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 water-soluble 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: fat-soluble 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

• 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.

H3C

CH3

CH3

OH

CH3CH3

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

OH

CH3CH3

Vitamin A1

H3C

CH3

CH3

OH

CH3CH3

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

O

CH3CH3OH

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

• (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.

HO

H

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 24,25-

dihydroxy-cholecalciferol, as well as 1,24,25-trihydroxylated 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.

DeficiencyClinical 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

• 3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-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.

O

CH3

CH3

H3C

OH3C

CH3

CH3

CH3 CH3 CH3

O

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

• L(+)-threose-2,3,4,5,6-pentahydroxyl-2-Hexylenoic acid-4-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.

O

HO OH

OHH

OH

O

*

* 1

23

Tautomerism

• Vitamin C mainly exists in enolic form of 3-oxo-L-gulofuranolactone in water solution.

• A 2-keto compound is more stable than a 3-keto 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.

O

HO OH

OHH

OH

O O

O O

OHH

OH

O[O]

[H]

Reason for Discoloration• Dehydration, hydrolization and decarboxy-

lization 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 occurrence and development of cancer.

Synthetic Route

Biotin

• [3αS-(3αa,4β,6αa)]-Hexahydro-2-oxo-1H-thieno[3,4-d]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.

HN

NH

S

H

HH

OH

O

O

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 biotin-responsive 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。