Amino acid/spermine conjugates: Polyamine amides as potent spermidine uptake inhibitors

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 MDAMB-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), sh owed this molecule will be an extremely useful tool for use in polyamine re search. It was shown that the use of 31 in combination with DFMO led to a c ytostatic growth inhibition of a variety of cancer cells, even when used in the presence of an extracellular source of transportable spermidine. It wa s furthermore shown that this combination effectively reduced the cellular levels of putrescine and spermidine while not affecting the levels of sperm ine. These facts together with the nontoxic nature of 31 make it a novel le ad for further anticancer development.