Chapter 5:Symmetrical- and Unsymmetrical Terminally Alkylated Polyamines

Since their introduction in the late 1980s, analogs of the natural polyamines putrescine, spermidine and spermine have facilitated the understanding of polyamine cellular function, and in some cases have also shown promise as therapeutic agents. Early examples of these analogs include the bis(ethyl)polyamines, which were developed as potential antitumor and antidiarrheal agents. The design of these analogs was based on the simple theory that alteration of the pKa values for the terminal nitrogens of spermidine and spermine through monoalkylation would produce analogs that could disrupt polyamine metabolism. The bis(ethyl)polyamines were shown to be taken up by the polyamine transporter, which is elevated in many proliferating cells, and then to downregulate polyamine biosynthesis. However, these agents did not substitute for the cellular functions of the natural polyamines, leading to polyamine depletion and cell death. The success of the bis(ethyl)polyamines led to the synthesis of unsymmetrically substituted alkylpolyamine analogs, which provided a venue for elucidating the structure/activity relationships for terminally alkylated polyamines. Exploration of the chemical space available for the terminal alkyl substituents has resulted in the discovery of potent second-generation agents and allowed the introduction of structural diversity into the resultant molecules. Finally, compounds featuring isosteric replacements for the terminal amine moieties of the alkylpolyamines has resulted in a new class of polyamine analog that exhibits potent antitumor, antiparasitic and epigenetic activity in vitro and in vivo. In this chapter, the evolution in structure of the alkylpolyamines, as well as their development as potential drugs, will be described.