Polyamine-iron chelator conjugate.
The current study demonstrates unequivocally that polyamines can serve as vectors for the intracellular delivery of the bidentate chelator 1,2-dimethyl-3-hydroxypyridin-4-one (L1). The polyamine-hydroxypyridinone conjugate 1-(12-amino-4,9-diazadodecyl)-2-methyl-3-hydroxy-4(1H)-pyridinone is assembled from spermine and 3-O-benzylmaltol. The conjugate is shown to form a 3:1 complex with Fe(III) and to be taken up by the polyamine transporter 1900-fold against a concentration gradient. The K(i) of the conjugate is 3.7 microM vs spermidine for the polyamine transporter. The conjugate is also at least 230 times more active in suppressing the growth of L1210 murine leukemia cells than is the parent ligand, decreases the activities of the polyamine biosynthetic enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase, and upregulates spermidine-spermine N (1)-acetyltransferase. However, the effect on native polyamine pools is a moderate one. These findings are in keeping with the idea that polyamines can also serve as efficient vectors for the intracellular delivery of other iron chelators.
Bergeron
Raymond J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. bergeron@mc.cop.ufl.edu
McManis
James S
JS
Franklin
April M
AM
Yao
Hua
H
Weimar
William R
WR
D000123:Acetyltransferases / Q000096:biosynthesis; D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005290:Ferric Compounds / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry*; D007939:Leukemia L1210; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D012437:Adenosylmethionine Decarboxylase; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D009955:Ornithine Decarboxylase; D011073:Polyamines; D011728:Pyridones; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C480550:1-(12-amino-4,9-diazadodecyl)-2-methyl-3-hydroxy-4(1H)-pyridinone