Many plants of the Euphorbiaceae (spurges) produce toxic and/or irritating substances which belong to a small family of closely related diterpene skeletons. The biological properties of these compounds are impressive, including the tumor-promoting properties of various phorbol esters, the tumor-promoting and antileukemic properties of lathyranoid compounds, and the antileukemic activity of jatrophane and other jatrophane diterpenoids. It has been suggested that these compounds derive biological activity from an ability to bind with kinase C or at prostaglandin receptor sites and then undergo reaction with nearby nucleophilic centers. We propose to conduct chemical syntheses of some representative diterpenoids of this group, and to develop methodology which might be used to synthesize still other members of the family. The syntheses are designed to afford the natural enantiomers of our objectives. We believe that thiS is essential, at least until the stereospecificity of the receptor site(s) is (are) established. Through bioassay of selected intermediates, we hope to increase our understanding of the mechanism(s) responsible for the observed biological activity. Ultimately, this may lead to the ability to design second generation substances with enhanced antileukemic activity, and to a better understanding of the process of tumor promotion.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA033743-04A2
Application #
3171528
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1983-02-01
Project End
1991-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242