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

• Published in: Journal of medicinal chemistry Vol. 44; no. 22; pp. 3632 - 3644
• Main Authors: Burns, Mark R, Carlson, C. Lance, Vanderwerf, Scott M, Ziemer, Josh R, Weeks, Reitha S, Cai, Feng, Webb, Heather K, Graminski, Gerard F
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.10.2001; Amer Chemical Soc
• Subjects: Amino Acids - chemistry; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological Transport; Chemistry, Medicinal; Drug Interactions; Drug Screening Assays, Antitumor; Eflornithine - pharmacology; General aspects; Humans; Life Sciences & Biomedicine; Lysine - analogs & derivatives; Lysine - chemical synthesis; Lysine - pharmacology; Medical sciences; Ornithine Decarboxylase Inhibitors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Putrescine - metabolism; Science & Technology; Spermidine - antagonists & inhibitors; Spermidine - metabolism; Spermine - analogs & derivatives; Spermine - chemical synthesis; Spermine - metabolism; Spermine - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured; PUTRESCINE TRANSPORT; TRANSPORT INHIBITORS; ESCHERICHIA-COLI; GASTROINTESTINAL-TRACT; GROWTH; SPIDER TOXIN; HIGH-AFFINITY; HUMAN FIBROBLASTS; L1210 LEUKEMIA-CELLS; MAMMALIAN-CELLS; Antineoplastic agent; Human; Polyamine; Aminoamide; Cytotoxicity; Epithelium; In vitro; α-Aminoacid; Cell line; Functionalization; Structure activity relation; Spermidine; Carboxamide; Mammary gland; Inhibition; Conjugated compound; Chemical synthesis; Tumor cell; Carrier protein
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0101040

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.