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442
Pharmaceutical Chemistry of Natural Products
as vitamin B
1
(thiamine). The term vitamine was originally given to these ‘accessory food factors’
because they were known to be vital for life and they were all believed to be amines (Greek: vita
means life).
It was later realized that only few of them are amines. However, the term vitamine is continued
without the fi nal letter ‘e’. The essential amino acids are organic substances, but due to their
requirement in large quantities, they do not fi t into this defi nition.
Vitamins are essential because man cannot synthesize these compounds which are necessary
for life (except vitamin D, vitamin K and biotin). The minute quantity requirement indicates a
catalytic role in the cell. Many function as co-enzymes or a part of co-enzyme system necessary
for various metabolic reactions.
Vitamins A and D instead of acting like co-enzyme behave more similar to that of hormones
and bring about their action by acting on intracellular receptor sites (however, many vitamins need
biological activation to carry out this function). In general, the daily requirements of vitamins vary
with age, sex and physiological conditions.
Vitamin K and biotin (vitamin B
7
) are synthesized by microorganisms in the intestinal tract. If
the person is under the treatment of oral antimicrobial agent, the intestinal microbial fl ora of the
person gets disturbed, which results in defi ciency of these vitamins.
Similarly, water-soluble vitamins are easily washed out in cooking water and are destroyed
at elevated temperature, while fat-soluble vitamins are relatively stable at usual cooking
temperature.
Avitaminosis (defi ciency of vitamins) arises from poor dietary intake, inadequate absorption in
gastrointestinal tract (GIT) due to prolonged diarrhoea during treatment, diseases of liver (chronic
alcoholism) and biliary tract, other conditions like anorexia, malabsorption, allergies and poor
teeth.
Though the diet is well balanced, increased demand for vitamins are seen during growth,
pregnancy, lactation, under stress, fever, etc.
NOMENCLATURE OF VITAMINS
In 1915, McCollum and Davis introduced the usage of A, B and C to vitamin. First they felt there
are only two vitamins, namely fat-soluble vitamin A and water-soluble vitamin B (antiberiberi
factor). But soon they found water-soluble, antiscurvy factor, named vitamin C. Later vitamin A
was found to possess two compounds, one which prevents night blindness (vitamin A) and the
other is the antirickets factor (vitamin D).
A fat-soluble factor called vitamin E, in the absence of which rats failed to reproduce properly
was discovered. In 1930, another fat-soluble vitamin concerned with coagulation was discovered
and it was named as vitamin K. In the sequence of alphabets it should have been F but K was
preferred to refl ect its function coagulation (German: koagulation).
Regarding water-soluble factors, vitamin C was identifi ed as a pure substance and named
as ascorbic acid. Vitamin B was found to be a complex mixture and nomenclature also became
complex.
Vitamins
443
Between 1920 and 1930 many investigators carried out intensive research and went on
naming them as the water-soluble vitamins B
2
, B
3
, B
4
, B
5
, B
6
, B
7
, B
8
, B
9
, B
10
, B
11
and B
12
. Among
this vitamin B
1
was clearly identifi ed as antiberiberi factor.
Few members of the B-complex series disappeared from the scene, because some of them
were found to be mixtures of already known as vitamins. Names are more commonly used for
other B-complex vitamins except B
1
, B
2
, B
6
and B
12
.
CLASSIFICATION OF VITAMINS
There are about 15 vitamins essential for humans which have been arbitrarily classifi ed into fat
soluble (A, D, E and K) and water soluble (C and B complex). The B-complex vitamin may be
further divided into energy releasing (B
1
, B
2
, B
3
, B
5
, B
6
and B
7
) and haematopoietic (folic acid and
B
12
). Many water-soluble vitamins exert their biological functions through their respective co-
enzyme while only one fat-soluble vitamin (K) has been identifi ed to function as co-enzyme.
However, biotin is an exception as it is insoluble in both fat and water. Choline, inositol and
lipoic acid are sometimes included under fat-soluble vitamins. However, as these compounds are
either synthesized in the body or present comparatively in larger amounts in food, they are not
considered as vitamins in the accepted sense. The classifi cation of vitamins is specifi ed in the
following scheme.
Scheme—Classifi cation of Vitamins
Vitamin
Fat soluble Water soluble
Non B-complex
Energy releasing Hematopoietic
B-complex
Vitamin A
Thiamine (B
1
)
Folic acid (B
9
)
Cyanocobalamin (B
12
)
Ribofl avin (B
2
)
Niacin (B
3
)
Pantothenic acid (B
5
)
Pyridoxine (B
6
)
Biotin (B
7
)
Inositol (B
8
)
Vitamin D
Vitamin E
Vitamin K
Vitamin C
(Ascorbic acid)
444
Pharmaceutical Chemistry of Natural Products
Fat-Soluble Vitamins
Vitamin A, D, E and K are soluble in fat or lipid. Their availability in the diet, absorption and
transport are associated with fat. These vitamins can be stored in the liver and adipose tissue
and are not readily excreted in urine. Excess consumption of vitamins A and D leads to their
accumulation and results in toxic effects. All fat-soluble vitamins contain isoprenoid units and
perform diverse function. Vitamin K has a specifi c co-enzyme function.
Biochemical function of fat-soluble vitamins
In contrast to the water-soluble vitamin, fat-soluble vitamins can be stored in the body especially
in the liver and adipose tissue. Since they can be stored until used, excess consumption of these
vitamins can produce toxic symptoms. Vitamin K defi ciencies in humans are rare, because the
intestinal bacteria produce the daily amounts required. During antibiotic treatment the bacterial
synthesis is inhibited, hence it might be necessary to supplement the intake of vitamin K. Normally
humans produce vitamin D from the 7-dehydrocholesterol found in the skin using sunlight.
Because it is ubiquitous in plant foods that form a part of human diet, defi ciency of vitamin E has
never been observed in humans.
Water-Soluble Vitamins
These are a heterogeneous group of compounds since they differ chemically from each other
but soluble in water. Most of them are readily excreted in urine and they are not toxic to the
body. They will not be stored in large quantities except B
12
in body. Their metabolic stores unlike
fat soluble are depleted within weeks and result in defi ciency symptoms. Hence, water-soluble
vitamins must be continuously supplied in the diet. In general, vitamin defi ciencies are multiple
rather than individual with overlapping symptoms. The general symptoms of the one or more
vitamins involved in energy metabolism are dermatitis, glossitis (red and swollen tongue),
cheilitis (rupture of corners of lips), diarrhoea, mental confusion, depression and malaise.
It is diffi cult to pinpoint the exact biochemical basis for these symptoms. It forms co-enzyme
that participates in a variety of biochemical reactions related to either energy generation or
haematopoiesis.
Biochemical function of water-soluble vitamins
Most of the water-soluble vitamins are components of large co-enzyme molecules. When they
are encountered as essential nutrients in an animal diet, they are biosynthesized into the co-
enzyme molecules where they function in essential metabolic reactions. With few exceptions,
the same co-enzyme occurs in plants where they are also assembled from the smaller vitamin
molecules. From carbon dioxide, ammonia and hydrogen sulphide, plants have the ability to
synthesize the vitamins and in fact serve as excellent source of these dietary essentials. Water-
soluble vitamins required by humans, their related co-enzymes and the enzymatic function that
they perform are listed in Table 9.1.
Vitamins
445
SOURCES OF VITAMINS AND THEIR DEFICIENCY DISEASES
The sources of vitamins and their defi ciency diseases are listed in Table 9.2.
Table 9.2 Sources and their defi ciency diseases of vitamins
S. no. Name of the vitamin Source Defi ciency diseases
1. Retinol (A
1
) Fish liver oil (particularly in shark liver oil) Night blindness
2. Retinal (A
2
) Liver of fresh water fi sh Night blindness
3. Thiamine (B
1
) Rice polishing, liver, kidney, yeast, milk, ground
nuts, eggs, green vegetables and dairy products
(except butter)
Beriberi
4. Ribofl avin (B
2
) Yeast, vegetables, milk, egg white, kidney, meat
and liver
Cheilosis, corneal opacity
5. Nicotinic acid (B
3
) Liver, kidney, spleen, brain, pancreas, heart and
tongue
Pellagra
6. Pantothenic acid (B
5
) Plant and animal tissues, meat products like liver,
meat and kidney, yeast, pulses, ground nut, cere-
als and coffee
Burning sensation, muscle weak-
ness, abdominal disorder and general
depression
7. Pyridoxine (B
6
) Cereal grains, molasses and yeast Severe dermatitis in rats and extreme
defi ciency causes convulsion
8. Biotin (B
7
) Yeast, kidney, milk and liver Dermatitis, loss of hair and
progressive paralysis
9. Inositol (B
8
) Skeletal and heart muscles, blood, milk, eggs Eye abnormalities, memory loss, ec-
zema, constipation, higher cholester-
ol level, excess fat and atherosclerosis
10. Folic acid (B
9
) Green leafy vegetables and fruits Macrocyclic anaemia
Table 9.1 Enzymes, co-enzymes and their functions
S. no. Name of the vitamin Name of the co-enzyme Types of reaction
1. Thiamine (B
1
) Thiamine pyrophosphate (TPP)
Decarboxylation of α-keto acids
2. Ribofl avin (B
2
) Flavin mononucleotide (FMN), fl avin adenine
dinucleotide (FAD)
Oxidation–reduction reactions
3. Nicotinic acid (B
3
) Nicotinamide adenine dinucleotide (NAD
+
),
nicotinamide adenine dinucleotide phosphate
(NADP
+
)
Oxidation–reduction reactions
4. Pantothenic acid (B
5
) Co-enzyme A (CoA) Transfer of acetyl groups
5. Pyridoxine (B
6
) Pyridoxal phosphate Decarboxylation, transamination of
amino acids and racemization
6. Biotin (H) Biotin
Carboxyl-carrier protein
Carbon dioxide fi xation reaction
7. Folic acid (B
9
) Tetrahydrofolic acid (THF) Various reaction involving single
carbon compounds
8. Cyanocobalamin (B
12
) 5-Deoxyadenosyl cobalamin, methylcobalamin Carbon chain isomerization
446
Pharmaceutical Chemistry of Natural Products
S. no. Name of the vitamin Source Defi ciency diseases
11. Cyanocobalamin (B
12
) All animal tissues especially in the liver of ox,
sheep, fi sh, pig, etc.
Pernicious anaemia
12. Ascorbic acid (C) Citrus fruits, green vegetables, etc. Scurvy
13. Calciferol (D) Fish liver oil Rickets
14. Tocopherol (E) Wheat germ oil, cotton seed oil, soya bean oil,
palm oil and rice
Sterility
15. Vitamin K Cereals, leafy tissues Haemorrhagic conditions
16. Vitamin P Grape fruit, orange, lemon, etc. Haemorrhagic conditions
Precursors or Provitamins
Some biologically inactive compounds which are similar to vitamins and are converted easily into
vitamins in vivo are known as provitamins or precursors.
Examples of provitamins
1. β-Carotene is the provitamin for vitamin A
2. Ergosterol is the provitamin for vitamin D
2
VITAMIN A
15
1
2
3
4
5
6
8
9
11 14
710
12
13
CH CH CCH
CH
3
CH CH C CH
CH OH
2
CH
3
Vitamin A
The vitamin A group consists of vitamin A
1
(retinol), vitamin A
2
(retinal), neovitamin Aα and
neovitamin Aβ. These vitamin A groups belong to the apocarotenoid group and are diterpenoids.
When we mention vitamin A, it indicates vitamin A
1
.
CH CH C
CH
3
CH CH
CH CH OH
2
CH C
CH
3
Vitamin A (Retinol)
1
CH CH C
CH
3
CH CH
CH CH OH
2
CH C
CH
3
Vitamin A (3,4-Dehydroretinol)
2
3
4
Vitamins
447
Vitamin A is a generic term for a group of lipid-soluble compounds related to retinol. Retinol
is often referred to as preformed vitamin A. It is found only in animal sources, mainly as retinyl
esters and in food supplements. Many cultures have used ox liver as an excellent source of vitamin
A to cure night blindness. β-Carotene and other carotenoids that can be converted into vitamin A
by an enzymatic process in the body are referred to as provitamin A. They are found only in plant
sources.
Vitamin A was isolated as yellow oil originally. But later, it was isolated as crystalline solid
(melting point: 63–64°C). It is sensitive to light and air but resistant to heat. It is optically inactive
and destroyed by UV light.
The term retinoids is often used to include the natural and synthetic forms of vitamin A.
1. Retinol
(a) 1° Alcohol containing β-ionone ring.
(b) Side chain has two isoprenoid units, four double bonds and hydroxyl group.
(c) Not destroyed by heat (vitamin A).
(d) Due to the presence of double bond, it is susceptible to oxidation.
(e) Retinol is present in animal tissue as retinyl ester with long-chain fatty acid.
2. Retinal
(a) Aldehyde form obtained by oxidation of retinol.
(b) Retinal and retinol are interconvertible.
(c) Its previous name is retinine.
3. Retinoic acid
(a) Produced by oxidation of retinal.
(b) Retinoic acid cannot give rise to the formation of retinal or retinol.
4. Provitamin A (β-carotene)
(a) Found in plants.
(b) Cleaved in intestine to produce two moles of retinal.
(c) In humans, this cleavage is ineffi cient, hence β-carotene possess about one-sixth of
vitamin A activity compared to retinol.
Dietary Source
1. Animal source: Vitamin A is present as such in animal sources such as liver, kidney, egg yolk,
milk, cheese, butter and fi sh (cod, shark) liver oils.
2. Vegetable source: It contains provitamin A (carotenes) such as yellow and dark green vegetables.
Fruits are also good sources of carotenes. Some of the examples are carrots, spinach,
amaranthus, pumpkins, mango and papaya.
3. Fortifi ed source: Foods fortifi ed with vitamin A (vanaspati, margarine and milk) are important
sources.
History
About 500 BC, Hippocrates cured night blindness. He prescribed ox liver (in honey) which is now
known to contain high quantity of vitamin A. In 1917, McCollum and Davis found that a fat-
soluble factor of butter was needed for the proper growth of rats and fed them with a synthetic
448
Pharmaceutical Chemistry of Natural Products
diet. In 1919, Stunbock discovered vitamin A activity of carotenoids. In 1931, Karrer discovered
vitamin A structure and its synthesis was achieved in 1937 by Kuhn and Morris.
Isolation
Vitamin A is extracted from the substance by hydrolysing with potassium hydroxide in the presence
of hydroquinone. Vitamin A remains in the unsaponifi ed portion from which it is isolated by any
one of the following methods.
Fractional crystallization method
The unsaponifi ed portion is dissolved in methyl alcohol and chilled to –73°C when the sterols
crystallize out. Finally, the solution is subjected to fractional distillation in vacuum to yield pure
vitamin A.
Chromatographic method
The unsaponifi ed portion in this method is adsorbed on alumina, followed by adsorption on
calcium hydroxide. This method suffers losses due to its destruction because of arrangement of
double bond and its slight oxidation. But it produces pure form of vitamin A.
Molecular distillation method
In molecular distillation method, the unsaponifi ed portion is dissolved in neutral residue and
constant yield oil. Then over long ranges of temperature, the solution obtained is subjected to step-
wise distillation. The vitamin so obtained is fi nally purifi ed by crystallizing it from ethyl acetate or
propylene oxide. In this method, both free vitamin and ester can be isolated. Vitamin A is fi nally
crystallized by ethyl formate or propylene oxide as yellow needles.
Estimation
A large number of colour reactions have been proposed for qualitative and quantitative
determination of vitamin A. Out of these methods, the most important one is Carr–Price method.
In this method 20–25% solution of antimony trichloride in chloroform is added to a solution of
vitamin A in chloroform. Blue colour is observed which is stable only for 10 sec, after which it
starts fading. The intensity of blue colour is measured in a colorimeter (e.g. Lovibond tintometer).
Generally the results are expressed in terms of cod liver oil or CLO units for which 2% solution of
the vitamin containing material in chloroform is employed.
Moreover, in 1938 Morton observed that vitamin A solution either in cyclohexane or ethyl or
isopropyl alcohol gives an absorption band in the UV region at 325–328 nm. This constitutes the
physical method for the qualitative and quantitative determination of vitamin A.
Vitamins
449
Biochemical Function
β-Carotene
(Antioxidant)
Retinal
(Visual cycle)
Retinoic acid (steroid
hormone for growth and
differentiation)
Retinyl phosphate
(Glycoprotein synthesis)
Retinol
(Steroid hormone—growth and differentiation)
Both retinol and retinoic acid function very similar to the way steroid hormones function.
They regulate protein synthesis, which is involved in cell growth and differentiation. Vitamin A
is essential to maintain healthy epithelial tissue. Due to the fact that retinol and retinoic acid are
required to prevent certain synthesis responsible for horny surface, retinyl phosphate is essential
for the formation of mucopolysaccharides, compounds of mucus secreted by epithelial cells to
maintain moist surface.
For the synthesis of certain glycoproteins which are required for growth and mucus secretion,
retinyl phosphate that was synthesized from retinol is necessary. Retinol and retinoic acid are
involved in the synthesis of transferrin (the iron transport protein). For the maintenance of proper
immune system to fi ght against various infections vitamin A is essential.
Vitamin A was required for cholesterol biosynthesis. In vitamin A defi ciency, mevalonate, an
intermediate in the cholesterol biosynthesis, is diverted for the synthesis of co-enzyme Q.
Carotenoids function as antioxidants and decrease the risk of cancer initiated by free radicals
and strong oxidant. β-Carotene is found to be benefi cial in preventing heart attacks. This is also
attributed to the antioxidant property. Retinal is used in visual cycle.
Wald’s visual cycle
In 1968, George Wald fi rst elucidated the biochemical function of vitamin A in the process of
vision and received Nobel Prize. The events occur in a cyclic process known as rhodopsin cycle or
Wald’s visual cycle (Figure 9.1).
450
Pharmaceutical Chemistry of Natural Products
11-cis retinal
11-cis retinol
All-trans retinal
Rhodopsin
(11-cis retinal-opsin)
Light
(Photon)
Nerve
impulse
Opsin
Retinal
isomerase
NADH H
NAD
Alcohol
dehydrogenase
(ADH)
Isomerase
(liver)
All-trans retinol
NADH H
NAD
Alcohol
dehydrogenase (liver)
(ADH)
Figure 9.1 Wald’s visual cycle. Abbreviations: NAD
+
, nicotinamide adenine dinucleotide; NADH, nicotinamide
adenine dinucleotide hydride.
Rhodopsin is a conjugated protein present in rods and its molecular weight is 35,000. It
contains 11-cis retinal and protein opsin. The –CHO group of retinal is linked to ε-amino group of
lysine (of opsin). The primary event in visual cycle is, when exposed to light, the isomerization
of 11-cis retinal to all-trans retinal and leads to conformational change in opsin which results in
generation of nerve impulses.
Retinal isomerase present in retinal epithelium immediately isomerizes all-trans retinal to
11-cis retinal. To regenerate rhodopsin, it combines with opsin and completes the visual cycle.
However, the conversion of all-trans retinal to 11-cis-retinal is incomplete. Hence most of the
all-trans retinal is transported to the liver and converted to all-trans retinol by ADH. The all-
trans-retinol undergoes isomerization to 11-cis retinol which is then oxidized to 11-cis retinal to
participate in the visual cycle.
Rods and cones
Retina of the eye contains two types of cells, i.e. rods and cones. About 10 million rods and 5
million cones are present in the human eye. Rods are present in periphery and cones are present in
centre of the retina. Rods are involved in dim light and colour vision, whereas cones are involved
in bright light and colour vision. Animals such as owls and cats mostly possess rods because night
vision is important for them.
Vitamins
451
Dark Adaptation Time (DAT)
When a person shifts from bright light to dim light (e.g. entering into a dim cinema theatre), vision
is impaired due to the depletion of rhodopsin stores. However, within a few minutes, known as
dark adaptation time (DAT), rhodopsin is resynthesized and vision is improved. DAT is increased in
vitamin A–defi cient individuals.
Bleaching of rhodopsin
The colour of rhodopsin changes from red to yellow when exposed to light by a process known as
bleaching. It occurs in a few millisecond and many unstable intermediates are formed during this
process.
Rhodopsin Prelumirhodopsin Lumirhodopsin Metarhodopsin-I
Metarhodopsin-II
All trans retinal + Opsin
Visual cascade and cyclic guanosine monophosphate
Membrane hyperpolarization occurs when light strikes the retina, results in the genesis of nerve
impulse. The hyperpolarization of the membrane is brought about by a visual cascade involving
cyclic guanosine monophosphate (cGMP; Figure 9.2). Metarhodopsin-II is produced when a pho-
ton (from light) is absorbed by rhodopsin. The protein transducin is activated by metarhodopsin-II.
The activated transducin activates cGMP phosphodiesterase. In the rod cells, this enzyme degrades
cGMP. In the membrane of the rod cells, rapid decrease in the cGMP closes the sodium channels
resulting in hyperpolarization, which is an excitatory response transmitted through the neuron
network to the visual cortex of the brain.
Rhodopsin
Metarhodopsin-II
GTP
GDP
Photon
Transducin
(inactive)
Transducin
(active)
Phosphodiesterase
(inactive)
Phosphodiesterase
(active)
3’,5’-cGMP 5’-GMP
(leads to decrease in 3’,5’-cGMP)
Figure 9.2 Visual cascade involving cyclic guanosine monophosphate (3′,5′-cGMP). Abbreviations: GDP,
guanosine diphosphate; GTP, guanosine triphosphate.