Fungal macrocycles

The trichoverroids and fungal macrocycles are products of Myrothecium and Stachybotrys spp., and one species each of Acremonium, Ceratopycnidium, Cercophora, Cylindrocarpon, Phoma, Phomopsis, and Verticinimonosporium. Acremonium, Ceratopycnidium, Cercophora and Phoma are new sources reported since 1991. 

The shrub Baccharis artemisioides is a new source of the known fungal macrocycles verrucarins A and J, and roridins A, D and E, as is the Baccharis spp. endophyte Ceratopycnidium baccharidicola 164). B. megapotamica and B. coridifolia remain the only sources of the baccharinoids. 

Micafungin (21 Mycamine / Funguard ) FR901379 Macrocyclic lipopeptido- lactone Semi-synthetic NP Microbial Antifungal Inhibits fungal cell wall synthesis 186, 208-210, 248-260... 

Several species of Fusarium infect com, wheat, barley, and rice. Under favorable conditions they elaborate a number of different types of tetracyclic sesquiterpenoid mycotoxins that are composed of the epoxytrichothecene skeleton and an olefinic bond with different side chain substitutions (fig. 9). Based on the presence of a macrocyclic ester or ester-ether bridge between C-4 and C-15, trichothecenes are generally classified as macrocyclic (type C) or nonmacrocyclic (types A and B) (table 5). Other fungal genera producing trichothecenes are Myrothecium, Trichoderma, Trichothecium, Acremonium, Verticimonosporium and Stachybotrys. The term trichothecenes is derived from trichothecin, the first compound isolated in this group [115, 147-153]. 

Stachybotrys chartarum (previously also called S. atrd), the fungal cause of stachybotryotoxicosis and sick building syndrome, is a black mold. There are two toxic chemo-types of S. chartarum, one elaborating highly toxic macrocyclic trichothecenes and the other less toxic atra-nones and simple, but not macrocychc, trichothecenes (Andersen et al, 2002). Exposure may be by ingestion, e.g. exposure to contaminated straw, or inhalation as when mold grows in water-damaged homes or air ducts. 

Dudley, M.W., Dueber, M.T. and West, C.A. (1986) Biosynthesis of the macrocyclic diterpene casbene in castor bean (Ricinus communis L.) seedlings changes in enzyme levels induced by fungal infection and intracellular localization of the pathway. Plant Physiol., 81, 335-42. 

Synthetic Applications. (5 )-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) was first described in 1971 as an intermediate in the synthesis of o-ribose from r-glutamic acid. Since then, this lactone and its (f )-enantiomer have found widespread use as chirons for constructing a rich variety of natural products ranging from simple pheromones to complex macrocycles and ionophore antibiotics. The chemical manipulation of these chirons often involves lactone cleavage at an early stage, - - as illustrated by the preparation of suitable intermediates for the synthesis of the Vespa orientalis pheromone (R)-S-n-hexadecanolactone (14) (eq 4), the antiviral fungal metabolite brefeldin A (15) (eq 5), and (7aa)-cp/-hemibrevetoxin B (16) (eq 6). ... 

A variety of macrocyclic natural products, either peptides or peptide-mimetic structures with HD AC inhibitory activity and promising pharmacological effects, have been reported. Some of them are shown in Fig. 5 for illustration for instance, romidepsin 9 (FK228) exhibits excellent class I inhibitory activity and has recently been approved by the FDA for the treatment of cutaneous T-cell lymphoma patients [58, 59]. Similarly, the marine natural product largazole 10 that demonstrates potent antiproliferative activity [60] and HC-toxin 11, a fungal metabolite with immunosuppressant activity, have been investigated as cytostatic agents [61, 62]. 

The antifungal properties of ferrocene derivatives have been studied. Compounds 27 and 28 (see above and Figure 12) have also been evaluated for their antifungal properties against six fungal strains. The antifungal activity was enhanced by up to 42% on chelation of a metal ion within the macrocyclic cavity. The activity of the chelate complexes closely approached that of the control dmg miconazole. 

A plausible sequence based on inspection of the structural formulae, and in which the roridin skeleton holds a central position, is shown in Scheme 6. The scheme assumes that the pathway in Baccharis, or its endophyte (see below), is essentially the same as in Myrothecium, and that all the fungal producers of macrocyclic trichothecenes use the same pathway. 

Several fungal metabolites have been found which enhance the passive uptake of potassium. Some, like nonactin and monactin 14.6), are macro-tetrolides others, like valinomycin, are depsipeptides. Valinomycin 14.7) (from Streptomycesfulvissimus) is a macrocycle composed of three residues of each of L-valine, D-valine, L-lactic acid, and D-a-hydroxy-isovaleric acid, linked alternatively by ester and amide bonds to form a 36-membered ring (Shemyakin... 

A number of polyoxygenated fungal metabolites are assembled from C2, C3, and C4 units. Starter units of propionyl-CoA and successive additions of methylmalonyl-CoA are especially important in the formation of many of these compounds (O Hagan, 1990). Most of these metabolites possess large rings and are potent antibiotics they are known collectively as macrocyclic or macrolide antibiotics. One well-known example of this group of compounds is erythromycin A (34) from Streptomyces erythreus (Fig. 5.18) (Omura, 1984 Simpson, 1984). An extensive literature deals with these antibiotic compounds but is beyond the scope of this text. 

Antibiotic A26771B inclndes in its structure a 2-ene-l,4-dione functionality, present in the cytochalasins, a group of fungal metabolites. Trost and Brickner reported a synthetic strategy for the construction of the macrocycle and simultaneously a creation of the... 

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