Fused ring polyketides

Today, despite recent developments in combinatorial and other chemosynthetic strategies, flmgi and streptomycetes remain the most prolific sources of new candidate drugs and agrochemicals. Both phyla elaborate bicyclic, tricyclic and tetracyclic fused ring polyketides, however, a preliminary survey of isotopically labelled precursor incorporation studies has revealed a consistent difference in the modes of cyclisation by which their characteristic polybenzenoid metabolites are formed. These and subsequent observations (yide infra) provide the basis for a novel biosynthetic classification of microbial fused ring polyketides. 

INCORPORATION OF INTACT C2-UNITS IN FUNGAL AND STREPTOMYCETE FUSED RING POLYKETIDES... 

A preliminary survey of [ C2]acetate incorporation studies indicated the consistent utilisation of mode F and S cyclisation pathways in the formation of the corresponding fused ring polyketides of fungi and streptomycetes. ... 

Figure 2. Distribution of C2-units in the carbon skeletons of microbial fused ring polyketides...

Representative fungal (mode F) and streptomycete (mode S) fused ring polyketides ... 

Figure 3. Classification of fused ring polyketides of streptomycetes and fungi based on the mode of cyclisation of the initial carbocyclic ring...

While it is likely that some polyketides such as ochrephilone (49) are derived from more than one chain, the majority of known fungal and streptomycete fused ring polyketides are formed through folding of single chain intermediates. 

If identical plant and microbial polyketides are indeed derived by common or closely related pathvwiys, it would appear that higher plant species can produce both types of synthases required for the formation of mode F and mode S-cyclised fused ring polyketides. The biosynthesis of aloesaponarin II by steptomycetes is known to involve an iterative type IIPKS and, by analogy with other fungal aromatic polyketide synthases, it is likely that a type I PKS is responsible for the formation of chrysophanol. However, at present little is known of the nature of PKSs responsible for the formation of fused ring polyketides in plants. 

Two chapters in section five describe different aspects of the biosynthesis of polyketides, which are numerically the most abimdant and structurally diverse class of natural products. The first chapter reports in vivo and in vitro studies aimed at enhancing our understanding of the basic pathways of polyketide assembly with a view to producing novel compounds. In the second chapter, a consistent difference in the modes of cyclisation of the fused ring polyketides of fungi and streptomycetes is described, which provides the basis for a new biosynthetic classification of these metabolites. 

Kosan Biosciences was formed almost 6 years ago, founded on an interest in polyketides, microbial metabolite-based drugs. Polyketides have many diverse chemical structures including erythromycin, which will be mentioned again later. These chemicals include fused-ring aromatic compounds, compounds decorated with sugars, and compounds with large stretches of double bonds. Each of these compounds has different biological activities and utilities, but they are all made in nature by very similar biochemistry. 

FUSED RING AROMATIC POLYKETIDES ARE FORMED BY DIFFERENT CYCLISATION PATHWAYS IN FUNGI AND STREPTOMYCETES... 

Structurally complex fused ring flm polyketides studied in this manner include the potent carcinogen aflatoxin Bi (7/ and its precursors averufin (8) and sterigmatocystin (9) (Scheme 4). The resulting couplings were consistent with... 

Streptomycetes also produce a variety of fused ring aromatic polyketides, the carbon skeletons of some of which closely parallel those of their fimgal counterparts. However, with very few exceptions, such as the melanin spore pigment precursor 1,3,6,8-tetrahydroxynaphthalene (10, Scheme 5) of Alternaria alternate and Streptomyces griseus, fimgi and streptomycetes have not been found to produce identical fiised ring structures. 

Additional fused ring streptomycete polyketides shown in Figure 1 include the tetracyclic decaketides aclacinomycin (19), tetracenomycin C (20) and the angucycline vineomycin Ai (21), " which are formed by mode S folding. Although the incorporation of [ C2]acetate into cetocycline (13) and tetracenomycin C (20) does not appear to have been studied per se, the proposed folding mode of 13 is supported by the... 

Figure 4 Fungal and bacterial non-fused ring carbocyclic polyketides (B = number of intact C2-units in each benzene ring)...

Among the above wild type streptomycete fused ring fermentation products, only the unusual 1,8-disubstituted naphthalene constituent 23a of the enediyne antibiotic neocarzinostatin provides a possible exception to the predominant S mode of cyclisation. However, the structures recently assigned to two hybrid streptomycete polyketides are similarly not in accord with the classification outlined in Figure 3. 

Fused Ring Aromatic Polyketides are Formed by Different Cyclisation Pathways in Fungi and Streptomycetes 249... 

Figure 5. (A) Proposed mechanism for the formation of aromatic polyketides by OKS and its mutants. The enzymes catalyze chain initiation/elongation, and possibly initiating the first aromatic ring formation reaction at the methyl end of the polyketide intermediate. The partially cyclized intermediate are then releasedfrom the active-site and undergo spontaneous cyclizations, which leads to formation of the fused ring systems. (B) Distribution pattern of aromatic polyketides produced by OKS and its mutants. (Reproduced from reference 7b. Copyright 2005 American Chemical Society.)...

Trichodermatides A—D (66—69) have been characterized from the fungus Trichoderma reesei, obtained from marine sediments in China. Octaketide derivatives such as 67—69 with an 0 ,/ -unsaturated cyclohexenone fused to a pyran ring have repeatedly been reported from the genus Trichodermabut do not seem to occur elsewhere in nature. 66 is the first example of a pentacyclic polyketide with a ketal moiety. 66—69 exhibited weak cytotoxicity toward the A375-S2 human melanoma cell line. 

Prorocentin (197), a C35 polyketide with four pendant methyl groups, possessing an all-trtfwrtriene moiety, an epoxide, a fnran ring, and the 6/6/6-trans-fused/spiro-linked tricyclic ether rings, was isolated from an okadaic acid-producing strain of P. The relative stereostructure was elucidated on the basis of spectral data. 

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