Polyketides coniine

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. 

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). 

Pinidine and Coniine.—Pinidine (8) and the hemlock alkaloid coniine (9) are unusual among simple piperidine alkaloids in being derived exclusively from acetate units. The combination is in each case a simple linear one and proceeds either via polyketide intermediates or, arguably in the case of coniine, via the fatty acid (10). Strong evidence from tracer and enzyme studies points to (11) as an intermediate... 

The H. a. are pseudoalkaloids, their carbon skeletons do not originate from amino acid metabolism but rather from polyketide metabolism (figure). Coniine is a highly toxic alkaloid and is rapidly resorbed by mucous membranes and intact skin. It acts at first as a stimulant for motoric nerve endings followed by cu-rare type paralysis of striated musculature. Death follows after 0.5-5 h in full consciousness through par-... 

Thujone is a terpene that is thought to be the poisonous principle in absinthe— the drink that reduced many artists and writers to idiocy in Paris around 1900. Coniine is an alkaloid and the poison in hemlock with which Socrates was executed. Thromboxane is a polyketide involved in blood-clot formation and is a human natural product. 

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. 

Pelletierine is biosynthesized through the incorporation of lysine. Among the several types of alkaloid possessing the piperidine nucleus, lobeline involves a similar biosynthetic pathway (Section 4.4) as that of pelletierine, whereas arecoline and coniine are biosynthesized through completely different pathways. The former alkaloid is derived lirom nicotinic acid (Section 10.3), and the latter alkaloid is biosynthesized via the polyketide pathway (Section 15.1). 

Arecoline is thought to be derived with nicotinic acid (niacin) as a precursor (Section 10.1). On the other hand, coniine, a toxic alkaloid of Conium maculatum (Apiaceae) and also possessing the piperidine skeleton, is biosynthesized through the polyketide pathway, which is completely different from that of arecoline. Coniine will be discussed in Chapter 15. 

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. 

On the other hand, when [l- C]acetate was fed to this plant, labeled coniine was obtained. In addition, through degradation studies, it was found that the even-numbered carbons of coniine were labeled [4]. Thus, through the experiments described above, it was clarified that although the skeleton of coniine is very similar to that of peDetierine, coniine is biosynthesized through the polyketide pathway instead of fiom lysine, as in the case of pelletierine. These biosynthetic studies on coniine and related alkaloids were reviewed by Leete [5]. 

A further example is pinidine, isolated from Pinus sabiniana and Pinus Jeffreyi (Pinaceae), which is derived through the same pathway as coniine [6-8]. It was demonstrated that pinidine was formed in P. jeffreyi through the polyketide pathway by feeding experiments with labeled precursors [9]. 

Biological Activity of Tropane Alkaloids Distribution of Tropane Alkaloids Piperidine Alkaloids Alkaloids from Piper Species Piperine Alkaloids Involving Condensation with Acetate/Malonate Sedum Alkaloids Lobelia Alkaloids Lycopodium Alkaloids Piperidine Alkaloids in Insects Polyketide-Derived Alkaloids Coniine... 

A number of polyketide-derived alkaloids are known to occur. Probably best known among these are coniine (48) and related compounds, found primarily in the Apiaceae (mostly in the genus Conium) (Leete, 1971). Other alkaloids with similar origin are pinidine (49) from pines, the Galbuli-... 

Although the alkaloids coniine (48) and y-coniceine (51) bear a structural resemblance to the piperidine alkaloids, these compounds are derived from a polyketide pathway (Fig. 29.17). Lysine is a poor precursor, and early attempts to show incorporation of this compound resulted in failure. Acetate is a much better precursor. Coniine is a highly toxic alkaloid and is one of the toxic components of poison hemlock (Conium maculatum, Apiaceae) (Cutler, 1992). Otherwise, alkaloids are very uncommon in the Apiaceae. Coniine does occur in several other plants, for example, Sarracenia (Sarracenia). y-Coniceine is found in several species of Aloe (Liliaceae) (Dring et al., 1984). Coniine is toxic to the aquatic plant Lemna (Wink, 1993). The LDioo p.o. in the... 

Polyketides of this group are either carbocyclic compounds (like 6-methyl-salicylic acid) hydroxylated acetophenones, or possess an 6-membered (asperlin, coniine) or 7-membered (stipitatonic acid) N- or 0-heterocyclic ring. Often dimeric compounds occur, e.g., lecanoric acid. 

Most polyketides of this type are produced in fungi living either in the free state or in symbiosis with green algae in lichens. Others, e.g., coniine and plumbagin... 

The entire skeleton of coniine 6.14) derives from acetate, with labelling of C-2, C-2, C-4, and C-6 by [l- C]acetate. A polyketide pathway immediately seems likely and 5-oxo-octanoic acid 6.11) and the corresponding aldehyde 6.12), with the necessary functionality for inclusion of the nitrogen atom, were shown, by tracer and enzymic evidence, to be implicated in coniine biosynthesis, as was y-coniceine 6.13) which is also a hemlock alkaloid. These results [6, 7] lead in a straightforward way to the pathway shown in Scheme 6.5. Most curiously, however, it has been found that octanoic acid... 

Coniine from the hemlock plant Conium maculatum is a simple example of an alkaloid, although its biosynthesis is unusual. It was thought that coniine would be derived from the amino-acid lysine, but labelled lysine was not converted to coniine. It is unusual in being derived from a type I polyketide (Chapter 4). Both [6- C]-5-oxo-octanoic acid and [6- C]-5-oxo-octanal are well-incorporated into labelled coniine (Figure 9.3). 

---