Natural products

Dr Rajendra Gyawali

Department of PharmacyDepartment of PharmacyKathmandu University

�The first commercial pure natural product morphine, marketed by

Merck in 1826.

���� The first semisynthetic drug based on a natural product is aspirin,

introduced by Bayer in 1899.

�Natural products represent over 50% of all drugs in use, with

higher plant-derived natural products representing 25% of the total.

Natural products

higher plant-derived natural products representing 25% of the total.

�Of the 20 top-selling drugs on the market in the year 2000 were

derived from natural products or developed from them.

�Plants, which are rich in alkaloids, tannins, flavonoids and phenolic

compounds are of particular interest due to their therapeutic effects.

� Natural Products not only include plants but it also include animals,

mictoorganisms etc.

A. Primary metabolities����Refers to the nucleic acids, amino acids,

proteins, carbohydrates����These are essential to the growth and

development of the plant����Provide some precursor molecules for the sec.

Plant metabolites

����Provide some precursor molecules for the sec. metabolic pathway

���� Primary metabolic pathway ends up with products like essential oils, resins, saponins and glycosides etc.

B. Secondary metabolities�Plant secondary metabolites is a generic term

used for more than 30,000 different substances which are exclusively produced by plants

�The plants form secondary metabolites e.g. for protection against pests, as colouring, scent, or

Plant metabolites

protection against pests, as colouring, scent, or attractants and as the plant's own hormones.

�These are nonessential compounds for the continuity of the lifecycle

���� Contribute biogenic resource for the discovery of novel drugs

*Biochemistry (Primary metabolism)

*Phytochemistry (Secondary metabolism)

*Phytomics ( biochemistry and phytochemistry)

Alkaloids :Cardiac stimulants, respiratory

Anthocyanosides :Support immune system, anti-oxidan ts

Cardiac glycosides :Congestive heart failure, diuret ics, tonics

Carotene :Anti-carcinogenic properties, food colori ng

Coumarin :Heart diseases, stroke and thrombosis

Flavonoids :Antioxidant, anti -inflammatory, analgesic

Important Secondary MetabolitesImportant Secondary Metabolites

Flavonoids :Antioxidant, anti -inflammatory, analgesic

Glycosides :Therapeutic, nutritional and clinical us e

Saponins :Anti-arrhythmic, analgesic, anti-inflammat ory

Tannins :Against the diarrhea, anti -cancer, astringent

Terpenoids :Insecticides, flavor and fragrances

Essential oils :Antimicrobial, aromat herapy

Class Example Compounds

Example Sources Some Effects and Uses

Alkaloids nicotine cocaine theobromine

tobacco coca plant chocolate (cocao)

interfere with neurotransmission, block enzyme action

TERPENOIDS

Monoterpenes menthol linalool

mint and relatives, many plants

interfere with neurotransmission, block ion transport, anesthetic

Sesquiterpenes parthenolid Parthenium and relatives (Asteraceae )

contact dermatitis

(Asteraceae )

Diterpenes gossypol cotton block phosphorylation; toxic

Triterpenes, cardiac glycosides

digitogenin Digitalis (foxglove) stimulate heart muscle, alter ion transport

Tetraterpenoids carotene many plants antioxidant; orange coloring

Terpene polymers rubber Hevea (rubber) trees, dandelion

gum up insects; airplane tires

Sterols spinasterol spinach interfere with animal hormone action

PHENOLICS

Phenolic acids caffeic, chlorogenic all plants cause oxidative damage, browning in fruits and wine

Coumarins umbelliferone carrots, parsnip cross-link DNA, block cell division

Lignans podophyllin urushiol

mayapple poison ivy

cathartic, vomiting, allergic dermatitis

Flavonoids anthocyanin, almost all plants flower, leaf color; inhibit enzymes, Flavonoids anthocyanin, catechin

almost all plants flower, leaf color; inhibit enzymes, anti- and pro-oxidants, estrogenic

Tannins gallotannin, condensed tannin

oak, hemlock trees, birdsfoot trefoil, legumes

bind to proteins, enzymes, block digestion, antioxidants

Lignin lignin all land plants structure, toughness, fiber

Alkaloids

• About 10,000 different alkaloids have been discovered from over 300 plants.

• Nitrogen atom in structure makes them pharmacologically active.

• Alkaloids are used in nervous stimulants, respiratory diseases. respiratory diseases.

• Bitter tasting, promote the secretion of saliva

• Increase appetite of food

Distribution of Alkaloids in Plant:

• All Parts e.g. Datura.• Barks e.g. Cinchona• Seeds e.g. Nux vomica• Roots e.g. Aconite• Roots e.g. Aconite• Fruits e.g. Black pepper• Leaves e.g. Tobacco• Latex e.g. Opium

Nomenclature:Trivial names should end by "ine" . These

names may refer to: • The genus of the plant, such as Atropine from Atropa

belladona.• The plant species , such as Cocaine from

Erythroxylon coca.Erythroxylon coca.• The common name of the drug, such as Ergotamine

from ergot.• The name of the discoverer , such as Pelletierine that

was discovered by Pelletier.• The physiological action , such as Emetine that acts

as emetic• A prominent physical character , such as Hygrine that

is hygroscopic.

Physical Properties:I- Condition:• Most alkaloids are crystalline solids .

– Few alkaloids are amorphous solids e.g. emetine. – Some are liquids that are either:

Volatile e.g. nicotine and coniine, orNon-volatile e.g. pilocarpine and hyoscine.Non-volatile e.g. pilocarpine and hyoscine.

II- Color:The majority of alkaloids are colorless but some are

colored e.g.:– Colchicine and berberine are yellow. – Canadine is orange.– The salts of sanguinarine are copper-red.

Physical Properties:III- Solubility:• Alkaloidal bases are soluble in alcohol and

insoluble in waterExceptions :– Bases soluble in water : caffeine, ephedrine,– Bases soluble in water : caffeine, ephedrine,

codeine, colchicine, pilocarpine and quaternaryammonium bases.

– Bases insoluble or sparingly soluble in certainorganic solvents : morphine in ether, theobromineand theophylline in benzene.

IV- Isomerization:

• Optically active isomers may show different physiological activities. – l-ephedrine is 3.5 times more active than d-ephedrine.– l-ergotamine is 3-4 times more active than d-ergotamine.– d- Tubocurarine is more active than the corresponding l- form. – Quinine (l-form) is antimalarial and its d- isomer quinidine is

antiarrythmic. – The racemic ( optically inactive) dl-atropine is physiologically

active.

In the outdated d/l system (+)-Ephedrine is also referred to as l-Ephedrine and (—)-Ephedrine as d-Ephedrine

Chemical Properties:I- Nitrogen:• Primary amines R-NH2 e.g. Norephedrine

• Secondary amines R2-NH e.g. Ephedrine

• Tertiary amines R3-N e.g. Atropine

• Besides the other elements eg. C, H, O, the alkaloids contain atleat one N atomatom

– One N atom: Cocaine– Two N atom: Strychnine– Five N-atom: Ergotamine ………………..….>

• Normally N as heterocyclic ring: Quinine,Reserpine, Strychnine, vinblastine

• N contain in aliphatic side: ephedrine, mescaline

Chemical Properties:

II- Basicity:• R2-NH > R-NH2 > R3-N (weak basic)

– Weak bases : Caffine– Weak bases : Caffine– Strong base: Atropine – Amphoteric: Morphine (react as an acid as well as

a base)– Neutral : Colchicines

III- Oxygen:

• Most alkaloids contain Oxygen and are solid in nature e.g. Atropine.

– Some alkaloids are free from Oxygen and are mostly liquids e.g. Nicotine, Coniine.mostly liquids e.g. Nicotine, Coniine.

IV- Stability:• Effect of heat :

Alkaloids are decomposed by heat, except Strychnine and caffeine

Aqueous solutions of Ergot alkaloids easily affected by light (U.V ight) and converted into lumi alkaloid (inactive) form

V- Effect of alkali:a) Cold dilute alkali:• Isomerization: Pilocarpine = Isopilocarpine• Solubilization: Phenolic alkaloid = Soluble

Phenate salt.b) Hot dilute alkali:b) Hot dilute alkali:• Causes hydrolysis of ester alkaloid. e.g.

Atropine = tropic acid and tropine base

c) Heating with caustic alkali:Open the lactone ring. e.g. Pilocarpine = pilocarpic acid

VI- Effect of acids

a) Cold dilute acids:Cold dil. acids affect hydrolysis of some alkaloids. e.g.

Colchicine ………> Methyl alcohol + Colchiceine (phenolic)

b) Hot dilute acids:

-Removal of methyl group: Pilocarpine = Pilocarpidine

c) Conc acids:-Concentrated acids generally cause characteristic color changes which is used for identification of alkaloids (Color changes which is used for identification of alkaloids (Color tests) and some confirmatory tests.

Strychnine with Nitric acid …………> faint yellow colour.

[VI ] Precipitation by specific reagentsI- General precipitation reagents- Mayer’s reagent: Potassium mercuric iodide solution. This reagent

givesa cream precipitate with most alkaloids. Caffeine doesn’t give positive with this reagent. Ephedrine gives precipitate only from a concentrated solution.

- Wagner’s reagent: Iodine potassium iodide solution. This reagent gives a reddish brown precipitate with alkaloids.- Dragendorff’s reagent: Potassium bismuth iodide solution. This reagent gives an orange to reddish brown precipitate with alkaloids

II- Color reagents:These color tests usually depend upon dehydration or oxidation witha resultant color, as most of these reagents contain conc. H2SO4.In some cases, the color can be used for quantitative determination ofalkaloids.- Mandalin’s reagent: Ammonium vanadate in conc.H2SO4:deep violet-

blue- Marqui’s reagent: Formaldehyde in conc. H2SO4: muddy brown- Erdmann’s reagent: Conc. HNO3 and conc. H2SO4. greenish yellow

Terpenoid• This family is the largest family of natural compo unds,

consisting of about 40,000 different molecules. • Were used as a fragrance over two thousand years.• Classified by number of five carbon units they cont ain:

1. Hemeterpenes:C52. Monoterpenes:C103. Sesquiterpenes:C154. Diterpenes:C205. Sesterterpenes:C256. Triterpenes: C307. Carotenoids: C40

• Terpenoids can have medicinal properties such as an ti-ulcer, anticancer, hepaticidal, antimicrobial or diuretic etc.

• Common terpenes include limonene, pinene, chamazule ne and farnesol possess remarkable anti-inflammatory, anti -bacterial, anti-fungal, anthelmintic, anti-malarial and mollus cicidal activities.

• Polymeric isoprene derivatives are a large family o f substances of little functional and structural common ground: steroids , carotenoids , gibberelic acid are just some of its members.

• Several thousand different types of molecules with their varied structures, all of them are synthesized by only a fe w pathways.

Carotenoids• Carotenoids are organic pigments occurring in plants and are mostly

found in red, orange and yellow fruits and vegetables. • Compounds contain 8 isoprene units. • About 600 compounds naturally occurring in fruits and vegetables are

known. • Many compounds are antioxidant. • Some compounds like lutein have the potential anticarcinogenic properties. • They can be used for the treatment or photosensitization, retinal diseases

and glaucoma. and glaucoma. • Source of Vitamin A• carotenes (pure carbohydrates without additional groups) and the

xanthophylls (carotenoids containing oxygen) are classes of caratenoids.

• Other vegetables such as broccoli, spinach or curly kale also contain carotenoids. Carotenoids have antioxidative effects and prevent cancer.

• In addition to this they boost the immune system and reduce the risk of getting heart attacks.

XANTHOPHYLLS• Xanthophylls are the typical yellow pigments of leaves.

• These are oxygenated carotenoids that are synthesized within the plastids.

• Xanthophylls in leaves have an important function as accessory pigments , capturing certain wavelengths of sunlight not absorbed by chlorophylls.sunlight not absorbed by chlorophylls.

– zeaxanthin = antioxidant, – Beta carotene: source of Vit A– Fucoxanthin: Helps you maintain healthy cholesterol and lipid

levels

Lutein

Steroids Phytosterols are found in plants; such as sunflower seeds, sesame, nuts

and Soya beans. Phytosterols protect against colon cancer and lower cholesterol levels.Phytosterols are chemically similar to cholesterol and therefore they

compete against each other for absorption in the body.Steroids in plants are modified triterpenes or triterpenoids. Steroid molecules consist of four rings marked A, B, C and D that have a

number of additional residues R. Steroids have been shown to occur both in gymnosperms and in angiosperms.

Plant phenolicseg Flavonoids , tannins, coumarins, lignans, lignins etc

• Flavanoids are polyphenol substances.• Flavonoids are organic pigments occurring in plants which give plants

a red, violet or blue colour. • Flavonoids have a particularly broad spectrum of efficacy. • Flavonoids inhibit the growth of bacteria and viruses, protect the cells

against the damages of free radicals, protect against cancers and heart against the damages of free radicals, protect against cancers and heart attacks, have a repressive effect against inflammations and they influence blood coagulation.

• More than 6500 different flavanoids have been described. • The plants containing 0.5-3% flavonoids are characterized as flavonoid

drugs.• Tannins are known as phenolic compounds of high molecular weight.• Tannins are used against the diarrhea and as an cure in poisoning by

heavy metals. • Their main characteristic is that they bind and precipitate proteins,

draw the tissues closer together and improve their resistance to infection.

Major classes of plant phenolicsBasic Skeleton Class Example

1. C6 Phenols Catechol

2. C6-C1 Phenolic acids P-Hydroxybenzoic acid

3. C6-C2 Phenylacetic aicds 2-hydroxyphenylacetic Acid

4. C6C3 a) Hydroxycinnamic acids

b) Coumarins

Caffeic acid

6,7-Dimethoxy coumarin

Major classes of plant phenolicsBasic Skeleton Class Example

5. C6C4 Naphthoquinones Juglone

6. C6-C1-C6 Xanthones Magniferin

7. C6-C2-C6 stilbenes Lunularic acid

8. C6-C3-C6 Flavanoidsa)Flavones

b)Flavanols

c)Catechins

d)Flavanones

e)Dihydroflavonols

Apigenin

Kaempferol

Catechin

Naringenin

Taxifolin

Glycosides

• Glycosides are compounds that yield one or more sugars among the product of hydrolysis.

• Some few plant species have the ability to produce cyanides. They are strong cytotoxins, competitive inhibitors of the FeIII of the heme group. cyanides. They are strong cytotoxins, competitive inhibitors of the FeIII of the heme group.

• The most frequently occuring group is beta-glucose, although rhamnose, digitoxose, cymarose also occurred.

• Non sugar component is aglycone, and sugar is glycone.

Examples of glycosides

Chemical classification

When the chemical nature of the aglycone group is used as the basis of systematization, the classification is as follows:

• Solubility:glycosides are water soluble compounds and insoluble in the organic solvents.

• Glycone part: water soluble, insoluble in the organic solvents.organic solvents.

• Aglycone part: water insoluble, soluble in the organic solvents.

• Some glycosides soluble in alcohol.

physico-chemical properties of glycosides(general)

• Colorless, solid, amorphous, nonvolatile (flavonoid- yellow, anthraquinone-red or orange)

• Give positive reaction with Molisch's and Fehling's solution test (after hydrolysis)

• Most of them have bitter taste (except: populin, glycyrrhizin, stevioside).

Cont...• Odorless except saponin (glycyrrhizin).• when a glycosides has a lot of sugars its

solubility in water decrease.• Glycosides hydrolyzed by using mineral acids

and temperature or by using enzymes such as:a- Emolsin Bitter almond seeds.a- Emolsin Bitter almond seeds.b- Myrosin or Myrosinase black mustard seeds.c- Rhamnase glycosides containing rhamnose as

sugar part.

The function or the role of glycosides in the plant organism

• Converting toxic materials to non or less toxic.• Transfer water insoluble substances by using

monosaccharide.• Source of energy (sugar reservoir).• Storing harmful products such as phenol.• Storing harmful products such as phenol.• Regulation for certain functions(growth).• Some have beautiful colours(pollenation

process).• Some glycosides have antibacterial activity, so

they protect the plants from bacteria and diseases.

Chemical classification

When the chemical nature of the aglycone group is used as the basis of systematization, the classification is as follows:

Anthracene glycosidePhenol SteroidSteroidFlavanoidCyonogeneticThioglycosidesSaponinAldehyde

Classifications of glycosides according to their therapeutic effects

A. Cardiac muscles stimulators such as:a-Digitalis glycosides: digoxin, digitoxin, gitoxin

(Fox glove leaves).b- Ouabain: Strophanthus gratus seeds.b- Ouabain: Strophanthus gratus seeds.c- K-strophanthin -Strophanthus kombe seeds.d- Scillaren A,B which isolated from red and white

Squill bulbs.e- Convolloside:Convallaria majalis – Lily of the

Valley.

Cont…

B. Laxative group of glycosides:a- Sennoside A,B,C,D (Senna leaves and

fruits).b- Cascaroside A,B (Cascara bark).b- Cascaroside A,B (Cascara bark).c- Frangulin and glucofrangulin(Frangula

bark).d- Aloin and barbaloin (Aloe vera and Aloe

barbadensis juice).

Cont…

C. Local irritant group:a-Sinigrin (Black mustered seeds_Brassica nigra)b-Sinalbin (White mustered seeds_Brasica alba)

D. Analgesics and antipyretics:Salicin Salisylic acid - Willow or Salix bark.hydrolysisSalicin Salisylic acid - Willow or Salix bark.

E. Keeping elasticity of blood vessels like:Rutin : Rutoside (Bitter orange peels, Lemon peels)

F. Anti-inflammatory group: a- Aloin for peptic ulcer

b-Glycyrrhizin

hydrolysis

Classification of glycosides according to glycone part

• Glucose _ glucoside group like in Sennoside.

• Rhamnose _ Rhamnoside like in frangullin. frangullin.

• Digitoxose _ Digitoxoside like in digoxin.• Glucose and Rhammnose _

Glucorhamnoside _ glucofrangulin.• Rhamnose and glucose _

Rhamnoglucoside _ Rutin.

Classification of glycosides on the basis of the linkage between glycone and aglycone part

• O-glycosides : in these glycosides the sugar part is linked with alcoholic or phenolic hydroxyl or carboxyl group.

• S-glycosides : in these glycosides the sugar attached to a Sulfur atom of aglycone such as in sinigrin.attached to a Sulfur atom of aglycone such as in sinigrin.

• N-glycosides : in these glycosides the sugar linked with Nitrogen atom of (-NH2,-NH-)amino group of aglycone like in nucleosides DNA,RNA

• C-glycosides : in these glycosides the sugar linked (condensed) directly to Carbon atom of aglycone like in aloin.