**2. Cyclodextrins discovery**

**1. Introduction**

120 Cyclodextrin - A Versatile Ingredient

The Neolithic Revolution marked the end of nomadic peoples and the beginning of sedentarization of *Homo sapiens*, having originated 10,000 years of food inventions. Nowadays, it produced sufficient food to feed each of the 7 billion human beings. However, malnutrition and food waste related to production and consumption are big issues that pose major challenges for the future. The big question then arises: why exists malnutrition, if there is enough

The Global Paradox of Malnutrition (**Figure 1**), i.e., the conditions of malnutrition and overweight/obesity, have causes and consequences strongly related with the existence of inadequate food systems. This Global Paradox of obesity *versus* undernutrition is portrayed through the numbers: around 33% of the world population suffers from malnutrition. While one part of the world population has no access to food in quantity and quality necessary for a healthy life, another large group of people chooses to excessively high-calorie foods low in nutrients and fiber. Metabolic disorders as obesity and related diseases can be prevented but recently became pandemic. Even more serious is the fact that recently the number of children suffering from these metabolic disorders (155 million) exceeded the number of children suffering from malnutrition (148 million). If this process is not stopped, through appropriate measures at the community level and at the individual level, it is expected that the economic

One approach to reduce malnutrition is the development of functional foods or novel food ingredients to reduce the risk of disease, providing longevity and a healthy lifestyle. In this

Cyclodextrins (CDs) are compounds derived from starch, modified industrially produced enzymatically. These starch derivatives are nontoxic ingredients, are not absorbed at the level of the upper gastrointestinal tract, and are completely metabolized by colonic microflora.

**Figure 1.** The Global Paradox: Obesity and Malnutrition. Obesity has doubled since 1980; In 2014 there were more than 1.9 billion adults overweight, of which 600 million people are obese; most people live in countries where overweight

causes more mortality than malnutrition (WHO Fact sheet n°311 2015).

context, glucose cyclic oligosaccharides, the cyclodextrins, play an important role.

food quantity and quality for all people around the world?

and social impact will be catastrophic.

Over 100 years have elapsed, since Villers first described the isolation of a crystalline substance from a medium of *Bacillus amylobacter* starch culture, corresponding to what is now recognized as cyclomalto-oligosaccharides or cyclodextrins. This crystalline substance was then called "cellusine" because of its similarity with the cellulose. Over the next 60 years, progress in purification products, elucidation of structures, and identification of unusual properties were remarkable and surprised the pioneering researchers in the field. Contributions from Schardinger, Pringshein, Freudenburg, and Cramer, in Germany, and from French in the United States of America are presented in a review article that has become a true classic, published in Advances in Carbohydrate Chemistry [1]. In this article, French anticipated that the cyclodextrins would serve, teach, delight, and intrigue the scientific community. It was from this time that the scientific community recognized one of the most characteristic properties of cyclodextrins: the ability to form inclusion compounds with a wide variety of substrates or guest molecules.

However, the path taken by the pioneers in the area was not easy. Cramer felt strong opposition when mentioned that cyclodextrins in solution could include other molecules. M.L. Bender recognized the synthesis of inclusion compounds based on cyclodextrins and the ability to discriminate enantiomers during the inclusion process and the catalytic capacity in reactions on bound substrates for the very first time. The result of these discoveries fascinated a large number of researchers: Bender and Breslow in the United States, Saenger in Germany, and Tabushi, Komiyama, and Hirai in Japan. They felt captivated by scientific research involving cyclodextrins [2].

During the decades of 60 and 70 of the last century, cyclodextrins have been widely studied as simulants enzyme systems (cyclophanes) or very similar to the behavior of the various enzymes The advent of high-pressure liquid chromatography techniques (HPLC), fast atom bombardment mass spectrometry atoms (FAMS), and nuclear magnetic resonance spectroscopy (NMR) has made possible the characterization of chemically modified cyclodextrins (e.g., methylated cyclodextrins). A complete and unambiguous characterization of the structures was made by X-ray diffraction and neutron diffraction techniques.

On the other hand, the commercial interest in cyclodextrins has grown and is growing at a phenomenal rate, particularly in Japan and Hungary, where Professor Joseph Szejtli's contribution was enormous. The pharmaceuticals, agrochemicals, food, and cosmetics industries have been influenced by these outstanding molecules to a lesser or greater extent [2].

Scientific and technological impact of cyclodextrins are associated, on the one hand, the diversity of situations in which they operate and on the other hand, the enormous challenge that its use has caused in the design of new molecular systems reminiscent functions of biological, chemical, or physical nature.
