Bioorganic & Medicinal Chemistry 2010-08-01

Synthesis and characterization of a triazine dendrimer that sequesters iron(III) using 12 desferrioxamine B groups.

Jongdoo Lim, Vincent J Venditto, Eric E Simanek

Index: Bioorg. Med. Chem. 18(15) , 5749-53, (2010)

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Abstract

The synthesis of a third generation triazine dendrimer, 1, containing multiple, iron-sequestering desferrioxamine B (DFO) groups is described. Benzoylation of the hydroxamic acid groups of DFO and formation of a reactive dichlorotriazine provide the intermediate for reaction with the second generation dendrimer displaying twelve amines. This strategy further generalizes the 'functional monomer' approach to generate biologically active triazine dendrimers. Dendrimer 1 is prepared in seven steps in 35% overall yield and displays 12 DFO groups making it 56% drug by weight. Spectrophotometric titrations (UV-vis) show that 1 sequesters iron(III) atoms with neither cooperativity nor significant interference from the dendrimer backbone. Evidence from NMR spectroscopy and mass spectrometry reveals a limitation to this functional monomer approach: trace amounts of O-to-N acyl migration from the protected hydroxamic acids to the amine-terminated dendrimer occurs during the coupling step leading to N-benzoylated dendrimers displaying fewer than 12 DFO groups.Copyright (c) 2010 Elsevier Ltd. All rights reserved.