Macrocyclic trichothecenes

There exist just a few total syntheses of macrocyclic trichothecenes. However, all of these deal with the synthesis of verrucarol (454), a hydrolysis product of the naturally occurring verrucarin A (380). Venucarol (454) represents the sesquiterpenoid moiety of most macrocyclic trichothecene derivatives. To date, there are several syntheses of this moiety. In 1998, the most recent total synthesis was published by Tadano et al. (327). 

In the next step, alkene 450 was formed via a Wittig reaction, then the MOM-groups were deprotected with TMSBr and the diol was obtained, which was monoprotected with TBSOTf to give 451. This diol is known as 12,13-deoxyverrucarol and was isolated as an alkaline hydrolysis product of verrucarin K by Breitenstein and Tamm (330). 

The following total syntheses of verrucarin A (380), roridin E (378), and baccharin B5 (379) all use verrucarol (454) as an intermediate. 

Verrucarin A (380) is one of the most important and best described macrocyclic trichothecenes. This compound was obtained for the first time in 1962 by isolation from Myrothecium roridum and M. verrucaria by Tamm et al. 331). This same group performed a considerable amount of research in this area and in 1982 they published the total synthesis of verrucarin A (380) 317). 

In 1983, Still et al. published methods for the total synthesis of roridin E (378) and baccharin B5 (379) (332). Roridin E (378) was isolated for the first time in 1965 from Myrothecium verrucaria and baccharin B5 (379) was obtained in 1976 from the plant Baccharis megapotamica (333,334). 

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However, the most interesting of the Baccharis species is most certainly B. coridifolia. This plant is well-known in Brazil as being one of that country s most toxic plants (49) and is a serious hazard to livestock who graze in pastures populated by B. coridifolia (49). Four separate collections were made of B. coridifolia (48). Three of these collections were "From several miles outside Curitaba and a fourth collection in a pasture near Santa Maria, the site of an earlier collection of 13. coridifolia (47), and several hundred miles away from Curitaba. ThTs latter collection and two of the three former collections contained appreciable quantities of roridins A and E. A third collection from near Curitaba appeared to contain no macrocyclic trichothecenes. From a 20 g sample of one of the collections of B. coridifolia... 

Our most recent work with B megapotamica has been with the isolation of large quantities of baccharinoids from a 1800 Kg collection. The workup of the crude extract (ca. 30 Kg of black tarry material) of this plant material was conducted by Dr. Fred Boettner of Polyscience, Inc. This near Herculean task required tremendous quantities of solvents, column packings and time to complete. An outline of the fractionation scheme is presented in Figure 2. Fractions F6-F11 contain a large number of baccharinoids. To date, we have characterized over twenty macrocyclic trichothecenes found in B mega-... 

Ex vivo studies have revealed that trichothecenes can both inhibit and stimulate leukocyte function.12 For example, trichothecenes are toxic to alveolar macrophages,13 but drive differentiation of human myeloid leukemic cells.14 Dose-dependent decreases or increases in B- and T-cell mitogen responses are observable in lymphocytes from animals exposed to T-2 toxin, DON, or various macrocyclic trichothecenes these toxins similarly impair or enhance mitogen-induced lymphocyte proliferation in vitro.12 Rank order of inhibitor potency in rodent and human lymphocyte proliferation assays is Type D > Type A group > Type B group and is dependent on degree of acylation as well as of uptake and metabolism. 

Grove JF (1996) Non-macrocyclic trichothecenes, part 2. Prog Chem Org Nat Prod 69, 1-70. 

Stachybotryotoxicosis Stachybotrys atra (Various macrocyclic trichothecenes)... 

It is not our intention to discuss all the data concerning the trichothecenes that are active against both plants and animals or to name them. They are metabolites of the fungi Acremonium, Cylindrocarpon, Dendrostilbella, Fusarium, Myrothecium, Trichoderma and Trichothecium, but only Cylindrocarpon, Fusarium, Myrothecium, and Trichothecium are considered phytopathogenic. And, as a further note, of 15 evaluated in the etiolated wheat coleoptile bioassay, all were significantly active (p< 0.01) to one degree or another, and the most active were the macrocyclic trichothecenes. Of the latter, verrucarin A and J, and trichoverrin B were highly potent. 

Recent studies indicate that some trichothecenes can bind covalently. Satratoxin G, a macrocyclic trichothecene, forms covalent adducts with proteins and potentially other cellular macromolecules (Gregory et al, 2004 Yike et al, 2006). The ability of satratoxin G to bind to albumin provides a potential biomarker of exposure to the toxin as well as to Stachybotrys chartarum. 

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. 

Experimentally, the macrocyclic trichothecenes satra-toxin G, isosatratoxin F, and roridin A have been shown to cause nasal and pulmonary toxicity when administered intranasally or intratracheally to mice. Intranasal exposure of satratoxin G and roridin A induced apoptosis of olfactory sensory neurons resulting in atrophy of the olfactory epithelium and olfactory nerve layer of the olfactory bulb in the frontal brain (Islam et al, 2006, 2007). Alveolar-type II cells and alveolar macrophages were injured following intratracheal instillation of isosatratoxin F or Stachybotrys spores with marked changes in surfactant synthesis and secretion (Rand et al, 2002). 

Islam, Z., Amuzie, C.J., Harkema, J.R., Pestka, J.J. (2007). Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin A kinetics and potentiation by bacterial lipopolysaccharide coexposure. Toxicol. Sci. 98 526-41. 

Trichothecene mycotoxins are a group of sesquiterpenoid mycotoxins produced by fungi from the Fusarium family. There are four types Type-B such as nivalenol differs from Type-A such as diacetoxyscirpenol by the presence of the keto-group in the C8 position. Type-C has an additional epoxide group, and Type-D are macrocyclic trichothecenes. Human and animal toxicoses by these toxins have been dne to the consnmption of contaminated grain. The structure of some of the Type-A and Type-B componnds is shown in Table 14.2. 

A mechanistically related and mild fragmentation is that of 2-trimethylsilylethyl esters (Tmse esters). The Tmse residue is a selectively cleavable carboxy-protecting group (see Volume 6, Chapter 3.2) Examples are known for the synthesis, via these esters, of peptides, macrolides such as curvularin and macrocyclic trichothecenes like verrucinol (Scheme 54). °... 

Trichothecenes from Pusarium, Stachybotrys, and Trichoderma, among others. Note Trichothecenes include sesquiterpenes with a trichothecane skeleton, olefinic groups at C-9 and C-10, and epoxies at C-12 and C-13. Macrocyclic trichothecenes have a carbon chain between C-4 and C-15 in an ester or ether linkage (e.g., T-2 toxin, DON, satratoxins G and H verrucarins B and J, trichoverrins A and B)). 

Mycotoxins may include butanol, estrogenic compounds (e.g., zearalenone), heptanone, lactones, lactams (patulin), stachybotrylactones, stachybotry-lactams, 2-pentylfuran, 2-hexanone, 2-methyl-1-propanol, 3-methylfuran, 2-methylisoborneol, 3-methyl-2-butanol, and macrocyclic trichothecenes (Satratoxins F, G. and H, Roridine, Verrucarinj, and Trichoverrols). 

Macrocyclic trichothecenes such as Satratoxin also were identified as causative toxicants. Since the 19th century, Alimentary Toxic Aleukia (ATA) or septic angina has been reported in the Soviet Union and symptoms of the disease were described as necrotic angina, leukopenia, hemorrhage, and exhaustion of bone marrow and death. 

Several studies investigated the in vivo toxicity of macrocyclic trichothecenes [135], It is assumed that their toxic effects are based on the inhibition of protein synthesis, with a slowly progressing respiratory depression and paralysis of skeletal muscles. The epidermal remains of these plant species that produce acute intoxication in rumiants were also quantified by microhistological analysis in the gastrointestinal content of sheep which had been experimentally poisoned [136]. 

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