Synthetic Bioactive Substances - rd.springer.com · Synthetic Bioactive Substances Shiming Li*...

Synthetic Bioactive Substances

Shiming Li*College of Life Sciences, Huanggang Normal University, Huanggang, Hubei, China

Abstract

Three traditional macronutrients, proteins, carbohydrates, and fatty acids, are sufficient or evenoversupplied for most of the current population globally, and consequently consumption of convention-ally nonessential nutrients becomes vital. These nutrients include vitamins, minerals, coenzymes, somesulfur-containing compounds, and melatonin, as examples. The dietary source of these compoundsusually includes vegetables, fruits, microorganisms, meats, and fish, and the content of these nutrientsvaries much. Some nutrients have sufficient supply from natural resource, but other nutrients have limitedcontents in the natural supply chain thus unable to meet the demand for health benefits. Fortunately,synthetic version of these nutrients has been available to use as early as the 1940s for human consumptionbut not until recent decades to reach a sufficient supply. This chapter is a summary of these nutrients thatare synthesized either through a chemical process or microbial fermentation or both to supplement theessential nutrients with insufficient resources from natural food diets.

Introduction

Bioactive substances are nonessential traditional nutrients or extra-nutritional constituents naturallypresent in foods and food products. They typically occur in very small percentages in daily food ingestionand are expected to keep the body healthy and prevent various lifestyle-related diseases. They have beenintensively evaluated for their effects on health-beneficial properties. The driving force behind thisscientific inquiry was the result of many epidemiologic studies that have shown protective effects ofthese bioactive substances on many chronic diseases such as inflammation, metabolic syndrome, cardio-vascular disease (CVD), and cancer. Many bioactive compounds have been discovered. These com-pounds vary widely in chemical structures and bio-functionalities and are grouped accordingly (Tringali2001).

The sources of vitamins, as an example, come from meats, vegetables, fruits, and nuts (vitamins A,B, C, E, K). Phenolic compounds, including their subcategory, flavonoids, are present in various plantsand have been studied extensively in cereals, legumes, nuts, olive oil, vegetables, fruits, tea, and red wine.Phenolic compounds by definition posses multiple hydroxyl groups on the benzene ring(s) and usuallyhave strong antioxidant property. In addition, a myriad of studies have demonstrated favorable effects ofpolyphenolic compounds on health-beneficial property such as prevention of thrombosis and tumorigen-esis and promotion of healthy cardiovascular system. Although some epidemiologic studies have reportedprotective associations between flavonoids or other phenolics and CVD and cancer, other studies have notfound these associations. Examples of polyphenols and health-promoting effects are stated below.Hydroxytyrosol, one of the many phenolics in olives and olive oil, is a potent antioxidant. Resveratrol,found in peanut, black grape, red wine, mulberry, and Polygonum cuspidatum, has antioxidant,antithrombotic, and anti-inflammatory properties. Lycopene, a potent antioxidant carotenoid in tomatoes

*Email: [email protected]

*Email: [email protected]

Handbook of Food ChemistryDOI 10.1007/978-3-642-41609-5_16-1# Springer-Verlag Berlin Heidelberg 2015

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and other fruits, is thought to prevent cardiovascular diseases, to protect against prostate and othercancers, and to inhibit tumor cell growth in animals. Organosulfur compounds in garlic and onions,isothiocyanates in cruciferous vegetables, and flavonoids in citrus fruits, cherries, and herbs haveantioxidant, anticarcinogenic actions and cardiovascular protective effects (Kris-Etherton et al. 2002).In summary, numerous bioactive compounds appear to have beneficial health effects.

Much scientific research of some bioactive substances has been convincingly conducted for dailydietary recommendations based on their efficacy and/or functionality, such as vitamins and minerals.However, some bioactive compounds need more scientific evidence to determine the amount ofrecommended daily intake (RDI), even with the confirmative recommendation of a diet rich in a varietyof fruits, vegetables, whole grains, legumes, natural unsaturated oils, and nuts, among others. It has to bepointed out that some bioactive substances have insufficient supply from natural source to provideconsumers the recommended amount, such as vitamin B12. Therefore, this chapter briefly reviewedsome critical bioactive substances existing in foods and functional foods but usually being obtained fromsynthetic routes due to their limited supply from natural resource. Synthetic substances covered in thischapter are majorly vitamins, including vitamins B, C, and E, particularly B vitamins, thiamin, riboflavin,niacin, pantothenic acid, biotin, folic acid, cobalamin, pyridoxal, and its derivatives (B6); sulfur-containing compounds, acetylcysteine, lipoic acid, methylsulfonylmethane, and adenosylmethionine;coenzyme Q10; melatonin; and raspberry ketone.

Synthetic Nutraceutical Substances

Synthetic Vitamins

CobalaminVitamin B12, or cobalamin in Fig. 1, is the most complex vitamin in chemical structure currently knownto man. Vitamin B12 is needed for building proteins and for forming nerve cells and red blood cells in thebody. Symptoms of vitamin B12 deficiency can lead to anemia, fatigue, mania, depression, weakness,constipation, loss of appetite, and weight loss, while a long-term deficiency of vitamin B12 can causepermanent damage to the brain and central nervous system, such as numbness and tingling in the hands

NN

N N

H2N

H2N

O NH2

O

NH2

NH2O

O

O

O

HO

NH

O

PO

O

−O O

N

N

HO

NH2

HOH

Co

CN

+

Fig. 1 Structure of vitamin B12 (cyanocobalamin)


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and feet. Additional signs of B12 deficiency include difficulty in maintaining balance, confusion,dementia, poor memory, and soreness of the mouth or tongue. It may be a short time period to haveslight signs of vitamin B12 deficiency, but can take as long as two to several years for vitamin B12deficiency to become seriously symptomatic. The recommended daily allowance (RDA) of vitamin B12for adults is 2.4 micrograms, whereas the dosage of B12 dietary supplement can be 100 times higherbecause of its bioavailability. Vitamin B12 can only be synthesized by bacteria. Natural food sources ofvitamin B12 are found primarily in meat and other animal products, which means those who follow aplant-based diet have to find their source elsewhere. Neither plants nor animals are independently capableof constructing vitamin B12. However, synthetic forms are readily available and added to many foods likecereals.

The chemical synthesis of B12 was reported by many organic chemists. But the synthesis adapted byRobert Burns Woodward and Albert Eschenmoser in 1972 remains one of the classic feats of organicsynthesis of B12. Industrial production of B12 is from fermentation of selected microorganisms.Streptomyces griseus, a bacterium once thought to be a yeast, was the commercial source of vitaminB12 for many years. The species Pseudomonas denitrificans and Propionibacterium shermanii are morecommonly used today. These are frequently grown under special conditions to enhance yield, andgenetically engineered versions of one or both of these species are used. Since a number of species ofPropionibacterium produce no exotoxins or endotoxins and are generally regarded as safe (GRAS) by theFood and Drug Administration of the United States, they are presently the FDA-preferred bacterialfermentation organisms for vitamin B12 production (Riaz et al. 2007).

Cyanocobalamin is the most common and widely produced chemical compound that has vitamin B12activity. Although cyanocobalamin is a synthetic substitute of vitamin B12, it can be transformed in thebody to vitamin B12 isomers that play the same role as vitamin B12 inside the body. Cyanocobalamin isalso produced by bacterial fermentation process, but the purification process is relatively easier than thatof vitamin B12. Fermentation by a variety of microorganisms yields a mixture of methyl-, hydroxy-, andadenosylcobalamin. These compounds are converted to cyanocobalamin by addition of potassiumcyanide in the presence of sodium nitrite when heating (http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/. Accessed 03 Mar 2015).

ThiaminVitamin B1, thiamin, or thiamine in Fig. 2 is an essential nutrient required for maintaining body cellularfunction and organ functions. Thiamin deficiency leads to metabolic coma, particularly the nervous andcirculatory systems, and even death in severe deficiency. Also, thiamin deficiency can lead to develop-ment of beriberi and/orWernicke-Korsakoff syndrome. Symptoms of both diseases include severe fatigueand degeneration of cardiovascular, nervous, muscular, and gastrointestinal systems. Thiamin overdose isvery rare and can cause weakness, headache, irregular heartbeat, and low blood pressure. Thiamin dosesin the US recommended daily allowance (RDA) taken by mouth are 1.2 mg for male adults 19 and olderand 1.1 mg for females.

Thiamin is a colorless compound with a chemical formula of C12H17N4OS. Its structure consists of adiaminopyrimidine molecule and a thiazole ring linked by a methylene group. The thiazole is substitutedwith a methyl group and a hydroxyethyl side chain. Thiamin is soluble in water, methanol, and glycerol

N

N

NH2

N+

S OH

Cl−

Fig. 2 Chemical structure of thiamine


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http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/

http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/

and insoluble in many organic solvents. It is stable at acidic pH and in cold storage condition, but unstablein alkaline, UV light, and gamma irradiation solutions. Thiamin is very reactive inMaillard-type reactions(Tanphaichitr 1999).

Diet sources of thiamin are widely spread, including liver, egg, fish, nuts, seeds, bread, green pea,squash, asparagus, beans, meat, vegetables, legumes, fruits, and grains. Complex thiamine biosynthesisoccurs in bacteria, some plants, and fungi. The thiazole and pyrimidine moieties are biosynthesizedseparately and then combined to form thiamin monophosphate by the action of thiamine-phosphatesynthase (EC 2.5.1.3). The biosynthetic pathways may differ among organisms. The enzymatic synthesisof thiamin monophosphate was developed, and its procedure can be briefly stated as hydroxymethyl-pyrimidine monophosphorylation and then diphosphorylation to obtain hydroxymethylpyrimidinediphosphate, which coupled with thiazole monophosphate under the enzyme catalysis in each step togenerate thiamin monophosphate (Leger 1961). Thiamin cannot be synthesized within animal tissues andthus is a universally essential dietary component throughout the animal kingdom. All living organisms usethiamin in their biochemistry, but it is synthesized in bacteria, fungi, and plants. Animals must obtain itfrom their diet, and, thus, for them it is a vitamin. Supply from natural source of thiamin is not sufficient.Chemical synthesis of thiamine is very complicated, involving 15–17 different steps. Thiamine salts arestable and survive at temperature above 100 �C. The chemical characterization and synthesis of thiaminwere carried out during the 1930s, with Roger Williams playing a major role. In the preferred synthesispathway, the pyrimidine ring is built first, largely from organic nitrile compounds; then the thiazole ring isadded by reaction with chloro-ketone, carbon disulfide, and ammonia; and finally an oxidation step withhydrogen peroxide removes a sulfur atom and introduces a ring and a double bond so as to complete thethiazole ring. Analysis of thiamin in food sources can be achieved by microbiological assay, fluorimetricassays, and high-performance liquid chromatography (Bates 2010).

RiboflavinRiboflavin, or vitamin B2 in Fig. 3, has a variety of functions in the body, including the metabolism ofcarbohydrates for the production of energy and the production of red blood cells. The human body needsriboflavin to use oxygen efficiently in the metabolism of amino acids, fatty acids, and carbohydrates.Riboflavin is involved in the synthesis of niacin. It activates vitamin B6 and helps the adrenal gland toproduce hormones. It also helps the body make antibodies to fight disease and infection, regulates thethyroid gland, and is important in maintaining healthy hair, nails, and skin. Riboflavin is especiallyimportant in rapid growth period because it is involved in the formation and growth of cells, particularlyred blood cells. People most likely to suffer from riboflavin deficiency problems are those with anorexia,older people with poor diets, alcoholics with impaired ability to absorb and use the vitamin, and newbornbabies being treated for jaundice by exposure to ultraviolet light.

Riboflavin is an orange-yellow crystal with a bitter taste. It is relatively stable when exposed to heat, buttends to decompose in the presence of light for extended periods of time. It was not until the 1930s that the

N N

N NH

O

O

OH

HOOH

OH

Fig. 3 Riboflavin structure


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chemical structure of riboflavin was determined by Paul Karrer and Richard Kuhn independently and thecompound was synthesized. Naturally, riboflavin can be synthesized in plants and microorganisms. Somefoods rich in riboflavin are yeast, dark green vegetables, mushrooms, meat, eggs, legumes, nuts, milk andother dairy products, sweet potatoes, and pumpkins, among others. Bacteria in the human digestive tractare also able to synthesize some riboflavin, but not enough to meet the body’s requirement.

Riboflavin is produced synthetically using either bacteria, yeast, or fungus. The bacteria or fungus iscultured in a large vat that has been seeded with small amounts of riboflavin. Over time, the organismsgenerate large quantities of riboflavin until some desired amount of the compound has been produced. Thevat is then heated to a temperature sufficient to kill the bacteria or fungi, leaving crystalline riboflavinbehind. The riboflavin is then separated and purified for human consumption (Fisher and Bacher 2008).

NiacinNiacin and niacinamide (Fig. 4) are forms of vitamin B3 and one of the eight B vitamins. All B vitaminshelp the body to convert carbohydrates into fuel glucose and to use fat and protein. These B vitamins,often referred to as B complex vitamins, are needed for healthy skin, hair, eyes, and liver. They also helpthe nervous system function properly. Niacin also helps the body to make various sex- and stress-relatedhormones in the adrenal glands and other parts of the body. Niacin helps improve circulation and hastherapeutic effects. High dose of niacin is used for lowering hyperlipidemia (high cholesterol). Niacin isalso used along with other treatments for circulation problems, migraine headache, and dizziness and toreduce the diarrhea associated with cholera. Niacinamide is used for treating diabetes and for preventingvitamin B3 deficiency and related conditions such as pellagra. Niacin or niacinamide is also used for acne,leprosy, attention deficit hyperactivity disorder (ADHD), memory loss, and arthritis, preventing premen-strual headache, improving digestion, protecting against toxins and pollutants, reducing the effects ofaging, lowering blood pressure, improving circulation, promoting relaxation, improving orgasm, andpreventing cataracts. In addition, niacinamide is applied to the skin for treating a skin condition calledinflammatory acne vulgaris (Gille et al. 2008).

Niacin can be found in many foods, including fungi (yeast, mushrooms), liver, meat, fish, milk, eggs,green vegetables, fruits, seeds (nuts, legumes, whole grain products), and cereal grains. Vitamin B3 isoften found in combination with other B vitamins, including thiamine, riboflavin, pantothenic acid,pyridoxine, cyanocobalamin, and folic acid. One recommended daily allowance of niacin is2–12 mg/day for children, 14 mg/day for women, 16 mg/day for men, and 18 mg/day for pregnant orbreast-feeding women. Symptoms of mild niacin deficiency include indigestion, fatigue, canker sores,vomiting, and depression. Severe deficiency can cause a condition known as pellagra. Pellagra ischaracterized by cracked, scaly skin, dementia, and diarrhea. It is generally treated with a nutritionallybalanced diet and niacin supplements. Niacin deficiency also causes burning in the mouth and a swollen,bright-red tongue. Pharmacological doses of niacin (1.5–6 g per day) lead to side effects that can includedermatological conditions such as skin flushing and itching, dry skin, and skin rashes including eczemaexacerbation and acanthosis nigricans.

Niacin, a water-soluble solid, is a derivative of pyridine with a carboxylic acid group (COOH) at the 3-position. Other forms of vitamin B3 include the corresponding amide, nicotinamide (niacinamide), whereat the 3-position is a carboxamide group (CONH2). Nicotinic acid and niacinamide are interchangeable in

N

OH

O

N

NH2

O

Fig. 4 Structures of niacin and niacinamide


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the body. The synthesis of niacin starts from 3-picoline (3-methylpyridine). Nicotinic acid was firstsynthesized in 1867 by oxidative degradation of nicotine. Niacin is prepared by hydrolysis ofnicotinonitrile, which, as described above, is generated by oxidation of 3-picoline. The catalysts usedin the reaction above are derived from the oxides of antimony, vanadium, and titanium (Eggersdorfer andAdam 2011).

Pantothenic AcidPantothenic acid (Fig. 5) is vital for the synthesis and maintenance of coenzyme A (CoA) thus essential toalmost all forms of life. Most tissues transport pantothenic acid into cells for the synthesis of CoA. Smallquantities of pantothenic acid are found in most foods. The major food source of pantothenic acid is meat.Other good sources of pantothenic acid are grains and some vegetables and fruits. Specific foods containpantothenic acids are beef, yeast, eggs, fresh vegetables, kidneys, legumes, liver, mushrooms, nuts, pork,royal jelly, saltwater fish, whole rye flour, and whole wheat.

Only (R)-pantothenic acid is biologically active and is extremely hygroscopic. Consequently, the majorcommercial form of pantothenic acid is calcium (R)-pantothenate. The key step in the present commercialchemical synthesis of (R)-pantothenic acid involves resolution of racemic pantolactone. Recent industrialsynthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone either by chemical or microbial reduction of ketopantolactone. Calcium (R)-pantothenate isused in food and feed enrichment. Panthenol and pantyl ether are industrially important derivatives ofpantothenic acid and are used in hair care products (Rawalpally 2001).

Panthenol, called provitamin B5, is the alcohol analog of pantothenic acid. In organisms it is quicklyoxidized to pantothenate. When ingested, it is metabolized to pantothenic acid. Panthenol is a highlyviscous transparent liquid at room temperature and soluble in water, alcohol, ether, and chloroform andslightly soluble in glycerin. Panthenol draws moisture from the atmosphere and readily binds to watermolecules. When applied to the hair, panthenol will help to moisturize it and give it a shine and gloss. Forthis reason, it has become a very popular ingredient in shampoos and conditioners. In ointments,panthenol is an effective skin penetrator. It is sometimes mixed with allantoin, in concentrations of upto 2–5 %, and is used for the treatment of sunburns, mild burns, and minor skin disorders. It improveshydration, reduces itching and inflammation of the skin, and accelerates epidermal wounds’ rate ofhealing. Panthenol is synthesized from a number of sources including honey, molasses, and rice.

Vitamin B6Vitamin B6, referred to as pyridoxal, pyridoxamine, and pyridoxine (Fig. 6), is involved in the metab-olism of amino acids, glucose, and lipids in the liver. It is also crucial in the synthesis of neurotransmitters,

HN

O

OH

O

HO

O

HO

HN OH

OH OH

Fig. 5 Structure of (R)-pantothenic acid and panthenol

O P

OOH

OHN

O

HO

N

HO

OH

OHOHHO

NH2

N

Fig. 6 Vitamin B6 (pyridoxal phosphate, pyridoxamine, and pyridoxine)


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hemoglobin, and histamine, as well as proper gene expression. Vitamin B6 plays a significant role in morethan 100 metabolic reactions and is also involved in brain development during pregnancy and infancy aswell as immune function. Hence, it is very important to consume enough of it on a daily basis. Vitamin B6is a water-soluble vitamin and naturally presents in many foods. Also it is added to many other foods.Usually, enough amounts of vitamin B6 are ingested by eating a variety of foods, including poultry, fish,and organ meats, potatoes and other starchy vegetables, and fruits other than citrus. The US FDA (Foodand Drug Administration) has established the following RDI (recommended daily intake) of vitamin B6:0.5 mg/day for children 1–3 years, 0.6 mg/day for children 4–8 years, 1 mg/day for children 9–13 years,1.2 mg/day for females 14–18 years, 1.3 mg/day for males 14–18 years, 1.3 mg/day for adults 19–50years, 1.5 mg/day for females 50 years and older, and 1.7 mg/day for men 50 years and older.

Although it is relatively rare, vitamin B6 deficiency can have detrimental effects. Deficiency of vitaminB6 can cause a range of symptoms, including anemia, itchy rashes, scaly skin on the lips, cracks at thecorners of the mouth, and a swollen tongue. Other symptoms of very low vitamin B6 levels includedepression, confusion, and a weak immune system. Infants who do not get enough vitamin B6 canbecome irritable or develop extremely sensitive hearing or seizures. Certain groups of people are at higherrisk for vitamin B6 deficiency, such as dialysis, arthritis, liver disease, ulcerative colitis, Crohn’s disease,and HIV patients, as well as individuals coping with alcoholism and those who take certain medicationslike penicillamine and hydrocortisone. Oral contraceptives and other estrogens are found to interfere withvitamin B6 metabolism, resulting in deficiency. People deficient in the vitamin should consider changingtheir diets to ensure that they are consuming enough of the nutrient from foods.

Many great sources of vitamin B6 are in a wide range of foods. Vitamin B6 is found in meat, poultry,fish, eggs, whole grains, legumes (bean and peas), potatoes, yeast, bananas, corn, cabbage, yams, prunes,watermelon, and avocado. One’s daily quota of vitamin B6 can be easily consumed through food,including these vitamin B6-rich food sources.

Some scientists had thought that certain B vitamins (such as folic acid, vitamin B12, and vitamin B6)might reduce heart disease risk by lowering levels of homocysteine, an amino acid in the blood. Althoughvitamin B supplements do lower blood homocysteine, research shows that they do not actually reduce therisk or severity of heart disease or stroke. Vitamin B6 can reduce nausea and vomiting for pregnantwoman. The American Congress of Obstetricians and Gynecologists (ACOG) recommends takingvitamin B6 supplements under a doctor’s care for nausea and vomiting during pregnancy. Both chemicaland microbial methods are available to prepare vitamin B6 compounds, but vitamin B6 is mainlyproduced by chemical synthesis (Mackey et al. 2005). For those who are interested in the chemicalstructure transformation, Fig. 7 illustrates the most popular synthetic route of pyridoxine up to date toprepare pyridoxine from amino acid alanine (Firestone et al. 1967).

BiotinBiotin, with other names of vitamin B7, vitamin H, or vitamin B8, is a colorless, water-soluble member ofthe B vitamin group. Figure 8 illustrates its chemical structure. There are eight different forms of biotin,but only one of them, D-biotin, occurs naturally and has full vitamin activity. Biotin can only besynthesized by bacteria, molds, yeasts, algae, and certain plants. Biotin is an essential growth factorfound in all living cells. It functions as a cofactor for a group of coenzymes that catalyze transcar-boxylation, decarboxylation, and carboxylation reactions related to biochemical processes such asglucogenesis and fatty acid synthesis. Sufficient intake of biotin is important as it has significant healthfunctions. The European Food Safety Authority (EFSA) has confirmed the clear health benefits of thedietary intake of biotin in the contribution of normal macronutrient metabolism, normal energy-yieldingmetabolism, the maintenance of normal skin and mucous membranes, the normal function of the nervoussystem, the maintenance of normal hair, and normal psychological functions.


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The food source of biotin includes raw egg yolk, animal liver, pork, salmon, sardine, nuts (almonds,peanuts, pecans, walnuts), soybean, other legumes (beans, black-eyed peas), whole grain, banana,mushroom, avocado, Swiss chard, raw cauliflower, and green leafy vegetables. Biotin is also availablein supplement form and can be found in most pharmacies. Although rare, the symptoms of biotindeficiency in biotin include hair loss, dry scaly skin, cracking in the corners of the mouth (called cheilitis),swollen and painful tongue that is magenta in color (glossitis), dry eyes, loss of appetite, fatigue,insomnia, and even depression.

Biotin synthesis comes either from fermentation process or from organic synthesis. Early syntheticprocess developed in the 1940s uses fumaric acid as a starting material. The synthetic route of biotin hasbeen modified or newly explored multiple times by different groups in which half comes from industryresearch groups to improve the efficiency of biotin synthesis. The detailed organic synthetic route hasbeen reviewed by Seki et al. (2004; Zempleni and Mock 1999).

FolateFolate is a naturally occurring B vitamin, and folic acid is the synthetic form of folate. Folate and folic acid(Fig. 9) are often interchanged. Naturally existing folate has many forms and is found in foods as well as inmetabolically active forms in the human body. Folic acid is a stable form of folate. Folate helps the bodymake new cells. Folate is crucial for proper brain function and plays an important role in mental andemotional health. It assists the production of DNA and RNA, the body’s genetic material, and is especiallyimportant when cells and tissues are growing rapidly, such as in infancy, adolescence, and pregnancy.Folic acid also works closely with vitamin B12 to help make red blood cells and help iron work properly inthe body. The function of folate coenzymes in the body is in mediating the transfer of one-carbon units.Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to themetabolism of nucleic acids and amino acids. There are two different pathways in folate coenzyme-assisted DNA metabolism: (1) the synthesis of DNA from its precursors (thymidine and purines) is

N

HO

OH

OH

OH

NH2 NH2

O

OEt

O

OEt

HN

O

O

CO2Et

NO

OEt

NO

OEt

CO2Et

NO

O

O

O

OEt

O

N O

O

OH

EtOH (CO2Et)2POCl3

Et3N

1) NaOH

2) HCl

HCl-H2O

EtOH

HCl

HCl

Fig. 7 Chemical synthetic route of pyridoxine

HN

NH

S

O

OH

OH

H

Fig. 8 Biotin structure


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dependent on folate coenzymes, and (2) a folate coenzyme is required for the synthesis of methionine, andmethionine is required for the synthesis of S-adenosylmethionine (SAMe). SAMe is a methyl group donorused in many biological methylation reactions, including the methylation of a number of sites withinDNA and RNA. Methylation of DNAmay be important in cancer prevention (Bailey and Gregory 1999).

Food sources of folate include vegetables (romaine lettuce, spinach, asparagus, broccoli, cauliflower,beets, green beans, cabbage, bell peppers, leeks, tomatoes, celery, and green peas), legumes (black beans,navy beans, kidney beans, pinto beans, etc.), fruits (strawberry, papaya, orange, citrus, banana, melon,cantaloupe, pineapple), seeds (peanut, sunflower seed, dried peas, etc.), and animal products (eggs,kidney, liver, pork, poultry, shellfish, etc.). Due to its link with the nervous system, folate deficiencycan be associated with irritability, mental fatigue, forgetfulness, confusion, depression, and insomnia.Folate deficiency can also result in intestinal tract symptoms (like diarrhea) or mouth-related symptomslike gingivitis or periodontal disease. The production of folic acid can be achieved either by chemicalsynthesis or by microorganisms (Lohner et al. 2012).

Vitamin CVitamin C (Fig. 10) is one of the many antioxidants, along with vitamin E, beta-carotene, and many otherplant-based nutrients. Antioxidants block some of the damage caused by free radicals and other reactiveoxygen species (ROS) that damage DNA. The buildup of free radicals and ROS over time may contributeto the aging process and the development of health conditions such as cancer, heart disease, and arthritis.Vitamin C is needed for the growth and repair of tissues in all parts of the human body. It is used to form animportant protein used to make skin, tendons, ligaments, and blood vessels; to heal wounds and form scartissue; and to repair and maintain cartilage, bones, and teeth. The body is not able to make vitamin C on itsown, and it does not store vitamin C. It is therefore important to include plenty of vitamin C-containingfoods in your daily diet.

Vitamin C is readily available from diet of fruits and vegetables. Dietary sources of vitamin C includeoranges, green peppers, watermelon, papaya, grapefruit, cantaloupe, strawberries, kiwi, mango, broccoli,tomatoes, Brussels sprouts, cauliflower, cabbage, and citrus juices or juices fortified with vitamin C. Rawand cooked leafy greens (turnip greens, spinach), red and green peppers, canned and fresh tomatoes,potatoes, raspberries, blueberries, cranberries, and pineapple are also rich sources of vitamin C. VitaminC is sensitive to light, air, and heat. Shortage of vitamin C is rare. Lack of vitamin C can cause muscleweakness, swollen and bleeding gums, loss of teeth, and bleeding under the skin, as well as tiredness anddepression. Wounds would heal slowly. Vitamin C deficiency can lead to a disease called scurvy, and thehealthcare professional may treat scurvy by prescribing vitamin C. Vitamin C is L-ascorbic acid, thenaturally occurring enantiomer. Most of the ascorbic acid on the market is synthetic version, and theindustrial synthesis of vitamin C mostly starts from glucose (Michels and Frei 2012; Tripathi et al. 2009).

Vitamin EVitamin E, composed of a collective name for a group of fat-soluble compounds, is biologically essentialantioxidants derived from 6‐chromanol. Naturally occurring vitamin E exists in eight chemicalforms showed in Fig. 11 (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and

OH

NN

NNH2N

NH

NH

O CO2H

CO2H

Fig. 9 Structure of folic acid


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delta-tocotrienol) that have various levels of biological activity. Alpha-tocopherol is the only form that isrecognized to meet human requirements. The concentration of alpha-tocopherol in blood depends on theliver, which takes up all forms of vitamin E after which are absorbed from the small intestine. The liverpreferentially releases only alpha-tocopherol through hepatic alpha-tocopherol transfer protein andmetabolizes and excretes the rest of other forms of vitamin E. As a result, blood and cellular concentra-tions of other forms of vitamin E are lower than those of alpha-tocopherol. Vitamin E is a fat-solubledistinctive antioxidant that reduces the concentration of ROS (reactive oxygen species) formed in theoxidation reaction inside the body. Scientists have been investigating whether, by controlling theconcentration of free radical species, vitamin E helps prevent or delay the chronic diseases associatedwith free radicals. In addition to its antioxidant activity, vitamin E is involved in immune function and, asshown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and othermetabolic processes. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved incell proliferation and differentiation in smooth muscle cells, platelets, and monocytes. Vitamin E alsoincreases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasingthe release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits plateletaggregation.

Vitamin E is found naturally in some foods, added to others, and available as a dietary supplement.Numerous foods provide vitamin E. Nuts, seeds, and vegetable oils are among the best sources of alpha-tocopherol, and significant amounts are available in green leafy vegetables and fortified cereals. Mostvitamin E in American diets is in the form of gamma-tocopherol from soybean, canola, corn, and othervegetable oils and food products. Vitamin E deficiency is rare, and overt deficiency symptoms have notbeen found in healthy people who obtain little vitamin E from their diets (Traber 2007).

The industrially most relevant alpha‐tocopherol is generally built up by coupling of arenes withaliphatic precursors. For the synthesis of active vitamin E components, various strategies are compiled.

OH

OH

OHHO

O O

Fig. 10 Ascorbic acid (vitamin C)

O

HO

O

HO

alpha-tocopherol

beta-tocopherol

HO

O

gamma-tocopherol

HO

O

delta-tocopherol

HO

O

delta-tocotrienol

O

HO

beta-tocotrienol

HO

O

gamma-tocotrienol

HO

O

alpha-tocotrienol

Fig. 11 Structure of alpha-tocopherol


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In approaches to chiral chroman and side-chain building blocks, many asymmetric syntheses wereemployed, such as optical resolution and the use of chiral starting materials and chiral auxiliaries instoichiometric or catalytic amounts, including catalysts from metal complexes, microorganisms, andenzymes. Most efforts were directed to alpha‐tocopherol owing to its prominent biological activity(Netscher 2007).

Coenzyme Q10

Coenzyme Q10, abbreviated as CoQ10, is found in almost every cell throughout the body, especially inthe heart, liver, kidney, and pancreas. It is present in most eukaryotic cells, primarily in mitochondria. Ithelps convert food into energy. A substance in the electron transport chain, it participates in aerobiccellular respiration, helping generate about 95 % of human body’s energy in the form of ATP. Hence, theorgans with the highest energy requirements, such as the heart, liver, and kidney, have the highest CoQ10

concentrations. It is a powerful antioxidant and can neutralize free radicals. It is a fat-soluble substanceprimarily synthesized by the body and also consumed in the diet. CoQ10 is required for mitochondrialATP synthesis and functions as an antioxidant in cell membranes and lipoproteins. Endogenous synthesisand dietary intake can provide sufficient CoQ10 in healthy people. But the CoQ10 level in tissue declineswith age. Some scientists believe that CoQ10 may help with heart-related conditions, because it canimprove energy production in cells, prevent blood clot formation, and act as an antioxidant. It is used as amedicine for treating heart and blood vessel conditions such as congestive heart failure, chest pain, highblood pressure, and heart problems linked to certain cancer drugs and also used for diabetes, gum disease,breast cancer, Huntington’s disease, Parkinson’s disease, muscular dystrophy, increasing exercise toler-ance, chronic fatigue syndrome, and Lyme disease, among others. There are three redox states of CoQ10:fully oxidized ubiquinone (Fig. 12), half-oxidized or half-reduced semiquinone (ubisemiquinone), andfully reduced ubiquinol (Fig. 12). The existence of this molecule in a completely oxidized form and acompletely reduced form enables it to perform its functions in the electron transport chain and as anantioxidant, respectively. Also, it has been found that the bioavailability of the reduced form ubiquinol ishigher than its oxidized form ubiquinone. These two forms are interchangeable in vivo and act as thefunction of CoQ10 (Monograph 2007).

Most people get enough CoQ10 through a balanced diet. CoQ10 is synthesized in most human tissues.Its biosynthesis involves three major steps: (1) synthesis of the benzoquinone skeleton from eithertyrosine or phenylalanine, (2) synthesis of the isoprene side chain from CoAvia the mevalonate pathway,and (3) the condensation of these two structural components. The enzyme hydroxymethylglutaryl(HMG)-CoA reductase plays a critical role in regulating the synthesis of CoQ10 and cholesterol synthesis.

Primary dietary sources of CoQ10 include oily fish, such as salmon and tuna, organs such as the liver,and whole grains. General rich sources of dietary CoQ10 include mainly meat, poultry, and fish. Otherrelatively rich sources include soybean and canola oils and nuts. Fruits, vegetables, eggs, and dairyproducts are moderate sources of CoQ10, which is unstable in heating conditions. Approximately14–32 % of CoQ10 was lost during frying of vegetables and eggs, but the CoQ10 content is unchanged

O

HO

OO

10HO

HO

OHO

10

Fig. 12 Structures of CoQ10 (ubiquinone) and ubiquinol


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when boiled. Some food examples with relatively rich CoQ10 content are beef, herring, chicken, soybean,broccoli, cauliflower, orange, strawberry, egg, etc. CoQ10 can be prepared by chemical synthesis orfermentation process (Crane 2001; Lipshutz et al. 2002; Shinde et al. 2005).

Sulfur-Containing Compounds

N-AcetylcysteineN-Acetylcysteine (NAC, Fig. 13) comes from the amino acid L-cysteine plus an acetyl (�COCH3) groupattached to the amino (NH2) group. NAC is more water soluble, less toxic, and less susceptible tooxidation than cysteine. NAC is reported to be safe, even in large doses, and a better source of cysteinethan cysteine itself. NAC is a precursor to glutathione (GSH). It is an antioxidant and used as aprescription drug and as a dietary supplement. As a drug, it is used as both an antidote foracetaminophen-induced hepatotoxicity and as a mucolytic agent for respiratory diseases. NAC is usedto counteract acetaminophen and carbon monoxide poisoning. It is also used for chest pain, bile ductblockage in infants, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), Alzheimer’s disease,allergic reactions to the antiseizure drug phenytoin (Dilantin), and an eye infection called keratoconjunc-tivitis. Clinical studies show NAC can treat drug-induced hepatotoxicity, prevent and treat conditions ofoxidative stress and reduced GSH levels caused by diseases such as HIV/AIDS and cancer, and alleviatetoxicity from chemo- and radiotherapy. Healthcare providers give N-acetylcysteine intravenously foracetaminophen overdose, acrylonitrile poisoning, amyotrophic lateral sclerosis (ALS, Lou Gehrig’sdisease), kidney failure in the presence of liver disease (hepatorenal syndrome), chest pain in combinationwith nitroglycerin, and heart attack in combination with nitroglycerin and streptokinase and for helping toprevent multiorgan failure leading to death.

Oral supplementation with N-acetylcysteine (NAC) provides an alternate means of boosting intracel-lular glutathione via elevated intracellular cysteine. NAC is rapidly absorbed after oral administration andreaches a maximum plasma level in 2–3 h, with a half-life of about 6 h. NAC readily enters cells and ishydrolyzed to cysteine. Food is not a significant source of N-acetylcysteine. Synthesis of NAC is aone-step reaction (Fig. 14) from the acetylation of cysteine (Baniasadi et al. 2010; Grandjean et al. 2000;Grant et al. 2009; Tonbary et al. 2009; Yarema et al. 2009).

HS

HN

OH

O

O

Fig. 13 N-acetylcysteine

HS

HN

OH

O

O

HS

NH2

OH

OCH3COCl

or Ac2O

Fig. 14 One-step synthesis of N-acetylcysteine


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Lipoic AcidLipoic acid (1,2-dithione-3-pentanoic acid, LA, Fig. 15), an organosulfur compound derived fromoctanoic acid, has an antioxidant with metal-chelating and anti-glycation capabilities in both lipid andaqueous phases. It has been given for mushroom poisoning, heavy metal intoxication, and diabeticneuropathy. LA reduces glycation by inhibiting the lipid peroxidation. The combination of anti-glycationand hydrophobic binding capacity of lipoic acid enables lipoic acid to prevent glycosylation of albumin inthe bloodstream (Abdul and Butterfield 2007). Lipoic acid is part of a redox pair, and the reduced form isdihydrolipoic acid (DHLA). LA is readily absorbed from diet and is rapidly converted to DHLA byNADH or NADPH in most tissues. Unlike glutathione, for which only the reduced form is an antioxidant,both the oxidized and reduced forms of lipoic acid are antioxidants. In general, DHLA has superiorantioxidant activity to LA. DHLA can regenerate vitamins C and E from their oxidized forms. DHLA isalso superior to GSH in regenerating vitamin C. DHLA can donate two hydrogens and neutralize freeradicals without a free radical generation (Biewenga et al. 1997).

Chemically, lipoic acid exists in two enantiomers (exact same confirmation in mirror images): theR-enantiomer and the S-enantiomer. Naturally occurring LA is the R-form, but synthetic lipoic acid(known as alpha lipoic acid or a-lipoic acid, ALA) is a racemic mixture of R- and S-form. R-form is morebiologically active than the S-enantiomer, but administration of alpha lipoic acid results in greaterformation of DHLA due to a synergistic effect which each enantiomer exerts on the reduction of theother (Bast and Haenen 2003). Both LA and DHLA can chelate heavy metals, but the R-form is moreeffective. LA is most effective in chelating Cu2+, Zn2+, and Pb2+, but cannot chelate Fe3+. DHLA can formcomplexes with Cu2+, Zn2+, Pb2+, Hg2+, and Fe3+, and the chelating compounds are poorly soluble inwater. DHLA not only can chelate Fe3+ but also can reduce Fe3+ to Fe2+ – a prooxidant effect it shares withascorbic acid. Small amounts of cadmium (Cd2+) can cause significant lipid peroxidation in the brain,which can be prevented by lipoic acid (Packer et al. 1997). Lipoic acid is also beneficial in reducingischemic-reperfusion injury by direct action as well as by glutathione protection and xanthine oxidaseinhibition. Protection against peroxynitrite damage by lipoic acid is highly dependent upon the targetmolecule. Supplementation with both lipoic acid and acetyl-L-carnitine is an effective way of improvingmitochondrial metabolic function without increasing oxidative stress (Hagen et al. 2002).

Lipoic acid is a cofactor for at least five enzyme systems. Two of these are in the citric acid cycle inwhich many organisms turn nutrients into energy. Lipoic acid is covalently attached to the enzymes, andthe lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes and methylamine group inthe glycine cleavage complex or glycine dehydrogenase. Lipoic acid serves as a cofactor to the acetoindehydrogenase complex catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehydeand acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source.

Lipoic acid is normally made in animals and is essential for aerobic metabolism. It is present in almostall foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract. It is readilydigested, absorbed, and transported to tissues. LA induces cystine/cysteine uptake, thereby increasingsynthesis of glutathione. Naturally occurring lipoic acid is always covalently bound and not readilyavailable from dietary sources. In addition, the amount of lipoic acid present in dietary sources is very low.As a result, all lipoic acid available as a supplement is chemically synthesized. The first syntheticprocedures appeared for both forms of LA in the mid-1950s. Advances in chiral chemistry led to more

S S

OH

O

Fig. 15 Structure of lipoic acid


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efficient technologies for manufacturing the single enantiomers by both classical resolution and asym-metric synthesis. In the twenty-first century, LA racemic and R- and S-form of LA with high chemicaland/or optical purities are available in industrial quantities. Although LA R-form is favored nutritionallydue to its “vitamin-like” role in metabolism, both LA R-form and LA racemic are widely available asdietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo andcontribute to the mechanisms of action, but evidence to date indicates LAR-formmay be the major isomer(Shay et al. 2008, 2009; Durrani et al. 2010).

S-Adenosylmethionine (SAMe)S-Adenosylmethionine (Fig. 16, also known as SAM and SAMe) is a molecule composed of adenosine(derived fromATP) and methionine. SAMe is the principal biological methyl donor in metabolism, whichdonates a methyl group (methylation) to molecules such as DNA, proteins, phospholipids, or neurotrans-mitters. It is synthesized in all mammalian cells, but most abundantly in the liver. Biosynthesis of SAMerequires enzyme methionine adenosyltransferase. DNA methylation declines with age, resulting incellular dysregulation. Low DNA methylation can lead to mutations and chromosome instability.Excessive SAMe methylation has shown to result in toxic methanol, formaldehyde, and formic acid inthe brain (Lee et al. 2008). Although SAMe is the principal methyl donor in all cells of the body, it ismainly synthesized, utilized, and degraded in the liver. Up to 80 % of methionine in the liver is convertedto SAMe, which is the source of glutathione, a principal antioxidant required for liver detoxificationreactions. SAMe has proven to be effective in the treatment of depression, with fewer side effects than isseen with conventional antidepressants (Papakostas et al. 2010). SAMe can cause insomnia if not taken inthe morning and is best taken on an empty stomach. The reactions that produce, consume, and regenerateSAMe are called the SAMe cycle.

Another major role of SAM is in polyamine biosynthesis. SAMe is decarboxylated by adenosyl-methionine decarboxylase (EC 4.1.1.50) and forms S-adenosylmethioninamine. This compound thendonates its n-propylamine group in the biosynthesis of polyamines such as spermidine and spermine fromputrescine. SAMe is required for cellular growth and repair. It is also involved in the biosynthesis ofseveral hormones and neurotransmitters that affect mood, such as epinephrine. Methyltransferases arealso responsible for the addition of methyl groups to the 20 hydroxyls of the first and second nucleotidesnext to the 50 cap in messenger RNA. SAMe has been studied in the treatment of osteoarthritis. It reducesthe pain associated with osteoarthritis. Although an optimal dose has yet to be determined, SAMe appearsas effective as the nonsteroidal anti-inflammatory drugs.

Several methods for the chemical and enzymatic synthesis of (�)-S-adenosylmethionine are describedand compared. Studies on the effects of solvents, pH, methylating reagents, and KI on the coupling ofsodium homocysteine thiolate and 50-chloro-50-deoxyadenosine led to an improved procedure for thesynthesis of (+/�)-SAMe (Matos et al. 1987).

N

N N

N

NH2

O

OH OH

S+ CO2−

NH3+

Fig. 16 Structure of S-adenosylmethionine


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Methylsulfonylmethane (MSM)Methylsulfonylmethane (MSM, Fig. 17) is an organic form of naturally occurring sulfur, found in plants,animals, and humans. MSM has many functions in the body, and the most important is the formation ofprotein structures of connective tissue. The proteins that mostly required MSM include collagen andkeratin. Proteins like collagen and keratin are part of structures like the skin, blood vessels, hair, nails,lymph tissue, and other connective structures. Thus,MSM consumption has multiple benefits: to boost thestructure of the skin, the nails, and the hair, to increase hair and nail strength and appearance, to increasethe mobility and flexibility of the joints, and to increase energy and better recovery from exercise. MSM isalso used for chronic pain, osteoarthritis, joint inflammation, rheumatoid arthritis, osteoporosis, bursitis,tendonitis, tenosynovitis, musculoskeletal pain, muscle cramps, scleroderma, scar tissue, stretch marks,hair loss, wrinkles, protection against sun/wind burn, eye inflammation, oral hygiene, periodontal disease,wounds, cuts, and abrasions/accelerated wound healing. Other uses of MSM are for eye inflammation,mucous membrane inflammation, temporomandibular joint problems, leg cramps, migraine, headaches,hangover, parasitic infections of the intestinal and urogenital tracts including Trichomonas vaginalis andGiardia, yeast infections, insect bites, radiation poisoning, and boosting the immune system.

There is no recommended dietary allowance (RDA) for MSM or sulfur. Sulfur deficiency has not beendescribed in the medical literature. MSM occurs naturally in many common foods such as tomatoes andmilk. However, its concentrations are so small that it is not feasible to commercially “extract it fromnature.” All MSM is manufactured by organic synthesis from two raw materials, dimethyl sulfoxide andhydrogen peroxide. This reaction forms MSM or dimethyl sulfone. After the reaction, a purificationprocess removes the impurities from the MSM. Two commonly purification processes used in mostchemical and food processing plants are distillation and crystallization. Distillation is the favored processfor producing high-purity MSM (Brien et al. 2008, 2011; Parcell 2002; Tsui et al. 2012).

Melatonin

Melatonin (Fig. 18) is a hormone secreted by the pineal gland in the brain. It helps regulate otherhormones and maintains the body’s circadian rhythm. The circadian rhythm is an internal 24-h “clock”that plays a critical role in our sleeping cycle. The level of melatonin starts to rise in the mid- to lateevening, remains high for most of the night, and then drops in the early morning hours. Light affects theamount of melatonin the body produces. Melatonin also helps control the timing and release of femalereproductive hormones. It is involved in the menstrual cycles and helps determine the timing a womanstarts to menstruate, the frequency and duration of menstrual cycles, and when a woman stops menstru-ating (menopause). Natural melatonin levels slowly drop with age. Melatonin supplements are used to

OS

O

Fig. 17 Methylsulfonylmethane

NH

HNO

O

Fig. 18 Melatonin


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adjust the body’s internal clock, such as jet lag and sleep-wake cycles in people whose daily workschedule changes, and for helping blind people establish a day and night cycle. Melatonin is also used forthe inability to fall asleep (insomnia), delayed sleep phase syndrome (DSPS), insomnia associated withattention deficit hyperactivity disorder (ADHD), insomnia due to certain high blood pressure medicationscalled beta-blockers, and sleep problems in children with developmental disorders including autism,cerebral palsy, and intellectual disabilities. It is also used as a sleep aid after discontinuing the use ofbenzodiazepine drugs and to reduce the side effects of stopping smoking. Scientists are also looking atother good uses for melatonin, such as treating seasonal affective disorder, controlling sleep patterns forpeople who work night shifts, preventing or reducing problems with sleeping and confusion after surgery,and reducing chronic cluster headaches.

Melatonin has strong antioxidant effects. Preliminary evidence suggests that it may help strengthen theimmune system. Other uses include breast cancer, brain cancer, lung cancer, prostate cancer, head cancer,neck cancer, and gastrointestinal cancer. Melatonin is also used for some of the side effects of cancertreatment (chemotherapy) including weight loss, nerve pain, and weakness. Melatonin is synthesizedchemically in three steps or less, which is suitable for massive production inexpensively (Buscemiet al. 2005, 2006).

Raspberry Ketone

Raspberry ketone (Fig. 19) is a chemical from red raspberries. It is reported to affect a body hormonecalled adiponectin. Hence, it is most commonly used for weight loss and obesity. It is also used to increaselean bodymass. Raspberry ketone is also applied to the scalp to improve hair growth. However, there is noreliable scientific evidence for it improves weight loss when taken by people. Raspberry ketone is alsoused in foods, cosmetics, and other manufacturing as a fragrance or flavoring agent. The average dailyintake of dietary raspberry ketone has been estimated as 0.42 mg/kg/day.

Raspberry ketone exists in a variety of fruits including raspberries, cranberries, and blackberries. Thecontent of raspberry ketone in raspberry is very low in a range of ppm, and only 1–4 mg of pure raspberryketone is extracted from about one kg of raspberries. Since the natural abundance of raspberry ketone inplants is very low, it is prepared chemically in industry by a variety of methods from various intermedi-ates. One of the ways this can be done is through a crossed aldol-catalytic hydrogenation. Under thecatalysis of sodium hydroxide, acetone and 4-hydroxybenzaldehyde can form the a,b-unsaturated ketone,which goes through catalytic hydrogenation to produce raspberry ketone (Fig. 20). This method producesa 99 % yield (Morimoto et al. 2005).

HO

O

Fig. 19 Raspberry ketone

HO

O

HO

O

Acetone

NaOH (aqu) HO

O

Hydrogenation

Catalyst

Fig. 20 Synthesis of Raspberry ketone


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Conclusion and Future Directions

This chapter has introduced nutraceutical substances that are essential to human health but insufficientfrom the diet of daily intake, including vitamins, antioxidants, sulfur-containing nutraceuticals, andcoenzyme Q10. The nutritional properties, natural resources, and synthesis of these nutraceuticals werediscussed, and their nutritional value is scientifically proved to be essential. Hence, these nutraceuticalsare readily available nowadays as forms of dietary supplements, food additives, and even medicines insome cases. Continued scientific research concerning the biological activity, bioavailability, and also highdosage adverse effects of these substances is ongoing with the development of modern technology andup-to-date scientific results. Therefore, new findings of these nutraceuticals will be prevailed constantly insuch aspects as health-promoting property from their interaction with gut microbiota, enhanced bioavail-ability from formulation or nano-emulsion, and more defined safety window of consumption from moreanimal and human trial studies.

Future research of nutraceuticals will be dedicated to more studies in biological activity, bioavailability,toxicity dosage, and also the resource with high quality and cost-effectiveness. Therefore, somenutraceuticals that cannot be obtained sufficiently from natural sources have to be made non-naturallyto satisfy the need of human health, either by microbial fermentation or chemical synthesis or both.Challenges of synthesis exist for some nutraceuticals, such as coenzyme Q10. Hence, the near future goalwill be to find efficient methods to make sufficient amount of each nutraceutical by adopting processessuch as organic synthesis and microbial fermentation.

Cross-References

▶Bioactive Substances of Animal Origin▶Bioactive Substances of Microbial Origin▶Bioactive Substances of Plant Origin▶Chemical Composition of Beverages and Drinks▶Chemical Composition of Vegetables and Their Products▶Nutritional and Toxicological Aspects of the Chemical Changes of Food Components and NutrientsDuring Drying

▶Nutritional and Toxicological Aspects of the Chemical Changes of Food Components and NutrientsDuring Freezing

▶Nutritional and Toxicological Aspects of the Chemical Changes of Food Components and NutrientsDuring Packaging

▶Nutritional and Toxicological Aspects of the Chemical Changes of Food Components and NutrientsDuring Heating and Cooking

▶Overview of Food Chemistry

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