molecule must correspond to that of the host cavity. If the guest interacts with the host outside the cavity, then the interaction is said to lead to an association complex. Moreover, the outer part of the host must be compatible with the solvent used to avoid problems of insolubility or aggregation. 10954


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of oligonucleotides, nucleic acid chemistry, etc.) and talents (chemist, philosopher, painter, etc.). He died on June 24, 2003 shortly before his 80th birthday. In 2003, Fritz Eckstein (MaxPlanck-Institute für Experimentelle Medizin, Göttingen)164 wrote: “Friedrich Cramer’s death coincides with the end of an era following the Second World War during which the rebuilding of respect and recognition for Germany was of prime concern. Cramer contributed greatly to this endeavour.”

in 1954 and accepted the position of professor of Organic Chemistry at the Technische Hochschule Darmstad in 1959. He continued to work on the chemistry of the CDs, and especially their uses in catalysis.218−225 For instance, in 1958, he was the first to observe a CD-accelerated reaction studying the hydrolysis of ethyl p-chloromandelate in the presence of αCD.219 Cramer also showed that CDs accelerated reactions such as decarboxylation, oxidation, and cleavage of organophosphates.218,220−224 In 1965, studying the accelerated hydrolysis of pyrophosphates in the presence of CD, he observed that cycloamyloses had a potential for acid−base catalysis similar to that of naturally occurring enzymes (ribonucleases, proteases).226,227 In each study, he concluded that the catalysis by CDs took place through inclusion complex formation of substrates. He showed that not only can CDs be used as accelerating agents but also as an asymmetric agent. It is acknowledged that the phenomenon of CD catalysis was recognized by Cramer. Excellent reviews on this topic have been published by Bender in 1973,228 Szejtli in 1982,181 and Sirlin in 1984.225 In 1962, Cramer became a member of the Max-PlanckGesellschaft and Director of the Department of Chemistry at the newly created Institute für Experimentelle Medizin in Göttingen. He continued to work on the inclusion complexes of the CDs, but focused his research mainly on the study of nucleic acids. In 1967, Cramer was studying the UV spectra of p-nitrophenolate at pH 11 in the presence of increasing quantities of α-CD. He demonstrated that the inclusion complex between sodium p-nitrophenolate and α-CD in aqueous solution led to a steady shift toward longer wavelengths as the concentration of α-CD was increased. Cramer also used fluorescence to determine the dissociation constant of the inclusion complex.229 That same year, he was able to detail the mechanism of formation of an inclusion complex and gave the first scientific explanation.230 He noted that the formation of a CD/substrate inclusion complex includes five elementary steps: (1) the substrate approaches the CD molecule; water molecules escape from the CD cavity and acquires a new energy level, corresponding to that of the gaseous state; the van der Waals interactions and the number of hydrogen bonds decrease, whereas the degrees of freedom of translation and rotation of the freed water molecules increase; (2) the guest molecule becomes released from the layer of water that envelops it and also acquires a different state; the layer of water becomes dispersed and rearranges; (3) the guest molecule, considered to be in a perfect gas state, enters the cavity, and the complex formed is stabilized by van der Waals forces and/or hydrogen bonds; (4) the expelled water molecules are rearranged and form hydrogen bonds between each other; and (5) the structure of the water is restored around the part of the substrate that remains in contact with the solvent and that is integrated into the hydration shell around the CD.231,232 Cramer’s work on inclusion complexes established much of our modern understanding of the behavior of CDs during complexation and includes many fundamental details on the structure and physicochemical properties (cavity size, solubility, reactivity, etc.) and remains a commonly cited source to this day. The first reports of their potential use as enzyme models, their solubilization effect toward waterinsoluble substrates, and their stabilization and destabilization effects on labile compounds were also attributed to Cramer. Professor Friedrich Cramer had many varied scientific interests (CD chemistry and CDs as enzyme models, synthesis

5.3. Benito Casu

In the mid-1960s, the works of Professor Benito Casu (G. Ronzoni Institute, Italy) on the structure and the conformations of amylose, using the then highly innovative spectrometric techniques, were acknowledged to have made an important contribution.233−251 Benito Casu, born in 1927 in Brescia (Italy), studied chemistry at the universities of Milan and Pavia and obtained the professorship in Chemical Spectroscopy in 1968. Casu was a Harold Hibbert Memorial Fellow (1968− 1969) at the Department of Chemistry of McGill University of Montreal, guest of Professor Arthur S. Perlin as visiting scientist. Casu showed that proton nuclear magnetic resonance (1H NMR) and infrared spectroscopy were powerful methods to study the conformations of not only amylose but also CDs.234,245,247 In 1964, he reported the infrared spectra of four different hydrates of α-CD. 233,234 In 1966, Casu demonstrated that the amylose molecule has a flexible structure, with a helical pattern, which can take various conformations through rotation of the monomeric blocks around the glucosidic linkages.235 IR and NMR spectra showed that the C1−H bond was equatorial and C1−O axial, also confirming the C1 chair conformation of the glucopyranose units. Casu also showed the existence of intermolecular hydrogen bonds contributing to the stabilization of the helical structures. He obtained similar results when studying the CDs, in particular α-CD, with the first IR and NMR spectroscopic studies.238,242−246 His works demonstrated that the Dglucopyranose units in CDs were in the C1 chair conformation and the primary and secondary hydroxyl groups had conformation similar to those in the crystalline state. These results were pertinent because most of the reactions in which CDs were involved were carried out in solution (mostly in water). Using NMR of α-CD in DMSO-d6 through hydrogen− deuterium exchanges of CDs and infrared spectra, Casu was first to show the existence in water of hydrogen bonds between the secondary hydroxyl functions, which brought about a slight chemical shift in the protons of these functions, and he determined the value of the deuteration equilibrium constant of the same functions. The hydrogen bonds in β-CD were also stronger than those in α-CD. On raising the temperature, the hydroxyl signals shifted to higher fields, which was indicative of a weakening of the hydrogen bonds. At the same time, the signals for the anomeric protons remained practically unchanged. The results were in accordance with the presence of intramolecular hydrogen bonding in CDs previously proposed, in 1965, by Hybl et al. on the basis of X-ray crystallography data.215 Three years later (1968), Cramer et al. also published similar results using optical rotator dispersion spectroscopy.231 One year later (1969), Takeo and Kuge,108,109 investigating the NMR spectra of β-CD and γ-CD (DMSO-d6 at 25 and 80 °C), showed that hydrogen bonds were stronger in γ-CD than in β-CD. Casu also showed that 1H NMR spectroscopy was applicable to quantitative analysis of 10955


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to a protein receptor, enzyme-catalyzed reactions, cell recognition, etc. Because of their specific characteristics, cyclodextrins also played an important role in the creation of molecular scaffolds for enzymology and catalysis alongside other cage molecules (e.g., ethers, clathrates, intercalates, zeolites, porphyrins, cyclophanes). Bender was also recognized for his work on the structure of CDs and inclusion complexes. Like Cramer, Bender demonstrated that one of the most important characteristics of CDs was the formation of inclusion complexes with various guests where these molecules were included inside the CD cavity (the host). In various publications, he showed that inclusion complex formation causes changes in ultraviolet absorption spectra of substrates.258,260 For instance, addition of α-CD to an aqueous solution of p-tert-butylphenol caused a spectral change almost identical to that observed when the phenol was dissolved in dioxane. Glucose, which has no cavity, showed no significant effect on the absorption spectrum. At that time, similar results were reported using fluorescence measurements229 and NMR techniques.262,263

concentrated solutions of mixtures of CDs in dimethyl sulfoxide.245 Casu was among the first to publish general notes and reviews on CDs.243,244,249,251 Other articles for a broader public were published a few years later by Raymond J. Bergeron (University of Maryland)252,253 and especially by József Szejtli (Cyclolab, Ltd., Hungary).254−256 Casu abandoned his research on cyclodextrins in the mid-1970s and focused his work on biologically active natural substances such as heparin. Indeed, Professor Benito Casu is recognized for his contribution to the chemistry and biochemistry of glycosaminoglycans (from 1992 to 2012, with Prof. Job Harenberg, Casu organized 20 symposia on glycosaminoglycans at Villa Vigoni, Italy). He received many distinctions and prizes (among which the degree of doctor in medicine Honoris causa at the University of Uppsala in 1998, the gold medal of the Carbohydrate Group of the Italian Chemical Society in 2003, and recognition plaques from the Italian Cyclodextrin Group in 2009, and the International Union of Angiology in 2012). Professor Casu has published an impressive number of articles and patents and is still Scientific Consultant of the Administration board of the G. Ronzoni Institute for Chemical and Biochemical Research in Milan.

5.5. Other Works during the Exploration Period

French’s state-of-the-art published in 1957 was continued a few years later by John A. Thoma and Lynn Stewart (Indiana School of Medicine, Indianapolis, IN)137 and George V. Caesar (Harbor Beach, MI).272 Research on cycloamyloses from 1956 to 1963 was described in 1965 in an excellent review based on 175 references by Thoma and Stewart137 covering various topics such as isolation, properties including qualitative and quantitative aspects of complex formation, characteristics of B. macerans amylase, and cycloamyloses as models for enzymes. An extensive list of publications on these topics was also compiled by Caesar272 three years later. In the mid-1960s, research started to look toward using CD polymers in the separation of molecules with the first publications appearing from Jürg Solms’264 lab in Switzerland and Niels Wiedenhof265 in The Netherlands. Our group has recently published a state-of-the-art covering over 50 years of research into applications of CD polymers for the environment.266 However, these polymers did not lead to actual industrial applications, even though numerous results were published and several patents filed, especially concerning chromatographic separation.266−271 Coming to the end of the maturation period (1950−1970), the structures and physicochemical properties of CDs and their ability to form inclusion complexes had been completely elucidated, as was their preparation and the mechanism of action of B. macerans.108,175 For instance, the protocols for CD synthesis were well-defined. CD preparation was divided into four main stages: (1) culture of the microorganism producing the enzyme CGTase; (2) the separation of the enzyme from the growth medium, its concentration, and purification; (3) enzymatic conversion of starch in aqueous solution into a mixture of cyclic and noncyclic dextrins; and finally (4) separation of the products, purification, and crystallization of the CDs. Obtaining CDs was admittedly not straightforward, but the difficulties were well understood: the production on an industrial scale of CGTase from B. macerans (heat labile); relatively low yield of CD from the starting material (mainly starches, the proportion of amylose varying between 15% and 25%); instability of the amylose solutions (amylose is subject to untimely precipitation and to aggregation over time); degradation of the starch by CGTase leading to a mixture of

5.4. Myron Lee Bender (1924−1988)

At the same time, much attention was focused on the use of dextrins for catalysis and as enzyme models. Indeed, several researchers observed that cycloamyloses had a potential for acid−base catalysis similar to that of naturally occurring enzymes.226 The discovery of the enzymes involved is attributed to Hudson and Tilden in the 1940s, and, as early as 1953, Cramer gave the basis for supramolecular catalysis involving CDs. However, one name stands out in particular in the enzymology and catalysis by cycloamyloses, that of the American chemist Myron Lee Bender of Northwestern University. His lab excelled in this subject with several of their studies that are still reference works today.228,257−260 Myron Lee Bender was born (May 20, 1924) and raised in St. Louis, MO. He obtained his Ph.D. degree in 1948 from Purdue University under the direction of Professor Henry B. Hass. After three postdoctoral research jobs (Harvard University, University of Chicago, and University of Connecticut), he joined the Department of Chemistry of the Illinois Institute of Technology in 1951. In 1960, he accepted a position in the Department of Chemistry at Northwestern University as Professor in Chemistry and Biochemistry, where he remained throughout the rest of his career.261 Bender’s research was concerned with the mechanism of organic reactions,257 particularly those of enzyme models, along with the mechanism of the enzymatic processes themselves. With Cramer, Bender was among the very first to recognize that the chemistry of the future would involve complexation phenomena. To mimic enzymatic behavior, Bender focused his works on cyclodextrins. In 1967, he wrote:259 “The reaction system constitutes a striking model for the lock and key theory of enzymatic specificity proposed by Emil Fisher.” From this, he initiated the era of biomimetic chemistry (including artificial enzymes, molecular recognition, and “bioinsipired” reactivity), and he paved the way for others. At the end of the 1960s, the works of Bender made the creation of artificial enzymes possible. Supramolecular chemistry allowed the design of artificial systems called “supermolecules” able to imitate or to copy elements of the living world and, above all, biological processes such as recognition processes, binding of a substrate 10956


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mechanism of formation both in solution and solid state.278−280 Using X-ray crystallography, he demonstrated that the ratios of guest to host were nonstoichiometric in the crystalline state in contrast to 1:1 inclusion complexes in solution. This was associated with the three-dimensional structure of crystalline inclusion complexes.283 Saenger suggested the presence of two different forms of inclusion complexes in the crystalline state, channel and cage-type structures.278 On the basis of the mechanism proposed in 1967 by Cramer, in 1976, Saenger gave three explanations for the formation of an inclusion complex with α-CD in aqueous solution: (1) the guest molecule directly replaces the water molecules in the cavity; (2) the CD molecules absorb the energy of the water molecules retained in the cavity and take on a relaxed conformation (in this state the water molecules can be easily substituted by another guest); and (3) the guest becomes associated with the outer surface of the CD and only enters the cavity once it has absorbed the activation energy (transfer of the conformation from a state of high energy of the CD−water complex to a state of lower energy of the CD−guest molecule complex). Saenger speaks of the release of the tension energy within the CD molecule upon formation of the complex. The same year, Bergeron and Rowan,284 performing an NMR study, showed that the London forces and the release of high-energy water molecules from the cavity are the main contributors to the inclusion of p-nitrophenolate into α-CD and β-CD without demonstrating the involvement of Saenger’s tension energy. Saenger’s description (like that of Bender two years later) of the formation of an inclusion complex mainly involved hydrophobic interactions. Much controversy and debate surrounded the nature of the binding forces. A nonpolar binding force is usually characterized by a highly favorable variation of entropy. However, it was noted that the formation of an inclusion complex paralleled a favorable change in enthalpy and an unfavorable change in entropy. Significant theoretical works were published by Saenger.285−292 For instance, X-ray crystallography and neutron studies were performed to determine the structure of α-CD hexahydrate. It was found that not all six glucose residues were equivalent; rather one of the six glucose residues in α-CD was rotated in such a way that its ring was more normal to the axis of the toroidal molecule than the other five glucose rings. Thus, the macrocyclic α-CD hexahydrate ring was distorted.280 In 1977, Saenger, using 1H NMR spectroscopy and computer simulation, showed (i) that all six glucose units had identical conformations, (ii) that the α-CD molecule had hexagonal symmetry, and (iii) the presence of intramolecular hydrogen bonding in CDs,285 confirming the previous conclusions of Hybl et al.,215 Casu,235 and Cramer.224 He concluded that the conformation of the glucopyranoses units was always a 4C1 chair, which, in the smaller cyclic oligomers α-CD and β-CD, was slightly distorted to close the macrocyclic frame. Between 1978 and 1982, Lindner and Saenger showed, from crystallographic studies, that β-CD is associated with 12 molecules of water; that is, it is a dodecahydrate.281,286 These 12 molecules occupy regular positions in the crystal lattice, the CD cavity being occupied by 6.5 molecules of water statistically distributed over eight sites. The other 5.5 water molecules are distributed among another 8 sites occurring between the CD molecules.287 Saenger also published in 1980 the very first review of industrial applications of CDs282 and in 1984 a thorough state-of-the-art of inclusion complexes.288 Since 1981, Saenger has held the chair for crystallography at the Freie

CDs, maltose, and various oligosaccharides that must then be fractionated; toxicity of the solvents used for selective precipitation (the first solvents used were trichloroethylene and bromobenzene); and difficulty to produce CDs of over 8 glucose units (purification difficulties). It was only in 1979 that industrial scale production really started when advances in genetic engineering allowed the tailoring of CGTases to increase activity, selectivity, and specificity toward different CDs, leading to high-purity products suitable for pharmaceutical and food uses. Currently, the synthesis protocols are welldefined and well controlled, and several large companies share the market. However, during this period, their apparent high toxicity cast doubt on the possibility of their consumption by humans.

6. THE PERIOD OF APPLICATION: FROM 1970 UNTIL NOW In this “applied research” period, work on the Bacillus macerans enzyme led to a new method of purification, development of the action pattern, and the cyclization of linear starch chains. Since 1970, effort has been focused on finding new microorganisms that produce cycloamylose glucanotransferases, to purify the enzymes using modern enzymological techniques, to examine the chemical properties of the enzymes, and to produce cycloamyloses on a large scale to meet the needs of industrial applications. However, as already mentioned, the presumed toxicity of CDs remained the main obstacle to their development, although in the middle of the 1960s several studies showed that it was the impurities that they trap that can make them toxic.184,185,274 From the 1970s, the nontoxicity of CDs became increasingly accepted, and several manufacturers started to produce and to market CDs (the Japanese Nihon Shokukin Kako, the German Wacker Chemie, the Hungarian Chinoin Pharmaceutical Chemical Works, the French Roquette Frères, etc.). With the industrialization of their production, the price of CDs dropped considerably (especially from 1984), contributing enormously to their development.275−277 It was during the period of application, from 1970 to current times, that two names stand out: Wolfram Saenger (born 1939) at the Max-Planck-Institut für Experimentelle Medizin of Göttingen, who studied under Cramer, and József Szejtli (1933−2004) at the Cyclodextrin Research and Development Laboratory of Budapest. However, at the time, apart from these two, especially Szejtli, very few researchers were convinced of the industrial potential of CDs. 6.1. Wolfram Saenger

In the mid-1970s, the German biochemist and crystallographer Wolfram Saenger clearly demonstrated that CDs are macrocyclic structures that form a cavity shaped like a truncated cone.6,278−282 They did this from analysis of the crystal structure, over 20 years after Cramer’s discovery.200 Wolfram Saenger was born in 1939 in Frankfurt and received his Ph.D. in 1965 in Darmstadt. After a postdoctoral stay at Harvard University with Professor Jack Z. Gougoutas, he joined the Max-Planck-Institut für Experimentelle Medizin (Göttingen) where he began studies on the X-ray crystal structure analysis of oligosaccharides, proteins, and nucleic acids. At the beginning of his scientific career, Saenger was also interested by cyclodextrins, and in particular their inclusion complexes. In a series of 46 publications (between 1973 and 2000) entitled “Topography of Cyclodextrin Inclusion Complexes”, Saenger examined the inclusion properties of the CDs and their 10957


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Figure 11. Schematic representation of CD inclusion complex formation: p-xylene is the guest molecule, and the small circles represent the water molecules. Reprinted with permission from ref 317. Copyright 2014 American Chemical Society.

Universität Berlin where he focuses on research in proteins. Indeed, Professor Saenger is also known for his research on Xray crystallography of membrane proteins and protein−nucleic acid complexes, for which he received many prizes (Humboldt Prize in 1988, etc.). He has authored over 500 publications and 10 books.

Professor Bender published more than 200 papers, 18 monographs, and 5 books. He was an active member of the journal Bioorganic Chemistry and received many distinctions and prizes such as the Midwest Award of the American Chemical Society. 6.3. József Szejtli (1933−2004)

6.2. The Works of Myron Lee Bender during the Period of Application

The list of prestigious researchers who have contributed to the development of CD of course includes Professor József Szejtli (1933−2004) of Chinoin Pharmaceutical Chemical Works, then the Cyclodextrin Research and Development Laboratory (CYCLOLAB, Ltd., Budapest). József Szejtli, born in 1933 in Nagykanizsa (Hungary), received his Ph.D. in 1961 at the Technical University of Budapest. After a postdoctoral stay at the Technical University of Trondheim (Norway, 1963−1964) and another in Germany (Institute of Nutrition of Potsdam, 1965−1966), he accepted a position of professor at the University of Havana (Cuba) from 1967 to 1970. He returned to Hungary in 1971 as Head of the Biochemistry Research Laboratory of Chinoin Pharmaceutical Chemical Works (1971−1988), and, in 1972, he founded the Cyclodextrin Research and Development Laboratory (CYCLOLAB, Ltd.). Szejtli started to study CDs in the middle of the 1960s,295−300 but it was only in the 1980s301−303 that he made an important contribution to the chemistry of CDs, to the dissemination of results and in their industrial application, notably by the creation of a company in 1972 (CYCLOLAB Ltd.) totally devoted to CDs (“from toy to tool with industrial interest”) and to the publication of numerous general reviews (Figure 11).304−320 CYCLOLAB was the first private research institute for the technological transfer between CD research and industry. In 1981, Szejtli organized the First International Cyclodextrin Symposium in Budapest. One year later, the first CD book written by Szejtli was published.181 Szejtli pursued and reformulated the interpretations made by Cramer, Saenger, and Bender on the mechanism of formation of inclusion complexes (Figure 10).181,309 In 1982, he explained the gain in enthalpy by the spontaneous arrival of the guest, displacing active water molecules retained in the nonpolar cavity of the CD in aqueous solution.181 The water molecules are in an unfavorable energy state due to the polar−apolar interactions and are thus easily displaced by more suitable molecules, that is, less polar than water. Moreover, organic substances dissolved in water show a preference for hydrophobic environments. Szejtli supports the idea that, although van der Waals interactions and hydrogen bonding play an important role, the main force behind the formation of the complexes is the stabilizing reduction of the whole system’s energy on the replacement of the high enthalpy water molecules in the cavity, by hydrophobic molecules leading to apolar−apolar bonding. He proposed that this bonding was too weak to be alone responsible for the

Bender showed that CDs can accelerate many kinds of chemical reactions such as cleavage of esters, amides, organophosphates, carbonates or sulfates, intramolecular acyl migration, and decarboxylation.216,293,294 Cyclodextrin-catalyzed reactions showed many of the kinetic features shown by enzymatic reactions including saturation, stereospecific catalyzes, and D,Lspecificity, as well as substrate−catalyst complex formation and competitive inhibition. Bender concluded that CDs can serve as models of certain enzymes and classified the reactions in two categories: covalent catalysis in which CDs catalyze reactions via formation of covalent intermediates and noncovalent catalysis in which CDs provide their cavities as apolar or sterically restricted reaction fields without the formation of any covalent intermediates. For the covalent catalysis reaction, a prerequisite is the proximity between the catalytic sites of the CDs and the reactive sites of the guest molecule; the first step of covalent catalysis for an ester cleavage by CDs is complex formation between CD and substrate; the second step is the nucleophilic attack by one of the hydroxyl groups of the CDs on the substrate resulting in a covalent intermediate. In 1978, Professor Bender and Dr. Makoto Komiyama (postdoctoral research associate in chemistry) edited the first book devoted entirely to the chemistry of CDs.216 In it, they cover all of the aspects of catalysis by cyclodextrins, and in particular the chemical modifications of cyclodextrins to make them better catalysts. In this book, Bender and Komiyama also described the conclusions of their studies of inclusion complexes. Bender’s lab had fully elucidated the mechanism of formation of the complexes initially proposed by Cramer and developed by Saenger. Bender and Komiyama were the first to observe and interpret the fact that the complexation reaction involved a gain in enthalpy and a loss of entropy. The further the guest molecule penetrates into the CD cavity, the greater is the change in enthalpy, and the higher is the stability of the complex. Moreover, the greater is the apolarity of the guest, the more this phenomenon is marked. Bender and Komiyama proposed four interpretations: (1) formation of weak bonding of the van der Waals type (dipole−dipole interactions) between host and guest; (2) the formation of hydrogen bonds between the guest molecule and the hydroxyls of the CD; (3) the release of high-energy water molecules displaced by the entering guest; and (4) the release of tension energy within the CD molecule upon formation of the complex. Over a period of 30 years, 10958


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Table 4. Selected Book Chapters and Reviews on Cyclodextrins Published by Szejtli year

book chapters

1984 1987

Industrial applications of cyclodextrins. Inclusion Compounds; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Eds.; Academic Press: London, Vol. 3, pp 331−390 The metabolism, toxicity and biological effects of cyclodextrins. Cyclodextrins and Their Industrial Uses; Duchêne, D., Ed.; Editions de Santé: Paris, Chapter 5, pp 173−210 The use of cyclodextrins in biotechnological operations. New Trends in Cyclodextrins and Derivatives; Duchêne, D., Ed.; Editions de Santé: Paris, Chapter 17, pp 595−626 Cyclodextrins and their applications in biotechnology. Minutes of the Sixth International Symposium on Cyclodextrins; Hedges, R. A., Ed.; Editions de Santé: Paris, pp 380−389 Use of cyclodextrins in chemical products and processes. Comprehensive Supramolecular Chemistry; Szejtli, J., Osa, T., Eds.; Pergamon Oxford: London, Vol. 3, pp 603−614 Cyclodextrins. Chemical and Functional Properties of Food Saccharides; Tomasik, P., Ed.; CRC Press: New York, Chapter 17, pp 271−290 year reviews

1991 1992 1996 2003

1982 1985 1986 1987 1990 1994 1997 1998 1999 2002 2004 2004 2004

Cyclodextrins in food, cosmetics and toiletries. Stärke 34, 379−385 Cyclodextrins: A new group of industrial basic materials. Nahrung Food 29, 911−924. Cyclodextrins in biotechnology. Stärke 38, 388−390 Cyclodextrins and the molecular encapsulation. Chimica Oggi, 17−21 Cyclodextrins in the reduction of environmental pollution. Carbohydrate Polymers 12, 375−392 Medicinal applications of cyclodextrins. Medicinal Research Reviews 14, 353−386 Utilization of cyclodextrins in industrial products and processes. Journal of Materials Chemistry 7, 575−587 Introduction and general overview of cyclodextrin chemistry. Chemical Reviews 98, 1743−1753 Highly soluble cyclodextrin derivatives: Chemistry, properties, and trends in development. Advanced Drug Delivery Reviews 36, 17−28 The role of cyclodextrins in chiral selective chromatography. Trends in Analytical Chemistry 21, 379−388 Cyclodextrins in the textile industry. Starch/Stärke 55, 191−196 Past, present, and future of cyclodextrin. Pure and Applied Chemistry 76, 1825−1845 Cyclodextrins as food ingredients. Trends in Food Science & Technology 15, 137−142

dipole interactions during the complexation of substrates with strong dipole moments (e.g., phenols).328 Native CDs are not ionic, but electrostatic interactions with the guest are possible because CDs do have a dipole moment. However, despite the numerous results published showing that a whole set of interactions are involved, there is still debate as to the extent to which each of the forces contributes to the formation of the complex. At the end of the 1980s, Szejtli reported numerous experimental data, and he wrote two other books182,309 on CDs, which are still considered as reference works in the CD community for the synthesis, description, characterization, properties, chemistry, biochemistry, biotechnology, and catalysis. In his second book “Cyclodextrin Technology” published in 1988, he described cyclodextrin-catalyzed reactions in details. He showed that CDs can accelerate or decelerate various kinds of reactions (oxidation, hydrolysis, decarboxylation, nitrosation, isomerization, etc.), in accordance with the conclusions previously reported by Bender. The reaction rates depend on the CD used and the kind and stability of the inclusion compound formed. In this monograph, Szejtli also expressed his doubts as to whether CDs larger than γ-CD exist. In 1998, he pursued the history of cyclodextrins written by French in 1957,317 which was also updated 9 years later by Loftsson and Duchêne.321 The history as written by Szejtli was divided into three major periods: discovery (1891−1935), exploration (1935−1970), and utilization (1970 to the present day). In the various reviews he has written (Table 4), Szejtli shows that the various applications mainly take advantage of the different possible consequences of the encapsulation of the guest molecule within the CD. They can be summed into five points: (1) the modification of the physicochemical properties of the guest molecule; substances with low solubility in water become more soluble after complexation; certain unpleasant tastes can be eliminated, the color of certain substances can be altered because inclusion can change the spectral properties of the guest, etc.; (2) the modification of the chemical activity of

higher stability of the complex and showed the parallel occurrence of steric interactions. Indeed, he also demonstrated in various publications that the preferred position for the guest compound inside the cavity also depended on steric interactions. Szejtli concluded that the complexation phenomenon results from a multitude of interactions between the three components of the system CD−substrate−solvent leading to a state that is more thermodynamically stable overall. In the 1990s and 2000s, there was a general agreement in the literature322−335 that during the formation of an inclusion complex a whole set of intermolecular interactions comes into play (hydrogen bonds, van der Waals forces, hydrophobic interactions, steric interactions, etc.) and that each one has its own role in the overall process. For instance, Buvari and Barcza in 1988 showed that delocalization of the resonance charge increases the electron density and the polarizability of the substrate, increasing the London forces and hence the stability of the complex.323 This is the reason for which sodium pnitrophenolate forms a more stable complex with β-CD than pnitrophenol. The same year, Palepu and Reinsborough reported that the conductivity of solutions of anionic surfactants was strongly affected by the formation of inclusion complexes with CD.335 They explained their results mainly by the amphiphilicity of the guest molecules, which leads to strongly associated species considerably affecting the conductivity of the solution. In 1991, Nishijo et al. showed that fluorescence also provides interesting data to characterize the formation of the 6-ptoluidinylnaphthalene-2-sulfonate and β-CD inclusion complex, using the geometry of the substrate and the various interactions.336,337 In 1992, Suzuki et al. stressed the importance of the van der Waals forces.325 However, they showed that these dipole−dipole interactions can lead to the formation of unexpected complexes: in azo dyes, despite its great bulk, the sulfonate part is inserted into the cavity. Although they are often the subject of debate, these forces also play a role in the stabilization of the complex. In 1997, Hamai and Satoh reported the preponderance of electrostatic dipole− 10959


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interior would be considerably shielded by the guest, indicating the formation of inclusion complexes, while the hydrogen atoms on the outer surface would not be so affected. They described the chemical shifts of protons H-3 and H-5 of CD as they varied with the different complexes studied.263 The H-3 and H-5 atoms of α-CD, which are directed toward the interior of the CD cavity, showed a significant upfield shift upon addition of substituted benzoic acids to CD solutions in D2O. The authors proposed that the large upfield shift for the H-3 and H-5 atoms could be ascribed to an anisotropic shielding effect of the benzene rings of the benzoic acids included in the cyclodextrin cavity. They also put forward hypotheses on the differences in hydrophobicity of the complexed molecules to explain the differences in the values of δ ppm. Thakkar and Demarco concluded that the most direct evidence for the inclusion of a guest into the CD cavity in solution was obtained by 1H NMR spectroscopy. Similar conclusions were reported by Bergeron et al.284,342,343 and Wood et al.285 Bergeron and collaborators studied in detail the molecular dispositions of guest compounds (ortho-, meta-, and para-isomers of nitrophenol and benzoic acid) in the CD cavities by the use of 1H NMR and 13C NMR spectroscopies.342,343 They demonstrated the formation of an inclusion complex, and their results were used to calculate the dissociation constant of the different complexes. Wood et al., studying the formation of the inclusion complex of p-iodoaniline with α-CD using NMR at 220 MHz, demonstrated that the chemical shifts of the H-1, H-2, and H-4 protons were unaffected, while the H-3 protons showed an upfield shift due to the anisotropic shielding effect of the benzene ring of p-iodoaniline and the H-5 protons a downfield shift interpreted in terms of the van der Waals deshielding effect of the iodine atom of p-iodoaniline.285 All pf the results and interpretations indicated the inclusion of the guest in the CD cavity. Wood et al. also showed the similarity of structure of α-CD in solution and in the solid state.285 A few years later, Li and Purdy studied the inclusion of N-(2,4-dinitrophenyl)-Lvaline into β-CD by NMR spectroscopy.344 They found that the formation of the complex paralleled the progressive shielding of the triplet of the H-3 proton of the CD and of the H-5 proton peak originally superimposed on that of proton H-6. Other techniques were also regularly applied to the study of inclusion complexes. For instance, Harata and Uedaira, studying the complex of β-CD with naphthalene substituted in position 1 or 2, showed that the modification of the circular dichroism that occurred depended on the geometry of both the host and the guest molecules.345 A positive circular dichroism band implies axial inclusion (along the Cn symmetry axis), whereas a negative band signifies equatorial inclusion (perpendicular to the Cn axis). Using induced circular dichroism studies, Szejtli also indicated that the sign and intensity of the induced Cotton effects were quite sensitive to the orientation of the guest chromophore in the CD cavity.181,309 If the electric dipole moment coincided with the axis of the CD, a positive Cotton effect was observed. When they were perpendicular to each other, a negative Cotton effect was observed. The circular dichroism spectra of 1- and 2naphthols were therefore quite different: the naphthalene ring in one case was accommodated crosswise, and in the other case lengthwise in the CD cavity. In the complexes of 2naphthalenes, the inclusion was axial (Figure 12). Pharmaceutical applications started to appear in the mid1970s and rapidly gained ground.348−352 Development was specially marked for use in enhancing the solubility of drugs,

the guest; reactive substances can be protected by inclusion reducing the risks when they are mixed with other substances; chemical reactions can be carried out selectively, the CDs playing the role of catalysts, etc.; (3) the stabilization of substances sensitive to light or to oxygen, etc.; (4) the uptake of volatile substances; storage and handling of certain toxic substances such as pesticides can be improved; savings can be made on the quantity of substance required due to reduced evaporation, etc.; and (5) the complexation, extraction, and transport of pollutants. Szejtli also showed that CDs are highly versatile molecules that lend themselves to being modified and used either in the dissolved form or as solids. This means that the different physical or chemical forms they can take can include particles (aggregates, microspheres), soluble or insoluble polymers, polymers with CDs grafted on, gels and hydrogels, CD-based materials (modified silica or organic resins, etc.) or membranes, molecular superstructures (polyrotaxanes, etc.), or nanoparticles. These different soluble and insoluble forms are very useful when considering pharmaceutical or biomedical applications. Professor József Szejtli was an eminent scientist and visionary. He was most likely the first to believe in the possibilities of industrial production and the multiple applications of CDs. He had many varied scientific interests (CDs for chemistry, food, biochemistry, enzymology, catalysis, chromatography, cosmetics, textile, agriculture, remediation, etc.). Szejtli is distinguished for his important contribution to the dissemination of knowledge about CD and gave numerous conferences throughout the world. His name is very often cited in the bibliographic references of articles speaking of CDs (Table 4). In fact, he is considered to be the “Godfather of Cyclodextrins”. In 1998, the journal Chemical Reviews published a special issue devoted to CDs. It contained 13 chapters and is still a reference today, including the excellent introductory review317 by Szejtli. In this well-cited review, Szejtli wrote: “Cyclodextrins can be consumed by humans as ingredients of drugs, foods, or cosmetics.” Professor József Szejtli was Editor of the Cyclodextrin News Database (a monthly abstracting service since 1985 dedicated exclusively to the cyclodextrin literature edited and published by CYCLOLAB, and available in electronic form) and published an impressive number of results (more than 500 articles, 6 books, 90 patents). He received many distinctions for his cyclodextrin research (Academic Award of Budapest in 1986, Gold Medal of the Incheba of Brastilava in 1988, the Moët-Hennessy Prize of Paris in 1991, etc.). 6.4. Cyclodextrins: From 1970 until Now

It was at the start of the 1970s, with the first machines suitable for routine NMR analysis appearing on the market, that numerous NMR studies of inclusion complexes were published.108,109,262,263,285,338 Assignments of the NMR signals for the individual protons in cyclodextrins were reported by Takeo and Kuge,109 Demarco and Thakkar,262 and Wood et al.285 This technique can nowadays be considered as the method of choice for the study of complexes.339−341 Thakkar and Demarco, for instance, were the first in 1971 in a pioneering work to demonstrate the formation of inclusion complexes between several organic substances and β-CD using NMR in D2O.263 Their work is considered as the first direct evidence of complexation within the CD annulus in solution. The idea was that if the guest molecules were accommodated in the cavity, then the hydrogen atoms located in the cavity 10960


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(∼10%), pharmaceutical (∼5%), and agricultural (∼5%, pesticide formulation) industries. It is can be stressed that 70% of all CDs produced are used in food and cosmetics, while only 10% of CD-related research papers are concern these fields.320 Many other European countries, including France, authorized the use of CDs in food in 1987 as a vehicle for flavors. Currently, Japan is still the first producer, consumer, and general user of CDs. During the 1970s many studies were also carried out into artificial enzymes and, more generally, in the domain of supramolecular chemistry. The remarkable work of Bender on CDs as model enzymes in fact opened the way to other researchers such as Professors Breslow, Cram, Lehn, Tabushi, Murakami, and Stoddart, some of whom would receive Nobel Prizes. For instance, cyclodextrins were choice materials in the development of models of biological processes; they led to a large number of investigations into molecular catalysis, where the laboratories of Bender228,378 and Ronald Breslow379−381 in the U.S. and Iwao Tabushi382,383 in Japan distinguished themselves. Breslow, at the University of Colombia in 1970, synthesized an artificial enzyme (a CD modified with a coenzyme) that mimicked the biochemical reactions catalyzed by naturally occurring transaminases.379,381 A year later, the same lab managed to realize the dreams of supramolecular chemists:384 they used a modified CD to catalyze a chemical reaction (a Diels−Alder cycloaddition), which no natural enzyme and no common catalyst could. In the 1980s, the first chromatographic applications arrived, and it was the start of a spectacular development. Indeed, unlike CD polymers, stationary phases grafted with CDs were a fantastic success.266,269,270 Three laboratories really stood out: the laboratories of Kazumi Fujimura (Kyoto University, Japan), Minoru Tanaka (Osaka University, Japan), and Daniel W. Armstrong (University of Missouri Rolla, U.S.). In 1984, Advanced Separation Technology Inc. marketed chromatographic columns with the trade name CYCLOBOND, based on CDs. It used the method developed and patented by Armstrong. Few novel stationary phases for chromatography had such a rapid and strong impact as these CD grafted columns. They were particularly appreciated for chiral separations. Several reviews focused on the progress made.385−392 Cyclodextrins also found applications in electrophoresis,393,394 gas chromatography,395 capillary-based techniques, and supercritical fluid chromatography as a consequence of the ability of CDs to bind chiral molecules stereoselectively.396,397 French’s state-of-the-art published in 1957 was also continued in the 1980s by Keiji Kainuma (National Food Research Institute, Japan)161 and Ronald J. Clarke, John H. Coates, and Stephen F. Lincoln (University of Adelaide, Australia).273 In 1984, Kainuma reviewed the preparation, isolation, chemical and physical properties, biochemical properties, and the possible uses of cycloamyloses.161 In particular, he reported the properties of cycloamylose glucanotransferases obtained from various microorganisms. Cycloamylose glucanotransferase was referred to as Bacillus macerans amylase, cyclodextrin glucanotransferase, cyclodextrin glycosyltransferases, cyclomaltodextrin glucanotransferase, or CGTases in the literature. Research on the inclusion complexes of the cyclomalto-oligosaccharides (CDs) before 1985 was comprehensively reviewed in 1988 by Clarke et al. including news topics on detection, thermodynamics, and kinetics of complex formation from a literature survey of 182 papers.273 These

Figure 12. Axial inclusion of a 2-substituted naphthalene and equatorial of a 1-substituted naphthalene.

which often used substances such as cosolvents and organic solvents (alcohols, propylene glycol, etc.) and nonionic surfactants (such as Tween 80 and Cremophor) that can cause irritation. The new approach consisted of replacing potentially toxic compounds by “natural” molecules, which rapidly proved to be promising.353−357 The pharmaceutical industry rapidly understood the advantages of using CDs. Their amphiphilic behavior, coming from the hydrophobic cavity and the hydrophilic outside, enables the dissolution of hydrophobic drugs through the formation of inclusion complexes. The increased solubility can improve the stability, bioavailability, and pharmacokinetic properties of drugs, thus increasing drug efficiency. CDs were also attractive for their versatility, being suitable for oral, parenteral, rectal, cutaneous, or sublingual administration.358 In addition, the active substance can be easily released from the cavity of the CD. In other words, it was recognized as a vehicle suitable for transporting a drug into a living organism, and at the same time enhancing its therapeutic efficiency. This property of forming inclusion complexes was widely applied in pharmaceuticals, and a broad range of CDbased products reached the market. In 1976, the first CD-based pharmaceutical was marketed in Japan by the company Ono Pharmaceutical Co. The drug concerned was Prostarmon (sublingual tablets), a complex of prostaglandin E2 with CD. Europe had to wait until 1988 for the first pharmaceutical to be developed by the Italian company Chiesi Farmaceutici (complex of piroxicam and β-CD, Brexin). The first CDcontaining formulation launched onto the U.S. market was itraconazole/2-HPβCD oral solution, which was approved in 1997. Currently, ∼40 different drugs are marketed worldwide as CD complexes. The main applications are in anti-inflammatory drugs, antibiotics, antifungal drugs, and in vasodilators. Soon to follow were applications ranging from food359,360 to catalysis,361,362 and including cosmetics,362,363 agriculture,363,364 chemical analysis,365−368 biotechnologies,369,370 supramolecular chemistry,371−375 and computational chemistry.376 Japan was the pioneer in the use and marketing of CDs and inclusion derivatives.376,377 The Japanese scientific community rapidly regarded CDs as natural substances originating from starch and thus considered as “non-toxic” natural products. In 2007, Loftsson and Duchêne321 wrote: “In Japan, there is a tradition for industrial usage of natural products and the Japanese regarded the parent cyclodextrins as natural materials originating from starch”, and this probably explains why the controversy on CD toxicity found little echo in Japan. By 1970 they were actively studying the production of CDs as well as their applications. Japan authorized the use of α- and β-CDs as a food additive in 1976 (Hungary in 1983 and Germany in 2000), and in 1983 authorized use in the pharmaceutical industries. Within the next decade Japan became the largest CD consumer in the world mainly for the food (∼60%), cosmetic 10961


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to 60 °C, whereas others, especially insoluble complexes, are stable at much higher temperatures. Chen et al., studying the behavior of substituted cationic β-CD/3H-indole complexes with temperature, showed that at low temperature 3/1-type complexes are obtained, while at higher temperatures, 2/1 complexes are more frequent.407 The polarity and the charge of the substrate (which depends on the pH) are also factors not to be ignored in the formation of inclusion complexes because they can affect the mechanisms involved. Molecules less polar than water are taken up by the CD, while those that are very hydrophilic, hydrated, or ionized are not or are only slightly able to form complexes. An example often given is that of sodium benzenesulfonate, which has two groups able to enter the cavity of α-CD: the benzene ring and the sulfonate group. Insertion of the benzene ring into the cavity is more stable than insertion of the polar sulfonate group: as the cavity is less polar than the surrounding aqueous medium, the higher is the polarity of the guest group, the less it tends to go toward the cavity, and thus the lower is the stability of the complex formed. Bergeron and Rowan284 however managed to find an exception in sodium p-nitrophenolate, which forms a complex 13-fold more stable than p-nitrophenol, whereas the opposite is true for benzoic acid and the corresponding anion. Szejtli gave an excellent overview of the data from the literature concerning the factors that influence the complexation of molecules by CDs. 309 He proposed that three types of factors be distinguished: those related to the substrate itself; in addition to steric considerations, there is also the hydrophobicity, hydrosolubility, and its ionization state; those related to the CDs (native, modified); and those related to the solution, pH, ionic strength, temperature, presence of a cosolvent, etc. In addition to inclusion complexes, numerous CD derivatives were described from the 1980s.408−410 Native β-CD, like α-CD and γ-CD, can be chemically modified through the hydroxyl groups in positions C-3, C-5, and C-6. Note that the difference in reactivity between primary and secondary hydroxyls is relatively small (with the primary functions being slightly more reactive), so selective substitution is not straightforward.181,216,411,412 Commercially available derivatives are in fact mixtures of substances. The system can be further complicated if the grafted radical has its own reactive function. Because of the high reactivity of the hydroxyls, various chemical reactions were studied: alkylation, hydroxyalkylation, sulfate addition, acetylation, amination, esterification, etherification, etc. As the three main native CDs bear 18 (α-CD), 21 (β-CD), or 24 (γ-CD) substitutable hydroxyl groups, the possible number of derivatives is practically unlimited. The excellent review of Khan et al. (University of Missouri, St. Louis, MO) published in 1998 can be referred to on this subject.413 These authors proposed a global schema for the modification of CDs and a classification of the different categories of selective reactions. In 2004, Szejtli estimated that over 15 000 CD derivatives had been sufficiently studied to be mentioned in the literature.320 In reality, most of these derivatives will never find applications, especially for reasons of production costs, essentially lengthy and difficult synthesis involving complicated steps, except for some particular derivatives such as hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylethercyclodextrins. In 1981, Professor Josef Pitha (University of Baltimore, MD) developed a new CD derivative, HPβCD, a potent solubilizer marketed under the names Encapsin or Cavitron.180,181,309 All that remained to be done was to find openings for their use and industrial applications. Professor

authors concluded that “Although much progress has been made on cyclodextrins, the fundamental forces underlying their complexing ability, their mechanism of complex formation, and the factors affecting their chiral selectivity are still not very well understood.” The 30 years from 1970 to the turn of the century saw the introduction of many industrial applications and numerous fundamental studies. An impressive number of purely theoretical university studies were published.398−403 Note that it was in the early 1980s when the first studies on spectrophotometric and colorimetric assays of CDs appeared.398−400 Fujiwara et al. in 1983 proved the existence of a new solvate for which 11 water molecules are associated with each β-CD molecule.401 This was confirmed some years later by Pande and Shangraw.402 Claudy et al. showed that dehydration of β-CD occurs in two steps: loss of seven molecules of water bound to the outer surface of the molecule, and then departure of four molecules of water bound within the cavity, the hydrated form stable at room temperature being the undecahydrate.403 A few years later, Steiner showed that in the crystal lattice, β-CD molecules form molecular cages that accept 7 molecules of water, statistically and dynamically distributed between 11 sites, among which they move.309 From 1980, several studies showed that complexes can form not only in solution, but also in the solid state, and different methods for the preparation of complexes were proposed. The choice depended mainly on the properties of the substrate. In general, the solvent chosen was water because the formation of complexes in a homogeneous aqueous solution is very rapid. However, it can be noted that compounds that are highly soluble are weakly complexed. Complexing can also take place in polar organic solvents like DMSO or DMF, although the list is not very long because many other solvents such as pyridine or toluene themselves form stable complexes with CD and are therefore in competition with the substrate. Moreover, the stability of the complexes in aqueous solution decreases sharply upon addition of an organic solvent. In the case of insoluble complexes, however, the addition of an organic cosolvent such as a short-chain alcohol is necessary to dissolve them. For instance, Dordunoo and Burt, studying the CD-aided dissolution of taxol in a 1:1 water:ethanol mixture, showed that the solubility of the taxol increased with the proportion of CD, whereas the formation constant of the complex was 300fold lower.404 The authors concluded that the alcohol acted as a competitor with taxol, strongly modifying the equilibrium of the complexation reaction. The methods most frequently used to prepare the complexes were preparation in solution (coprecipitation), in suspension, by kneading (mixing a paste), and by dry grinding. Recently, complexation methods using critical CO2 have been experimented with.405 A frequent research theme was also the detection of factors that may influence the stability of the inclusion complexes. The stability of a complex is of course closely dependent on the shape of the guest, but other factors should not be ignored. For instance, the ionic strength of the solution, in particular its variation, is an important criterion in the stability of CD complexes. Zia et al. showed that with neutral substrates, an increase in ionic strength leads to a decrease in the solubility of the guest molecules in the aqueous phase and thus to an increase in the formation constant.406 In general, an increase in the temperature increases the solubility of the complexes but can also destabilize them. Moreover, the sensitivity to heat varies from one complex to another: some can start to decompose from 50 10962


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Valentino J. Stella (University of Kansas, KS) in the early 1990s filed two patents on the synthesis of sulfobutylether-cyclodextrins, an industrial process of production known under the name Captisol (CYDEX Co., U.S.).414,415 These derivatives opened the way to new applications, particularly in drug formulation and the manufacture of chiral separators (capillary electrophoresis). Currently, these derivatives serve as solubilizing excipients in medicinal products (Geodon, Vfend, Nexterone, etc.). At the same moment, CD derivatives found applications in cosmetics and toiletry industries: for instance, to reduce eye irritation from shampoos, to stabilize the taste and the color of tooth paste, to protect creams against photodegradation, to trap smells (deodorants), or to increase the shelf life of perfumes.362,416−422 CDs and CD derivatives also found applications in the textile industry.419−424 During the 1990s, cyclodextrins were proposed for the synthesis of new supramolecular molecules and materials such as interlocked molecules (catenanes, rotaxanes), scaffolds and templates to self-assemble supramolecular architectures, and also in biomimetism.371−375 The term catenane (a particular structure mechanically interlocked molecules consisted of two macrocyles) is derived from the Latin catena for chain and the term rotaxane (a macrocyclic ring mechanically entrapped by a chain bearing bulky end groups) from the Latin rota for wheel and axis for axle. The first case of a CD-based catenane synthesis was reported by Stoddart (University of California) in 1993.372 A variety of supramolecular polymer architectures were also designed, constructed, and proposed by Akira Harada (Osaka University, Japan) using CDs and CD derivatives. Dimers, oligomers, rings, helices, and filaments were created, and these supramolecular systems were successfully applied to catalysis, energy conversion, and sensors. Numerous studies of the host−guest complexes based on CDs were reported not only between CDs and molecules and ions, but also between CDs and polymers. For instance, in 1990, Akira Harada was the first to report that α-CD could form host−guest complexes with poly(ethylene glycol); such structures were precursor polyrotaxanes (sliding gels).346,347 From the point of view of the dissemination of knowledge about CDs, we should also cite the books of Dominique Duchêne (Université de Paris Sud, France) on the applications of CDs and his numerous publications and reviews in pharmacology.425−437 His articles stress the advantages of using CDs in pharmacy: easier preparation of crystalline products, decrease in the sensitivity to certain drugs, improved solubility of active principles, enhanced drug bioavailability, increase of the therapeutic effect, reduced side effects, attenuation of the bitterness or unpleasant taste of medication, etc. The notion of transport and release is also important. Encapsulation of molecules by CD will allow their transport closer to their target; this gave rise to the notion of molecular targeting. Other excellent articles and communications for a broader public were published by Laszlo Szente438−443 (CYCLOLAB, Hungary) and Thorsteinn Loftsson444−450 (University of Iceland). The existence of CDs with over 8 glucose units, called large ring CDs, was described for the first time in the 1950s by Freudenberg and Cramer96 and studied by French in the 1960s,177,194 but it was only toward the middle of the 1990s that these CDs were studied in any depth. The difficulties to purify them and the low yields prevented their study until then.451−454 The Japanese lab of Harushisa Ueda (Hoshi University, Tokyo) must be mentioned in these studies.454−457

Some reports indicate the existence of CDs of over 100 glucose units, CDs obtained by means of specific enzymes or using particular conditions of temperature and incubation time.458−460 However, the purification of these large molecules at the industrial scale remains a hurdle that has yet to be crossed to enable their development. In 2002, Larsen (Institute of Life Sciences, Aalborg University, Denmark) published an interesting review on large cyclodextrins. At the end of the 1990s, several laboratories proposed clarifications of the nomenclature of CDs. At the beginning and in the middle of the 19th century, the terms Schardinger dextrins then cycloamyloses were used to designate cyclodextrins, the latter term being used from the 1950s. For many years, the term of cyclodextrin has been used to refer to cyclic oligosaccharides made up of 6, 7, or 8 units of D-glucose joined by α-(1→4) linkages (also known as the 4C1 conformation) termed α-, β-, and γ-cyclodextrin, respectively. However, the term cyclodextrin only specifies the nature of the sugars but does not give any information on the bonding between them. Thus, the name cyclomaltohexaose was suggested in 1997 following an international recommendation to describe the three CDs. This name is composed of first the term cyclo followed by a term indicating the type of linkage (malto for glucose units bound by α-(1→4) linkages), the number of sugar units (here for example hexa for 6) with the ending ose. This final term, present in cyclomaltohexaose, implies a free anomeric center, which is not present in CDs. Other nomenclatures have also been proposed, for instance, that where the name of the glycosyl residue is preceded by the type of linkage between brackets, in turn preceded by the term cyclo plus an indication of the number (cyclohexakis, etc.). In this nomenclature, α-CD becomes cyclohexakis-(1→4)-α-D-glycosyl. Frieder W. Lichtenthaler and co-workers (Technische Universität Darmstadt, Germany) proposed α-CD be named cyclo-α-(1→4)-glucohexaoside.167,168 To distinguish the three native CDs from those containing a larger number of glucose units, they are known as large cycle cyclodextrins. These CDs have also been designated using a Greek prefix. However, this designation can lead to confusion because it does not actually describe the size of the macrocycle. This is why large-ring CDs are more simply designated by the term cycloamyloses and by the abbreviation CAn, where n indicates the number of glucose units in the macrocycle. The literature uses all of these nomenclatures. It is difficult to cite all of the laboratories that have contributed to progress in research into CDs. We can however finish by pointing out the works of the following researchers: Koki Horikoshi (Yokosuka, Japan) and Sumio Kitahata (Osaka, Japan) for enzymology, Makoto Komiyama (Tokyo, Japan) and Kenneth A. Connors (Wisconsin) for the chemistry and thermodynamics of CDs (two of Bender’s alumni), Kazuaki Harata (Tsukuba, Japan) for the structure of the CD complexes, Yoshihisa Inoue (Osaka, Japan) for molecular recognition, Tsuneji Nagai (Hoshi, Japan), Kaneto Uekama (Kumamoto, Japan), Karl-Heinz Frömming (Berlin, Germany), Dominique Duchêne (Paris, France), Thorsteinn Loftsson (Reykjavik, Island), Marcus E. Brewster (Beerse, Belgium), and Erem Bilensoy (Ankara, Turkey) for pharmacy, James Fraser Stoddart (CA), Akira Harada (Osaka, Japan), Hiroshi Ikeda (Yokohama, Japan), Alan E. Tonelli (Raleigh, NC), Gerhard Wenz (Saarbrücken, Germany), Kim Lambersten Larsen (Aalborg, Denmark), and Helmut Ritter (Düsseldorf, Germany) for their work on supermolecules, superstructures, and 10963


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Table 5. Selected Examples of Books on Cyclodextrins year

book

author(s)

1931

Die Polysaccharide

Hans Pringsheim

1954 1978 1982 1984

Einschlussverbindungen Cyclodextrin Chemistry Cyclodextrin and Their Inclusion Complexes Inclusion Compounds

1987 1988

Cyclodextrins and Their Industrial Uses Cyclodextrin Technology

Friedrich Cramer Myron Lee Bender and Makoto Komiyama József Szejtli Jerry L. Atwood, J. Eric E. Davies, and David D. MacNicol Dominique Duchêne József Szejtli

1991 1994

New Trends in Cyclodextrins and Derivatives Cyclodextrins in Pharmacy

Dominique Duchêne Karl-Heinz Frömming and József Szejtli

1997 2000

La Chimie Supramoléculaire Principles and Methods in Supramolecular Chemistry

2004 2006

Encyclopedia of Supramolecular Chemistry Cyclodextrins and Their Complexes - Chemistry, Analytical Methods and Applications Use of Cyclodextrins Polymers in Separation of Organic Species Cyclodextrins in Pharmaceutics, Cosmetics and Biomedicine Applications of Supramolecular Chemistry

Jean-Marie Lehn Hans-Jörg Schneider and Anatoly K. Yatsimirsky Jerry L. Atwood and Jonathan W. Steed Helena Dodziuk

2010 2011 2012

Cezary A. Kozlowski and Wanda Sliwa Erem Bilensoy Hans-Jörg Schneider

editor Verlag von Julius Springer, Berlin Springer-Verlag, Berlin Springer-Verlag, Berlin Akadémiai Kiadó, Budapest Academic Press, Michigan Éditions de Santé, Paris Kluwer Academic Publishers, Dordrecht Éditions de Santé, Paris Kluwer Academic Publishers, Dordrecht De Boeck, Paris John Wiley & Sons, Chichester John Wiley & Sons, Chichester Wiley-VCH, Weinheim Nova Science Publishers, Inc. John Wiley & Sons, New Jersey CRC Press, Boca Raton, FL

7. CYCLODEXTRINS − PRESENT SITUATION, TRENDS, AND OUTLOOK: PERSONAL REMARKS As was already mentioned, it is known and widely reported in the literature that cyclodextrins and their derivatives have a wide variety of practical applications: pharmacy, medicine, foods, cosmetics, toiletries, chemistry, catalysis, biotechnology, textile industry, etc. Research on CD is also very active in fields such as the formulation of detergents, glues and adhesives, the sector of plastics, and the industry of fibers and paper. The vast majority of these chemical and biological applied applications are based on the ability to form inclusion complexes. CDs are also the object of numerous fundamental studies. In recent years, a relatively large number of generalist reviews has been published on practically all of these aspects of CDs, so many that it would not be feasible to cite them all. I chose to highlight those that concern research in chemistry and macromolecular chemistry,463−465 supramolecular chemistry,466−470 catalysis,471,472 membranes,473,474 aromas,475 foods,476,477 agrochemistry,478 biotechnology,479 enzyme technology,480 cosmetics, 4 1 6 − 4 2 2 , 4 8 1 pharmacy and medicine, 4 8 2 − 4 8 8 textiles,420−424,489−491 chromatography,492−494 microencapsulation,495 nanotechnologies,496−500 click chemistry,501 analytical chemistry,502 remediation,461,503 and decontamination.266,504 Several books (Table 5)181,216,434,436,505,506 and series507−513 can also be consulted on the different aspects of CDs including their description, characterization, properties, derivatives, supramolecular chemistry, and applications.

polymers, Josef Pitha (Baltimore) and Valentino J. Stella (Kansas) for their work on CD derivatives, in particular HP-βCD and the sulphobutyl derivatives, Frieder W. Lichtenthaler (Darmstadt, Germany) for molecular modeling, Kenny B. Lipkowitz (Indianapolis) for computational chemistry, Daniel W. Armstrong (Arlington), Wilfried A. König (Hamburg, Germany), Volker Schurig (Tü b ingen, Germany), Eva Smolkova-Keulemansova (Prague, Czech Republic), Bernard Sébille (Paris, France), Alain Berthod (Lyon, France), and Salvatore Fanali (Roma, Italy) for chromatography, Bruno Perly (deceased in 2009, Saclay, France) and Hans-Jörg Schneider (Saarbrücken, Germany) for NMR, Keiko Takahashi (Kanagawa, Japan) and Valerian T. D’Souza (Missouri) for CD chemistry, organic reactions, and catalysis, Cezary A. Kozlowski (Czestochowa, Poland) and André Deratani (Montpellier, France) for membranes, Hitoshi Hashimoto (Yokohama, Japan), Allan R. Hedges (Hammond), and Philippe J. Sicard (Lestrem, France) for industry, Éva Fenyvesi (Budapest, Hungary), José Ramon Isasi (Pamplona, Spain), Danielle Bonenfant (deceased in 2012, Montreal, Canada), Lee D. Wilson (Saskatchewan, Canada), Tomasz Girek (Czestochowa, Poland), and Francesco Trotta (Torino, Italy) for environmental applications, Hans-Jürgen Buschmann (Krefeld, Germany) and Bojana Voncina (Maribor, Slovenia) for textile, Lajos Szente (Budapest, Hungary) for, in particular, the dissemination of knowledge about CDs, and more recently Éric Monflier (Lille, France) for catalysis, David Landy (Dunkerque, France) for calorimetry, Steven U. Walkley (Bronx, NY), James E. K. Hildreth (California Davis), and Vladimir A. Karginov (Massachusetts) for their work on CDbased therapeutic agents, Hagan Bayley (Oxford, United Kingdom) and Sophie Fourmentin (Dunkerque, France) for retention of aroma by CDs, Bernard Martel (Lille, France) and ̈ Florence Djedaini-Pilard (Amiens, France) for the synthesis of innovative materials for the biomedical sector and for textiles, and Elena Vismara (Milano, Italy) and Giangiacomo Torri (Milano, Italy) for their work on CD-based molecular adaptors in protein pores and cell surface heparin-binding proteins.

7.1. Cyclodextrins and Their Capacity To Form Inclusion Complexes

At the turn of the last century, several studies cast doubt on the mechanisms proposed to explain the formation of inclusion complexes. Indeed, the mechanisms and the forces that act to achieve complexation were and still are the subject of debate and controversy. An example that is often quoted is the occurrence of hydrophobic interactions: their role is rather controversial due to their very definition. Hydrophobicity is the result of the structure taken on by water molecules in the vicinity of nonpolar molecules, which favors the aggregation of 10964


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assemble to form microparticles. These properties have changed the way we perform CD pharmaceutical research and have given rise to new CD formulation opportunities as recently summarized by Kurkov and Loftsson.450 It is well-known that CDs can be used in antifungal formulations as auxiliary substances to modify and to improve physicochemical properties of the active compound (solubility, stability, etc.). The biological effects of CDs, important for their use within antimycotic formulations, can be divided into: (i) effects based on the ability of CDs to form inclusion complexes with endogenous substances (membrane lipids, cellular cholesterol), effects based on formation of inclusion complexes with component parts of fungi cells, and (ii) effects based on the chemical nature of CDs and their derivatives. The advances in research of biological activity of CDs with focus on their properties responsible for their synergistic effect with antimycotic compounds were recently discussed by Macaev et al.485 The number of publications on the use of CDs in antifungal formulations is still growing.

the nonpolar molecules, thus minimizing the additional energy that would result from the formation of a structured hydration shell. Several studies have shown that, upon complexation, it the most hydrophobic part of the host molecule that is preferentially included in the cavity of the CD and the encapsulated molecules are oriented in such a way as to maximize the contact between their hydrophobic parts and the apolar CD cavity. Similarly, the more the guest molecule is hydrophobic, the more the complex will be stable. Rekharsky and Inoue concluded, for instance, that hydrophobic and van der Waals interactions predominate in the formation of complexes with respect to steric effects and hydrogen bonding.329 On the basis of a hundred or so publications, Liu and Guo333 demonstrated that the water present inside the cavity does not intervene to any extent in the complexation phenomena and thus questioned the main conclusion of the studies of Szejtli (that the driving force behind the formation of the complexes is the energy stabilization of the system through the replacement of the water molecules in the cavity by hydrophobic substrates). Inclusion compounds may be characterized by the stability of their interactions. Stability is of crucial importance for the efficiency of CD applications. Consequently, evaluation of formation constants has been thoroughly investigated. Numerous approaches may be found in the literature on the evaluation of formation constants and the description of the major concepts associated.

7.4. Cyclodextrins and Nanotechnology

CDs and their derivatives have been successfully employed to create novel nanomaterials.498−500 A broad spectrum of CDcontaining materials with versatile supramolecular architectures (nanoparticles, nanosponges, nanomicelles, nanovesicles, etc.) has been synthesized to assemble functional platforms. These materials have found applications in pharmaceutical formulations, and in particular for drug delivery.496,497 At present, nanotechnology is receiving considerable acknowledgment due to its potential to combine features that are difficult to achieve by making use of a drug alone. CD-based nanosponges are a contemporary approach for highlighting the advancements that could be brought about in a drug delivery system. Chilajwar et al. recently reported that statistical analyses have shown that around 40% of currently marketed drugs and about 90% of drugs in their developmental phase encounter solubility-related problems.500 CD-based nanosponges have the capacity to emerge as an innovative approach over conventional CDs by overcoming the disadvantages associated with the latter. These novel class structures have been also developed because their use can improve a drug’s bioavailability by modifying the pharmacokinetic parameters of actives. Nanosponges offer high drug loading as compared to other nanocarriers and are thus suitable for solving issues related to solubility, stability, and delayed release of actives.499 The methods of preparation are well-known: nanosponges can be formulated as oral, parenteral, topical, or inhalation dosage forms. However, more information on their characterization is required to optimize their performance for therapeutic purposes and to demonstrate the role of the nanocavity in the complexation. Neutral, cationic, and/or anionic amphiphilic CDs have been also proposed to increase interactions of CDs with biological membranes.

7.2. Cyclodextrins and Their Tendency To Form Aggregates

The simplest way to obtain inclusion complexes is to place the molecule to be complexed in an aqueous solution of CD. However, it should be stressed, as pointed out by Loftsson,447,450,462 that the inclusion complexes formed in this way provide a simplified explanation of a much more complex phenomenon. CDs are indeed able to form host/guest inclusion complexes but also noninclusion complexes (already indicated by Cramer205 in 1956). The hydroxyl groups present on the outer surface can form hydrogen bonds with other molecules, which makes them able, just like dextrins, noncyclic oligosaccharides, and polysaccharides, to form complexes (molecular structures) with lipophilic substances insoluble in water. Another possibility that is mentioned is the formation of aggregates able to dissolve water-insoluble lipophilic molecules (structures similar to micelles). In recent years, it has been observed, in pharmaceutical applications, that other types of CD complexes such as noninclusion complexes are also participating in CD solubilization of poorly soluble drugs. There are some indications that formation of CD/drug complex aggregates might play an important role in CD enhancement of drug bioavailability. The CD aggregates present the ability to form complexes, and nanosized aggregates and nanotube-type host/guest architectures can be envisaged. This is a generally unexplored domain and often causes controversies because the results obtained are closely dependent on the technique used. The most important features of these CD-based aggregates and the main conclusions can be found in the reviews by Loftsson.447,450,462

7.5. Biomedical Applications and Biomedicine

Currently, the field of medicine is closely concerned with CD inclusion complexes. The best known example is that containing the active compound sugammadex (Bridion): it is a modified γ-CD used as an antidote to certain curare-like muscle relaxants and has been used in anesthesia since 2008. After intravenous administration, it neutralizes steroid curarelike agents (rocuronium, vecuronium) by forming an inactive complex in the plasma, which is then eliminated in the urine. Another interesting example concerns the preparation of vaccines Daptacel (Sanofi Group, Pasteur) for protection

7.3. Cyclodextrins and Pharmacy

Although CDs can be found in at least 40 pharmaceutical products, they are still regarded as novel pharmaceutical excipients.486−488 Recently, it has been observed that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self10965


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recently summarized in a review by Xiao et al.493 The number of publications continues to grow not only in high performance liquid chromatography, capillary chromatography, and gas chromatography, but also in ultrahigh performance liquid chromatography and supercritical fluid chromatography (SFC). Actually, SFC is considered a green separation technique (as it avoids the use of organic mobile phase) and is an ideal alternative technique (fast and efficient separation) for the preparation and separation of pure substances (enantioselective separations, chiral extraction, etc.). Xiao et al. concluded that the employment of high performance CD-based stationary phases for preparative SFC will likely play an important role for future pharmaceutical industry.493 The interest of SFC for screening methods and for the preparative scale was also recently showed by West.494 While the pharmaceutical sector is the main application area of enantioselective separations, other industries such as agrochemicals and fragrances are also concerned.

against diphtheria, tetanus, and whooping cough (inclusion complex with dimethyl-β-CD). Interesting recent studies were devoted to the physicochemical properties of local anesthetics (LA) and their inclusion complexes with CDs to understand their behavior.488 Their capacity to reach and to block sodium channels and act as anesthetics depends on their protonation state. Different studies showed that the extent of complexation with CDs varies greatly with the protonation state of the involved molecules, an interesting fact in the administration of LA, as recently reported by Brandariz and Iglesisas.488 Actually, CDs are perceived as dream molecules for the development of applications in biomedicine and nanomedicine (nanovectorization, etc.), such as nanoparticles for drug delivery, innovative biosensors for molecular diagnosis and medical imaging, gene therapy, or tissue engineering. Medical devices (catheters, prosthesis, vascular grafts, bone implants) can also benefit from surface grafting or thermofixation of CDs. This explains the recent increase in the number of research papers dealing with these topics. However, most of these studies are in the proof-of-concept stage, and only a few therapeutic nanosystems have been comprehensively investigated. The successful translation of these laboratory innovations to clinical reality remains challenging. The cost is an important factor that limits the successful translation of new materials containing CDs. Another problem concerns the lack of data on the biocompatibility evaluation and on the toxicity of these nanomaterials. Despite these, Zhang and Ma recently concluded that the future of CD-based supramolecular systems in drug and gene delivery is promising in view of the notable clinical success.486 The CD-based nanomaterials have found applications not only in biomedical sector, pharmacy, pharmacotherapy, biology, and biotechnology, but also in the textile industry by providing clothes for transdermal delivery (this was suggested by Szejtli320 in 2004).

7.8. Controlled Release of Fragrances and Aromas

The fragrance and flavor industry is a large and innovate sector of the chemical industry.475 Fragrance chemicals are added to consumer products such as personal care products, perfumes, deodorants, laundry detergents, etc. Encapsulation techniques using CDs are increasingly used by this industry for improving the efficiency of odorant and aroma substances. Most of the additives in many consumer products are toxic and not biodegradable. The main advantages of CDs are not only their ability to encapsulate a guest in their cavity to form an inclusion complex but also their nontoxicity. Besides affording a protective effect, encapsulation within CDs modifies the physicochemical and/or biological properties of the guest. Encapsulation of flavors by CDs is an essential process that helps protect fragile molecules, ensure controlled release, reduce volatility, and increase solubility, dissolution, and bioavailability. Consequently, these molecules are widely used for the encapsulation of aroma/flavor compounds, which have long been used in food and pharmaceuticals. Cyclodextrins also find applications in cosmetics and toiletry industries (eye-drop solutions, CD-based formulations for stabilization of flavors and fragrances or the elimination of undesired tastes, products for fragrance delivery or for odor control in perfumes or laundry detergents with several brand names, etc.),481 and today it is the biggest market for CDs. The use of these host compounds is also promising for various applications, especially in emerging fields such as aromatherapy and cosmetotextiles.

7.6. Cyclodextrins and Food

In recent years, the growth of the functional foods industry has increased research into new compounds with high added value for use in the fortification of traditional products. One of the most promising functional food groups is those enriched in antioxidant compounds of a lipophilic nature. Despite the numerous advantages reported for such antioxidant molecules, they may also have disadvantages that impede their use in functional foods, although these problems may well avoided by the use of encapsulant agents such as CDs. Manuel LopezNicolas et al. published an excellent review477 of the most recent studies on the complexes formed between several important types of antioxidant compounds and CDs, focusing on the contradictory data reported in the literature concerning the antioxidant activity of the host/guest molecule complexes, the different complexation constants reported for identical complexes, the bioavailability of the antioxidant compound in the presence of CDs, and recommendation concerning the use of natural or modified CDs. The authors also concluded that CDs will act as secondary antioxidants, enhancing the ability of traditional antioxidants to prevent enzymatic browning in different foods.

7.9. Textiles and Cosmetotextiles

Indeed, more research and practical use results indicate that CDs might also act as active compounds in textiles and cosmetotextiles.489−491 Chemical finishing is crucial for giving textiles new functionalities and making them appropriate for special applications, such as antimicrobial resistance, flame retardancy, and others. Textile finishing is also an important process as it improves appearance, performance, or hand. CD is considered as a promising reagent in textile finishing. Cosmetotextiles also meet an increasing demand on the market. Neither cosmetics nor textiles, the microencapsulated ingredients on cosmetotextiles ensure their slimming, hydrating, or perfuming progressive effect on the skin. The cosmetic and textile industries are at the forefront of the research on this topic. Voncina and Vivod recently reviewed the CD literature to identify and discuss some of those delivery systems used in consumer health products.489 There are many possibilities for

7.7. Cyclodextrins and Chromatography

Although hundreds of papers related to CD-based chromatography have been published since the 1980s, this sector continues to interest the scientific community.492−494 Various synthetic and functional groups immobilization strategies of novel CD chiral stationary phases for chromatography were 10966


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the development of new textile and cosmetic products with advanced properties based on CDs. 7.10. Cyclodextrin-Based Supramolecular Architectures

Although extensive work has been done on CD-based supramolecular architectures, future research needs to into their precise physicochemical characterization.466−470 Indeed, the understanding and the design of supramolecular systems require a detailed characterization with respect to stoichiometry, affinity, structure, heterogeneity, and supramolecular dynamics. Recently, fluorescence correlation spectroscopy has been proposed to the study of the dynamics of different systems.505,506 Among the different techniques used, fluorescence spectroscopy is perhaps the most promising because of its high sensitivity and selectivity, although many supramolecular systems are themselves nonfluorescent. The state of the art review of the design of complex macromolecular architectures based on CD was recently presented by Schmidt et al. and comprehensively discussed.514

Figure 13. Schematic structures of materials containing CD obtained using (a) reticulation (polymerization), (b) grafting, and (c) coating reactions.

remediation of polluted soils and the treatment of gases and smells, CD-based materials are not really managing to find themselves a place in the decontamination of wastewater.266,505 Currently, fundamental research is focusing on CD-based nanoparticles for environmental applications.502,506,461 Indeed, nanosponges have not only been explored for their pharmaceutical applications but for water purification and wastewater treatment. This emerging technology of CD-based nanosponges is expected to provide technical solutions to water treatment. Soil flushing using CD-based aqueous solutions was recently employed to solubilize pollutants. CD molecules are used as additives to enhance efficiencies and reduce the treatment time as compared to the use of water alone or conventional surfactants.503 Recent synthesis and modification methods of magnetic chitosan materials containing CDs were reviewed along with some applications in analytical separations by Tong and Chen.502

7.11. Cyclodextrins and Click Chemistry

CDs can be used in the click reaction in carbohydrate chemistry for drug discovery and for the generation of various glycoconjugates (glycopep tides, glycodendrimers, etc.).501,505,506 It is believed that CDs will play a very important role in these new developments.506 7.12. Cyclodextrins and Sugar-Based Surfactants

Carbohydrate-based surfactants are today an important class of amphiphilic compounds. The growing interest in such compounds is due to, inter alia, their preparation from renewable raw materials, their ready biodegradability and biocompatibility, as well as other more basic reasons of practical, economic, and environmental order.505 When complexed with cyclodextrins, carbohydrate-based surfactants considerably increase their performance and potential application range. The use of these new systems is promising.479,480,505

7.15. The Cyclodextrin Scientific Community

The first international symposium on CDs was held in Budapest, Hungary, in 1981 following Szejtli’s initiative (the second in Tokyo, Japan, in 1984). This symposium was a great success, with participants coming from all over the world. Since 1984, a broad community of researchers has met every two years to exchange and share their work on CDs. The 17th and most recent International Symposium on cyclodextrins organized by Gerhard Wenz was held in 2014 in Saarbrücken, Germany. The third European conference on cyclodextrins met in Antalya, Turkey, in 2013 and the 15th colloquium of the Club Français des Cyclodextrins brought together over 70 participants in Montpellier in 2013 (the next will be organized ̈ by Florence Djedaini-Pilard and Véronique Bonnet in Amiens, in October 2014). There are several national groups that are very active, in France, Italy, and Japan, which enables a good quality of communication and exchange on current research into CDs in each country.

7.13. Cyclodextrins and Membranes

Membrane technology has spread to reach many domains including separation, purification, and fraction enrichment. This is due to the ability of membranes to work in continuous processes and because they are modular, energy-efficient, and environmentally friendly. It is known that the incorporation of complexing sites in membranes leads to the facilitation of the transport of certain species as compared to others and to the improvement of membrane performance. The presence of immobilized CD within the membrane can affect molecular transport through supported liquid membranes and dense or porous membranes.473,474 CD-functionalized membranes are opening new perspectives in various separation-oriented processes.506

8. CONCLUSIONS In this Review, I have divided the history of cyclodextrins into five quite distinct periods, each period being illustrated by examples of studies taken from the literature that I have chosen to highlight. The first period, from 1891 to 1911, covers their discovery by Antoine Villiers and characterization by Franz Schardinger. From 1911 to 1935 came a period of doubt and disagreement, in particular between the laboratories of Hans Pringsheim and of Paul Karrer. The third period, from 1935 to 1950, was marked by the results obtained by Karl Freudenberg, and by Dexter French. The period of exploration between 1950 and 1970 focused on inclusion complexes with the work of Friedrich Cramer in the forefront. Finally, the period of utilization has been in progress since 1970 and has seen

7.14. Cyclodextrins and Remediation

Our group described recent developments in the use of crosslinked CD-based polymers as complexing polymeric matrixes for pollutant removal by oriented-adsorption processes.266 This recent review summarized the features of these polymers (Figure 13) and how they were used in decontamination applications. From the year 2000 to the present day, numerous researchers have investigated CD materials and polymers for applications that concern complexation of pollutants from the environment. The study of these materials, especially by solidstate NMR, has shed new light on their behavior.266,270,506 However, apart from a few applications concerning the 10967


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cyclodextrins find numerous industrial applications. To mention a few more names of researchers who have made a major contribution to the development of cyclodextrins, we should add Benito Casu, Wolfram Saenger, Myron Lee Bender, and József Szejtli. Expensive to produce, the three main CDs (α-CD, β-CD, and γ-CD) were long considered just laboratory curiosities. In fact, they were only produced on an industrial scale after 1979. From 1980, the German Wacker Chemie became the first European manufacturer of CDs. Three factors traditionally stood in the way of industrial development: (i) their high production costs; (ii) incomplete toxicological studies; and (iii) lack of sufficient scientific knowledge of native CDs and their derivatives. At the start of the 1980s, with a more accurate picture of their toxicity and better understanding of molecular encapsulation, several inclusion complexes appeared on the market, especially in the form of drug preparations. The introduction of CDs into pharmaceutical chemistry and medicine in general led to spectacular progress, and now the pharmaceutical industry, along with the food processing industry, is one of the sectors that consumes the most CDs. From the 1980s, the number of publications started to increase exponentially, as did the filing of patents (by the end of 1986, about 750 patents were published)309 and the number of communications, in various fields of applications. The numerous international meetings, local European or Asian, and also national meetings coming together to talk about CDs show the importance of the scientific community, always interested in CDs throughout the world. Indeed, CDs are still the object of numerous studies, both fundamental and applied. They continue to be of interest in cosmetics and biotechnology and are proving attractive in new fields such as the environment (treatment of pollutants). In this latter field, research is very active due to the increasingly strict legislation covering the socalled dangerous emergent chemicals (organic micropollutants). Studies are also turning toward the synthesis of innovative materials for the biomedical sector (prostheses, therapeutic agents, etc.) and for textiles (“intelligent” materials, cosmetotextiles). Moreover, research into CDs is very active in supramolecular chemistry and in nanotechnologies (pharmaceutical, medical, cosmetic, and environmental applications). Finally, with the impending possibilities of gene therapy, the particular properties of certain CD derivatives are extremely attractive as they are able to interact with the membranes of specific cells (e.g., enhancing the deep penetration of oligonucleotides into cells, molecular adaptors in protein pores). There are many possibilities for the development of new CD-based products, and the future of CDs will be even promising. I conclude with a citation of Professor Benito Casu in Milano (when I was a Ph.D. student in 1993): “Cyclodextrins have been a source of fascination for over a hundred years as the heart of these molecules is easy to penetrate although they are hard to crack.”

Biography

Grégorio Crini was born in Roubaix (France) in 1966. He graduated in Organic Chemistry and Macromolecular Chemistry from the University of Lille and received his Ph.D. in chromatography under the supervision of Michel Morcellet in 1995. He then spent 2 years as a postdoctoral fellow at the “G. Ronzoni” Institute for Chemical and Biochemical Research in Milan (Italy) working with Giangiacomo Torri and Benito Casu on the NMR characterization of cyclodextrinbased materials. In 1997, he joined the University of Franche-Comté where he set up a research group working on polysaccharide-based adsorption processes for pollutant removal. He was made Research Director in 2000. His current interests focus on the design of novel biopolymer networks and the environmental aspects of polysaccharide chemistry for applied research. He has also conducted consulting projects for many companies. He is a highly cited researcher (the total citation of his publications is over 4100 according to ISI Web of Science; h-index: 27) and has published as author or coauthor over 100 articles (including nine reviews), 25 proceedings, 15 book chapters, a patent, and the coordinated three books on wastewater treatment, chitosan applications, and adsorption processes.

ACKNOWLEDGMENTS I thank the following colleagues for much of the information collected, reprints of their works, and/or critical reading of early drafts of this Review: Nadia Morin, Sylvie Bastello-Duflot, Marlène Gruet, and Brigitte Jolibois (Université de FrancheComté, France), Michel Morcellet, Joëlle Morcellet, and Michèle Delporte (Université de Lille 1, France), Sophie Fourmentin (Université du Littoral-Côte-d’Opale, France), Bruno Perly (CEA, Saclay, France), Yahya Lekchiri (Université d’Oudja, Morocco), Peter Winterton (Université de Toulouse III, France), Danielle Bonenfant (É cole de Technologie Supérieure de Montréal, Canada), Wilfried A. König (University of Hamburg, Germany), Gerhard Wenz (University of Saarbrücken, Germany), Benito Casu and Giangiacomo Torri (Istituto di Chimica e Biochimica G. Ronzoni, Milan, Italy), Giuseppe Trunfio (University of Messina, Italy), and Corina Bradu (University of Bucharest, Romania). Special thanks are due to Marc Fourmentin (Université du Littoral-Côte-d’Opale, France) for illustration graphics and to my wife Nadia MorinCrini. This is dedicated to my teacher Professor Benito Casu (G. Ronzoni Institute, Milan, Italy) on the occasion of his 87th birthday.

AUTHOR INFORMATION Corresponding Author

REFERENCES

*E-mail: [email protected].

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Notes

The authors declare no competing financial interest. 10968


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