soo ALKALOIDS Dalton, D.R. (1979). The Alkaloids - The Fundamental Chemistry, a Biogenetic Approach, Marcel Dekker, New York. Mothes, K., Schütte, H.R. et Luckner, M., Eds. (1985). Biochemistry of Alkaloids, VCH, Berlin. Phillipson, J.D., Roberts, M.F. et Zenk, M.H., Eds. (1985). The Chemistry and Biology of Isoquinoline Alkaloids, Springer Verlag, Berlin. Roberts, M.F. et Vink, M. (1998). Alkaloids. Biochemistry, Ecology, and Medicinal Applications, Plenum Press, New York. Waterman, P.O., Ed. (1993). Alkaloids and Sulphur Compounds (Methods in Plant Biochemistry, vol. 8), Academic Press, London. ■ Series The Alkaloids. Chemistry and Pharmacology, 1950 —>, (became The Alkaloids - Chemistry and Physiology in 1983 [vol. 21 —>] then The Alkaloids - Chemistry and Biology [vol. 51 —>]). Initially edited by Manske, R.H.F. (1-17), then by Manske, R.H.F. and Rodrigo, R.G.A. (18-20), Brossi, A. (21-36 then 38-40), Brossi, A. and Suffness, M. (37), Brossi, A. and Cordeil, G.A. (41, 45), Cordell, G.A. (42-44, 46—>), Academic Press, London (the latest volume is vol. 52 [1999]). Alkaloids—Chemical and Biological Perspectives, 1983 —>, (Pelletier, S.W., Ed.), John Wiley and Sons, New York (the latest volume is vol. 12 [1998]). See also Alkaloids, The Royal Society of Chemistry, London, 13 volumes from 1972 to 1983; since 1984, the series has been merged with: Natural Products Reports (volume 16 in 1999). I ■ i Alkaloids Derived from Ornithine and Lysine ntroduction Two amino acids with four or five carbon atoms—ornithine and lysine—axe at the origin of many alkaloids whose structure may be simple (pyrrolidines, such as hygrine from coca leaves, piperidines such as pelletierine from the pomegranate tree) or more complex. Structural complexity, in this group, translates into the formation, from several molecules of the amino acid, of polycyclic edifices: pyrrolizidines, indolizidines, quinolizidines (bi-, tri-, tetra-, and pentacyclic). The complexity may also arise from the participation of other precursors: acetate (tropanes, homotropanes, elaeocarpine), phenylalanine (phenanthroindolizidine, phenanthroquinolizidine), tryptophan (elaeocarpidine), nicotinic acid (nicotine, anabasine), or phenylpropanoic acid (alkaloids of the Lythraceae). Also known are compounds in which a ring arising from ornithine (pyrrolidine) or lysine (piperidine) is combined with complex structures of the flavone type* (buchenavianine of Buchenavia sp. Eichl., Combretaceae, or ficine from Ficus pantoniana King., Moraceae), benzylisoquinoline (macrostomine from Papaver macrostomum Boiss. & E. Huet, Papaveraceae), or harmane (brevicolline from a Cyperaceae of the genus Carex). * Structures of the same type are formed when nicotinic acid is involved, for example, the pyridine-type chromones of a medicinal plant from western Africa, Schumanniophyton magnificunuQU. Schumann) Harms (Rubiaceae). SU2 ALKALOIDS GENERALITIES N-CH3 H3CO O Buchenavianine CH3O CH3O O CH3 ( \ 0 N-CH3 Brevicolline Macrostomine Experiments with 15N-labeled amino acids show that it is the terminal nitrogen atom (5 or e) which is incorporated; tritium labeling shows that as a general rule, the proton at C-2 is retained, which excludes the possibility that oc-ketoacids (2-oxo-5-aminopentanoic or 2-oxo-6-aminohexanoic) are the precursors of the rings: it is more likely that aldehydes (4-aminobutanal and 5-aminopentanal), in equilibrium with the cyclic forms (A'-pyrrolidine and A'-piperidine), are the true precursors of the pyrrolidine- and piperidine-type structures. To account for the results of several labeling experiments, a global scheme has been proposed; it emphasizes the major role of enzymes whose coenzyme is pyridoxal phosphate. The latter forms an intermediate Schiff base whose hydrolysis to a diamine (putrescine or cadaverine) is less rapid than its cyclization, which explains why the incorporation of the precursor is very often asymmetrical. It is not uncommon, however, for the initial labeling (in the 6-position of lysine or in the 5-position of ormthine) to be evenly distributed (at the 2- and 6-position of piperidine, and at the 2-and 5-position of pyrrolidine, respectively), which proves that in certain plants, diamines, namely cadaverine and putrescine, are biosynthetic intermediates (see, among others, the origin of tropane alkaloids, p. 809, and the references on p. 831). CHO Pyridoxal phosphate * the same mechanism can be applied to ornithine Elaeocarpaceae alkaloids Simple pyrrolidines Ncotine x Phenanthroindolizidines (Asclepiadaceae) H3C-W OR Tropane alkaloids (Solanaceae) (OCOR) H3C-N C02R' O-R Pyrrolidines (Asteraceae, Boraginaceae...) Piperidines: a, Lobeliaceae b, Crassulaceae o Amides ex.: Piperaceae Lycopodiaceae alkaloids Subsequently, the mechanisms that are likely to lead to the more complex structures can be envisioned through simple chemical reactions (formation of Schiff bases, Mannich condensation, aldol condensation). The N-methyl groups that are often found are generally provided by S-adenosylmethionine. Mannich type ,CH2- CH-COSCoA I CO-R Reactivity of the Schiff base C—CH- C-NH-R' Aldol type cocaine COSCoA ^*říP N 0 H2C COSCoA C02H The pharmacological and therapeutic interest of the alkaloids derived from ornithine and lysine is very uneven. Some are currently used in therapy (atropine, scopolamine), while others are now of limited use (sparteine) or only of historical interest (lobeline, arecoline). Many ought to be known only because of their toxicity: pyrrolidine alkaloids from Boraginaceae and Asteraceae that are often gifted with medicinal virtues, quinolizidine alkaloids of Fabaceae that are common in our environment because of their ornamental character, not forgetting nicotine in tobacco. A small number have an interesting potential, for example, some indolizidines (castanospermine) which are efficacious against retroviruses, or huperzine, which has been tested in the context of Alzheimer's disease. Thus, we shall limit our coverage to these few examples, and we shall follow a chemical classification. The figure on page 803 gamers the most common alkaloid structural types that are related to ornithine and lysine. i 1 Tropane Alkaloids 1. Structure of Tropane Alkaloids...................................................................................806 A. Tropanols.......................................................................................................806 B. Acids..............................................................................................................807 C. Alkaloids........................................................................................................807 2. Biosynthetic Origin......................................................................................................809 3. Official Solanaceae Containing Tropane Alkaloids: Deadly Nightshade, Thorn Apple, Henbane ......................................................811 The Plants........................................................................................813 The Drugs ........................................................................................813 Chemical Composition....................................................................815 Assay................................................................................................8l* Pharmacological Activity ................................................................SI7 Uses of the Drugs (818), Uses of the Alkaloids..............................821 4. Solanaceae that are Industrial Sources of Tropane Alkaloids ....................................822 Brugmansia sanguinea........................................................................................822 Egyptian Henbane, Corkwood Tree...................................................................823 Other Modes of Obtention of Tropane Alkaloids...............................................824 Semisynthetic Anticholinergics..........................................................................824 5. Other Solanaceae.........................................................................................................824 6. Alkaloid-containing Erythroxylaceae: Coca..............................................................825 7. Polyhydroxynortropanes..............................................................................•"•..............830 8. Bibliography................................................................................................................831 Tropane alkaloids have in common a nitrogen-containing bicyclic structural element, namely azabicyclo[3,2,l]octane: they are 8-methyl-8-azabicyclo[3,2,l]octanes. Approximately 200 alkaloids are known in this group, and they are distributed in a small number of Angiosperm families: Solanaceae (they are found in about twenty genera, e.g., Anthocercis, Atropa, Brugmansia, Datura, Mandragora, Physalis,