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 MDA-MB-231 breast cancer cells. The presence of an amide in the functionalized polyamine appeared to add to the affinity for...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-10, Vol.44 (22), p.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: Article
Language:English
Subjects:
Amino Acids - chemistry
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Biological Transport
Drug Interactions
Drug Screening Assays, Antitumor
Eflornithine - pharmacology
General aspects
Humans
Lysine - analogs & derivatives
Lysine - chemical synthesis
Lysine - pharmacology
Medical sciences
Ornithine Decarboxylase Inhibitors
Pharmacology. Drug treatments
Putrescine - metabolism
Spermidine - antagonists & inhibitors
Spermidine - metabolism
Spermine - analogs & derivatives
Spermine - chemical synthesis
Spermine - metabolism
Spermine - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0101040