The macrocyclic trichothecenes area a class of potent antibiotics which possess a wide range of bioactivity including insecticidal, antifungul, antibacterial, and antiviral. They also are phytotoxic and cytoxic and exhibit a high degree of cytostacitity; the latter property makes them attractive antitumor candidates. We are to acquire large quantities of macrocyclic trichothecenes from two principal sources: 3800 lbs (dry weight) of the Brazilian shrub, Baccharis megapotamica and via fermentation of the fungus species of Myrothecium. The macrocyclic trichothecenes will be chemically or biologically modified to enhance their in vivo anticancer activity. The biosynthetic origin of the macrocyclic trichothecenes in M. verrucania has been partially established, and the route involves the trichoverrins which appear to undergo dehydrative ring-closure to give roridines E and isoE. Trichoverrins are to be synthesized with appropriate radiolabels, and the biosynthetic pathway to the various macrocyclic trichothecenes will be delineated. The bioproduction of macrocyclic trichothecenes from species of Stachybotrys and Myrothecium is to be studied with respect to increasing yields of difficult to obtain macrocyclic trichothecenes. The former organism is responsible for a number of serious cases of mycotoxicoses in Eastern Europe, and this organism has been shown to produce the macrocyclic trichothecene satratoxins, albeit, in low yield on solid media. We recently have shown that a unique strain of M. roridum (P-D/W-L-514) in liquid culture produces all the classes of the known marocyclic trichothecenes: roridins, verrucarins, satratoxins, and vertisporins. This and related strains of M. roridum as well as several toxigenic strains of Stachybotrys will be employed to produce the rare satratoxins and vertisporins to be used for anticancer drug development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025967-05
Application #
3167115
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-07-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
5
Fiscal Year
1985
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