Amino Acid/Spermine Conjugates:  Polyamine Amides as Potent Spermidine Uptake Inhibitors

Abstract

In this paper we describe the synthesis and characterization of a series of simple spermine/amino acid conjugates, some of which potently inhibit the uptake of spermidine into MDA-MB-231 breast cancer cells. The presence of an amide in the functionalized polyamine appeared to add to the affinity for the polyamine transporter. The extensive biological characterization of an especially potent analogue from this series, the Lys-Spm conjugate (31), showed this molecule will be an extremely useful tool for use in polyamine research. It was shown that the use of 31 in combination with DFMO led to a cytostatic growth inhibition of a variety of cancer cells, even when used in the presence of an extracellular source of transportable spermidine. It was furthermore shown that this combination effectively reduced the cellular levels of putrescine and spermidine while not affecting the levels of spermine. These facts together with the nontoxic nature of 31 make it a novel lead for further anticancer development.

Polyamine metabolism and cancer

“…Recently, Burns et al [97] described the synthesis and characterization of a series of spermine/ amino acid conjugates. The presence of the amide group enhanced the affinity of the compound for the polyamine transporter.…”

Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

“…MQT 1426 was synthesized using an adaptation of the method previously described for the synthesis of L-Lys-spm (ORI 1202). 11,12 The synthesis can be summarized as follows. The 4-nitrophenyl ester of a,‹-Boc-D-lysine was coupled to the free base of spermine in methanol.…”

“…12 We selected MQT 1426 (D-lysine-spermine; Fig. 1) for our studies because of its desirable PTI properties: using previously published methods, 10 the K i for inhibition of spermidine uptake in MDA-MB-231 cells was determined to be 28 6 11 nM (n 5 3) and the EC 50 for growth inhibition in the same cell line was 3.1 6 1.5 lM (n 5 3).…”

Lipophilic Lysine−Spermine Conjugates Are Potent Polyamine Transport Inhibitors for Use in Combination with a Polyamine Biosynthesis Inhibitor

“…We have extended our earlier discovery of amino acid-spermine conjugates11 by attaching lipophilic substituents to the ε-amino group of the lysine portion of our earlier lead compound d -Lys-Spm 5 . These agents were characterized by their ability to inhibit cell growth in combination with DFMO even in the presence of extracellular spermidine (EC 50 values).…”