Title

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

Authors

Authors

A. Muth; J. Kamel; N. Kaur; A. C. Shicora; I. S. Ayene; S. K. Gilmour;O. Phanstiel

Comments

Authors: contact us about adding a copy of your work at STARS@ucf.edu

Abbreviated Journal Title

J. Med. Chem.

Keywords

HUMAN-MELANOMA CELLS; HAMSTER OVARY CELLS; BIOLOGICAL EVALUATION; MAMMALIAN-CELLS; MOLECULAR REQUIREMENTS; SPERMINE ANALOGS; EFFICIENT; PROLIFERATION; CYTOTOXICITY; RECOGNITION; Chemistry, Medicinal

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.

Journal Title

Journal of Medicinal Chemistry

Volume

56

Issue/Number

14

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

5819

Last Page

5828

WOS Identifier

WOS:000322503000015

ISSN

0022-2623

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