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 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 μM) in inhibiting the uptake of spermidine (1 μM) in DFMO-treated L3.6pl human pancreatic cancer cells.

Targeting polyamine metabolism for cancer therapy and prevention

“…Phanstiel and colleagues have synthesized and evaluated compounds designed as inhibitors of polyamine transport that differ significantly from the lysyl–spermine conjugates reported by Burns and colleagues [60,61]. However, similar to AMXT 1501, the combination of these transport inhibitors with DFMO also produces significant growth inhibition in a variety of tumor cell types.…”

Pharmacological and dietary agents for colorectal cancer chemoprevention: Effects on polyamine metabolism (Review)

“…In tumor-bearing animal models, it has been demonstrated that a polyamine deficient diet significantly enhances the antitumoral effect of DFMO plus neomycin (113). Overall, the use of polyamine transport inhibitors, alone or in combination with DFMO, provides a method to target cancers with high polyamine requirements (114).…”

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

“…In support of this idea, we demonstrated in L3.6pl human PDAC cells that a significant reservoir of intracellular spermidine exists and that the DFMO + PTI combination therapy needed to deplete >80% of intracellular spermidine to affect PDAC cell growth . In addition, we identified a murine pancreatic cancer cell line (PanO2) with high polyamine transport activity .…”

“…The trimer44NMe PTI 1 (Fig. ), which competitively inhibits import of 3 H‐labeled spermidine, was shown to work synergistically with DFMO to deplete PDAC cells of intracellular polyamine pools and reduce their growth …”