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.
