Polyketides cytochalasins

Cytochalasins.—Previous results have shown that the cytochalasins, e.g. cyto-chalasin B (126), are partially polyketide in origin cf. Vol. 7, p. 29 Vol. 6, p. 44). It has now been shown that [2-2H3,2-13C]acetic acid is incorporated into cyto-chalasin B (126) in Phoma exigua and into cytochalasin D in Zygosporium masonii. Labelling of the expected sites by 13C was observed for both metabolites, but, in keeping with results on other acetate metabolites, most of the deuterium was lost, being retained only in the polyketide chain at C-l 1, which is part of the starter acetate unit.102... 

C16 polyketides respectively) with methionine providing, respectively, two and three Cl units. Results with [l,2- C2]acetate more rigorously defined the constitution of the polyketide fragment of cytochalasin D as that shown in (148). The reported intact incorporation of palmitic acid into brefeldin A (subsequently refuted) prompted the examination of l- C/ C-labelled palmitic and myristic acids together with butyric acid as cytochalasin D precursors. In each case incorporation was through C-1 labelled acetate resulting from fragmentation by way... 

Cytochalasins. — The cytochalasins so far examined are made up of a polyketide plus phenylalanine (cf. Vol. 7, p.28 Vol. 6, p.44). A similar origin for chaetoglobosin A (127) is apparent with tryptophan replacing phenylalanine. Results of experiments... 

Cytochalasins.—The cytochalasins are a group of microbial metabolites of biological interest. Biosynthetic experiments with radioactively labelled materials have indicated that cytochalasin B (186) is formed from phenylalanine (the carboxy-group being retained), nine acetate units, and two Ci units which derive from methionine label from malonate was also incorporated. From these results, which are summarized in (188), it was suggested that cytochalasin B is derived from a Cjg (or Ci6, if C-19 and C-19a represent a separate acetate unit) polyketide chain, initiated by acetate and propagated by malonate. 

Investigation of the biosynthesis of cytochalasin D (187) has revealed a pattern of biosynthesis similar to that of (186). Thus phenylalanine and methionine were found to be precursors. Of particular interest was the observation that methionine provided the C-18 methyl group, which could a priori have arisen perhaps by the incorporation of a propionate unit into the polyketide chain, although it is known... 

The A. A u. B are antibacterial and antifungal metabolites from Aspergillus microcysticus while A. C, D and E have no antimicrobial activity. They belong to the class of cytochalasins. The are formed biogenet-ically from leucine and a polyketide chain. A. A C24H33NO4, Mr 399.53, light yellow powder, [a]p -20°. 

L, and M from Diplodia macmspora (Sphaeropsi-dales) Ch. C is also formed by Penicillium aurantio-virens (on spoiled pecan nuts). The Ch. are myco-toxins related to the cytochalasins and are all cytotoxic, some also have antimicrobial (Ch. A) and phytotoxic (Ch. K) activities. They are formed biosynthet-ically from tryptophan and a polyketide chain (nona-ketides). Some C. induce the formation of multinu-clear cells in mammalian cell cultures. 

Cytochalasins, a complex group of polyketide-derived microbial metabolites, exert profound effects on a variety of cellular processes (Fig. 5.26) and are used widely as cytolog-... 

The very largest of the polyketides are the macrolide antibiotics, e.g. nystatin 3.106). Further examples are the ansamycins which derive by a mixed acetate-propionate pathway (Section 7.6.1). Intermediate in size are the cytochalasins which derive by an acetate (malo-nate) pathway (Section 7.6.2). Where propionate units account for C3 fragments in the ansamycins, methionine and acetate serve in the cytochalasins. The macrolide antibiotics discussed below all follow the former way of generating C3 units. It is clear that, if methyl groups are introduced by two different pathways, this is not adventitious. The methyl groups must have a function possibly like the double bonds in dictating the conformation of the macrocycle. 

The structures of cytochalasins B (26) and D (6), and the results of the corresponding incorporation experiments, clearly demonstrate closely related biogenetic pathways from a polyketide-derived chain with, respectively, two and three introduced Cj units, which is combined with phenylalanine. The assembly of the pieces poses a problem because it involves two chemically difficult condensations—methylene-to-methylene to form the bond between C(8) and C(9), and carbonyl-to-carbonyl to form the bond between C(4) and C(5)—rather than the preferred methylene-to-carbonyl condensations. 

Chaetoglobosins A-J and cytochalasin G, which contain an indole ring system in place of the phenyl ring, appear to be biosynthesized from tryptophan, rather than from phenylalanine, and a polyketide. But no experimental proof is available at present. 

The was Incorporated as indicated with the heavy dots in the above structure. C-11 and the methyl group of the O-acetyl group were the main sites of deuterium. No significant amount of deuterium was detected (by n.m.r.)elsewhere, indicating that the methylene groups of the polyketide exchange with the media) [U- C]Phenylalanine Cytochalasin D 396... 

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