Group 1 3DPH Amican, Aegan Matthew Ares, Karen Gem Ballester, Ruvie Ann Barcelona, Mark Joseph Calleja,

Katherine Carmen Isabel Capuno, Christelle Venus

ALKALOIDS I. Characteristics and Properties These are the organic product of natural and synthetic origin which are basic in nature and contain one or more than one nitrogen compound normally in heterocyclic in nature, and posses specific physiological action on human and animal body, when use in small quantities A. Physical Property Color - In general, Alkaloids are colorless but some may be colored. Physical Form - Most are crystalline solids - Few are amorphous Solubility Free alkaloid bases are invariably found to be fairly soluble in organic solvents, such as: either, chloroform, relatively non-polar solvents (hexane, benzene, petroleum ether), immiscible solvent, lower alcohols (methanol, ethanol); but they are either practically insoluble or very sparingly soluble in water.

Alkaloidal salts are almost freely soluble in water, relatively less soluble in alcohol and mostly either insoluble or sparingly soluble in organic solvents: Examples Atropine sulphate and morphine hydrochloride are much more soluble in water than their corresponding bases i.e., atropine and morphine.

There are a few exceptions to the above stated generalizations, namely: (i) Certain alkaloid bases are water soluble, but these may be solely regarded as exceptions rather than any specific rule, such as: ephedrine, colchicine, pilocarpine;the quaternary alkaloid-base like berberine and tubocurarine; caffeine-base readily extracted from tea with water. Narceine and pilocarpine are insoluble in organic solvents, whereas morphine is sparingly soluble in organic solvents viz., solubility in either 1:5000.

(ii)

(iii) (iv)

Certain alkaloidal salts, for instance: lobeline hydrochloride and apoatropine hydrochloride are found to be soluble in organic solvent like chloroform. Some alkaloidal salts are sparingly soluble in water whereas others are extremely watersoluble, such as: Quinine sulphate-soluble in 1:1000 parts of water, Quinine hydrochloride soluble in 1:1 part of water.

B. Chemical Property N-in the Molecule - The number of N-atoms vary from the bear minimum one in a molecule e.g., cocaine, to even five in a molecule e.g.,ergotamine. - these N-atoms are normally present as a part of the heterocyclic ring in the alkaloid molecule e.g., quinine,reserpine,strychnine,vinblastinean d yohimbine - whereas there are certain alkaloids that contain the N-atom in the aliphatic side chain o e.g., ephedrine, mescaline. - N-atom in the tertiary-amine form (R3N) o e.g.,morphine, reserpine; lesser in the secondary-amine form (R2NH o e.g., ephedrine; and very rarely in the primary-amine form (RNH2)

o e.g., nor-pseudo-ephedrine. Furthermore, whenever N-atom occurs either in the tertiary- or secondary-form, it essentially constitutes as an integral part of the ringsystem, precisely the heterocyclic ring system. Noticeably, the tertiary N-atoms wherein only two of the bonds are involved in a ring, the methyl moiety is usually found as the third component, for instance: N-methyl group in morphine, cocaine, colchicine, dextro methorphan, codeine, physostigmine, vinblastine, vindesine etc. Hence, methyl moiety seems to be the only alkyl group that has been found to be substituted on the N-atom. In some very specific cases, the N-atom occurs in the quaternary ammonium form (R4N+ . X) e.g., tubocurarine chloride Nevertheless, the quaternary ammonium compounds are logically and technically not regarded as alkaloids by virtue of the following two particular reasons, namely: N-atom does not possess a H-atom, and Chemical properties are quite different.

O-in the Molecule Invariably, these specific alkaloids are found in the solid state, with a few exceptions where the oxygenated alkaloids usually occur as non-volatile liquids, such as: pilocarpine. Basicity (Alkalinity) In general, the alkaloids are basic (alkaline) in reaction, by virtue of the presence of N-atom present in the molecule. Hence, these are prone to the formation of their respective salts with various acids. Degree of Basicity: mostly depends upon the prevailing influence caused due to the electrostatic status of the N-atom present in the alkaloid molecule, for instance, the number of N-atom present in the alkaloid, whether the N-atom is located in the ring or in the side-chain, the presence of alkyl group (e.g., methyl) to the N-atom etc. Another vital factor, is the presence of pri-, sec-, tert-, or quaternary N-atom or atoms in it. They are eventually reflected by the different dissociation constant values (i.e., pKa values) with regard to various alkaloids II. Classification Chemical Classification This is a most accepted way of classification of alkaloids. The main criterion for chemical classification is the type of fundamental(normally heterocyclic) ring structure present in alkaloids. The alkaloidal drugs are broadly categorized into two divisions.
o o

True alkaloids(heterocyclic alkaloids) are divided into twelve group according to the nature of their heterocyclic ring Protoalkaloids or biological amine and pseudoalkaloids

Taxonomic Based in their Family e.g. Solanaceous,Papilionaceous without reference their chemical type of alkaloids present & another according to genus. e.g.. ephedra, cinchona etc. Pharmacological based: Their pharmacological activity or response. For example: 1. Analgesic alkaloids 2. Cardio active alkaloids etc. Do not have chemical similarity in their group. Biosynthetic Classification

This method gives significance to the precious from which the alkaloids are biosynthesized in the plant. Hence, the varity of alkaloids with different taxonomic distribution and physiological activities can be brought under same group if they are derived from same procedure. E.g. all indole alkaloids from tryptophan are grouped together. The alkaloidal drugs are catagorised on the fact whether are derived from amino acid procedure as ornithine, lysine, tyrosine, phenylalanine, tryptophen, etc.According to this alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.
o

o o o o

o o

Pyridine group: piperine,coniine,trigonelline,arecaidine,guvacine,pilocarpine,cytisine,nicotine, sparteine,pelletierine Pyrrolidine group: hygrine,cuscohygrine,nicotine Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine,brucine, veratrine, cevadine Isoquinoline group: The opium alkaloids (morphine, codeine, thebaine, Isopapa-dimethoxy-aniline, papaverine, narcotine, sanguinarine, narceine, hydrastine, berberine), emetine, berbamine,oxyacanthin Phenethylamine group: mescaline, ephedrine, dopamine, amphetamine Indole group: Tryptamines: DMT, N-methyltryptamine, psilocybin, serotonin Ergolines: the ergot alkaloids (ergine, ergotamine, lysergic acid, LSD etc. o Beta-carbolines: harmine, harmaline, yohimbine, reserpine o Rauwolfia alkaloids: Reserpine Purine group: o Xanthines: caffeine, theobromine, theophylline Terpenoid group: o Aconite alkaloids: aconitine
o o

o o

Steroids: solanine, samandaris (quaternary ammonium compounds): muscarine, choline, neurine Vinca alkaloids: vinblastine, vincristine. They are antineoplastic and binds free tubulin dimers thereby disrupting balance between microtuble polymerization and delpolymerization resulting in arrest of cells in metaphase. Miscellaneous: capsaicin, cynarin, phytolaccine, phytolaccotoxin

III.

Structures

1. Are basic nitrogen containing compounds 2. Show great diverse structure and origins as well as pharmacological actions 3. The only common factor found is the presence of the Nitrogen atom R RNH CH CH2 R

Alkaloids are a group of nitrogen- containing bases. But few of them are derived from purines or pyrimidines, while the majority of them are produced from amino acids . Classifications of Alkaloids based on presence of nitrogen atom in a heterocyclic ring system 1. Non Heterocyclic Alkaloids or Atypical Alkaloids/ Proto-alkaloids - These molecules have nitrogen atoms which are not a part of any ring system Examples :

Ephedrine:

Colchicine: 2. Heterocyclic Alkaloids or Typical Alkaloids - These have nitrogen as part of a cyclic ring system. Further divided into 14 groups based on ring structure containing nitrogen Heterocycle Example

Pyrrolizidine

Tropane (Piperidine/ N-methyl-pyrrolidine)

Quinoline

Isoquinoline

Aporphine(reduced isoquinoline/naphthalene)

Quinolizidine

Indole or Benzopyrole

Indozolidine

Imidazole or glyoxaline

Purine (pyrimidine/imidazole)

Steroidal (some combined as glycosides)

Terpenoid

IV.

Uses

Some alkaloids focus their range in a particular part of the body. Those that most affect us are: 1. Nervous sytem - Exert a stimulation role in the CNS (Caffeine, theobromine, strychnine) that in very small doses can be convulsive. - Scopolamine of henbane (Hyoscamus niger) have a calming role, hence they are used as sedatives. - Opium, which is extracted from the latex of the capsule of the poppy is the main ingredient of some sleeping pills - Aconitine, initially stimulating but later can be paralyzing - Strychnine causes violent and painful spasms

- Scopolamine is responsible for mydriasis or dilation of the pupil - Eserin from calabar bean is used to contract the pupils of the eyes - Digitalis acts on the heart muscle 2. Digestive System - Some are very toxic to the digestive system causing violent irritation to the gastric mucosa with typical manifestations such as diarrhea and vomiting. - Among these are castor oil plant (Ricinus communis) that contain alkaloid ricinine which has been used as a purgative but extremely dangerous because a couple of chewed seeds can be fatal to a child. 3. Circulatory sytem - Resperine from (Rowulfa vomitoria) is used to lower blood pressure - Sparteine is used to increase metabolism and encourage the elimination of fluids in people with obesity 4. Respiratory system -scoparin contained in the flowers of common broom (Cytisis scoparuis) hass been used to combat respiratory diseases -ephedrine has been used as a decongestant as a treatment for bronchial asthma and has been later banned by the FDA because it possesses stimulant properties. 5. Psychotropicsn- affects the mind, altering perception a. Hallucinogens- distorted illusion of reality -mescaline from peyote (Lophophora williamsii) -canabine from cannabis (Cannabis sativa) - harmaline from Syrian rue (Paganum harmala) - ergotoxine from ergot (Claviceps purpurea) -muscarine from mushroom amanita (Amanina muscarina) b. Narcotics- induces a dreamy state -Opium -Morphine -Codeine c. Stimulants-state of euphoria and well being - cocaine is extracted form coca leaves (Erythroxylon coca) -nicotine is obtained from tobacco (Nicotiana tobacum) -solanaceae is an addictive stimulant and a dangerous poison even in low doses - caffeine is present in coffee, tea, cacao, orange tree, lemon

V.

Example of Plants a) Nervous system: o Stimulating role in CNS- caffeine (coffee and especially tea), theobromine (cacao) or strychnine(nux vomica), o Calming role, sedatives- scopolamine from henbane leaf, foliage, root and seed (Hyoscyamus Niger), morphine from the latex of poppy (Papaver somniferum main ingredient of sleeping pills) o Initially stimulating but paralyzing - aconitine from the root of aconite ( Aconitum carmichaelii) o In muscles(pupil), to dilate - scopolamine of henbane (Hyoscyamus Niger)

b)

c)

d)

e)

Contracts muscles eserine from calabar bean (Physostigma venenosum) in pupil, digitalis (Digitalis sp) on the heart Digestive system: o Poisonous ricine in seeds of castor oil plant (Ricinus communis), colchicines of autumn crocus (Colchicum autumnale), cynoglossine from heliotrope (Heliotropium europaeum) Circulatory System: o Circulatory vessels reserpine from Rauwolfia vomitoria ( lowers blood pressure), sparteine of common broom Branch ends, Leaf, foliage, Seed (Cytisis scoparius) has opposite effect useful to inc. metabolism and elimination of fluids in people with obesity Respiratory System: o Dilating bronchial tubes scoparin in the flowers of common broom (Cytisis scoparius), ephedrine from different species of the genus Ephedra (FDA in USA banned) Psychotropics: o Hallucinogens strong poisonous drugs: mescaline from peyote (Lophophora williamsii), cannabine from cannabis ( Cannabis sativa), harmaline from Syrian rue (Peganum harmala), ergotoxine from ergot (Claviceps purpurea), muscarine from mushroom Amanita ( Amanina muscarina) o Narcotics morphine produced from opium extracted the latex of the poppy (Papaver somniferum), codeine and heroin are derived from it(morphine) o Stimulants- cocaine from coca leaves (Erythroxylon coca), nicotine from tobacco leaf and foliage (Nicotiana tabacum) o

VI.

Extraction Procedure 1. Sample Preparation The plant material is reduced to a moderately coarse powder using grinders and sieves, to facilitate maximum effective contact of the solvent with the ruptured alkaloid bearing tissues and cells. In the case of plant substances that are rich in oils and fats, such as: seeds, kernels, these non-alkaloidal chemical components need to be eliminated completely by extraction with a suitable non-polar solvent like n-hexane, light petroleum ether, in a soxhlet apparatus, which would not extract the alkaloids in question. 2. Liberation of Free Alkaloidal Base Alkaloids invariably occur as the salt of acids, such as oxalates and tannates. Therefore, when the plant substance is exposed to an alkaline medium, the alkaloidal salts are readily converted to the corresponding alkaloid bases.

Factors Affecting the Choice of Alkali to be Used (a) Natural state of the alkaloids- the salt of a strongly basic alkaloid with a mineral acid usually tends to undergo cleavage under the influences of a stronger base. Likewise, the corresponding salt of a weakly basic alkaloid and a relatively weak organic acid shall require a rather weaker base for its cleavage. (b) Chemical characteristics of the alkaloidal base: The usage of strong alkali e.g., NaOH or KOH should be avoided as far as possible by virtue of the fact that certain alkaloids undergo hydrolysis on prolonged contact with a strong base.

3. Extraction of Alkaloidal Base The extraction of alkaloidal base may be accomplished by three different types of solvents: (a) Extraction with Water-Miscible Solvents (b) Extraction with Water-Immiscible (c) Extraction with Water

4. Purification of Alkaloidal Extract (a) Extraction with Acid Solution-dilute H2SO4 is always preferred over HCl for general use in the extraction of alkaloids. The acid solution is rendered alkaline with dilute NH4OH solution to liberate the alkaloids which is then extracted with an organic solvent. The solvent is removed under reduced pressure and the traces of moisture are removed with anhydrous sodium sulphate. (b) Precipitation of Alkaloid with Precipitating Reagent -accomplished by the addition of a suitable precipitating reagent. It is further purified by filtration, recrystallization and ultimately decomposed to obtain the desired free alkaloid(s). (c) Formation of Crystallized Alkaloidal Salt- by addition of an appropriate mineral or organic acid, such as: hydrochloric, hydrobromic, perchloric, sulphuric, oxalic and tartaric acids. (d) Various separation techniques- partition, ion-exchange and column chromatography are invariably used for the purification of a host of alkaloids. 5. Fractionation of Crude Alkaloids (a) Fractional crystallization (b) Fractional distillation (c) Derivatization with low solubility products Latest methods employed: High performance liquid chromatography (HPLC)\ High performance thin-layer chromatography (HPTLC) Chromatotron Counter-current distribution Column chromatography Ion-exchange chromatography Methods of Extraction (a) Soxhlet Extraction Process -generally suitable for the extraction of alkaloids from powdered plant materials with the help of organic solvents -the powdered drug is usually moistened with dilute ammonia solution and then packed loosely in the thimble of the Soxhlet apparatus; -and the organic solvent affords a deep penetration of the moist drug thereby allowing the greatest possible extraction of the alkaloids from the exposed surfaces of the cells and tissues of the crude drug. -the solvent is filtered and evaporated in a Rotary Thin-Film Evaporator and the residue is treated further for the isolation of individual alkaloids.

(b) Stas-Otto Process -treating the powdered and sieved drug substance with 9095% (v/v) ethanol, previously acidified with tartaric acid. -proportion of crude drug to solvent should be maintained as 1 Kg to 1 L. -alcohol is distilled off under vacuum and the resulting aqueous residue is treated with petroleum-ether (60-80C) to remove the fatty components completely. -the combined aqueous extract is filtered and evaporated to dryness preferably in a Rotary Thin-Film Evaporator under vacuum. -residue is extracted with absolute ethanol thereby dissolving the total alkaloids. (c) Kippenbergers Process -powdered and sieved plant substance is digested with solution of tannin (100 g) in glycerol (500 g) at a constant temperature of 40C for a duration of 48 hours. -resulting mixture is further heated to 50C so as to help in the complete coagulation of proteinous substances, cooled to ambient temperature and finally filtered. -resulting filtrate is thoroughly shaken with petroleum ether to get rid of faulty materials, and the last traces of petroleum ether is removed from the extract by heating either on a water-bath or exposure to Infra-Red Lamp. -the fat-free crude plant extract is subsequently acidified and shaken with chloroform, successively to remove the bulk of the alkaloids, namely, atropine, codeine, colchicine, narcotine, nicotine, papaverine, spartenine and thebaine. -the resulting residual extract may still contain narceine, curarine and morphine. However, narceine and morphine may be isolated by passing freshly generated CO2 directly into extract so as to convert the alkali hydroxide into their corresponding carbonate, which is then ultimately subjected to solvent extraction using a mixture of alcohol and chloroform. Finally, the third alkaloid, curarine, may be extracted by agitation with a mixture of equal volumes of ether and chloroform. -combination of Kippenbergers process and Stas-Otto process by its application to the final alcoholic extract obtained by the latter process is found to give better separation of alkaloids. VII. References

http://www.botanical-online.com/english/alkaloids.htm http://www.epharmacognosy.com/2012/07/general-characteristics-of-alkaloids.html http://www.thecabinchiangmai.com/archive/opiates___opioids__morphine__codeine____other_ medications http://www.liberherbarum.com/Minor/UK/IN0001.htm http://www.erowid.org/archive/rhodium/chemistry/alkastract.html http://www.weizmann.ac.il/plants/aharoni/PlantMetabolomeCourse/June192007.pdf http://www.epharmacognosy.com/2012/07/general-characteristics-of-alkaloids.html http://www.epharmacognosy.com/2012/07/classification-of-alkaloids.html http://www.authorstream.com/Presentation/prem07-1580026-complete-info-alkaloids-ppt/ http://www.us.elsevierhealth.com/media/us/samplechapters/9780702029332/9780702029332_2 .pdf