The general goals of the next grant period will continue to be the development of expedient regio- and stereochemically controlled synthetic methods for several of the most significant mycotoxins: trichothecenes, aflatoxins, PR-toxin and its analogs, and austalides. The synthetic routes to be pursued towards these environmental mycotoxins, with the exception of aflatoxins, will further focus upon the exploration of novel types of inter- and intramolecular Diels-Alder reactions. In particular, emphasis will be placed on the use of specific control elements to affect the stereochemical outcome of the intramolecular cycloaddition reaction. With regard to the study on the aflatoxins, we have unraveled a novel, biomimetic rearrangement reaction which has significant bearing on the biosynthetic process of the bis-furanoid or branched chain formation in the aflatoxins. This unique biomimetic reaction will be employed in the synthesis of aflatoxin B1 and its analogs. We would like to continue our studies in the area of mycotoxins with the following specific aims: 1) to complete the synthesis of verrucarol and anguidine through the use of the intramolecular Diels-Alder approach we have developed, 2) to develop new, regio- and stereochemically controlled synthetic methods amenable to the synthesis of the optically active 7,8-di- and 8-monooxygenated trichothecenes such as vomitoxin and T-2 toxin, 3) to develop novel enantiospecific synthetic routes to PR-toxin and austalide B and their respective analogs, and 4) to synthesize aflatoxin B1 and its analogs, in optically active forms, using a new rearrangement chemistry we have unraveled. Substances arising out of the proposed research, including many of the intermediates will be tested for their toxic-pharmacological activities as well as carcinogenic/antitumor activity by appropriate research groups.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002851-05
Application #
3250092
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1982-06-23
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109