Polyamine Transport Inhibitors: Design, Synthesis, and Combination Therapies with Difluoromethylornithine

    Authors

    A. Muth; M. Madan; J. J. Archer; N. Ocampo; L. Rodriguez;O. Phanstiel

    Comments

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    Abbreviated Journal Title

    J. Med. Chem.

    Keywords

    SQUAMOUS-CELL CARCINOMA; HAMSTER OVARY CELLS; MAMMALIAN-CELLS; ALPHA-DIFLUOROMETHYLORNITHINE; BIOLOGICAL EVALUATION; MOLECULAR; REQUIREMENTS; CANCER CHEMOPREVENTION; SELECTIVE DELIVERY; FLUORESCENT-PROBE; DIAMINE OXIDASE; Chemistry, Medicinal

    Abstract

    The development of polyamine transport inhibitors (PTIs), in combination with the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), provides a method to target cancers with high polyamine requirements. The DFMO+PTI combination therapy results in sustained intracellular polyamine depletion and cell death. A series of substituted benzene derivatives were evaluated for their ability to inhibit the import of spermidine in DFMO-treated Chinese hamster ovary (CHO) and L3.6pl human pancreatic cancer cells. Several design features were discovered which strongly influenced PTI potency, sensitivity to amine oxidases, and cytotoxicity. These included changes in (a) the number of polyamine chains appended to the ring system, (b) the polyamine sequence, (c) the attachment linkage of the polyamine to the aryl core, and (d) the presence of a terminal N-methyl group. Of the series tested, the optimal design was N-1,N-1',N-1 ''-(benzene-1,3,5-triyltris(methylene))tris(N-4-(4-(methylamino)butyl)butane-1,4-diamine, 6b, which contained three N-methylhomospermidine motifs. This PTI exhibited decreased sensitivity to amine oxidases and low toxicity as well as high potency (EC50 = 1.4 mu M) in inhibiting the uptake of spermidine (1 mu M) in DFMO-treated L3.6pl human pancreatic cancer cells.

    Journal Title

    Journal of Medicinal Chemistry

    Volume

    57

    Issue/Number

    2

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    348

    Last Page

    363

    WOS Identifier

    WOS:000330252500008

    ISSN

    0022-2623

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