Polyketide-terpenoid

The area covered by natural products chemistry is boundless as it deals with nature itself. There is literally no limit to the topics to be dealt with. This volume 29 continues the tradition of supplying us with superb review articles written by experts. The articles in this volume deal with the screening, isolation, structure, synthesis, biosynthesis, and pharmacology of plant and microbial natural products that exhibit antimitotic, cancer chemotherapeutic, enzyme inhibitory, antiinflammatory, antibiotic and molting hormone activities. The compound types also cover a huge range of natural products, i.e., polyketides, terpenoids, sugars, alkaloids, proteins, and enzymes. 

Biosynthetic studies have indicated a mixed polyketide-terpenoid origin for the unusual fungal metabolite andobenin (51) (Scheme 8). The two extra methyl groups ( ) are derived from methionine. Andobenin co-occurs with andilesin (52) whose structure has been recently elucidated by X-ray and c.d. analysis. ... 

The term meroterpenoids is generally used to denote a wide range of natural products of mixed (polyketide-terpenoid) biogenesis [121]. In our laboratory, the titanocene-catalyzed 6-endo/6-endo cyclization of 31, ob-... 

The Hajos-Parrish reaction can be regarded as the enantioselective version of the Robinson annulation. In the early stages of the synthetic effort targeting the mixed polyketide-terpenoid metabolite (-)-austalide B, L.A. Paquette and co-workers used this transformation to prepare the key bicyclic precursor in enantiopure form. Ethyl vinyl ketone was reacted with 2-methyl-1,3-cyclopentanedione in the presence of catalytic amounts of L-valine to afford the bicyclic diketone with a 75% ee. 

The labelling studies described above provide definitive evidence for the mixed polyketide-terpenoid biogenesis of the andibenins, andilesins, andi-tomins, austin and terretonin. The formation of the bicyclo [2.2.2] octane system in the first two classes of metabolite provides a rare example of a biosynthetic Diels-Alder reaction. The biosynthetic relationship of austin and andibenin was supported by the isolation of austin from another mutant strain of A. variecolor [81]. Further metabolites related to austin have been isolated from Emericella dentata [82] and Penicillium diversum [81]. Other complex metabolites which are almost certainly further products of the meroterpenoid pathway are fumiga-tonin (102) and paraherquonin (103) which have been isolated from Aspergillus... 

Biosynthesis of polyketide-terpenoid (meroterpenoid) metabolites, andibenin A... 

Natural products presumably biosynthesized through a [4 + 2] cycloaddition frequently occur in the literature. Several reviews on natural Diels-Alder-type cycloadducts covered more than 300 cycloadducts, including polyketides, terpenoids, phenylpropanoids, alkaloids, and natural products formed through mixed biosynthetic pathways. Representative examples of natural [4 + 2] adducts are shown in Figure 1. These include intramolecular adducts pinnatoxin (5) and nargenicin (6), a simple intermolecular adduct... 

Signal transduction enzyme inhibition assays guided the isolation of two novel hybrid polyketide-terpenoid metabolites from a Penicillium sp. growing in the deepest waters (>750 ft) of Berkeley Pit Lake [9], Their structures were deduced by spectroscopic analysis and confirmed by single crystal x-ray analysis on berkeleydione (13). Both compounds inhibited signal transduction enzymes caspase-1 and matrix metalloproteinase-3. Berkeleydione (13) was also active against non-small cell lung cancer in NCI s 60 cell line anti-tumor screen. 

The phytochemical diversity of C. saliva is well illustrated by more than 500 com-potmds isolated from this plant, encompassing all major classes of phytochemicals (polyketides, terpenoids, alkaloids, flavonoids, stilbenoids, oxylipins). Undoubtedly, the most important and peculiar secondary metabolites of C. saliva are cannabinoids, a class of mono- to tetracyclic C21 (or C22) meroterpenoids encompassing more than 100 members. These compounds are synthesized in secretory cells of glandular trichomes, most concentrated in unfertilized female cannabis flowers prior to senescence. A number of detailed accounts on the cannabinoid chemistry have been reported in the literature [6-8], also recently by Appendino et al. [9]. In this paragraph, we will provide an updated, although not comprehensive, account of the chemistry of this fascinating class of secondary metabolites. 

Figure 4 Halogenated terpenoid and polyketide metabolites isolated from red algae in the genera Laureucia and Plocamium...

The late cannabinoid pathway starts with the alkylation of ohvetolic acid (3.2 in Fig. 4) as polyketide by geranyl diphosphate (3.1) as the terpenoid unit. Terpenoids can be found in all organisms, and in plants two terpenoid pathways are known, the so called mevalonate (MEV) and non-mevalonate (DXP) pathway as described by Eisenrich, lichtenthaler and Rohdich [23,24,29,30]. The mevalonate pathway is located in the cytoplasm of the plant cells [30], whereas the DXP pathway as major pathway is located in the plastids of the plant cells [29] and delivers geranyl diphosphate as one important precursor in the biosynthesis. 

Figure 11.1 Representative secondary metabolites produced by Streptomyces ceolicolor and other microorganisms, including aromatic polyketides actinorhodin and tetrohydroxynaphthalene (a), side-rophore desferrioxamines (b), polyunsaturated fatty acid eicosapentaenoic acid (c) and terpenoids beta-...

One current estimate of NP diversity totals ryo.ooo different structures, yet this huge chemical diversity is generated from only a few biochemical pathways that branch from the metabolism shared by most organisms. About 60% of the known NP diversity comes from one ancient pathway (the isoprenoids or terpenoids), another 30% comes from some other ancient pathways related to each other (the polyphenols, phenylpropanoids or polyketides) and less than 10% of NPs (alkaloids) comes from a more diverse family of pathways. There seems to be a rough correlation between the number of species possessing one pathway and the total diversity of NPs made by that route. Consequently, the minor groups of NPs that comprise less than 1% of the total NP diversity (e.g., the glucosinolates) tend to be restricted to a small number of species. 

Although far less numerous than the terpenoid/isoprenoid or polyketide NPs, the alkaloids (with an estimated 20,000 different structures) have a special place in NP research because a few are of great value to humans—for example, morphine, theobromine, caffeine, vincristine, quinine, codeine, cocaine, nicotine and strychnine. These often complex chemicals are found in about 20% of vascular plants and a smaller number of fungi, marine invertebrates and a few bacteria. ... 

In the 1970s the biosynthesis of cannabinoids was investigated with radiolabeling experiments. 14C-labeled mevalonate and malonate were shown to be incorporated into tetrahydrocannabinolic acid and cannabichromenic acid at very low rates (< 0.02%). Until 1990 the precursors of all terpenoids, isopentenyl diphosphate and dimethyl-allyl diphosphate were believed to be biosynthesized via the mevalonate pathway. Subsequent studies, however, proved that many plant terpenoids are biosynthesized via the recently discovered deoxyxylulose phosphate pathway (Eisenreich et al., 1998 Rohmer, 1999). It was shown that the Cio-terpenoid moiety of cannabinoids is biosynthesized entirely or predominantly (>98%) via this pathway (Fellermeister et al., 2001). The phenolic moiety is generated by a polyketide-type reaction sequence. 

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