Development of Polyamine Transport Ligands with Improved Metabolic Stability and Selectivity against Specific Human Cancers

• Published in: Journal of medicinal chemistry 2013-07, Vol.56 (14), p.5819-5828
• Main Authors: Muth, Aaron, Kamel, Joseph, Kaur, Navneet, Shicora, Allyson C, Ayene, Iraimoudi S, Gilmour, Susan K, Phanstiel, Otto
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Drug Discovery; Humans; Ligands; Mice; Polyamines - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400496a

Polyamine homeostasis is critical for life and is accomplished via a balance of polyamine biosynthesis, degradation, and transport. Rapidly dividing cancer cells have been shown to have high polyamine transport activity compared to normal cells, likely due to their high requirement for polyamine metabolites. The polyamine transport system (PTS) is a therapeutically relevant target, as it can provide selective drug delivery to cancer cells. This report describes the synthesis and biological evaluation of multimeric polyamine derivatives as efficient PTS ligands. Arylmethyl-polyamine derivatives were synthesized to address two important concerns in PTS drug design: (a) PTS selectivity and (b) stability to amine oxidases. N 1,N 1′-[Naphthalene-1,4-diylbis(methylene)]bis{N 4-[4-(methylamino)butyl])butane-1,4-diamine}, 3b, was found to have an optimal balance between these parameters and demonstrated excellent targeting of melanoma (e.g., MALME-3M) and breast cancer cells (e.g., T47D) over other cancer cell lines. These results provide a method to selectively target cancers via their intrinsic need for polyamine metabolites.