Indole Alkaloids from Secologanin Precursors
Monoterpene-derived indole alkaloids
At least 4100 compounds of this structural type are known. They are most common in the families Apocynaceae, Loganiaceae, and Rubiaceae, but are also encountered in the Icacinaceae, Nyssaceae, Alangiaceae, and possibly other families.
Biosynthetic pathway
Strictosidine is the first intermediate in the pathway. This compound has a 3
µ configuration. This compound is formed specifically by stictosidine synthase.
The enzyme is found in the plant vacuole. Despite early reports, vincoside is not a precursor.
The pathway to the major classes of indole alkaloids includes:
tryptamine and secologanin ----> strictosidine ----> 4,21-dehydrogeissoschizine ----> iminium form of cathenamine ---->
preakuammicine ----> stemmadenine (all to here are class 1) ----> dehydrosecodine (class 2)
----> iboga types (class 5) (such as
catharanthine) and ----> class 3, such as tabersonine ----> vindoline and class 3 and class
5 ----> alkaloids such as vincristine and vinblastine
Compounds such as 4,21-dehydrocorynantheine, geissoschizine, ajmalacine, serpentine,
and akuammicine are now known to represent side pathways and are not involved directly in the
formation of stemmadenine and Class 2, 3, and 5 indole alkaloids.
Classes of monoterpene-derived indole alkaloids
Alkaloids of Class 1 contain the iridoid-derived portion of the structure with the carbons in the same relative relationship as in seco-loganin.
The only common Class 2 indole alkaloid is dehydrosecodine, an intermediate in the formation of Class 3 and Class 5 indole alkaloids. Class 4 indole alkaloids (such as fruticosine) are also relatively uncommon.
The advantage to the Class system used and the numbering system used is that the carbons retain
the same numbers in the different systems. Carbon 3 of a Class 1 alkaloid is the same as carbon
3 of a Class 3 or a Class 5 indole alkaloid.
Class 3 and Class 5 indole alkaloids are derived from dehydrosecodine (Class 2) by apparent
Diels-Alder reactions.
Tabersonine is a Class 3 indole alkaloid derived from dehydrosecodine. This alkaloid is common in Catharanthus roseus. Vindoline, derived in this plant from tabersonine also is a Class 3 alkaloid.
Catharanthine, in the same plant, is an iboga or Class 5 indole alkaloid. Two major antipodal series of iboga alkaloids are known. Ibogamine is another alkaloid of this Class.
Distribution of monoterpene-derived indole alkaloids
Class 1 alkaloids are found in Apocynaceae, Loganiaceae, and Rubiaceae (as well as a few other families)
Class 5 - the iboga alkaloids - are found only in Apocynaceae
Class 3 - only found in the Apocynaceae
Rubiaceae ----> quinine and related alkaloids
in the Apocynaceae, 4 of 7 tribes have indole alkaloids
Class 1 monoterpene-derived alkaloids
Ajmalacine, a class 1 indole alkaloid, is no longer considered an intermediate in the synthesis of other classes of indole alkaloids. Ajmalacine is found in members of the Apocynaceae and Rubiaceae. It is used for the treatment of circulatory disorders. It has hypotensive and vasodilator actions.
Yohimbine, from Tabernanthe yohimbe, Rubiaceae, has been used in the treatment of arteriosclerosis. It is reputed to be an aphrodisiac. This alkaloid has been isolated from a number of species in the Apocynaceae, Loganiaceae, and Rubiaceae.
Reserpine, from species of the genus Rauvolfia, has potent hypotensive activity. The alkaloid produces sedation and tranquilization. It also is a stimulator of prolactin release and may be carcinogenic.
Strychnine, a class 1 indole alkaloid, has a portion based on malonyl CoA linked to the molecule. It is well known to be toxic and has been employed as a rotenticide. Strychnine excites the nervous system and binds to the glycine receptor. It is not in present medical use. The compound is best known from Strychnos nux-vomica of the Loganiaceae. The dimethoxy-derivative brucine is even more toxic.
Class 3 monoterpene-derived alkaloids
Vincamine, a Class 3 indole alkaloid, in only found in the Apocynaceae, mostly in Vinca minor. It is used to treat headaches and vertigo. Its principal action is to moderate cerebral vasodilation.
Class 5 monoterpene-derived alkaloids
Ajmaline, a Class 5 (I think?) indole alkaloid, has powerful coronary dilating and antiarrhythmic
effects. Ajmaline is not currently used medicinally because it is too toxic.
Curares
Curares involving Strychnos species have been used in South America and other areas of the tropics. In South America many of these were stored in small gourds, leading to the name "calabash curare". There isn't an obligate linkage of the curare and the container, however. Curares are used to poison darts and arrow and spear tips, primarily for hunting. The active compounds produce paralysis of the game animals.
The active ingredients of many calabash curares are bisindole alkaloids. Compounds such as C-toxiferine and C-alkaloid G are many times more active than d-tubocurarine (see bisbenzylisoquinoline alkaloids). Toxiferine binds to the acetylcholine receptor. Other bisindole alkaloids have demonstrated antitumor activity.
Olivacine and ellipticine have been isolated from plants in the Apocynaceae and Loganiaceae. They are modified Class 1 indole alkaloids. Derivatives of these alkaloids are used clinically as anti- tumor alkaloids in Europe. Ellipticine appears to inhibit topoisomerase II. These alkaloids also inhibit DNA synthesis by intercalation into DNA.
Catharanthus alkaloids
Two clinically useful bisindole alkaloids, vincristine and vinblastine, are among the most expensive
of all plant-derived drugs. They are used to treat childhood leukemia and other cancerous conditions.
These come from Catharanthus roseus, Apocynaceae. The compounds are dimers of
Class 3 and Class 5 precursors. They bind to and dimerize tubulin. They inhibit DNA synthesis
and DNA-dependent RNA polymerase.
Gelsemium alkaloids
A number of highly toxic alkaloids is found in Gelsemium sempervirens, Loganiaceae, a common
vine of the southeastern U.S. Similar alkaloids are found in a Chinese species of this genus. The
alkaloids have antispasmodic and analgesic properties.
Iboga alkaloids
Iboga alkaloids, from Tabernanthe iboga, Apocynaceae, are used to combat fatigue, sleep and hunger, as well as being associated with secret societies and religious practice in West and Central Africa. In larger quantities the drug is hallucinogenic. Extracts of the plant also are used while stalking game. The principal alkaloid is ibogaine. Some of these are central nervous system stimulants, some are cholineesterase inhibitors, others cause hypotension and bradycardia. These alkaloids are found in a number of other genera in the family Apocynaceae.
Camptothecine
Camptothecine, from the Chinese tree Camptotheca acuminata, Nyssaceae, has pronounced antitumor activity. It exerts its action on DNA topoisomerase I. The compound is a strong inhibitor of DNA synthesis in mammalian cells.
Cinchona alkaloids
Alkaloids of the genus Cinchona, Rubiaceae, have been used to treat malaria for several
hundred years in Western medicine. The use of Cinchona bark was first recorded in 1633.
Quinine, isolated from this source, was the first efficacious treatment for malaria. At least
40 alkaloids have been isolated from this source. Quinine is used as a standard for bitterness.
Although these alkaloids have a quinoline structure, they are modified monoterpene-derived
alkaloids. The biosynthetic pathway leading to quinine and related compounds is complex.
Quinine intercalates with DNA, modulates ion channels, and inhibits glucose response in
chemosensory cells. Quinidine, another alkaloid of this series, is used to treat heart conditions.
Cinchophyllines
Cinchophyllines
This series of alkaloids resemble emetine, cephaeline, and related isoquinoline alkaloids, except that they are formed from tryptamine and secologanin instead of L-DOPA. They are found in Cinchona species, but also in other members of the Rubiaceae and Loganiaceae. Several of these alkaloids have pronounced amebicidal and cytotoxic activity. Usambarensine has antimalarial activity.
Biosynthesis of tabersonine and vindoline
Biosynthesis of stemmadenine and Class 2, 3, and 5 indole alkaloids
Akuammine, akuammidine, and other indole alkaloids
Origin of strychnine and brucine
Biosynthesis of iboga alkaloids
Vincristine and vinblastine origin
C-Toxiferine I and related alkaloids
Tubulosine and usambarensine formation
Lecture Slides
Plants with Monoterpene-Derived
Indole Alkaloids
© David S. Seigler, Plant Biology 363, Plant Secondary Metabolism, Department of Plant Biology,
265 Morrill Hall, 505 S. Goodwin Ave., University of Illinois, Urbana, Illinois 61801, USA.
217-333-7577. seigler@life.uiuc.edu.
