Cardioactive Glycosides

Many of the plants known to contain cardiac or cardiotonic glycosides have long been used as arrow poisons (e.g. Strophanthus) or as heart drugs (e.g. Digitalis). They are used to strengthen a weakened heart and allow it to function more efficiently, though the dosage must be controlled very

Smilax Regelii
Figure 5.89

Sarsaparilla

Sarsaparilla consists of the dried roots of various Smilax species (Liliaceae/Smilacaceae), including S. aristolochiaefolia, S. regelii, and S. febrífuga, known respectively as Mexican, Honduran, and Ecuadorian sarsaparilla. The plants are woody climbers indigenous to Central America. Sarsaparilla has a history of use in the treatment of syphilis, rheumatism, and skin diseases, but is now mainly employed as a flavouring in the manufacture of non-alcoholic drinks. It has some potential as a raw material for the semi-synthesis of medicinal steroids, being a source of sarsasapogenin and smilagenin (Figure 5.87). The roots contain 1.8-2.4% steroidal saponins, including parillin (Figure 5.90).

Sarsasapogenin Glycosides
Figure 5.90

Yucca

Yucca brevifolia (Agavaceae) has been explored as a potential source of sarsasapogenin for steroid production, especially at times when market prices of diosgenin from Dioscorea became prohibitively expensive. The plant grows extensively in the Mojave desert in California, and high levels of sarsasapogenin (8-13%) are present in the seeds. This means the plants can be harvested regularly without damage. The subsequent stabilization of Dioscorea prices in the 1970s stopped further commercial utilization.

carefully since the therapeutic dose is so close to the toxic dose. The cardioactive effects of Digitalis were discovered as a result of its application in the treatment of dropsy, an accumulation of water in the body tissues. Digitalis alleviated dropsy indirectly by its effect on the heart, improving the blood supply to the kidneys and so removing excess fluid.

The therapeutic action of cardioactive glyco-sides depends on the structure of the aglycone, and on the type and number of sugar units attached. Two types of aglycone are recognized, cardeno-lides, e.g. digitoxigenin from Digitalis purpurea, which are C23 compounds, and bufadienolides, e.g. hellebrigenin from Helleborus niger, which are C24 structures (Figure 5.91). Stereochemistry is very important for activity, and these compounds have cis fusions for both the A/B and C/D rings, 3P- and 14P-hydroxyl groups with the glycoside function at C-3, and an ^-unsaturated lactone grouping at C-17P. This lactone ring is five mem-bered in the cardenolides, and six membered in the bufadienolides. The hellebrigenin structure shows two other modifications not found in the basic steroid skeleton, namely a hydroxyl at the bridgehead carbon C-5, and a formyl group at C-10, being an oxidized form of the normal methyl. The three-dimensional shape of digitoxigenin is shown in Figure 5.91. These basic structures arise biosyn-thetically by metabolism of cholesterol, in which the side-chain is cleaved to a two-carbon acetyl group, followed by incorporation of either two or three carbons for cardenolides or bufadienolides respectively (Figure 5.92).

Shortening of the cholesterol side-chain is accomplished by stepwise hydroxylation at C-22 and then C-20, then cleavage of the C-20/22 bond giving pregnenolone, which is then oxidized in ring A giving progesterone (Figure 5.92). This can be reduced to give the cis-fused A/B system as in 3P-hydroxy-5P-pregnan-20-one (compare Figure 5.89) which is the substrate for 14P-hydroxylation, i.e. inverting the stereochemistry at this centre. Inversion is atypical for hydroxy-lation by mono-oxygenases, which are found to hydroxylate with retention of configuration. Whatever the mechanism of this hydroxylation, no A8 or A15 double bond intermediates are involved. Hydroxylation in the side-chain at C-21 follows. The lactone ring is created at this stage. An intermediate malonate ester is involved, and ring formation probably occurs via the aldol addition process shown in Figure 5.93 giving the cardenolide dig-itoxigenin, the carboxyl carbon of the malonate ester being lost by decarboxylation during the process (compare malonate in the acetate pathway). Alternatively, three carbons from oxaloacetate can be incorporated by a similar esterification/aldol reaction sequence. This would produce bufalin (Figure 5.92), a bufadienolide structure found in the skin of toads (Bufo spp.), from which this class of compound was originally isolated and

Cardenolide

cardenolide - digitoxigenin

cardenolide - digitoxigenin

Structures Involved Pathway

bufadienolide - hellebrigenin

bufadienolide - hellebrigenin

Characteristic features of cardiac glycosides:

• unsaturated lactone at C-17P

• sugar residues on 3P-hydroxyl

Cardioactive Glycosides

digitoxigenin

digitoxigenin

O2 NADPH

cholesterol stepwise hydroxylation via 22 22-hydroxycholesterol

O2 NADPH

oxidative cleavage between hydroxyls, perhaps via peroxide

Tv cholesterol

reduction of A4,5 gives O cis-fused A/B rings

NADPH

reduction of A4,5 gives O cis-fused A/B rings

NADPH

progesterone pregnenolone NAD+

enol-keto tautomerism

5ß-pregnan-3,20-dione

NADPH

keto-enol tautomerism

tautomerism progesterone reduction of 3-ketone to 3ß-hydroxyl

NADPH

O 14ß-hydroxylation with inversion of stereochemistry

3ß-hydroxy-5ß-pregnan-20-one

O 14ß-hydroxylation with inversion of stereochemistry

3ß-hydroxy-5ß-pregnan-20-one

Pregnan Dione Hso

3ß,14ß-dihydroxy-5 ß-pregnan-20-one malonyl-CoA

HO2C

digitoxigenin

HO2C

malonyl-CoA

O oxaloacetyl-CoA

SCoA

O oxaloacetyl-CoA

digitoxigenin

12ß-hydroxylation

12ß-hydroxylation

Conjugated Ring Oxidations

digoxigenin

16ß-hydroxylation

digoxigenin

16ß-hydroxylation

gitoxigenin bufalin 5ß-hydroxylation and C-19 oxidation

gitoxigenin

OH hellebrigenin

OH CoAS

aldol reaction with concomitant decarboxylation; compare malonyl-CoA as chain extender in acetate pathway dehydration favoured by

O 0 ? formation of conjugated system

malonyl-CoA

kJ H

yS ester formation S ^J"

malonate ester y

- h2o y cardenolide y cardenolide

oxaloacetyl-CoA

ester formation

oxaloacetate ester aldol reaction with O concomitant O

decarboxylation

CO2H

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  • amy
    How the cardioactive glycoside is synthesis?
    8 years ago

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