Recent Advances in the Development of Polyamine Analogues as Antitumor Agents

Since the publication of our previous Perspective dealing with polyamine drug discovery,1 the field has undergone numerous changes. Most prominent among these changes, from a medicinal chemistry point of view, is that polyamine drug discovery efforts have partially shifted away from an emphasis on inhibitors of polyamine biosynthetic and catabolic enzymes. This shift is in part due to the fact that multiple compensatory mechanisms are available that are able to maintain homeostasis in cellular polyamine pools,2 and thus the utility of specific enzyme inhibitors as drugs is limited. Specific inhibitors are available for every enzyme in the polyamine biosynthetic pathway,1, 3-6 and for the polyamine transport system.7-9 Although these inhibitors have significant effects on their respective target enzymes, only one inhibitor, α-difluoromethylornithine (DFMO) has reached the market. DFMO was originally designed as an antitumor agent, but the drug was not effective enough to warrant continued Phase II trials. However, it has been shown to be an effective cure for infection caused by Trypanosoma brucei gambiense (West African Sleeping Sickness),10, 11 and has recently shown considerable potential as a cancer chemopreventive agent (see below).12-14 Although no other polyamine biosynthesis inhibitor has been advanced to the market, the ubiquitous nature of the natural polyamines would lead one to conclude that these molecules have numerous cellular effector sites that are frequently dysregulated in cancer, and as such should provide a target rich environment for therapeutic intervention. Recent medicinal chemistry efforts in the polyamine field have focused on the discovery of compounds that produce cellular effects that are either independent of, or in addition to the polyamine metabolic enzymes. In addition, polyamine chains have been used to make hybrid drug molecules in order to improve cellular import, increase affinity for chromatin or to serve as carriers. This Perspective will focus on developments in polyamine drug discovery since our previous article.1