Polyamine-vectored iron chelators: The role of charge

Raymond J. Bergeron, Neelam Bharti, Jan Wiegand, James S. McManis, Hua Yao, Laszlo Prokai

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The utility of polyamines as vectors for the intracellular transport of iron chelators is further described. Consistent with earlier results with polyamine analogues, these studies underscore the importance of charge in the design of polyamine-vectored chelators. Four polyamine conjugates are synthesized, two of terephthalic acid [N1-(4-carboxy)benzoylspermine (7) and its methyl ester (6)] and two of (S)-2-(2,4-dihydroxyphenyl)-4,5- dihydro-4-methyl-4-thiazole- carboxylic acid [(S)-4′-(HO)-DADFT] [(S)-4,5-dihydro-2-[2-hydroxy-4-(12-amino-5,9-diazadodecyloxy)phenyl] -4-methyl-4-thiazolecarboxylic acid (10) and its ethyl ester (9)]. These four molecules were evaluated in murine leukemia L1210 cells for their impact on cell proliferation (48- and 96-h IC50 values), their ability to compete with spermidine for the polyamine transport apparatus (Ki), and their intracellular accumulation. The data revealed that when neutral molecules (cargo fragments) were fixed to the polyamine vector, the conjugates competed well with spermidine for transport and were accumulated intracellularly to millimolar levels. However, this was not the case when the cargo fragments were negatively charged. Metabolic studies of the polyamine-vectored (S)-4′-(HO)-DADFTs in rodents indicated that not only did the expected deaminopropylation step occur, but also a surprisingly high level of oxidative deamination at the terminal primary nitrogens took place. Finally, the iron-clearing efficiency of the (S)-4′-(HO)-DADFT conjugates was determined in a bile-duct-cannulated rodent model. Attaching the ligand to a polyamine vector had a profound effect on increasing the iron-clearing efficiency of this chelator relative to its parent drug.

Original languageEnglish
Pages (from-to)4120-4137
Number of pages18
JournalJournal of Medicinal Chemistry
Volume48
Issue number12
DOIs
StatePublished - 16 Jun 2005

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    Bergeron, R. J., Bharti, N., Wiegand, J., McManis, J. S., Yao, H., & Prokai, L. (2005). Polyamine-vectored iron chelators: The role of charge. Journal of Medicinal Chemistry, 48(12), 4120-4137. https://doi.org/10.1021/jm048974f