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 activities of these compounds are impressive, including the tumor-promoting properties of various phorbol esters, the tumor-promoting and antileukemic activity of lathyranoid compounds, and the antileukemic activity of jatrophone and related jatrophane dietepenoids. It has been suggested that these compounds might derive their biological activity from an ability to bind at prostaglandin receptor sites on cell membranes, and undergo reaction with nearby nucleophilic centers. We propose to conduct a chemical synthesis of two representative diterpenoids of this group. This will allow us to begin development of the methodology required for synthesis of the entire family of diterpenoids. Our syntheses are designed to produce the natural enantiomers of our objectives; we believe that this is essential at least until the stereospecificity of the receptor site(s) is established. Through bioassay of selected synthetic 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 related substances with enhanced antileukemic activity, and to better understanding of the process of tumor promotion.
