Medicinal chemistry
Chapter 12 Vitamins
Chapter 12 Vitamins
• Section 1 Fat Soluble Vitamins
• Section 2 Water Soluble Vitamins
Vitamin
• Vitamin is Any of various fat-soluble or watersoluble organic substances essential in minute
amounts for normal growth and activity of the
body and obtained naturally from plant and
animal foods.
• Vitamins act as catalysts; very often either the
vitamins themselves are coenzymes, or they
form integral parts of coenzymes.
Classification
• Vitamins are divided into two groups: fatsoluble vitamins and water-soluble vitamins.
• The fat-soluble vitamins include vitamin A, D, E,
and K.
• The water-soluble vitamins include the vitamin
B complex and vitamin C, etc.
Section 1 Fat Soluble Vitamins
• Fat-soluble vitamins are stored in the liver and
fatty tissues, and are eliminated much more
slowly than water-soluble vitamins.
• Diseases caused by a lack of fat-soluble vitamins
are rare, but some health problems may
decrease the absorption of fat, and in turn,
decrease the absorption of vitamins A, D, E and
K and result in deficiency.
Definition of Vitamin A
• Vitamin A is the collective name for a group of
fat-soluble vitamins. The most useful form of
the vitamin is retinol, often called vitamin A1 as
it is the active form in the body.
• Retinol (an alcohol) can only be found in animal
sources and can be converted by the body into
retinal (an aldehyde) and retinoic acid (a
carboxylic acid), other active forms of vitamin A.
Structure of Vitamin A1
H3C
CH3
CH3
CH3
OH
CH3
• Vitamin A1 has four double bounds (all trans ) at
positions 2,4,6,8 on unsaturated side chain
containing 9 carbon atoms.
• There are three methyl groups at positions 2´,
6´, 6´ of Cyclohexenyl ring attached to position
9 on the side chain.
Vitamin A deficiency (VAD)
• VAD is the leading cause of preventable
blindness in children and raises the risk of
disease and death from severe infections. In
pregnant women VAD may increase the risk of
maternal mortality.
• VAD is a public health problem in 118 countries,
especially in Africa and South-east Asia.
• Vitamin A is used for treatment of VAD.
History
• In 1913, vitamin A was found in fish liver oil or
yolk.
• In 1931, retinol was isolated in mammal and salt
water fish, which was called vitamin A1.
• Afterward, 3-dehydroretinol was isolated in fresh
water fish, which was called vitamin A2.
H3C
CH3
CH3
H3C
CH3
CH3
CH3
CH3
OH
OH
CH3
Vitamin A1
CH3
Vitamin A2
• Beta carotene is called provitamin A, which can
be converted to retinol by the body.
• In the liver, one molecule of beta carotene can
be cleaved by an intestinal enzyme into two
molecules of retinol, so beta carotene can also
be good sources of retinol.
Stability
• Vitamin A is sensitive to ultraviolet or oxidation
by the air. So the compound should be stored in
an aluminium container or vitamin E oil.
• Vitamin A is not stable to acid and dehydration of
vitamin A results in a dehydrate of vitamin A that
is only 0.4% potency of vitamin A.
Metabolism
• Vitamin A acetate is hydrolyzed by enzymes into
vitamin A and further is oxidized to retinal and
retinoic acid. Finally the conjugates of retinoic
acid with glycuronic acid is excreted in bile or
urine.
Vitamin A analogs
• Vitamin A acid: it mainly influences skeletal
growth and metabolism of epithelial tissue. It
has better effect on prevention and cure of
canner.
• The compound is a choice drug for treatment of
acute promyelocytic leukemia (APL).
H3C
CH3
CH3
CH3
OH
O
CH3
Vitamin D
• In 1922, vitamin D was found in fish liver oil.
• In 1930, vitamin D2 (ergocalciferol) was isolated.
• In 1932, vitamin D3 (cholecalciferol) was isolated.
• Only difference between two vitamins is that
there are a methyl group and a double bond on
side chain of vitamin D2.
Vitamin D3
H
HO
• (3β,5Z,7E)-9,10-Seco-cholesta-5,7,10(19)-trien-3β- ol
• There is a conjugated triene system in the
structure in which there are a hydroxy group at
C-3 on A ring, a methenyl group at C-10.
Biosynthesis
• Vitamin D3 is the product of solar ultraviolet
irradiation of 7-dehydrocholesterol in the skin.
So 7-dehydrocholesterol is also called
provitamin D3.
• Vitamin D2 is the product of solar ultraviolet
irradiation of ergosterin in the skin. So
ergosterin is also called provitamin D2.
Bioactivation
• In 1966, it was first recognized that vitamin D
must undergo activation via two oxidative
metabolic steps.
• The first oxidation to 25-hydroxycholecal
( 25(OH)D3 ) occurs in the liver and is catalyzed
by vitamin D 25-hydroxylase.
• This activation step is not regulated by plasma
calcium concentrations. 25(OH)D3 is the major
circulating form, as well as the primary storage
form of vitamin D.
• The second oxidation step is activated in the
kidney, catalyzed by vitamin D 1α-hydroxylase.
• The product of this reaction, 1,25-calcitriol
(1,25 (OH)2D3) is the active form of vitamin D.
• The biosynthesis of vitamin D is tightly
regulated based on the serum concentrations
of calcium, phosphate and active vitamin D .
Flowchart for Bioactivation
Mechanism of action
• Vitamin D receptors (VDR) mediate the biologic
action of vitamin D.
• The active hormone is transported from the
cytoplasm to the nucleus via the VDR and, as a
result of the interaction of the hormone with
target genes, a variety of proteins are produced
that stimulate the transport of calcium in each of
the target tissues.
• Active vitamin D works in concert with
parathyroid hormone to enhance active intestinal
absorption of calcium, to stimulate bone
resorption and to prohibit renal excretion of
calcium.
• If serum calcium or 1,25-calcitriol concentrations
are elevated, then vitamin D 24-hydroxylase is
activated to oxidize 25(OH)D3 to inactive 24,25dihydroxy-cholecalciferol, as well as 1,24,25trihydroxylated derivative.
Physiological Effects
• The most dramatic effect of vitamin D is to
facilitate intestinal absorption of calcium. In the
absence of vitamin D, dietary calcium is not
absorbed at all efficiently.
• Vitamin D stimulates the expression of a number
of proteins involved in transporting calcium from
the lumen of the intestine, across the epithelial
cells and into blood.
Deficiency
• The classical manifestations of vitamin D
deficiency is rickets, which is seen in children
and results in bony deformation including
bowed long bones.
• Deficiency in adults leads to the disease
osteomalacia.
Vitamin E
• The term vitamin E describes a family of eight
antioxidants, four tocopherols, alpha-, beta-,
gamma- and delta-, and four tocotrienols (also
alpha-, beta-, gamma- and delta-).
• Alpha-tocopherol is the only form of vitamin E
that is actively maintained in the human body.
Physiological Effects
• It has an important role in cellular respiration of
muscles, especially the cardiac muscle.
• It protects all the other fat-soluble vitamins
against oxidation.
• It reduces scar tissue formation both internally
and externally.
• It increases formation of new blood vessels
around damaged areas.
Deficiency
Clinical sign of deficiency is
• the rupturing of the red blood cells;
• swelling of the cardiac muscle which can
become necrotic;
• retarded growth in children;
• faulty absorption of fat and fat-soluble vitamins;
• lack of sex drive.
Vitamin E Acetate
CH3
H3C
O
CH3
O
H3C
O
CH3
CH3
CH3
CH3
CH3
• 3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol acetate
• There is a side chain containing 16 carbon atoms
attached to C-2 on benzopyran ring.
• Vitamin E acetate is a racemic of vitamin E and
40% potency of naturally occuring product.
Section 2
Water Soluble Vitamins
• Vitamin C
• Biotin (Vitamin H)
Vitamin C
• Vitamin C or ascorbic acid, is the enolic form
of 3-oxo-L-gulofuranolactone. It can be
prepared by synthesis from glucose, or
extracted from plant sources such as rose hips
or citrus fruits.
Structural Feature
OH
H
*
OH
O
*
3
HO
1
O
2
OH
• L(+)-threose-2,3,4,5,6-pentahydroxyl-2-Hexylenoic acid4-actone
• Polyhydroxy compound containing six carbon
atoms with acidity.
• Two chiral centers result in four isomers. Among
the isomers, L-(+)-ascorbic acid has the most
activity.
Tautomerism
• Vitamin C mainly exists in enolic form of 3-oxoL-gulofuranolactone in water solution.
• A 2-keto compound is more stable than a 3keto compound.
Acidity
• Vitamin C shows acidity in water solution as a
result of an enolic structure in the molecule.
• Hydroxy group at position 3 has more acidity
because the hydroxy group at position 2 may
form an intramolecular hydrogen bond with the
hydroxy group at position 1.
Hydrolysis
• Hydrolization of vitamin C in strong basic
solution results in an oxoacid salt.
Reducibility
• Oxidation of vitamin C by oxygen in the air
results in dehydroascorbic acid (DHAA).
Oxidative form and reductive form of vitamin C
have the same biologic activity and may be
reciprocal transformation.
OH
H
OH
O
OH
[O]
H
OH
O
O
O
[H]
HO
OH
O
O
Reason for Discoloration
• Dehydration, hydrolization and
decarboxylization of vitamin C under anoxia condition
result in furfural polymer that shows yellow
spots in vitamin C product.
Actions and Uses
• Vitamin C is essential for the formation of
collagen and intercellular material, bone and
teeth and for the healing of wounds.
• It helps maintain elasticity of the skin, aids the
absorption of iron and improves resistance to
infection.
• It is used for the treatment of scurvy that is
characterized by hemorrhagic manifestations
and abnormal osteoid and dentin formation.
• It may prevent the
development of cancer.
occurrence
and
Synthetic Route
Biotin
O
H
N
H
H
OH
O
S
N
H
H
• [3αS-(3αa,4β,6αa)]-Hexahydro-2-oxo-1H-thieno[3,4d]imimdazole-4-valenic acid
• The parent nucleus is a tetrahydroimidazole ring
fused to thiophane ring.
• There are a carbonyl group at position 2 of the
parent nucleus and a side chain of valeric acid at
position 4.
Stability
• Biotin is stable at room temperature, but is
unstable under basic condition.
• Biotin in water solution shows acidity.
• Biotin may discolor bromine water. The reaction,
therefore, may be used as identification.
Actions and Uses
• Biotin is the coenzyme for four carboxylases.
• Biotin is used for the treatment of biotinresponsive inborn errors of metabolism.
• It has putative glucose tolerance-modulating
activity.
• It may also have activity in the management of
brittle fingernails and the uncombable hair
syndrome.
学习要求
• 掌握代表药物维生素A醋酸酯、维生素D3、维生
素E醋酸酯、维生素C、的化学结构、命名、理化
性质、体内代谢。
• 熟悉上述代表药物的结构类型、作用机制，临床
应用，构效关系和结构改造方法和化学合成方法。