Alkaloids derivation from polyketides

There are several classes of alkaloids. Among these are purines such as xanthine and caffeine, ter-penes (Chapter 22), polyketides (Chapter 21), and alkaloids derived from amino acids. The basic amino acids ornithine, arginine, histidine, and lysine as well as the aromatic amino acids, anthranilate, and nicoti-nate are some of the starting materials.199 201 Robinson202 203 in 1917 recognized that many alkaloids are derived directly from aromatic amino acids. He proposed that alkaloids arise from Mannich reactions (Eq. 25-12) in which an amine and an aldehyde (probably through a Schiff base) react with a nucleophilic carbon such as that of an enolate anion. Many of the... 

It is usual to classify alkaloids (basic nitrogenous metabolites) according to the amino acids (or their derivatives) from which they arise. Thus, the most important classes are derived from the amino acids ornithine, lysine, phenylalanine, tyrosine and tryptophan, and the skeletons of these amino acids are retained largely intact in the alkaloids derived from them. However, this type of classification is often criticized because it fails to include those alkaloids that are derived from a mixed biogenetic pathway (e.g. polyketide or terpenoid) with incorporation of a nitrogen atom, ultimately from ammonia. The alkaloids that are the subject of this review are excellent examples of such compounds and they are often known as pseudoalkaloids. 

Those alkaloids formed by introducing nitrogen (in the form of an amine or ammonia, etc.) into preformed terpenoid moieties are known as terpenoid alkaloids. In these alkaloids, the origin of the nitrogen in the molecule is not through the incorporation of the carbon skeleton of an amino acid. Similarly, alkaloids derived through the polyketide pathway, and the alkaloids derived from a C5-C1 unit, which are described in the following chapters, are also not directly amino acid derived. 

A number of alkaloids are biosynthesized without incorporating an amino acid into the basic skeleton. Some examples are those alkaloids derived from a terpenoid nucleus, as described in the previous chapter coniine, isolated from Conium maculatum and nigrifactin and the piericidins produced by Actinomycetes, which are described in this chapter. The skeleta of these alkaloids are formed through the polyketide pathway, and nitrogen is incorporated subsequently. 

Scheme 19 Biogenesis of alkylquinolin-4(lH)-one alkaloids derived from a polyketide...

Biosynthesis of Polyketides Phenolic Compounds derived from Shikimate. The Biosynthesis of CB - Cjg Terpenoid Compounds Trrterpenoids Steroids, and Carotenoids Non-protein Amino-acids, Cyanogenic Glycosides, and Glucosinolates Biosynihesis of 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 monomeric acridone alkaloids are derived from anthranilic acid and acetate via a polyketide. First studies, in which [ C]-acetate was utilized by cell cultures of Ruta graveolens, indicated that the C-ring of the acridone nucleus was acetate derived. Further research revealed that anthranilic acid is specifically incorporated into the A-ring of rutacridone (Baumert et al, 1982). 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

Coccinelline.—Coccinelline (16) is an alkaloid isolated from the defensive secretion of the Coccinellidae. [l- C]Acetate has been found to be incorporated into this arthropod alkaloid with 16% of the activity confined to C-2 plus C-10. This is consistent with derivation via the polyketide (17) (or the alternative with the carboxy-group at what becomes C-10 of coccinelline). 

It has been suggested 10, 13) that the aromatic and dienone alkaloids having the elaeocarpine-isoelaeocarpine ring skeleton can be formally derived from appropriate condensations of an ornithine unit and a polyketide chain (Chart 2a) and the C alkaloids of Elaeomrpus could similarly be derived from ornithine and a C polyketide (Chart 2b). Elaeocarpidine was considered to be derived from condensation of tryptamine, ornithine, and a C unit as indicated in Chart 2c (15). Onaka 8) has drawn attention to the possibility that, by analogy with elaeocarpidine, elaeocarpine could be derived as shown in Chart 2d and he has noted that elaeocarpidine and 2-methyl-6-hydroxyacetophenone have both been isolated from the same plant as ( )-elaeocarpine and (+ )-isoelaeocarpine 4). This alternative biosynthetic route seems less attractive, however, when the C dienone alkaloids are taken into account. 

The excellent reviews of Berlinck [1-5] have surveyed a great number of guanidine-type natural products. In addition, some guanidine-derived marine alkaloids have been reviewed by Kobayashi and Ishibashi [6,7]. Also, a recent book gave accounts of marine alkaloids including the phakellins, palau amines and oroidin-like dimers derived from bromopyrroles and polyketide-derived polycyclic guanidine alkaloids [8]. 

Pyne et al. proposed an alternative biosynthetic pathway for pyrido[l,2-fl] azepine stemona alkaloids starting from the polyketide derivative 21. Condensation of the latter with 1,4-diaminopropane, a biosynthetic product from the HSS production of homospermidine 3, could provide the piperidine ring intermediate 22. 

One of the oldest recorded incidents of the deliberate use of a toxic plant concerns the simple alkaloid coniine. Based on the writings of Plato in the Phaedo, it is known that the Greek philosopher Socrates (470-399 BC) died by taking an extract of C. maculatum.Thc main toxic component of C. maculatum is coniine (Chapter 15.1), whose basic skeleton is derived from a polyketide precursor. 

Through these experiments, it was confirmed that pseudanVII was biosynthesized from an anthranilyl CoA unit and an unbranched chain that was derived through the polyketide biosynthetic pathway. The remaining part of the quinoline chromophore was derived from malonyl CoA [1]. During the experiments regarding the biosynthesis of this alkaloid, it was found that about twice the level of radioisotope was incorporated when [2-i C] acetate was fed compared with the experiments when ace-... 

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