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

    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 [email protected]

    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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