Design of polyamine-based therapeutic agents: new targets and new directions

Abstract

Enzymes in the biosynthetic and catabolic polyamine pathway have long been considered targets for drug development, and early drug discovery efforts in the polyamine area focused on the design and development of specific inhibitors of the biosynthetic pathway, or polyamine analogues that specifically bind DNA. More recently, it has become clear that the natural polyamines are involved in numerous known and unknown cellular processes, and disruption of polyamine functions at their effector sites can potentially produce beneficial therapeutic effects. As new targets for polyamine drug discovery continue to evolve, the rational design of polyamine analogues will result in more structurally diverse agents. In addition, the physical linkage of polyamine-like structures to putative drug molecules can have beneficial effects resulting from increases in DNA affinity and selective cellular uptake. The present chapter will summarize recent advances in the development of alkylpolyamine analogues as antitumour agents, and describe subsequent advances that have resulted from incorporating polyamine character into more diverse drug molecules. Specifically, new polyamine analogues, and the role of polyamine fragments in the design of antiparasitic agents, antitumour metal complexes, histone deacetylase inhibitors and lysine-specific demethylase 1 inhibitors, will be described.

Figure 1

Structures of the classical inhibitors of polyamine biosynthesis

Figure 2

Structures and 96 h IC₅₀ values against the NCI H157 lung tumour cell line for selected alkylpolyamines with antitumour activity

Figure 3

Structures of alkylpolyamine analogues with antiparasitic activity in vitro and/or in vivo.

Figure 4

Polyamine–transition metal complexes with antitumour activity

Figure 5

General structure for polyamine-based HDAC inhibitors, and selected PAHA and PABA analogues

Figure 6

Structures of compound 47 (1c), 33 (2d) and 1c analogues 48–52