True alkaloids

When discussing seco alkaloids the question of their genesis should not be disregarded. Are they true alkaloids or artifacts of isolation It is difficult to answer this question with certainty. Some of them, e.g., secophthalide-isoquinoline ene lactams, are postulated to be formed during the extraction process however, most of them are believed to be metabolites produced naturally. This may be evidenced by the fact that some of these alkaloids retain optical activity, and in addition many of them can be synthesized in biomimetic syntheses in the laboratory. Thus, one can generalize the opinion of Shamma (10), whose significant contribution to the field of secoisoquinoline alkaloids should be acknowledged, that [a process]. .. could presumably occur in vivo at least as readily as it could in vitro. ... 

In Table VI secophthalideisoquinoline alkaloids and their precursors are presented. They form four series of seco bases from enol lactones to diketo adds ending with ene lactams, which in all probability are not true alkaloids but products arising during the extraction process. The classic precursors of... 

C. roseus plants to the extent of 0.3-0.6%. Although the experiments do not indicate that 17 is in the pathway, since the conversion of 17 to vinblastine (1) did not occur in vitro, it is established that vinblastine (1) is a true alkaloid. 

Key words alkaloid, alkaloid derivation, alkaloid occurrence, heterocycles, molecular precursors, protoalkaloids, pseudoalkaloids, true alkaloids... 

Alkaloids are generally classified by their common molecular precursors, based on the biological pathway used to construct the molecule. From a structural point of view, alkaloids are divided according to their shapes and origins. There are three main types of alkaloids (1) true alkaloids, (2) protoalkaloids and (3) pseudoalkaloids. True alkaloids and protoalkaloids are derived from amino acids, whereas pseudoalkaloids are not derived from these compounds (Table 1). 

True alkaloids derive from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which has a brown liquid. True alkaloids form water-soluble salts. Moreover, most of them are well-defined crystalline substances which unite with acids to form salts. True alkaloids may occur in plants (1) in the free state, (2) as salts and (3) as N-oxides. These alkaloids occur in a limited number of species and families, and are those compounds in which decarboxylated amino acids are condensed with a non-nitrogenous structural moiety. The primary precursors of true alkaloids are such amino acids as L-ornithine, L-lysine, L-phenylalanine/L-tyrosine, L-tryptophan and L-histidine . Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, dopamine, morphine and usambarensine (Figure 4). A fuller list of examples appears in Table 1. 

True alkaloids L-ornithine Pyrrohdine alkaloids Pyrrohdine Cuscohygrine Hygrine... 

Figure 4. An example of a true alkaloid. L-tyrosine-derived alkaloid usambarensine has strong anti-malarial potential. Usambarensine was extracted from the root bark of African Strychnos usambaremis, a small tree in East and South Africa, and a small bush in West Africa.

The precursors of true alkaloids and protoalkaloids are aminoacids (both their precursors and postcursors), while transamination reactions precede pseudoalkaloids (Tables 1 and 10). It is not difficult to see that from all aminoacids only a small part is known as alkaloid precursors (Table 19). Both true and proto alkaloids are synthesized mainly from the aromatic amino acids, phenylalanine, tyrosine (isoquinoline alkaloids) and tryptophan (indole alkaloids). Lysine is the... 

Protein amino acids L-alanine L-arginine Arginine-derived alkaloids True alkaloids... 

L-tyrosine Tyrosine-derived alkaloids Indole alkaloids Quinoline alkaloids /3-carboline alkaloids Pyrroloindole alkaloids Ergot alkaloids Iboga alkaloids Corynanthe alkaloids Aspidosperma alkaloids Protoalkaloids Terpenoid indole alkaloids True alkaloids... 

L-ornithine Ornithine-derived alkaloids True alkaloids Pyrrolidine alkaloids Tropane alkaloids Pyrrolizidine alkaloids... 

Anthranilic Anthranilic acid-derived True alkaloids... 

Nicotinic acid Nicotinic acid-derived alkaloids True alkaloids Pyridine alkaloids Sesquiterpene pyridine alkaloids... 

Of the 42 species of Ilex tested, only four were regarded as positive I. cassine, I. coriacea, I. crenata, and./, glabra (2/3). I. cassine and I. crenata had previously been reported as alkaloid-positive. The purines do not give definitive alkaloid tests with the Dragcndorff reagent and are not considered true alkaloids by some investigators. 

Paspalin cannot be regarded as a true alkaloid, its unique structure— a seco-steroid annelated to an indole nucleus—deserves, however, attention as it demonstrates the great versatility of the ergot fungus. 

Returning to the question in the title of this section, capsaicin does not fall into any of the three classic types of nitrogen-bearing plant natural products, being neither a true alkaloid, a protoalkaloid, or a pseudoalkaloid. Capsaicin is oflimited distribution in Nature and shows pharmacological activity, but is non-basic, structurally unsophisticated, and not directly derived from an amino acidic precursor. On the other hand, the lack of attributes such as basicity, complexity, and an amino acidic pedigree can also be found in compounds commonly perceived as alkaloids. Thus, colchicine is neutral, ephedrine is structurally unsophisticated, and the nitrogen atom of the potato alkaloid solanine is not derived from an amino acid, but rather incorporated into as non-amino acidic framework by a transamination reaction. For the sake of clarity and consistency, it seems therefore convenient to adopt the modern definition of alkaloids, and consider capsaicin, as well as alkylamides such as piperine (18) and pellitorine (19), as such. 

It is possible that some of the alkaloids at least are artifacts produced from true alkaloids by the isolation procedures. How ever, it appears from the subsequently ascertained reactivities of the functional groups present that the relatively mild methods of isolation would not have... 

Taifine (48), isotaifine (49) and 8-methoxytaifine (50)are claimed as alkaloids from Ruta ohalepensis (B.A.H. El-Tawil et al., Z. Naturforsch., Teil.B, 1981, 36, 1159). However, since N-ethyl groups are unusua l it seems probable that these compounds were formed during their isolation by treatment of the corresponding NH compounds with hot ethanolic potassium hydroxide. The secondary amines are thus the true alkaloids of the plant. 

It has been proposed from a biosynthetic point of view to divide alkaloids into protoalkaloids, pseudoalkaloids and true alkaloids. 

The true alkaloids contain the nitrogen bound in heterocyclic form. Their carbon... 

It is obvious from the above aesoribed properties of these substanoes that they are true alkaloids (see p. 381), among which also belong tba diaminea and triamines (see p. 249). 

Desmodiurntriflorum Nicotine (44 R = Me), nornicotine (44 R = H),anabasine (45), and two unidentified alkaloids have been isolated from Nicotiana noctiflora. Confirmation that myosmine (46) is true alkaloid in various Nicotiana species and not a decomposition product of nicotine has been obtained." Anabasine (45) has also been found in Verbascum songaricum. ... 

Whether leurosine, Catharine, and their congeners are true alkaloids, or artefacts derived from anhydrovinblastine, the fact remains that the aerial oxidation of anhydrovinblastine is a facile process which does not need to be enzyme-mediated, and a further examination of this reaction has revealed that all the alkaloids of the vinblastine group are produced. The oxidations were performed in acetonitrile solution, and in one experiment, conducted at 26 for 48 hours, the composition of the alkaloid mixture obtained was roughly similar to the relative abundances of the dimeric alkaloids isolated from Catharanthus species. In the oxidation the lone electrons on Nb are presumably involved, since anhydrovinblastine Nb-oxide is inert towards oxidation by air, and while the presence of moisture promotes the reaction, oxygen from the water is not incorporated into the oxidized alkaloids. On the basis of the available evidence, a mechanism, shown in truncated form in Scheme 37, was proposed for the oxidative transformation of anhydrovinblastine into the various alkaloids iso-lated. "°... 

True alkaloids derive from amino acid and share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine, which is a brown liquid. True alkaloids... 

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