title: 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.
authors.affiliation: Oridigm Corporation, 4010 Stone Way North, Suite 220, Seattle, WA 98103, USA. markburns@oridigm.com
authors.forename: M R
authors.initials: MR
authors.lastname: Burns
authors.forename: C L
authors.initials: CL
authors.lastname: Carlson
authors.forename: S M
authors.initials: SM
authors.lastname: Vanderwerf
authors.forename: J R
authors.initials: JR
authors.lastname: Ziemer
authors.forename: R S
authors.initials: RS
authors.lastname: Weeks
authors.forename: F
authors.initials: F
authors.lastname: Cai
authors.forename: H K
authors.initials: HK
authors.lastname: Webb
authors.forename: G F
authors.initials: GF
authors.lastname: Graminski
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001692:Biological Transport; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D000518:Eflornithine / Q000494:pharmacology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; C438945:N(1)-spermine-lysinylamide; D065108:Ornithine Decarboxylase Inhibitors; D013096:Spermine; D008239:Lysine; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine