Polyamine Drug Discovery: Synthetic Approaches to Therapeutic Modulators of Polyamine Metabolism

Numerous synthetic compounds have been described that either act as inhibitors of enzymes involved in polyamine metabolism or otherwise modulate these pathways. Development of agents that affect polyamine metabolism began with an attempt to identify specific inhibitors for the enzymes in the forward polyamine biosynthetic pathway, including ornithine decarboxylase, S-adenosylmethionine decarboxylase and the aminopropyltransferases spermidine synthase and spermine synthase. However, advances in our knowledge of polyamine metabolism have changed the focus of drug discovery in the polyamine area from an enzyme-inhibition strategy to a systematic search for polyamine analogs that exert antitumor effects through a variety of mechanisms, including the induction of apoptosis, inhibition of polyamine catabolism or epigenetic effects on gene expression. The purpose of this chapter is to describe syntheses that have been useful in the discovery of agents that disrupt polyamine metabolism, and relegating a description of the detailed biological effects of these agents to the following chapters. In this section, the syntheses of nucleosides, guanylhydrazones, alkylpolyamines, polyaminoguanidines, polyaminobiguanides, polyaminohydroxamates and polyaminobenzamides that have significant effects on polyamine metabolism are described.