title: Development of polyamine transport ligands with improved metabolic stability and selectivity against specific human cancers.
abstract: 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.
authors.affiliation: Department of Medical Education, University of Central Florida College of Medicine , 12722 Research Parkway, Orlando, Florida 32826-3227, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Muth
authors.forename: Joseph
authors.initials: J
authors.lastname: Kamel
authors.forename: Navneet
authors.initials: N
authors.lastname: Kaur
authors.forename: Allyson C
authors.initials: AC
authors.lastname: Shicora
authors.forename: Iraimoudi S
authors.initials: IS
authors.lastname: Ayene
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
authors.forename: Otto
authors.initials: O
authors.lastname: Phanstiel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D051379:Mice; D011073:Polyamines / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D011073:Polyamines