lecture №29 general characteristic and classification of glycosides. cardiac glycosides:...

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Lecture Lecture №29 №29 General characteristic and General characteristic and classification of glycosides. classification of glycosides. Cardiac glycosides: correlation Cardiac glycosides: correlation between the structure and action, between the structure and action, role of the steric factors. Obtaining role of the steric factors. Obtaining of the appropriate drugs, their of the appropriate drugs, their properties, standardization by the properties, standardization by the usage of the different methods, usage of the different methods, special features of the storage in a special features of the storage in a pharmacy and usage in a medical pharmacy and usage in a medical practice. practice. prepared: assist. Medvid I prepared: assist. Medvid I . . I. I.

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Page 1: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

LectureLecture №29 №29General characteristic and classification of General characteristic and classification of glycosides.  Cardiac glycosides: correlation glycosides.  Cardiac glycosides: correlation

between the structure and action, role of the between the structure and action, role of the steric factors. Obtaining of the appropriate steric factors. Obtaining of the appropriate drugs, their properties, standardization by drugs, their properties, standardization by the usage of the different methods, special the usage of the different methods, special features of the storage in a pharmacy and features of the storage in a pharmacy and

usage in a medical practice.usage in a medical practice.

prepared: assist. Medvid Iprepared: assist. Medvid I..I.I.

Page 2: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Glycoside - a natural substances that contain carbohydrates where glycosidic part of the molecule (cyclic form of sugars) is connected with an organic radical that is not a sugar (aglycone or henin).By the nature of the sugar glycosides are divided into two groups: piranosides and furanosides. There are also α- and β-glycosides depending on the configuration of carbon connected to the aglycone. Sugar part of the molecules may contain one or more interconnected sugars (monosaccharides, disaccharides, etc.).Pentosides - pentose glycosides, hexosides - hexose glycosides, biosides - glycosides of disaccharides.Bound of the sugar residue with henin is made through oxygen (O-glycosides) or nitrogen (N-glycosides: ATPh, antibiotics-aminoglycosides), or sulfur (thioglycosides: sinigrin from mustard).

Page 3: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

O-glycosides by the nature of aglycone are divided into:

1) phenyl glycosides contain the phenyl radical in aglycone (bearberry glycosides - Arbutin);

2) Anthraquinone glycosides contain the aglycone, anthraquinone derivative (glycosides buckthorn, rhubarb, aloe);

3) flavone glycosides, which aglycone is derivative of flavone (catechins, rutin);

4) nitrogencontaining, cyanogenic glycosides (amigdaline);

5) glucoalkaloids, glycosides, in which the sugar component bound with the remainder of alkaloid (solasodine);

6) steroid glycosides (cardiac glycosides);7) tannins (tannin);8) saponins.

Page 4: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Cardiac glycosides (CG) - biologically active substances contained in some types of plants or secretions of some species of frogs; in small doses can show a specific effect on the heart muscle.

Sources of cardiac glycosides extraction: different types of digitalis, spring adonis, oleander, valley, erysimum, strofant, hellebore, and others.

In the plants primary (genuinic) glycosides are contained, which are very labile and down easily (under the action of enzymes, acids, alkalis) to form secondary glycosides. The latter may hydrolyse to aglycons and sugar components .

In 1875 y. from digitalis purpurea secondary glycoside are identified - digitoxin and in 40-th years of the twentieth century – from digitalis lanata - digoxin.

The first study of the chemical structure of cardiac glycosides Windaus completed in 1915 y., then in 30-th years Jacobs and Chesnet found that they contain steroid structure.

Page 5: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Current directions in the research of CGCurrent directions in the research of CG Search of the new natural sources of CG and their extraction. Over the past 20 years the number of selected glycosides are doubled and is more than 2500. Shown, that biologically more active are ones from CG that are more unstable in conformation and thermodynamic relation, on the base of which the "alternatives" of natural strophanthin was synthesized - number of active 19-norcardenolides.Chemical and biochemical transformations of the natural CG to improve their pharmacological properties. Thus, created nitroethers of CG combine cardiotonic, coronarolytic and respiratory effects .Increasing of the CG content in cultured species by agrotechnical methods and introduction of the new species. New species of the digitalis lanata contains in 15-20 times more digoxin and lanatoside C than known species of the plant. Developing of the new, more perfect methods of selection from the raw materials of CG used in medical practice. So, original ways of getting of digitoxin, digoxin, gitoxin, strofantidin, lanatoside C, erysimine, adenoside, cordigidin are developed. Cardiotonic drug corglycone was obtained.

Page 6: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Synthesis of some CG though conducted, but due to the presence of many stages and low output of the practical value is not received. The only industrial source of CG obtaining is plant material. The process of selection is difficult, because the plants contain enzymes that can change the chemical structure of glycosides and these changes are not reverse. Such changes can occur under the action of light, temperature, etc.. In the plants, usually a few CG are located and a number of related substances. To separate the mixtures of glycosides using chromatographic techniques. By the chemical structure heart (and others) glycosides are esters in which aglycone and residues of mono-, di-, tri- or tetrasugars are bounded between each other by glycosidic connection. In some primary glycosides to the sugar component the balance of acetate acid attached.Sugars that are a part of cardiac glycosides, except glucose and ramnose are specific for these group of compounds. These sugars are 6-deoxyhexoses (L-ramnose), 2,6-deoxyhexoses (D-digitoxose) or 3-O-methyl ethers (D-cymarose, L-oleandrose). From the cardiac glycosides more than 50 carbohydrates are allocated.Aglycons (henins) of the cardiac glycosides have a steroid structure that are derivatives of cyclopentane perhydro-phenanthrene.

Page 7: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

O

OH OH

OH

OH

CH2OH

OOH OH

OHOH

CH3

OOH OH

OCH3

CH3

O

OH OH

OH

CH3

O

OH OH

OCH3

CH3

O

OH OH

OCOCH3

CH3

Monosaccharides, which more often are a part of cardiac glycosides

AcetyldigitoxoseAcetyldigitoxose DD--cymarosecymarose LL--oleandroseoleandrose

DD--glucoseglucose LL--ramnoseramnose DD--digitoxosedigitoxose

Page 8: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

By the chemical structure aglycones can be divided into two groups, which are different according to the structure of attached in the position 17 lactone cycle. Cardiac glycosides containing fivemember lactone ring are called cardenolides and, as such, containing sixmember lactone ring with two double bonds - bufadienolides:

In position 3 to aglycones the sugar component is attached. Radical R – СН3 or СОН, and Х1, Х2, Х3 – Н or ОН.

R

OH

CH3

HO

O

O

X3

X2

X1

2

34

1

56

7

89

10

1112

13

14 15

16

17

R

OH

CH3

HO

X3

X2

X1

O

O

Page 9: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Cardenolides are found in the various types of digitalis Cardenolides are found in the various types of digitalis (Digitalis), strophanth (Strophanthus), valley(Digitalis), strophanth (Strophanthus), valley (Convallaria), (Convallaria), erysimum (Erysimum), oleander (Nerium oleander), spring erysimum (Erysimum), oleander (Nerium oleander), spring adonis (Adonis vernaris)adonis (Adonis vernaris)..

Page 10: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Bufadienolides are a part of hellebore (Helléborus), squill Bufadienolides are a part of hellebore (Helléborus), squill (Scillae bulbus), and also are found in frogs (their venom (Scillae bulbus), and also are found in frogs (their venom contains bufohenins having steroid structure with contains bufohenins having steroid structure with sixmember lactone cyclesixmember lactone cycle).).

Page 11: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Connect between the structure and action of cardiac Connect between the structure and action of cardiac

glycosidesglycosides Carrier of biological activity is aglycone. The sugar component that is attached in position 3 to the aglycone influences on the rate of absorption, respectively, on the duration of action. The bigger quantity of sugar residues in the glycoside molecule cases their bigger activity. Specific action of glycoside on the heart is caused by the presence of lactone cycle in the aglycone molecule in position 17 and OH-group in position 14. On the cardiotonic action substitute in position 10 has a great influence. For the most of aglycones this is methyl or aldehyde group. Aldehyde group oxidation to carboxylic group significantly weakens the effect on the heart muscle. Replacing of the aglycons steroid cycle by the derivatives of benzene, naphthalene, and also like lactone cycle by other radicals and even the change of character of the connection between steroid nucleus and lactone, leads to the loss of physiological activity. This indicates the specificity of the molecular structure of cardiac glycosides and aglycones and on the complexity of obtaining them by synthetic way.

Page 12: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

In medical practice use different In medical practice use different ggalenalen,, neo neogalengalen preparations preparations (extracts, tinctures), which contain (extracts, tinctures), which contain CGCG and preparations and preparations of of individualindividual CG CG, , which by their which by their chemical structure chemical structure areare cardenolides.cardenolides.

InIn AdditionAddition 1 1 toto SPhU SPhU ddigitoxinigitoxin, digoxin, , digoxin, qquabainuabaine are includede are included. . From the leaves of various kinds of digitalis extract:From the leaves of various kinds of digitalis extract:CelanideCelanide (Сеlanidum) (Сеlanidum) ( (digilanide or lanatosidedigilanide or lanatoside С) - С) - primary primary

glycosideglycoside of the of the Digitalis lanata. Digitalis lanata. TablTabl. . byby 0,00025  0,00025 gg (0,25 (0,25 mgmg); ); 0,05 % 0,05 % solutionsolution in flin fl. . byby 10  10 mlml (0,5 (0,5 mgmg inin 1  1 mlml) ) for internalfor internal usage usage andand 0,02 %  0,02 % solutionsolution in ampin amp. . byby 1  1 mlml..

Digitoxin andDigitoxin and digoxindigoxin – – secondary glycosides in digitalis purpurea secondary glycosides in digitalis purpurea and lanataand lanata (Digitalis purpurea L., Digitalis lanata). (Digitalis purpurea L., Digitalis lanata). DigoxinDigoxin: : tabltabl. . byby 0,25 0,25 mgmg and byand by 0,1 0,1 mgmg for childrenfor children; 0,025% ; 0,025% solutionsolution in ampin amp. . byby 1 1 mlml. . DigitoxinDigitoxin – – tabltabl. . byby 0,1 0,1 mgmg andand suppositories bysuppositories by 0,15 0,15 mgmg. .

Digalen-neoDigalen-neo.. Neo-galenicNeo-galenic preparation from the leaves ofpreparation from the leaves of Digitalis Digitalis ferniginea. ferniginea. AmpAmp. . byby 1  1 mlml ff//inin.; .; flaconsflacons byby 15  15 ml of preparationml of preparation, , for internalfor internal usageusage. .

The chemical structure and obtaining of CGThe chemical structure and obtaining of CG

Page 13: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Chemical content of the primary digitalis glycosides

Kind of digitalis Primary glycosides Products of hydrolysis

Secondary glycosides

Digitalis purpurea

Purpureaglycoside АPurpureaglycoside В

GlucoseGlucose

DigitoxinGitoxin

Digitalis lanata Digilanide А

Digilanide В

Digilanide С (celanide)

СН3СООН+

GlucoseСН3СООН+

GlucoseСН3СООН+

Glucose

Digitoxin

Gitoxin

Digoxin

Secondary digitalis glycosides of both species after the loss of these products of hydrolysis consist of aglycones and sugar part, which is the same in all three kinds of secondary glycosides.

Page 14: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

From the seeds of various kinds From the seeds of various kinds of of strostrophantphant extractextract::

StrophanthinStrophanthin-К-К (Strophanthinus К) (Strophanthinus К) ––mixture of cardiac glycosides mixture of cardiac glycosides isolated from strophanth Kombe (Strophanthus Kombe Oliverisolated from strophanth Kombe (Strophanthus Kombe Oliver). ). IssueIssue: : ampamp. . byby 1 1 ml ofml of 0,025% 0,025% solutionsolution forfor ii//vv oror ii//mm injectionsinjections..

QuabaineQuabaine ( (Ouabainum)Ouabainum) (Strophanthin-G) – (Strophanthin-G) – glycoside fromglycoside from Strophanthus Strophanthus gratus. gratus. Ampoules byAmpoules by 1 1 mlml ofof 250 250 mcgmcg/м/мml solutionml solution forfor ii//vv injectionsinjections..

From the leaves of From the leaves of Convallaria majalis Convallaria majalis extractextract::CorglyconeCorglycone (Corglусоnum) (Corglусоnum) -- the sum of not less than five glycosides the sum of not less than five glycosides. .

Ampoules byAmpoules by 1 1 ml ofml of 0,06% 0,06% solution forsolution for ii//vv injectionsinjections..ConvallatoxinConvallatoxin ( (ConvallatoxinumConvallatoxinum) –) –the main glycoside of liliesthe main glycoside of lilies. .

Ampoules byAmpoules by 1 1 ml ofml of 0,03% 0,03% aqueous solution of the substanceaqueous solution of the substance for ifor i//v v njectionsnjections..

AdonisideAdoniside (Аdonisidum)(Аdonisidum) – – neo-galenic preparationneo-galenic preparation of spring adonis of spring adonis grassgrass (А (Аdonis vernalis).donis vernalis). Flacons byFlacons by 15 15 mlml..

FromFrom ErysimumErysimum - erysimine - erysimine, , cardiovalenecardiovalene –the –the sum ofsum of glycosides. glycosides.

Page 15: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Chemical content of the medical drugs from cardiac glycosides

Medical preparation

Aglycon Sugar part

DigitoxinDigoxinCelanide

Quabaine

ConvallatoxinCorglycone К

K-strophanthin-К-strophanthoside

DigitoxigenineDigoxigenineDigoxigenine

Quabagenine(strophanthidol)

Strophanthidine

StrophanthidineStrophanthidine

3 molecules of D-digitoxose3 molecules of D-digitoxoseD-glucose, acetyldigitoxose,

2 molecules of D-digitoxose

L-ramnose

L-ramnose

D-glucose, D-cymaroseTwo molecules of D-glucose, D-cymarose

Page 16: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Digitoxin (Digitoxinum)(SPhU)

3β-[(О-2,6-dideoxy- β-D-ribo-hexopyranosyl -(1→4)-О-2,6-dideoxy- β-D-ribo-hexopyranosyl-(1→4)-О-2,6-dideoxy- β-D-ribo-hexopyranosyl)oxy-14-hydroxy-5β,14β-card-20(22)-enolide

CH3

OH

CH3

O

O

O

H

H

H

H

H

O

O

O

CH3

CH3

CH3

OH

OH

OH

O

O

OH

Page 17: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Digoxin (Digoxinum)(SPhU)

3β-[(О-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-О-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-О-2,6-dideoxy-β-D-ribo-hexopyranosyl)-oxy-12β,14-dihydroxy-5β-card-20(22)-enolide

CH3

OH

CH3

O

O

O

H

H

H

H

H

O

O

O

CH3

CH3

CH3

OH

OH

OH

O

O

OH

OH

H

Page 18: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Quabaine (Ouabainum) (SPhU)Strophanthin G (Strophanthinum G)

OH

CH3

O

O

H

H

OH

H

O

O

CH3

OH

OH OH

H

H

HO

HO

H

HO

* 8 H2O

3β-[(6-deoxy- α-L-mannopyranosyl)oxy]-1,5,11,14,19-pentahydroxy-(1β,3β,5β,11α)-card-20(22)-enolide octahydrate

Page 19: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Celanide (Сеlanidum) (digilanide or lanatoside С)

Colorless or white crystalline powder. Very few soluble in water, few soluble in alcohol. Act on the heart similar to other glycosides of digitalis, showing rapid effect and has relatively low capacity for accumulation.

CH3

OH

CH3

O

O

H

H

O

OH

O

OH

CH3

O

CH3

O

OH

CH2OH

OH

OH

HO

CH3

O

OCOCH3

Page 20: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Convallatoxin (Convallatoxinum)

Crystal. white powder. Moderately soluble in water and in ethanol. According to the chemical structure and therapeutic effect is similar to strophanthin and has a high activity - in 1 g contains about 75 000 FUA or 10 600 CUA. The cumulative effect is very few expressed.

C

OH

CH3

O

O

H

OH

H

O

O

CH3

OH

OH OH

HO

Page 21: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Properties of the CG Properties of the CG pharmacopoeial preparationspharmacopoeial preparations

1.1. DigitoxinDigitoxin -- white or almost white powderwhite or almost white powder. Practically insoluble in water, easily soluble in the mixture of equal volumes of methanol and methylene chloride, few soluble in 96% alcohol and methanol.

2.2. DigoxinDigoxin – –white or almost white powderwhite or almost white powder or colorless crystals or colorless crystals. Practically insoluble in water, easily soluble in the mixture of equail volumes of methanol and methylene chloride, few soluble in alcohol.

3.3. QuabaineQuabaine – – crystalline white powder orcrystalline white powder or colorless crystals. Moderately soluble in water and ethanol, practically insoluble in ether andethylacetate.

Assay Spectrophotometry in the visible part of spectrum. The

content of all three drugs in the substance is calculated, taking into account the results of measurements of optical density and concentration of the studied solution and solution of PhSE of the appropriate drug (standard method).

Page 22: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Identification of the pharmacopoeial preparations of Identification of the pharmacopoeial preparations of CGCG

1. IR-spectroscopy (digoxin, digitoxin) –spectrum should be identical to the spectrum of PhSE drug.

2. TLC (digoxin, digitoxin, quabaine).3. Cedde reaction (on the fivemember lactone cycle) with alkaline

solution of 3,5-dinitrobenzoic acid (digitoxin, digoxin) – purple color.

4. Raymond's reaction (on the fivemember lactone cycle) with alkaline solution of dinitrobenzene (quabaine) – blue color.

5. Keller-Kiliani reaction (on deoxysugars) (digoxin, digitoxin).

6. Solution of quabaine substance in H2SO4 conc. – pink color, which quickly becomes red, this solution in the UV-light gives a green fluorescence (steroid cycle).

7. Reaction on deoxysugars (quabaine). After the acidic hydrolysis with Fehling’s reagent - red sediment.

Page 23: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Purity test Purity test of the of the pharmacopoeial pharmacopoeial preparations preparations of CGof CG

Digitoxin. Impurities (gitoxin, other glycosides) – TLC.

Digoxin. Impurities (gitoxin, digitoxin and other glycosides) – TLC.

Quabaine. Impurities (gitoxin, digitoxin and other glycosides) – TLC. Alkaloids and Strophenthin-К – with solution of tannin acid precipitate will not formed .

Storage All three drugs remain in the protected dark place.

Poisonous substances. List А.

Page 24: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Reactions on steroid cycle1. Liberman-Burkhard reaction:a small amount of substance is

dissolved in a few drops of ice acetate acid and mixed with a mixture of acetic anhydride and concentrated sulfate acid. Slowly the coloration appears, which goes from pink to green or blue. This reaction glycosides give, which are in the processing by strong acids capable to dehydration (corglycone, strophenthin-К).

2. Rosenheim reaction:to the chloroform solution of substance add 96% trichloracetic acid - color appears, which gradually changes from pink to lilac and blue. This reaction is typical for steroids containing diene group or can form it under the influence of reagent.

3. Steroid cycle in cardenolides can be detected by fluorimetric method by the usage as a reagent mixture of phosphate and sulfate acids with iron (III) chloride; iron perchlorate solution in sulfate acid and so on.

GeneralGeneral chemical reactions for CG chemical reactions for CG identificationidentification

Page 25: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Reactions on the fivemember lactone cycle of cardenolides

1. Legal reaction - the interaction in an alkaline medium with sodium nitroprusside red coloration appears and gradually fades.

2. Raymond's reaction - in alkaline medium with m-dinitrobenzene reddish-purple coloration appears.

3. Cedde reaction - in alkaline medium with 3,5-dinitrobenzoic caid purple color appears.

4. Baljet reaction (Balje) -with alkaline picric acid solution orange-red color appears.

The disadvantage of the above reactions is that almost all glycosides with close structure give the same color. Therefore, this reaction can not be used to identify individual glycosides. Therefore, Reichstein proposed for recognition of individual glycosides use concentrated or 84% sulfuric acid, which gives color reactions with various glycosides, which are held in time and color change.

Page 26: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Mechanism of the Mechanism of the Baljet reactionBaljet reaction ( (BaljeBalje))

Page 27: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Reaction on the sixmember lacton cycle of bufadienolides

Glycoside is dissolved in chloroform and add gradually saturated solution of antimony (III) chloride, at the heating dark-red color appears.

Reactions of sugar component After the acidic hydrolysis can be used inherent sugar reactions,

based on their reductive properties:

a) With Fehling reagent – formation of the red sediment Сu2O;b) With Tollense reagent – “silver mirror“ reaction. c) Specific for 2-deoxysugars contained in the molecules of most

cardiac glycosides, are:d) Keller - Kiliani reactionreaction:glycoside solution in concentrated acetate

acid containing iron (III) chloride thicken on concentrated sulfate acid. On the boundary of two layers dark red or brown ring appears, the top layer paints in blue or blue-green color. The reaction occurs only when deoxysugar is in the free state or takes extreme position in the molecule of glycosides.

Page 28: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

b) Febba and Levy reaction (for those glycosides, in which 2-deoxysugars from both sides linked with other sugars) - with trichloroacetic acid and p-nitrophenylhydrazine.

c) Pezets reaction: at the heating of glycoside with xanthydrol or anthrone in the presence of concentrated acetic acid with the following addition of several drops of sulfate acid or phosphate acid red or green, blue-green coloring appears. During the reaction under the action of concentrated acids, sugar component forms furfural or its derivatives, which are condensed with xanthydrol or anthrone.

Page 29: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Identification of the medicinal substances from CG groups can be done by the usage of specific rotation. Perspective is also a technique, based on the building of chromatographic diagrams that show the dependence of Rf from the system of solvents. IR- and UV-spectroscopy are also used.

Investigation of the good quality of CG Particular attention is drawn to the presence of impurities

of extraneous glycosides. This applies primarily to the preparations derived from plants that contain more similar in structure CG. For the determination of impurities using TLC, determining of the related glycosides on the chromatogram by the Rf value and the nature of the fluorescence spots in UV-light after the treatment by appropriate reagents (chloramine B, m-dynitrobenzene).

Page 30: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Incompatibility of CGIncompatibility of CG

Cardenolides areCardenolides are incompatible with acids and incompatible with acids and compoundscompounds, , which give acidic reaction of the which give acidic reaction of the environmentenvironment. . Hydrolysis by glycoside bound Hydrolysis by glycoside bound takes placetakes place. . Reaction goes without any visible Reaction goes without any visible changeschanges ( (withwith ascorbic acid and other vitamins ascorbic acid and other vitamins with acidicwith acidic рН рН of environment of environment).).Cardiac glycosidesCardiac glycosides are incompatible with are incompatible with alkalis and compoundsalkalis and compounds, , which give alkaline which give alkaline reaction of the environmentreaction of the environment((NaHCONaHCO33, barbital, barbital--sodiumsodium and othersand others).).

Page 31: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Assay of CGPerform by spectrophotometric, photocolorimetric methods by the products of interaction in an alkaline environment with nitroderivatives of aromatic series. Qualitative and quantitative assessment of CG also are conducted by the high effective liquid chromatography (HELC), which allow to determine not only the main but also related glycosides.Biological control is used to determine the lowest doses of standard and investigated substances that cause systolic shutdown of the heart of experimental animals. Then calculate the content of frog (FUA), cat (CUA), pigeon (PUA) units in 1 g of envestigated substance, in one tablet or 1 ml.Some of the CG and their dosage forms can be defined by polarographic method. The advantage of this method is that the determination made by the reduction of double bond, conjugate with the carbonyl group of lacton cycle. This system is known, is one of the factors that determine the biological activity of cardiac glycosides. Polarography also is combined with the previous chromatographic separation of CG.

Page 32: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

Storage and aplication of CG CG and their drugs are stored in tightly corked container that protect from light and moisture (corglycon – not more than +5 º C). Such conditions would prevent their hydrolytic cleavage.As cardiotonic means at the acute and chronic circulatory failure or cardiovascular failure. They differ in strength, duration, speed of action, influence on the central nervous system.Medical drugs of CG are more effective at the i/v introduction. For this the drugs are pre-dissolved in 20-40% glucose solution or isotonic solution to the concentration of 0,025%. Higher single doses of individual CG are 0,5 mg, daily - 1,0 mg. Overdose causes severe dysfunction of cardiac activity. This requires them to be ascribed to toxic substances. You must consider the ability of CG gradually accumulate in the body (the degree of accumulation).

Page 33: Lecture №29 General characteristic and classification of glycosides. Cardiac glycosides: correlation between the structure and action, role of the steric

ThankThank you for you for attentionattention!!