47

Cinnamoyl-CoA

(shikimate pathway) (acetate pathways)

Biosynthesis of Flavonoids

1000 times sweeter

than table sugar Bitter 48

Anthocyanidins

• The hydroxyl groups are usually found on positions 5, 7 of ring A or at 4-, (3-, 4-), on ring B and sometimes they maybe in the form of methoxy or alkoxy, and the sugar is usually attached to the OH groups to form the glycosides.

• Anthocyanins are glycosides of anthocyanidins.

• They could be found in different parts of the plant specially in cell sap (the watery fluid within the central vacuole of a plant cell).

• Many of them are diuretic, diaphoretic and some have the ability to decrease the bleeding tendency of blood vessels and to affect the permeability of the capillaries like Rutin and Hesperidin which decrease the capillary fragility.

• In plants, in addition to being flower pigments and attracting pollinating birds and insects, other suggested roles e.g. control of plant growth, inhibiting and activating plants enzymes, some have fungicidal effect and protect plant against attack by parasites.

Either (-) or (+)-catechin

49

Drugs containing anthocynidins

1. Pelargonin

• This anthocyanin glycoside is found in the flowers of Pelargonium (Family: Geraniaceae).

• It is the 3,5-O-diglucoside of pelargonidin, and it contains one hydroxyl group on the benzene ring B.

Pelargonin

Pelargonidin

50

2. Cyanidin

• Is found in cornflowers and it has 2 hydroxyl groups on benzene ring B.

51

3. Delphinidin

• It occurs in the plants Delphinium and Viola species.

• This glycoside contains 3 hydroxyl group on benzene ring B.

52

4 . Malv id in : B l u e B e r r y, B i l b e r r y, E u ro p e a n B e r r y ( Vacc i n i um m yrt i l l u s )

• Blue berry is rich in phenolic acids, flavonoids (hyperin, quercitin) and anthocynin 0.5 % such as cyanidin, delphinidin and malvidin.

Malvidin

Vaccinium myrtillus

53

Pharmacological activity:

Blue berry anthocyanins have:

1. Vascular protection.

2. Antiedemic effect.

3. Anti-inflammatory effect.

4. Clinically, it is used for eye disease such as retina bleeding risk.

5. It has a free radical-scavenging activity (Anti-oxidant).

6. It alleviates the cognitive decline occurring in Alzheimer

disease and other conditions of aging.

7. It prevents urinary tract infection.

8. It lowers cholesterol and total lipid levels. 54

Roselle (Hibiscus subdariffa : كركديه (

• The part used is the calyx (cup) of flowers, which is widely used for the treatment of hypertension.

• This is due to angiotensin-converting enzyme activity (ACE Inhibitor) due to delphinidin-3-O-sambubioside and cyanidin-3-O-sambubioside.

Delphinidin-3-o-sambubioside 55

Leucoanthocyanidins

Leucoanthocynidins are a group of water-soluble plant pigments, very closely related to anthocynidins.

They are converted to the related anthocynidins when boiled with aqueous or alcoholic HCl acid.

Chemically, they are flavan-3,4-diols like melacacidin from Acacia species.

Melacacidin

56

Catechins

• Catechins are flavan-3-ol deravatives.

• Catechin itself is 3,5,7,3’,4’ pentahydroxyflavan.

• FlavAnols (with an "a") are not to be confused with flavOnols (with an "o"), a class of flavonoids containing a ketone group.

• Catechin is found in tea {Thea senesis}.

• It has heart-protective effect.

Catechin

57

Phytoalexins

• They are antibiotics produced by plants that act as toxins against the attacking organisms.

1. Pterocarpans:

• Pterocarpans are derivatives of isoflavonoids

• found in the Fabaceae family. • Like medicarpin and pisatin.

Medicarpin 2. Rotenone:

• Is an odorless, colorless, crystalline derivatives of

isoflavone used as a broad-

spectrum insecticide, piscicide لألسماك مبيد , and

pesticide.

• Found in Derris and Lonchocarpus species of Derris

• They are insecticide.

• Roots from both plants contain 3-5 % of rotenone,

and are also used as fish poisoning material.

• They are not toxic to humans as they are

metabolized rapidly after ingestion. 58

Lonchocarpus

Derris

59

60

Cyanogenic/Cyanophore Glycosides

Cyanogenic glycosides (or Cyanophore Glycosides) are O-glycosides

yielding HCN gas on hydrolysis .

Cyanogenesis is the ability of some plants to synthesize cyanogenic

glycosides.

They are condensation products of HCN to a carbonyl compounds

producing Cyanohydrin (unstable) which upon glycosylation gives

Cyanogenic glycosides (stable).

Cyanogenesis is one of the mechanisms of plant as a protective device

against predators such as the herbivores.

Cyanogenic glycosides or cyanoglycosides account for approximately

90% of the wider group of plant toxins known as cyanogens.

C

R

R

O C

R

R OH

CN

HCN

C

R

R O-Sug

CN

Glycosylation

Cyanohydrine(Unstable)

Cyanogenic glycoside(Stable)

61

Cyanogenic/Cyanophore Glycosides

Cyanogenic glycosides when enzymically hydrolyzed, release

cyanohydric acid (HCN). In most cases, hydrolysis is accomplished by

the β-glucosidase, producing sugars and a cyanohydrin that

spontaneously decomposes to HCN and a ketone or aldehyde.

The second step can also be catalysed by the hydroxynitrile lyase,

which is widespread in cyanogenic plants.

In the intact plant, the enzyme and the cyanogenic glycoside

remain separated, but if the plant tissue is damaged both are put in

contact and cyanohydric acid is released.

62

Cyanogenic/Cyanophore Glycosides

Cyanohydric acid is extremely toxic to a wide spectrum of

organisms, due to its ability of linking with metals (Fe++, Mn++

and Cu++) that are functional groups of many enzymes,

inhibiting the reduction of oxygen in the cytochrome respiratory chain

inhibiting the electron transport in the photosynthesis, and

inhibiting the activity of enzymes like catalase, oxidase. The level of

cyanogenic glycosides produced is dependent upon the age and

variety of the plant, as well as environmental factors.

Cyanogenic glycosides are widely distributed among 100 families of

flowering plants.

They are also found in some species of ferns, fungi and bacteria.

There are many economical important plants highly cyanogenic,

including white clover, linum, almond, sorghum, the rubber tree and

cassava. 63

Cyanogenic/Cyanophore Glycosides

The best known drugs derived from such glycosides are volatile oils

of bitter almond and wild cherry, both are used as sedatives,

specially in various cough syrups and similar preparations.

Wild cherry

64

Amygdalin

This glycoside is found in bitter almond

and in the kernels (nuclei) of fruits like

apricot, cherries, peaches, plums.

Family: Rosaceae.

Peaches Plums

Amygdalin

65

Hydrolysis of Amygdalin

The enzyme emulsin (obtained from almond kernals), consists of

a mixture of 2 enzymes, amygdalase responsible for the first step

and prunase for the second step.

CH

CN

O glc glc

CH

CN

O glc

AmygdalinPrunasin

(Mandelonitrile glucoside)

1-6 linkage

CH

CN

O H

Mandilonitril

CHOHCN +

Amygdalase Prunase

Since one of the products is benzaldehyde, thus amygdalin

containing drugs are classified with aldehyde glycoside group. 66

Amygdalin

We have 2 types of mandelonitrile: D & L relative configurations

in relation to mandelic acid which is used for aromatic and not for

aliphatic compounds.

The group of cyanophore glycosides are represented by

amygdalin which is found in large quantities in bitter almond, and

also by prunasin which is found in Prunus padus (Bird cherry)

Prunus padus

Mandelic acid

67

Wild Cherry:

Dried stem bark of Prunus serotina

Family: Rosaceae

The plant is indigenous to USA and Canada.

The plant was used by the red Indians as a domestic medicine and it

contains:

D-mandelonitrile glucoside (prunasin)

Emulsin

β-methyl aesculetin (methylether of dihydroxy coumarin).

It also contains L-mandelic acid and p-coumaric acid,

trimethylgallic acid.

The HCN acid liberated from this plant is between 0.23 - 0.32%

from the inner bark and 0.03% from the outer bark.

Uses: most important uses as syrup, flavoring agent, sedative

expectorant.

68

Typical levels for some plant materials consumed by humans are:

Cyanogenic/Cyanophore Glycosides

70

71

Isothiocyanate Glycosides This group of glycosides are sometimes called thiocyanate or

sulphurated glycosides where the aglycones are thiocyanates.

Thioglycosides are particularly abundant in the families Brassicaceae (also called Cruciferae) and Capparidaceae

It is believed that these glycosides protect plants against parasites.

Biosynthesis

The biosynthesis of these glycosides was proven to be from shikimic acid for the aromatic glycosides like sinalbin, while the acetate units are the precursors for the sinigrin which are found in the white and black mustard respectively.

Sinalbin in seeds of white mustard

Sinigrin in seeds of black mustard

72

73

OS C

O H

O H

H O

C H 2 O HN

O

CH 2

CH

C H 2

S

O K

O

O

S C

N

H 2 C CH

C H 2

M u s t e r e d o i l( a l l y l i s o t h i o c y a n a t e )S i n i s r i n

M y r o s i n a s e

74

75

76

77

78

79

Simple phenolic/aldehyde glycosides

This group of glycosides contains phenolic, alcoholic, or aldehyde, group as an aglycone part of glycosides.

All are derived from shikimic acid pathway.

80

81

ALCOHOL GLYCOSIDES

1. Salicin

It is O-hydroxy benzoylglucoside. It is found in different species of Willow bark صفصاف like the following:

1. Salix purpurea Family: Salicaceae

2. Salix fragilis Family: Salicaceae

3. Populus species.

Usually it is hydrolyzed by the enzyme emulsin to D-glucose and saligenin.

Act as an analgesic, antipyretic and anti-inflammatory agent in human body.

82

83

S. purpurea الصفصاف االرجواني

S. fragilis الصفصاف الهش

2. Popul in:

It is benzoyl salicin and is a phenolic alcoholic glucoside.

It is found in the bark and leaves of Populus species and Family: Salicaceae.

Hydro l ys i s :

1 . By a l k a l i : it gives benzoic acid and salicin.

2 . By ac i d : it gives benzoic acid, saligenin (salicyl alcohol) and

glucose.

84 P o p u l i n

Populus deltoides

85

3.Coniferin :

It is m-methoxy-p-hydroxy cinnamyl alcohol glycoside .

This is found in most coniferous plants الصنوبرية النباتات

Is used for preparation of vanillin.

86

Phenol Glycosides

Arbutin

Extracted from the dried leaf of Arctostaphylos uva-ursi

Family Ericaceae الخلنجية.

USES

1. The leaves of uva ursi are traditionally brewed into a tea and useful treatment option for urinary tract infections (UTIs).

2. It inhibits tyrosinase and thus prevents the formation of melanin. Arbutin is therefore used as a skin-lightening agent.

87

Its glycoside arbutin which is upon hydrolysis yields hydroquinone and glucose.

USES:

Uva ursi has antibacterial properties because of its main bioactive, arbutin.

Arbutin creates a metabolite called hydroquinone glucuronide. When this metabolite is eliminated through urine, it also prevents bacteria from adhering to tissue in the area. This is why uva ursi may be effective at alleviating UTIs. 88

Aldehyde glycosides

Glucovanillin

Fruits of Vanilla planifolia Andrews, known in Commerce as Mexican or Bourbon vanilla.

Vanilla tahitensis J. W. Moore known in commerce as Tahiti vanilla

Family: Orchidaceae

Vanilla contains Glucovanillin (avenin) as o-glycoside which upon enzymatic hydrolysis gives vanillin (aldehyde aglycone) and glucose.

Vanillin is used as a flavoring agent specially in bakery.

89

Green vanilla pods

Bitter in taste

(odourless)

Brown vanilla pods

Sweet in taste

(Vanilla odour)

At the same time, vanillin can be prepared synthetically from

isoeugenol or coniferin or guaicol as follows:

Commercial Preparation of Vanillin

CH2-CH=CH2

OH

OCH3

CH=CH-CH3

OH

OCH3

OH

OCH3

CH=CH-CH2OH

O-glc

OCH3

Eugenol

KOH

Iso-eugenol

Oxidation

Vanillin

VanillinCHCl3+ NaOH

Reflux

Guaiacol

VanillinH2SO4/K2Cr2O7

Coniferin

90

91

92

COUMARINS (Bitter principles)

Coumarin is a fragrant organic chemical compound in the

benzopyrone chemical class, which is a colourless crystalline substance

in its standard state. It is a natural substance found in many plants.

The name comes from a French term for the tonka bean, coumarou, one

of the sources from which coumarin was first isolated as a natural

product in 1820.

It has a sweet odour, readily recognised as the scent of new-mown hay,

and has been used in perfumes since 1882. Sweet woodruff,

Meadowsweet, sweet grass and sweet-clover in particular are named for

their sweet (i.e., pleasant) smell, which in turn is due to their high

coumarin content.

When it occurs in high concentrations in forage plants, coumarin is a

somewhat bitter-tasting appetite suppressant, and is presumed to be

produced by plants as a defence chemical to discourage predation. 93

Some coumarins are phytoalexins and are synthesized de novo by

the plant following infection by a bacterium or fungus.

Phytoalexins: any of a group of compounds formed in plants in

response to fungal infection, physical damage, chemical injury, or a

pathogenic process. Phytoalexins inhibit or destroy the invading

agent.

Coumarin is used in certain perfumes and fabric conditioners.

Coumarin has been used as an aroma enhancer in pipe tobaccos and

certain alcoholic drinks.

It is banned as a flavorant food additive, due to concerns regarding its

hepatotoxicity in animal models.

Coumarin was first synthesized in 1868. It is used in the

pharmaceutical industry as a precursor reagent in the synthesis of a

number of synthetic pharmaceutical agents or drugs such as

anticoagulants (similar to dicoumarol), warfarin (brand name

Coumadin) and potent rodenticides. 94

Although coumarin is widely

distributed in plants, glycosides

containing coumarin as such are

rare.

Several glycosides of hydroxylated

coumarin derivatives, however,

occur in plant materials, and none

of the hydroxylated coumarin

glycosides is of particular

medicinal importance.

Examples of these coumarin

glycosides: skimmin in Japanese

star-anise and aesculin (saponin)

in horse chestnut tree.

95

Japanese star-anise

Scopoletin

• It is a phytoalexins found in the Quassia wood (Quassia is a

collective term for 2 plants: Picrasma excelsa and Quassia amara L. Family: Simaroubaceae), stem wood of Picrasma excelsa (Picconia excelsa or Aeshrion excelsa) (Simaroubaceae).

Uses:

• It is used as antispasmodic for its uterine sedative activity.

• It also has antimicrobial activity. 96

Psoralens

• These are photosensitizing furocoumarins that occur in a number of plant families like Umbelliferae (Apiaceae), where they are a common cause of phototoxicity.

Methoxsalen: 8-methoxy psoralen (oxsoralen ®) or xanthotoxin, a constituent of cremocarps (a description of the fruit of fennel etc.) of Ammi majus Linne (Family: Umbelliferae). It is used to

facilitate repigmentation in idiopathic vitiligo (leukoderma) and

for symptomatic control of severe disabling psoriasis.

Methoxsalen may be applied topically or taken internally, and with exposure to U.V. light.

Risks are inherent in therapy with methoxsalen including carcinogenesis.

97 Psoralens Methoxsalen

Idiopathic vitiligo (leukoderma) Psoriasis

98

99

Cremocarp