The two major objectives of this proposal are: (1) Implementation of organoiron methodology developed in our laboratory for the synthesis of unnatural trichothecene analogs and their natural product counterparts, and evaluation of the analogs so produced as antiviral and antitumor agents and for the production of antisera. The synthetic analogs already prepared will be subjected to biological evaluation by determining in vitro toxicity using human spleen cell cultures (performed by Dr. A Brimfield Uniformed Services University of the Health Sciences) in order to determine their potential for producing antibodies to trichothecenes. Such antibodies cannot be produced using the natural products owing to their extreme toxicity, and their development would provide a means of tackling some of the health hazards presented by the occurrence in grain of the highly toxic trichothecene, vomitoxin. (2) Full development of a general approach to several trichothecene natural products via a common advanced intermediate, exploiting an ester directed iodohydrin formation to initiate the sequence of stereo-controlled cyclopentrene functionalization procedures. The chemical studies in (1) are designed to explore more fully the scope of cycle hexadienyliron complexes as cyclohexenone Y-cation equivalents. We plan to overcome some of the major problems associated with this methodology by investigating (a) the effect of metal ligand environment on hydride abstraction and subsequent carbon nucleo phile additions, and (b) free radical coupling reactions between the organometallic complex and acceptor molecules. These studies are expected to lead to new methods for carbon-carbon bond formation which will find application over a broad range of natural products synthesis, with special emphasis on trichothecenes. The chemical studies in (2) will be intimately associated with an investigation on controlled alkene oxidation methods which were fortuitously uncovered during the 01 year of this project and which also promise general synthetic application.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM030757-04
Application #
3278616
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1983-04-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106