title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48202, USA. pwoster@wayne.edu
authors.forename: M D Thulani
authors.initials: MD
authors.lastname: Senanayake
authors.forename: Hemali
authors.initials: H
authors.lastname: Amunugama
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Boncher
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008670:Metals / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms
chemical_list: D000977:Antiparasitic Agents; D056572:Histone Deacetylase Inhibitors; D008670:Metals; D011073:Polyamines; D020033:Protein Isoforms; D004247:DNA