DESIGN OF ENEDIYNE PRODRUGS

An important feature of the enediyne antitumor antibiotics is that a c hemical activation step is necessary to allow the formation of cytotox ic diradicals to take place. Therefore they are interesting as lead co mpounds for the development of novel antitumor agents. This review dis cusses the activation principle of the natural enediynes and sorts out the factors that govern the reactivity of enediynes. It can be seen t hat steric as well as electronic effects can be used to modulate the r eactivity of an enediyne. The known models that allow to estimate the steric effects on the reactivity are summarized. Moreover, the strateg ies that enable the generation of reactive enediynes from stable precu rsors are presented. These include the transformation of 1,5-diynes to enediynes, the removal of a bridgehead double bond (calicheamicin ana logs) or the opening of an epoxide in a strained precursor (dynemicin analogs). Finally, enediyne prodrugs are presented that have originate d by de-novo design.