The macrocyclic trichothecenes are a class of potent antibiotics which possess a wide range of bioactivity including insecticidal, antifungal, antibacterial, and antiviral. They also are phytoxic and cytotoxic and exhibit a high degree of cytostacitity; the latter property makes them attractive antitumor candidates. The cytotoxicity of a series of trichothecenes, which includes both simple (e.g. T-2 toxin, anguidine, verrucarol, etc.) and macrocyclic trichothecenes, has been shown to correlate strongly and inversely with the rates of acid-catalyzed rearrangements to the nontoxic apotrichothecenes. A model to explain the structure-activity relationship for the chemical reactivity is proposed and a series of trichothecene derivatives, some having rigid conformations, are to be prepared and their chemical and biological activities are to be measured. In a collaborative study, metabolism studies in dogs are to be conducted on verrucarol, a relatively weakly toxic trichothecene, which will evaluate the relevance of the trichothecene with apotrichothecene reaction to the in vivo metabolism. A series of chemical modifications are to be carried out with a new class of highly toxic macrocyclic trichothecenes, the myrotoxins, which, based on our previous models, will yield highly active in vivo anticancer agents of high potency. In related work, we are collaborating with scientists at the Center for Disease Control (CDC) in Atlanta, GA and with workers at NIOSH in Morgantown, WV in the evaluation of the role played by toxigenic isolates of Stachybotrys atra in the etiology of legionnaire's disease (CDC) and indoor air pollution (NIOSH). Recent evidence suggests that this organism, in certain circumstances, may be a source of some health problems for people living or working in buildings contaminated with this fungus.
