PPT. Alkaloids

 

Prof. Abdel Nasser Singab

 

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Why we study alkaloids? Importance of alkaloids as medicine? The poppy plant, Papaver somniferum , is the source for non-synthetic narcotics. Tropane alkaloids (antispasmodic etc) Taxol the best anti-ovarian cancer CNS stimulant ( caffeine, ephedrine etc) Identification of alkaloids, chemical test (specific). Isolation from natural origin Biosynthesis of certain alkaloids NEW MARINE ALKALOIDS).

 

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Alkaloids are a group of molecules distributed everywhere. Alkaloids a group of natural products that affairs had a great influence, all over history onrepresent the economic, medical, political and social of humans. Millions of people around the Globe use purine alkaloids every day whether starting the day with a cup of coffee or drinking a cup of tea in the afternoon. Many have potent physiological effects and therefore, are considered as important therapeutic agents e.g. atropine, morphine, quinine etc etc.. They are widely used to treat diseases ranging from malaria to cancer.

 

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Alkaloids are biomolecules of secondary metabolites which are derived from amino acids or from the transamination process and are classified according to the amino acids that provide their nitrogen atom and part of their skeleton. Similar alkaloids have different biosynthetic pathways. Alkaloids are derived from l-lysine, l-ornithine, l-tyrosine, l-tryptophane, l-histidine, l-phenylalanine, nicotinic acid, anthranilic acid or acetate. Alkaloids also occur in the animal kingdom. Differently from plants, the source of these molecules in an animal’s body can be endogenous or exogenous.

 

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Alkaloids (mean (mean alkali-like substances), substances), are basic nitrogenous compounds of plant or animal origin and generally possessing a marked physiological action on man or animals

 

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All alkaloids are nitrogenous, but not all the nitrogenous compounds are alkaloids. Plants are a rich source of alkaloids but some have been found in

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animals eand .g. (musc (muscopyrid opyridine) ine) of deer er and fungi e.g. Ergot got alk alkalo aloids idse.g. alm almost ost all alkalo alk aloids idsmusk hav haveede been syn synthe thesiz sized. ed. Er Most but not all all possess basic basic prop properties erties due to the pre presence sence of an

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amino nitrogen nitrogen but ccertain ertain ar aree amphoter amphoteric ic e.g. ceph cephaline aline and psychotrine psycho trine or even aci acidic dic e.g. co colchicin lchicines es and reci recinine. nine.

 

A) Plant sources  The important alkaloid-bearing families are: Liliaceae, Amarylidaceae, Asteraceae, Ranunculaceae, Papaveraceae, Leguminosae, Rutaceae, Loganiaceae, Apocyanaceae, Solanaceae and Rubiaceae. B) Ani Animal mal sou source rcess  Recent Recently ly alkalo alkaloids ids were fou found nd in animals and insec insects ts e.g, Pyocy Pyocyanine anine  

from the bacterium Pseudomonas aeruginosa. Ergot alkaloids; ergotamine and ergometrine from Ergot fungus . Lycopodine from Lycopodium spores, and muscopyridine from the Musk deer.

 

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In general, alkaloids occur in a salt form with organic or inorganic acids, or in combination with specific acids e.g. Opium alkaloids occur with meconic acid and Cinchona alkaloids with cinchotannic acid.

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Some occur in combination with sugars as glycosides e.g. solanine Function of alkaloids in plants:

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They play the following functions in plants: 1) Protective for the plant against against insects insects 2) As eend nd products products ooff metabolism. metabolism. 3) As waste products. 4) Source for energy and reserve of nitrogen.

 

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Nomenclature:  Al alo o i d s t er erm m i n at ate e wi w i t h t h e su s u f f i x -i -in n e, th t h ei eirr n am ames es m ay b e der d erii v ed f r o m :  A l k al

Genus name

e.g., Atropine from Atropa.

Species name Common name

e.g., Cocaine from Coca. e.g., Ergotamine from Ergot.

Physiological activity

e.g., Emet Emetine ine (emetic) (emetic)..

Discoverer

e.g., Pelletierine from Pelletier.

 

Different systems of classification based on: The chemical structure (type of nitrogen, heterocyclic or non-heterocyclic).  The pharmacological action (biological activity).  The biochemical origin (biosynthetic pathway of production in the plant).  The taxonomical origin (plant families rich in alkaloids). According to chemical structure, two broad divisions may be recognized 

Heterocyclic or typical alkaloids: They are sub-classified into different groups according to their ring structure. Non-heterocyclic or atypical alkaloids: They are sometimes sometimes cal called led “protoa “protoalkaloi lkaloids” ds” or biolog biological ical amines.

 

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They are simple amines, or biological, amines. The amino acid nitrogen atom is not in a heterocyclic ring. Protoalkaloids are compounds, in which the N atom derived from an amino acid is not a part of the heterocyclic. Such kinds of alkaloid include compounds derived from l-tyrosine and l-tryptophan , e.g mescaline, ephedrine and N, N-dimethytryptamine, are certain examples of proto-alkaloids.

2. Pseudo-alkaloids   

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These alkaloids derived from non-amino acid precursors. Alkaloids of this type are very weak in its basic characters. Examples of pseudoalkaloids include such compounds as solanidine, caffeine, theophylline and theobromine. The N atom is inserted into the molecule at a relatively late stage, for example, in case of steroidal or terpenoid skeletons. Certainly, the N atom can also be donated by an amino acid source across a transamination reaction, if there is a suitable aldehyde or ketone group

 

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True alkaloids derived from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid; with the exception of some are liquids. True alkaloids may occur in plants (a) free state, (b) as salts and (c) as Noxides. Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, atropine and morphine.

 

Prefixes:   

"Nor-" Designates N-demethylation e.g. nor pseudoephedrine and nor nicotine "Apo-"

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Désignâtes dehydration apomorphine. "Iso-, "Is o-, pse pseudo udo-, -, neo- and e.g. epi epi-" -"  Indicate different types of isomers. Suffixes:  "-dine"  Refer to isomerism as in the case of the Cinchona alkaloids, quinidine and cinchonidine are the optical isomers of quinine and cinchonine, respectively.

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"-inine" Indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine.

 

Amides: made from Amine + Carboxylic acid.

Amides are produced by reaction of a carboxylic acid with ammonia or an amine using heat  

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Nitrogen in alkaloids: Number of nitrogen nitrogen atoms: atoms: Alkaloid Alkaloidss usually con contain tain one nitrog nitrogen en atom. Yet, certain alkaloids may contain more than one up to 5 nitrogen atoms in their molecule e.g. nicotine contains 2 N atoms and ergotamine 5. Nitrogen in alkaloids exists in the form of amine as follow:

H

H

R

R1

R1

R1

N

N

N

N

N

H

H

H

R2

H

R2

R3

R2

R3 R4

 Ammonia  Amm onia Primary amine

Secondary amine

Tertiary amine

Quaternary amm ammoni onium um ion i on

.

 

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Amides: made from Amine + Carboxylic acid. Amides are produced by reaction of a carboxylic acid with ammonia or an

amine using heat. O CH3 C OH

O

heat + NH3

CH3

+ H2O

C NH2 O CH3 C OH

+ CH3

NH 2

heat

O CH3 C NH CH3 +

H2O

 

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Physicochemical Properties: Physical characters: 1) Condition: Most alkaloids are crystalline solids. Some are liquids like:

- Volatile e.g. nicotine nicotine and coniine, coniine, or or - Non-vo Non-volatile latile e.g. e.g. piloca pilocarpine rpine an andd hyoscine. hyoscine. 2) Color: The majority of alkaloids alkaloids are col colorless orless but some some are colored e.g.: - Colchici Colchicine ne and berb berberin erinee are yellow. yellow. Canad Canadine ine is orang orange. e. - The salt saltss ooff sa sangu nguinar inarine ine are copper copper-red -red.. Bet Betanin aninee is red. red. 3) Solubility: The solubility of alkaloids and their salts is of considerable importance because: - They are ofte oftenn administered administered in solution solution (injection (injection form form).). - The di difference fferencess in solubility solubility between between alkal alkaloids oids and their their sa salts lts are used used as a base for their isolation and purification from non-alkaloidal substances.

 

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Due to the great variation variation in their structure, structure, the solubility solubility of different different alkaloids and salts are variable. Both alkaloidal bases and their salts are soluble in alcohol.A general rule: the bases are soluble in organic solvents and insoluble in water. Exceptions: Bases soluble in waterCaffeine, ephedrine, codeine, colchicine, pilocarpine and quaternary ammonium bases.Bases insoluble or sparingly soluble in certain organic solvents: Morphine and psychotrine insoluble ether, theobromine and theophylline insoluble benzene.

 

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Alkaloidal salts and the quaternary alkaloid are soluble in H2O, and, insoluble or sparingly soluble in organic solvents. Exceptions: Salts insoluble in waterQuinine waterQuinine monosulphate.Salts monosulphate.Salts soluble in organic solvents Lobeline and apoatropine hydrochlorides are soluble in chloroform. chloroform. Generally,, salts Generally salts of w weak eak bbase asess are ea easil silyy hydr hydroly olyzed zed in so soluti lution on without alkalinization and release the bases, which are extracted with organic solvents solvents e.g. colc colchicine hicine is solu soluble ble as a base or hydr hydrochlor ochloride ide salt in H2O and CHCl3.

 

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Optical are activeindue to the presenceactivity: presenc e of one −orMany mor moreealkaloids asymmet asymmetric ric optically carb carbon on atoms ttheir heir molecu molecule. le. Generally,, the levo (-) form is more active than the dextro (+). Generally (-) Ephe Ephedrin drinee is 3.5 tim times es m more ore act active ive than (+) iso isomer mer d-ep d-ephedr hedrine ine (-) ergo er gota tamin minee is 3-4 titimes mes mo more re ac actitive ve than than (+ (+)) - isom isomer er d-erg d-ergot otam amine ine.. Exceptions: d- Tubocur Tubocurarine arine is m more ore active than the ccorres orresponding ponding l- form. Both quinine (l-form) (l-form) and its d- isomer qui quinidine nidine are act active. ive. The race racemic mic dlatropine is physiologically active.

 

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A) Basicity of alkaloids:

The basicity of alkaloids is due to the presence of a lone pair of electrons on the nitrogen atom. Amines and, consequently, alkaloids resemble ammonia [NH3] in chemical characters. They form salts with acids without liberation of water. In plants, alkaloids occur as free bases, salts or N-oxides (N→O). O). Whe henn the salt of an alkaloid is treated with hydroxyl ion, nitrogen gives up a hydrogen ion and the free amine is liberated. + N:  Am in e

+

+ H Cl

-

Hydrochloric acid

N

H

Cl - usually represented by

 Am in e hy hydr dr ochl oc hl or i de

N

. HCl

 

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→

In as free N-oxides (N upO). O)a. hydrogen When When the thene ion saltplants, of an alkaloids alkaloid isoccur alkaloid treated w with ith bases, hydroxyl hydroxysalts l ion,ornitrogen nitroge n gives hydrog and the free amine is liberated. Quaternary ammonium compounds (R4N+X-), e.g. tubocurarine chloride and berberine chloride have four chemical groups covalently bonded to nitrogen. The positive charge of this ion is balanced by some negative ion. The quaternary ammonium ion, have no proton to give up. Thus; it is not affected by hydroxyl ion; so quaternary ammonium compounds have chemical properties quite different from those of the amines.

 

Factors influence the degree of basicity:

OCH3 CN

N N

Piperidine

O

N

Pyridine

CH3

  Ricinine

 

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The degree of basicity varies greatly depending on the structure of the molecule such as the degree of unsaturation of the heterocyclic ring. Unsaturation decreases the basicity e.g. piperidine alkaloids are more basic than pyridine alkaloids. The presence and position of other substituents and functional groups e.g.: The electron donating donating groups, groups, such as alkyl groups, groups, increase increase the basicity. basicity. The electron withdrawal groups, such as the carbonyl groups, decrease the basicity. Adjacent nitrogen decrease basicity withdrawing withdra wing so thegroups availability availabtoility of electrons on the nitrogen nitrogas enelectron decreases decreases and therefore, the alkaloid be neutral or slightly acidic e.g. recinine alkaloid in castor seeds. Strong basic basic alkaloids can can form salts even even with very wea weakk acids, while weak bases require more acidic medium. Some alkaloids are amphoteric due to the presence of acidic groups in their molecule. Examples are: The phenolic alkaloids such as: morphine, psychotrine and cephaline. The alkaloids containing a carboxylic group such as: narceine.

 

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Due to their basic character, alkaloids react with

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acids acid s to to for form m sa salt lts. s. Weak bases require stronger acids.Dibasic alkal alkaloids oids may form two series of salts.Very weak bases form

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unstable salts, e.g. piperine, papaverine, narcotine and caffeine.Amphoteric alkaloids (e.g. containing phenolic or carboxylic groups) can form salts with both acids and alkalis e.g morphine Alkaloids showing acidic characters characters do not form salts with acids e.g. ricinine.

 

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The influence of different factors such as exposure to light, l ight, heat, oxygen, acids and alkalis should be considered during preservation and manipulation of alkaloids. In general, alkaloids are less stable in solution than in the dry state. Effect of heat Alkaloids are decomposed by heat, except caffeine that sublimes without decomposition. Effect of heat and light in presence of oxygen: Most tertiary amine alkaloids are easily transformed to the N oxides when exposed to light and oxygen at elevated temperature. N-oxides are usually water-soluble, they are characterized by their delayed release properties, low toxicity and low addictive properties as compared to the parent tertiary alkaloids. Effect of acids , Hot, dilute acids and concentrated mineral acids may cause: Dehydration to produce produce anhydro anhydro-- or apo-alk apo-alkaloids aloids,, e.g.: dehydration of morphine to produce apomorphine and that of atropine to yield apoatropine. certain alkaloi alkaloids ds such as qui quinine, nine, na narcotin rcotinee and code codeine ine to produce produce phen phenolic olic O  -demethylation of certain alkaloids by treatment with HI e.g. conversion of codeine to morphine. Hydrolysis of ester alkaloids, such as atropine and reserpine, and glycoalkaloids, such as solanine. Effect of alkalis Weak alkalis: liberate most alkaloids from their salts e.g. NH3.They also can form salts with alkaloids containing a carboxylic group e.g. narceine, when treated with NaHCO3, yields yiel ds the corresponding sodium salt. Strong alkalis: such as aqueous NaOH and KOH form salts with phenolic alkaloids. Hot alkalis: resulted in hydrolysis of ester alkaloids e.g. atropine, cocaine and physostigmine and cleavage of lactone ring, if present, to produce the corresponding acid e.g. pilocarpine is transformed to pilocarpic acid.

 

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Chemical tests commonly performed for detection of alkaloids involve two types of reactions: 1) Precipitation reactions: Most alkaloids alkaloids are pre precipit cipitated ated from the theirir- neutr neutral al or acidic

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solutions by a number of reagents which contain certain heavy metals such as mercury (Hg), platinum (Pt), bismuth (Bi), and gold (Au), by forming double salts with them. The composition of the most common alkaloidal precipitants

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Care must be taken in the application of these tests as: Certain alkaloids such as caffeine and some others do not react. False positive response may be obtained o btained in certain cases as most of the reagents used precipitate proteins, tannins, coumarins and certain flavonoids.

 

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These reactions are usually performed by the addition of color reagents (Table 1) to the solid free bases not to their salts to produce characteristic colored solutions. The reagents used generally contain concentrated sulphuric acid and an oxidizing agent. They give colors with most alkaloids, or may be specific for one alkaloid or a group of related alkaloids.

 

Composition of common reagents used for detection of alkaloids. Name of

Composition

Remarks

reagent Mayer's Wagner's

Potassium-mercuric iodide Iodine in potassium iodide

Hager's Dragendorffs Marmé's

Saturated solution of picric acid except caffeine and dilute ephedrine). Potassium bismuth iodide Reddish brown Potassium cadmium iodide

Creamy white (positive with most alkaloids,

Yellow Orange-reddish brown Yellow precipitate.

 

Color reagents: Froehd's Mandalin's 

Marquis' Erdmann's Mecke's Shaer's Rosenthaler's Dragendorff's

Ammonium molybdate / conc. H2SO4 Ammonium vanadate / conc. H2SO4 Formaldehyde / conc. H2SO4 2SO4 Conc. nitricacid acid/ /conc. conc.H HSO Selenious 2 4 Hydrogen peroxide / conc. H2SO4 Potassium arsenate / conc. H2SO4 Potassium bismuth iodide

The colors formed are characteristic. The tests are sensitive to amounts andmicro can be used for colorimetric assay

 

3) Special colour reagents: Erlich's reagent (Van-Urk reagent):

It gives characteristic blue or grayish-green

(Acidified p -dimethyl(Acidified p  -dimethylaminobenzaldehyde).

color with ergot alkaloids

Acid Ac idifi ified ed cerric cerric ammon ammonium ium su sulp lphat hate. e.

Chara Charact cteri erist stic ic for indo indole le alkalo alkaloid ids, s, it gi gives ves a

Vitali-Morin reagent.

yellow or orange/red colour. Characteristic for Tropane alkaloids

Thaleoquine reaction.

Characteristic for Cinchona alkaloids.

Murexide reaction.

Characteristic for Purine bases

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