lecture 21 - 23 anthraquinone glycosides

Download Lecture 21 - 23 Anthraquinone Glycosides

Post on 13-Jul-2015

1.090 views

Category:

Documents

1 download

Embed Size (px)

TRANSCRIPT

PHARM. D Chemical Pharmacognosy- I Lecture 21-23 April 25th, 2011

ANTHRAQUINONE GLYCOSIDESM. Ahsan Khalid, B.Pharm, Pharm. D B.Pharm,M.Phil Scholar (RIPS/RIU) HIPSHIPS-HUKIC

Anthraquinone Structure

Anthracene (Anthraquinone) Glycosides

Anthracene glycosides are oxygenated derivatives of pharmacological importance that are used as laxatives or cathartics, anti-inflammatory, antibacterial, antifungal and also antias natural dyes. dyes.Otautomerization

OHOxidation Reduction

O

H

H Anthranol

H

OH

Anthrone

Oxanthrone

Reduction

O8 9 10 5 4 1

Oxidation

O Anthraquinone

Anthracene glycosides

Purgative principles Found in several plant drugs Occur in glycoside form

and less commonly in aglycone form free aglycones have to be removed in assay because inactive

2-3%w/w (both forms) based on anthracene molecule

Introduction to Anthraquinones

Historically: Rhubarb, Senna, Aloes and Cascara were all used as purgative drugs. Monocotyledons: Only Liliaceae.

Most commonly C-glycoside: barbaloin. C-

Dicotyledons: Rubiaceae, Leguminosae, Polygonaceae, Rhamnaceae, Ericaceae, Euphorbiaceae, Lythraceae, Saxifragaceae, Scrophulariaceae and Verbenacacea. Also in certain fungi and lichen.

Anthranonls and Anthrones

Reduced anthraquinone derivatives Occur either freely (aglycones) or as glycosides. Isomers Anthrone: Parent structure (pale yellow, nonnonsoluble in alkali, non-fluorescent) nonAnthronol: brown-yellow, soluble in alkali, brownstrongly fluorescent

Anthronol derivatives (e.g. in Aloe have similar properties fluorescence used for identification)

Oxanthrones

Found in Cascara bark Intermediate products (between anthraquinones and anthranols) When oxidised form anthraquinones

Accomplished via Modified Borntragers Test (oxanthrones oxidised using hydrogen peroxide)

Dianthrones

Derived from 2 anthrone molecules 2 molecules may/not be identical Form easily due to mild oxidation of anthrones Form important aglycones

Cassia Rheum Rhamnus

3 oxygenated or substituted forms of the anthracene molecule exist

Anthraquinone (most common)

Anthrone (reduced form occurring in plant)

Dianthrone (reduced dimer)

all flat, planar structures

flat molecule can get into gut mucosa and irritate eventually causing peristalsis

4 aglycone structuresall existing in any of the 3 forms phenolic group is the irritant principle

Chrysophanol Rhein anthraquinone

Aloe-emodin

Emodin

The activity decreases as oxidation level increase.

Forms of Anthracene derivatives in Plants:

Aglycones:

OH

O

OH

OH

O

OH

OH

O

OH

OH

O

OH

HO

O

CH3

O

CH 2OH

O

CH3

O

COOH

Emodin

Aloe-emodin

Chrysophanol

Rhein

biologically active part is the glycoside tend

to have simple sugars attached

1- monoglucoside at C8 O-linked

2- diglucoside at C1 andC8

3- C- glycosides C

have a direct C linkage aloins

* resistant to hydrolysis (need to use ferric chloride)

all types combined to give complex mixture in the plant assays different since each compound has different purgative potency

Dimeric Anthracene derivatives:

They are derived from two anthracene unites connected by covalent C-C bond through C-10. C-

HomoHomo-Dianthrones:The two anthrone moieties are similar. e.g. Sennidins A&B and their similar. corresponding glycosides Sennosides A&B. They are all formed of A&B. two Rhein monomers. The A group are (l)-form while the B group are monomers. (l)meso compounds with zero optical rotation. rotation.OR O OH

HOOC

H

H

COOH

OHR= H R= Glc R= H R= Glc = = = =

O

ORSennidin A Sennoside A Sennidin B Sennoside B

Hetero-Dianthrones: Hetero-Dianthrones:The two anthrone moieties are different. e.g. Sennidins C&D and their different. corresponding glycosides Sennosides C&D. They are all formed of one C&D. Rhein and one Aloe-emodin monomers. The C group are (l)-form while Aloemonomers. (l)the D group are meso compounds with zero optical rotation. rotation.

OR

O

OH

HOOC

H

H

CH2OH

OHR= H R= Glc R= H R= Glc = = = =

O

ORSennidin C Sennoside C Sennidin D Sennoside D

Glycosides:

O-glycosides:e.g. Cascarosides A & B. They are both O- and C-glycosides. Each one OCcontain two sugar unites. OH Glc O O

R1R= Glc, R1= H R= H, R1= Glc

R

CH2OHCascaroside A Cascaroside B

C-glycosides:OH O OH

e.g. Barbaloin it is formed from the removal of one sugar from Cascarosides. Cascarosides.

CH2OH H Glc

Mechanism of action

Molecules have to possess certain features for activity:1- Glycosides 2- Carbonyl keto function on centre ring 3- 1,-8- positions have to have OH 1,-

Potency:

anthrone > anthraquinone> dianthrone anthraquinone>

Aglycones not therapeutically active in animals lipid soluble absorbed in stomach and never reach colon to produce a local effect

Mechanism of Action:

The glycosides are absorbed from the small intestine and re-excreted in the large reintestine where they increase the motility so produce laxation. laxation. Aglycones produce griping effect so it is recommended to prescripe antispasmodic with them.

Highly active phenolic group irritant to mucosa Glycosides very water soluble reach large intestine where they are hydrolysed by E.coli enzymes become lipid soluble absorbed into circulation on way through gut wall disturb Aubach nerve plexus causing smooth muscle to contract peristalsis 5-8 hours to act

take night before in low doses drug metabolised by liver and recirculated via bile to give more effect people esp elderly can become reliant on them needing higher dose to produce an effect carcinogenic Melanosis coli

StructureStructure-Activity Relationship:

Glycosylation is essential for activity. Hydroxylation at C-1 and C-8 is essential for activity. CCOxidation level at C-9 and C-10 is important: CC

Highest level of oxidation (anthraquinones) have the lowest activity. Oxanthrones are less active than anthrones. Complete reduction of C-9 and C-10 eliminates the activity. CC-

Substitution at C-3 have great impact on activity: CCH2OH > CH3 > COOH

Extraction

Most quite polar

due to phenols and sugars

Water/alcohol or mixtures of them used Dried plant material percolation in industrial columns with dilute alcohol Tincture produced Partitioned with chloroform/ether to clean up (remove green pigment, fats, lipids) Clean yellow tincture subjected to column chromatography Gradual elution of individual glycosides Crystallised for purity

Identification:

Easy coloured orange-yellow orangeChemical test: Borntragers test in alkali (KOH, NH3) phenolic groups -> phenate complex (bright red) TLC using silica gel plates do not have to be sprayed since yellow but can confirm with KOH (red spot) Mass spectrometry

Assay

Isolating each active component too expensive

powdered plant material (tablets or capsules) or aqueous (fluid) extracts used

Difficult each component in mixture has different potency Safest assay is:

[i] biological assay of dry materialwet faeces method cage full of mice or rats on a grid with collecting tray below feed eg senna in food collect faeces and weigh calculate ED50 oral dose in food correlating to faeces produced

[ii] chemical assay

spectroscopy quick and cheap, more accurate but gives same emphasis to each compound

To remove aglycones

make an extract, shake with ether

discard ether phase containing free aglycones then acid hydrolyse aqueous phase containing glycosides with ferric chloride for direct C- bonds C and with dilute HCl

extract in CHCl3

gives aglycones from glycosides then measure on spectrophotometer peak 515nm

colour with magnesium acetate OR do colourimetric assay red in alkali - 250nm

Chemical test:Borntragers and Modified Borntragers test:

For Aglycones:

Extract plant material with organic solvent. Shake with NH4OH OR KOH. Boil plant material with dil. HCl for 10 min, filter and shake with organic solvent (Ether or Benzene). Separate the organic solvent. Shake with NH4OH OR KOH. Boil plant material with dil. HCl/FeCl3, filter and shake with organic solvent (Ether or Benzene). Separate the organic solvent. Shake with NH4OH OR KOH.

For O-Glycosides: O

For C-Glycosides: C

Positive result indicated by Rose Red colour in the aqueous alkaline layer.

Some Drugs containing Anthracene derivatives:

Senna: Senna:

Leaves and pods contain Sennosides A-D. The C-C bond protect the anthrone from oxidation. C-

Cascara bark: bark:

Contain Cascarosides A- D. Barbaloin present as a secondary glycoside in Cascara. Cascara. They are O- and C-glycosides. OCThe C-linked glucose at C-10 protect anthrones from CCoxidation.

Aloes:

The major glycoside in Aloes is the C-glycoside Barbaloin. CBarbaloin. Barbaloin is primary glycoside in Aloes. The C-linked glucose at C-10 protect anthrones from CCoxidation.

Rhubarb: Rhubarb: It

is purgative only in large doses. It contains high amount of tannins th

Recommended

View more >