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. N1,N1′-[Naphthalene-1, 4-diylbis(methylene)]bis{N4-[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. © 2013 American Chemical Society.

Publication Date

7-25-2013

Publication Title

Journal of Medicinal Chemistry

Volume

56

Issue

14

Number of Pages

5819-5828

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm400496a

Socpus ID

84880896085 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84880896085

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