Title

Polyamine Transport Inhibitors: Design, Synthesis, And Combination Therapies With Difluoromethylornithine

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 N1,N1′,N1″-(benzene-1,3, 5-triyltris(methylene))tris(N4-(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 μM) in inhibiting the uptake of spermidine (1 μM) in DFMO-treated L3.6pl human pancreatic cancer cells. © 2014 American Chemical Society.

Publication Date

1-23-2014

Publication Title

Journal of Medicinal Chemistry

Volume

57

Issue

2

Number of Pages

348-363

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm401174a

Socpus ID

84893079505 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84893079505

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