Steroidal Alkaloids

Derived from Ornithine
  - Pyrrolidine & Tropane
  - Pyrrolizidine
Derived from Lysine
  - Piperidine
  - Quinolizidine
  - Indolizidine
Derived from Nicotinic Acid
  - Pyridine
Derived from Tyrosine
  - PEA & Simple TIQ
  - Modified BTIQ
  - Phenethylisoquinoline
  - Terpenoid TIQ
  - Amaryllidaceae
Derived from Tryptophan
  - Simple Indole
  - Simple β-Carboline
  - Terpenoid Indole
  - Quinoline
  - Pyrroloindole
  - Ergot
Derived from Anthranilic Acid
  - Quinazoline
  - Quinoline & Acridine
Derived from Histidine
  - Imidazole
Derived by Amination Reactions
  - Acetate-derived
  - Phenylalanine-derived
  - Terpenoid
  - Steroidal
Purine Alkaloids
  - Saxitoxin & Tetrodotoxin

Many plants in the Solanaceae accumulate steroidal alkaloids based on a C27 cholestane skeleton, e.g. solasodine and tomatidine (Figure 126). These are essentially nitrogen analogues of steroidal saponins and have already been briefly considered along with these compounds. In contrast to the oxygen analogues, these compounds all have the same stereochemistry at C-25 (methyl always equatorial), but C-22 isomers do exist, as solasodine and tomatidine exemplify. They are usually present as glycosides which have surface activity and haemolytic properties as do the saponins, but these compounds are also toxic if ingested. Solasonine from Solanumspecies and tomatine (Figure 126) from tomato (Lycopersicon esculente) are typical examples of such glycosides.As with the sapogenins, this group of steroidal alkaloids is derived from cholesterol, with appropriate side-chain modifications during the sequence (Figure 127).

Amination appears to employ L-arginine as the nitrogen source, probably via a substitution process on 26-hydroxycholesterol. A second substitution allows 26-amino-22-hydroxycholesterol to cyclize, generating a piperidine ring. After 16β-hydroxylation, the secondary amine is oxidized to an imine, and the spiro-system can be envisaged as the result of a nucleophilic addition of the 16β-hydroxyl on to the imine (or iminium via protonation). Whether the 22R (as in solasodine) or 22S (as in tomatidine) configuration is established may depend on this reaction.

Figure 126

A variant on the way the cholesterol sidechain is cyclized can be found in solanidine(Figure 126), which contains a condensed ring system with nitrogen at the bridgehead. Solanidine is found in potatoes (Solanum tuberosum), typically as the glycoside α-solanine (Figure 126). This condensed ring system appears to be produces by a branch from the main pathway to solasodine/tomatidine structures. Thus, a substitution process will allow generation of the new ring system
(Figure 128).

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 tomatidinecould also be employed for commercial steroid production. Similarly, other Solanum alkaloids* such as solanidine with nitrogen in a condensed ring system might also be exploited.

Figure 127

Figure 128

Several plants in the Liliaceae, notably the genus Veratrum (Liliaceae/Melanthiaceae), contain a remarkable group of steroidal alkaloids in which a fundamental change to the basic steroid nucleus has taken place. This change expands ring D by one carbon at the expense of ring C, which consequently becomes five-membered. The resulting skeleton is termed a C-nor-Dhomosteroid in keeping with these alterations in ring size. Cholesterol is a precursor of this group of alkaloids, and a mechanism accounting for the ring modifications is shown in Figure 129, where the changes are initiated by loss of a suitable leaving group from C-12. Typical representatives of Cnor- D-homosteroids are jervine and cyclopamine (Figure 130) from Veratrum californicum, toxic components in this plant that are responsible for severe teratogenic effects. Animals grazing on V. californicum and some other species of Veratrum frequently give birth to young with cyclopia, a malformation characterized by a single eye in the centre of the forehead. The teratogenic effects of jervine, cyclopamine, and cyclopamine glucoside (cycloposine) on the developing fetus have now been well established. Other Veratrumalkaloids, especially those found in V. album and V. viride, have been employed medicinally as hypotensive agents, and used in the same way as Rauwolfia alkaloids, often in combination with Rauwolfia. These medicinal alkaloids, e.g. protoveratrine A and protoveratrine B (Figure 130), which are esters of protoverine, are characterized by fusion of two more six-membered rings on to the C-nor- D-homosteroid skeleton. This hexacyclic system is extensively oxygenated, and a novel hemiketal linkage bridges C-9 with C-4. Both the jervine and protoverine skeletons are readily rationalized through additional cyclization reactions involving a piperidine ring, probably formed by processes analogous to those seen with the Solanum alkaloids (Figure 127). These are outlined in Figure 131, which suggests the participation of the piperidine intermediate from Figure 127. Typically, both types of alkaloid are found co-occurring in Veratrum species.

Figure 129

Figure 130

Figure 131

Figure 132

Many steroidal derivatives are formed by truncation of the original C8 side-chain, and C21 pregnane derivatives are important animal hormones or intermediates on the way to other natural steroidal derivatives, e.g. cardioactive glycosides. Alkaloids based on a pregnane skeleton are found in plants, particularly in the Apocynaceae and Buxaceae, and pregnenolone (Figure 132) is usually involved in their production. Holaphyllamine from Holarrhena floribunda (Apocynaceae) is obtained from pregnenolone by replacement of the 3-hydroxyl with an amino group (Figure 132). Conessine(Figure 132) from Holarrhena antidysenterica is also derived from pregnenolone, and requires two amination reactions, one at C-3 as for holaphyllamine, plus a further one, originally at C-20, probably via the C-20 alcohol. The new ring system in conessine is then the result of attack of the C-20 amine on to the C-18 methyl, suitably activated, of course. The bark of H. antidysenterica has long been used, especially in India, as a treatment for amoebic dysentery.

The novel steroidal polyamine squalamine (Figure 133) has been isolated in very small amounts (about 0.001%) from the liver of the dogfish shark (Squalus acanthias), and is attracting attention because of its remarkable antimicrobial activity. This compound is a broadspectrum agent effective at very low concentrations against Gram-positive and Gram-negative bacteria, and also fungi, protozoa, and viruses including HIV. The sulphated side-chain helps to make squalamine water soluble. The polyamine portion is spermidine, a compound widely distributed in both animals and plants. Related aminosterol derivatives with similar high antimicrobial activity have also been isolated from the liver extracts.

Figure 133