Anthranilic acid tryptophan-derived alkaloids

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

Alkaloids derived from L-tryptophan hold the indole nucleus in a ring system. The ring system originates in the shikimate secondary compounds building block and the anthranilic acid pathway. It is known that the shikimate block. 

Of all the alkaloid-producing families, one of the most prolific is the Rutaceae (Waterman, 1975). The alkaloids obtained included 1-benzyltetrahydroisoquinoline, simple tryptophan derivatives, imidazoles and, most commonly, quinoline alkaloids originating from anthranilic acid. The Rutaceae was the only family in which the direct use of anthranilic acid in alkaloid production occurs to any extent. 

Highly significant results have been obtained by Monkovic and Spenser 160) from a study of the biosynthesis of dictamnine using tracer methods. Mature plants of Dictamnus albus incorporate carboxyl- C-labeled anthranilic acid to give radioactive dictamnine, specifically labeled at C-4, strongly supporting the derivation of the alkaloid directly from anthranilic acid failure to incorporate radioactivity from tryptophan-jS- C shows that the 4-hydroxyquinoline unit is not derived... 

Phenylalanine and tyrosine acts as precursor for opium alkaloid biosynthesis. Tryptophan is a significant source of Vinca alkaloids. Alkaloids are derived from anthranilic acid, which is an intermediate in biosynthesis of tryptophan. Some alkaloids are derived from acetate, terpene or shikimic acid. Shikimic acid is a significant metabolite as most of the aromatic constituents are derived from shikimic acid pathway. 

C]Tryptophan gave inactive alkaloids but tritiated 2,4-dihydroxy-quinoline (34) and its N-methyl derivative were incorporated into (47) (0.009 % and 0.020% respectively) an early route had suggested the derivation of what was essentially (34) from tryptophan. Radioisotope dilution showed the presence of both these quinoline precursors together with iV-acetyl- and N-methyl-anthranilic acid in A. baueri. A satisfactory incorporation of N-methylanthranilic acid into (47) was found in Evodia xanthoxyloides, and this, together with its natural occurrence, indicates that early methylation may be important in the biosynthesis of acridone alkaloids. 

Quinazoline Alkaloids.— The biosynthesis of vasicine (=peganine) (163) has been investigated in Adhatoda vasica (Acanthaceae) and Peganum harmala (Zygo-phyllaceae). In both plants the anthranoyl portion is known to derive from anthranilic acid [the reported incorporation of tryptophan (0.017 %) suggested as via anthranilic acid seems of questionable significance]. The remaining atoms of vasicine, however, appear to arise by different pathways in the two plants. 

Since tryptophan is recognized as a main constituent of plant proteins and as a common biogenetic precursor of the complex indole alkaloids, the wide occurrence of tryptamine derivatives in the plant kingdom is not unexpected. The presently known cases of these simple indole alkaloids have been ones in which a tryptamine unit formally appears as a slightly modified structure (e.g., by oxidation or methylation), as a cyclized form or a dimeric variation thereof, or as a modification which incorporates short carbon chains (e.g., C4, C2) or a simple aromatic structure (anthranilic acid) respectively. The great majority of the simple indole alkaloids are confined to the dicotyledon plants. 

Biosynthesis Like other aromatic amino acids, e.g., Phe and Tyr, Trp is formed on the shikimic acid pathway. There is a branching point at chorismic acid one branch leads to Phe and Tyr, the other to Trp choris-mic acid - anthranilic acid (anthranilic acid synthase, EC 4.1.3.27)- A-(5 -0-phosphoribosyl)-anthranilic acid (anthranilic acid phosphoribosyl transferase, EC 2.4.2.18)- 1 -o-carboxyphenylamino-1 -deoxyribu-lose 5-phosphate [A-(5 -phosphoribosyl)anthranilic acid isomerase]- indole-3-glycerol phosphate (in-dole-3-glycerol phosphate synthase, EC 4.1.1.48) - indole (tryptophan synthase, EC 4.2.1,20)+serine - Trp. Many biologically active indole compounds are derived from Trp, e. g., 5-hydroxytryptophan, 5-hydroxy-tryptamine ( serotonin), and melatonin as well as many indole alkaloids. 

Groger, D. Alkaloids Derived from Tryptophan and Anthranilic Acid. In Encyclopedia of Plant Physiology, New Series, Vol. 8 (Bell, E. A., B. V. Charlwood, eds.), p. 128. Berlin-Heidelberg Springer-Verlag. 1980. 

This approach though also has some complications, particularly when the alkaloid has more than one nitrogen and more than one biosynthetic amino acid precursor unit. For example, evodiamine and rutaecarpine, from the fruits of Euodia mtaecarpa (Rutaceae), can be classified as alkaloids derived from tryptophan. In addition, one of the nitrogen atoms of each alkaloid is derived from an anthranihc acid unit. Therefore, these alkaloids can be classified as alkaloids derived fiom tryptophan and as alkaloids derived from anthranilic acid. In this volume, these alkaloids are discussed in Chapter 2.19 as alkaloids derived from tryptophan. 

Most alkaloids are derived biosynthetically from ornithine, lysine, nicotinic acid, anthranilic acid, phenylalanine, tyrosine, and tryptophan (Fig. 27.1) (Leete, 1983). In some groups, however, the source of the nitrogen is not from an amino acid. 

Members of the family contain alkaloids based on several major pathways such as benzylisoquinoline (tyrosine derived), quinolone, furoquinoline, quinazoline (all from anthranilic acid), imidazole (histidine), indoloquinazoline (tryptophan), and both simple aliphatic and aromatic amines. In the tribe Ruteae (Rutoideae), no fewer than five types of alkaloids are common to the three major genera. Quinolone, furoquinoline, and acridone alkaloids are especially widespread within the family, being found in four of the five... 

Grocer, D., Alkaloids derived from tryptophan and anthranilic acid, in Secondary Plant Products (E. A. Bell and B. V. Chari-wood, eds.). Encyclopedia of Plant Physiology, N. S., Vol. 8, 128-159, Springer-Verlag, Berlin, 1980. 

Groger, D. Alkaloids derived from tryptophan and anthranilic acid. In Encyclopedia of Plant Physiology, New Series, Vol. 8, Secondary Plant Products (E. A. Bell, B. V. Charlwood, eds.), pp. 128-159. Springer, Berlin-Heidelberg-New York 1980 Johne, S., Groger, D. Natiirlich vorkommende Chinazolin-Derivate. Pharmazie 25, 22-44 (1970) Luckner, M., Johne, S. Alkaloids derived from anthranilic acid. In Biochemistry of Alkaloids (K. Mothes, H. R. Schiitte, M. Luckner, eds.), Deutscher Verlag der Wissenschaften, Berlin 1985... 

Presently, alkaloids are classified into three main categories as shown in Fig. 8.2 [6]. This chemical classification of alkaloids is universally adapted and mainly depends on the type of heterocyclic ring structure present (Fig. 8.3). Alkaloids are further classified according to the amino acids (or their derivatives) from which they originate (Fig. 8.4) [6]. The most important classes are derived from the amino acids, ornithine and lysine, or from the aromatic amino acids, phenylalanine and tyrosine, or from tryptophan and a moiety of mavelonoid origin. A number of alkaloid-based compounds are also derived from anthranilic acid or from nicotinic acid. 

Figure 1.6a. Structures of some Rutaceae alkaloids. This order is recognized for accumulating alkaloids derived from different biosynthetic pathways, e.g., from anthranilic acid, tyrosine, tryptophan, and histidine.

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