Steroidal Saponins

Steroidal saponins have similar biological properties to the triterpenoid saponins (see page 219), but are less widely distributed in nature. They are found in many monocotyledon families, especially the Dioscoreaceae (e.g. Dioscorea), the Agavaceae (e.g. Agave, Yucca) and the Liliaceae (e.g. Smi-lax, Trillium). Their sapogenins are C27 sterols in which the side-chain of cholesterol has undergone modification to produce a spiroketal, e.g. dioscin (Figure 5.83) from Dioscorea. Acid hydrolysis of dioscin liberates the aglycone diosgenin. All the steroidal saponins have the same configuration at the spiro centre C-22, but stereoisomers at C-25 exist, e.g. yamogenin (Figure 5.84), and often mixtures of the C-25 stereoisomers cooccur in the plant. The sugar moiety is usually at position 3, and typically contains fewer monosaccharide units than found with triterpenoid saponins. One to three monosaccharide units are most common. The three-dimensional shape of diosgenin is indicated in Figure 5.83.

The spiroketal function is derived from the cholesterol side-chain by a series of oxygenation reactions, hydroxylating C-16 and one of the

Testosterone Shape Stereochemistry
• sugar residues on 3ß-hydroxyl diosgenin
yamogemn
Spiroketal Steroid Diosgenin

hecogenin Figure 5.84

hecogenin Figure 5.84

terminal methyls, and then producing a ketone function at C-22 (Figure 5.85). This proposed intermediate is transformed into the hemiketal and then the spiroketal. The chirality at C-22 is fixed by the stereospecificity in the formation of the ketal whilst the different possible stereochemistries at C-25 are dictated by whether C-26 or C-27 is hydroxylated in the earlier step. Glycoside derivatives, e.g. protodioscin (Figure 5.86) have been isolated from plants. These are readily hydrolysed, and then spontaneously cyclize to the spiroketal (Figure 5.86). Allowing homogenized fresh plant tissues to stand and autolyse through the action of endogenous glycosidase enzymes not only achieves cyclization of such open-chain saponins, but can hydrolyse off the sugar units at C-3, thus yielding the aglycone or sapogenin. This is a standard approach employed in commercial production of steroidal sapogenins, important starting materials for the semi-synthesis of steroidal drugs. Dios-genin is the principal example and is obtained from Mexican yams (Dioscorea spp.; Dioscoreaceae)*. Fenugreek* (Trigonella foenum-graecum; Legumi-nosae/Fabaceae) is another potentially useful commercial source. Sisal* (Agave sisalana; Agavaceae) is also used commercially, yielding hecogenin (Figure 5.84), a 12-keto derivative with transfused A/B rings, the result of reduction of the A5 double bond.

Dioscorea Composita
diosgenin / yamogenin

OGlc

Dioscin Fermentation

protodioscin dioscin

Figure 5.86

L-Rha protodioscin dioscin

Figure 5.86

Dioscorea

About 600 species of Dioscorea (Dioscoreaceae) are known, and a number of these are cultivated for their large starchy tubers, commonly called yams, which are an important food crop in many parts of the world. Important edible species are Dioscorea alata and D. esculenta (S E Asia), D. rotundata and D. cayenensis (W Africa) and D. trifida (America). A number of species accumulate quite high levels of saponins in their tubers, which make them bitter and inedible, but these provide suitable sources of steroidal material for drug manufacture.

Dioscoreas are herbaceous, climbing, vinelike plants, the tuber being totally buried, or sometimes protruding from the ground. Tubers weigh anything up to 5 kg, but in some species, tubers have been recorded to reach weights as high as 40-50 kg. Drug material is obtained from both wild and cultivated plants, with plants collected from the wild having been exploited considerably more than cultivated ones. Commercial cultivation is less economic, requiring a 4-5 year growing period, and some form of support for the climbing stems. Much of the world's production has come from Mexico, where tubers from D. composita (barbasco), D. mexicana, and D. floribunda, mainly harvested from wild plants, are utilized. The saponin content of the tubers varies, usually increasing as tubers become older. Typically, tubers of D. composita may contain 4-6% total saponins, and D. floribunda 6-8%. Other important sources of Dioscorea used commercially now include India (D. deltoidea), South Africa (D. sylvatica) and China (D. collettii, D. pathaica, and D. nipponica).

Sapogenins are isolated by chopping the tubers, allowing them to ferment for several days, then completing the hydrolysis of saponins by heating with aqueous acid. The sapogenins can then be solvent extracted. The principal sapogenin in the species given above is diosgenin (Figure 5.83), with small quantities of the 25^-epimer yamogenin (Figure 5.84). Demand for diosgenin for pharmaceuticals is huge, equivalent to 10 000 tonnes of Dioscorea tuber per annum, and it is estimated that about 60% of all steroidal drugs are derived from diosgenin.

Powdered Dioscorea (wild yam) root or extract is also marketed to treat the symptoms of menopause as an alternative to hormone replacement therapy (see page 279). Although there is a belief that this increases levels of progesterone, which is then used as a biosynthetic precursor of other hormones, there is no evidence that diosgenin is metabolized in the human body to progesterone, and any beneficial effects may arise from diosgenin itself.

Fenugreek

The seeds of fenugreek (Trigonella foenum-graecum; Leguminosae/Fabaceae) are an important spice material, and are ingredients in curries and other dishes. The plant is an annual, and is grown widely, especially in India, both as a spice and as a forage crop. Seeds can yield, after hydrolysis, 1-2% of sapogenins, principally diosgenin (Figure 5.83) and yamogenin (Figure 5.84). Although yields are considerably lower than from Dioscorea, the ease of cultivation of fenugreek and its rapid growth make the plant a potentially viable crop for steroid production in temperate countries. Field trials of selected high-yielding strains have been conducted.

Sisal

Sisal (Agave sisalana; Agavaceae) has long been cultivated for fibre production, being the source of sisal hemp, used for making ropes, sacking and matting. The plant is a large, rosette-forming succulent with long, tough, spine-tipped leaves containing the very strong fibres. The main area of sisal cultivation is East Africa (Tanzania, Kenya), with smaller plantations in other parts of the world. The sapogenin hecogenin (Figure 5.84) was initially produced from the leaf waste (0.1-0.2% hecogenin) after the fibres had been stripped out. The leaf waste was concentrated, allowed to ferment for several days, then treated with steam under pressure to complete hydrolysis of the saponins. Filtration then produced a material containing about 12% hecogenin, plus other sapogenins. This was refined further in the pharmaceutical industry. Other sapogenins present include tigogenin and neotigogenin (Figure 5.87).

As the demand for natural fibres declined due to the availability of synthetics, so did the supply of sisal waste and thus hecogenin. In due course, hecogenin became a more valuable commodity than sisal, and efforts were directed specifically towards hecogenin production. This has resulted in the cultivation of Agave hybrids with much improved hecogenin content.

The fermented sap of several species of Mexican Agave provides the alcoholic beverage pulque. Distillation of the fermented sap produces tequila.

A/B cis, smilagenin A/B trans, tigogenin

aibh I H

aibh i H

A/B cis, sarsasapogenin A/B trans, neotigogenin

A/B cis, smilagenin A/B trans, tigogenin

aibh i H

A/B cis, sarsasapogenin A/B trans, neotigogenin

Figure 5.87

Some steroidal alkaloids are nitrogen analogues of steroidal saponins, and display similar properties such as surface activity and haemolytic activity, but these compounds are toxic when ingested. These types of compound, e.g. solasonine (Figure 5.88) (aglycone solasodine), are found in many plants of the genus Solanum (Solanaceae), and such plants must thus be regarded as potentially toxic. In contrast to the oxygen analogues, all compounds have the same stereochemistry at C-25 (methyl always equatorial), whilst isomers at C-22 do exist, e.g. tomatine

D-Gal

HO D-Glc

D-Gal

Solasodine Alkaloid

solasodine solasonine

solasonine

Tomatidine Tomatine

tomatine

Figure 5.88

tomatine

Figure 5.88

(Figure 5.88) (aglycone tomatidine) from tomato (Lycopersicon esculente; Solanaceae). The nitrogen atom is introduced by a transamination reaction, typically employing an amino acid as donor (see page 20). Since the production of medicinal steroids from steroidal saponins requires preliminary degradation to remove the ring systems containing the original cholesterol side-chain, it is immaterial whether these rings contain oxygen or nitrogen. Thus, plants rich in solasodine or tomatidine could also be employed for commercial steroid production (see page 391).

Smilagenin and sarsasapogenin (Figure 5.87) found in sarsaparilla* (Smilax spp.; Liliaceae/ Smi-lacaceae) are reduced forms of diosgenin and yamogenin respectively. These contain cis-fused A/B rings, whilst the corresponding trans-fused systems are present in tigogenin and neotigogenin (Figure 5.87) found in Digitalis purpurea along with cardioactive glycosides (see page 246). All four stereoisomers are derived from cholesterol, and the stereochemistry of the A/B ring fusion appears to be controlled by the nature of the substrate being reduced. Direct enzymic reduction of the A5 double bond yields the trans-fused system, whereas reduction of a A4 double bond gives the alternative cis-fused system (Figure 5.89). Accordingly, to obtain the A/B cis fusion, the A5 unsaturation of cholesterol is changed to A4 by oxidation of the 3-hydroxyl and allylic isomerization to the conjugated 4-ene-3-one system, and this is followed by reduction of both functional groups (Figure 5.89) (compare biosynthesis of progesterone, page 243). The sarsaparilla saponins are not present in sufficient quantities to be commercially important for steroid production, but quite large amounts of sarsasapogenin can be extracted from the seeds of Yucca brevifolia* (Agavaceae).

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  • valentin
    Is hecogenin a steroidal saponin?
    3 years ago

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