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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025967-09
Application #
3167118
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-07-01
Project End
1989-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Type
Earth Sciences/Resources
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742
Bergmann, F; Yagen, B; Jarvis, B B (1992) The toxicity of macrocyclic trichothecenes administered directly into the rat brain. Toxicon 30:1291-4
el-Maghraby, O M; Bean, G A; Jarvis, B B et al. (1991) Macrocyclic trichothecenes produced by Stachybotrys isolated from Egypt and eastern Europe. Mycopathologia 113:109-15
Hughes, B J; Jarvis, B B; Sharma, R P (1990) Effects of macrocyclic trichothecene congeners on the viability and mitogenesis of murine splenic lymphocytes. Toxicol Lett 50:57-67
Hughes, B J; Hsieh, G C; Jarvis, B B et al. (1989) Effects of macrocyclic trichothecene mycotoxins on the murine immune system. Arch Environ Contam Toxicol 18:388-95
Schiefer, H B; Hancock, D S; Jarvis, B B (1989) Toxicology of novel macrocyclic trichothecenes, baccharinoid B4, myrotoxin B, and roritoxin B. Zentralbl Veterinarmed A 36:152-60
Jarvis, B B; Midiwo, J O; Guo, M D (1989) 12,13-Deoxytrichoverrins from Myrothecium verrucaria. J Nat Prod 52:663-5
Jarvis, B B; Midiwo, J O; Bean, G A et al. (1988) The mystery of trichothecene antibiotics in Baccharis species. J Nat Prod 51:736-44
Jarvis, B B; Comezoglu, S N; Ammon, H L et al. (1987) New macrocyclic trichothecenes from Baccharis megapotamica. J Nat Prod 50:815-28
Sorenson, W G; Frazer, D G; Jarvis, B B et al. (1987) Trichothecene mycotoxins in aerosolized conidia of Stachybotrys atra. Appl Environ Microbiol 53:1370-5
Jarvis, B B; Lee, Y W; Yatawara, C S et al. (1985) 7 alpha-hydroxytrichodermol, a new trichothecene from Myrothecium roridum. Appl Environ Microbiol 50:1225-8