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

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.

Two Decades of Triazine Dendrimers

“…Using the G2 dendrimer available at the kilogram scale, Mr. Jongdoo Lim and Mr. Vince Venditto installed the iron chelator desferrioxamine B (in protected form, Chart 7 ) as a dichlorotriazine and reacted with 12 primary amines presented on the dendrimer periphery [ 37 ]. The poly(monochlorotriazine) that resulted was ‘capped’ with 4-hydroxylmethylpiperidine, leading to a construct that was 56 wt% drug.…”

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

“…Dendrimers are highly defined hierarchical structures, much more regular than structurally somehow-related hyperbranched polymers, with the hydrodynamic radius usually below the renal threshold and therefore with renal elimination as the primary way of elimination. Iron-chelating dendrimers were synthesized [102,115] with deferoxamine iron-chelating moieties. Nanogels are gel-structured nanoparticles and with appropriate iron-chelating moieties [116][117][118][119]; however, due to their larger size, they must be biodegradable to allow elimination.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…Later studies revealed that polymeric sequestrants based on the hydroxypyridinone hexadentate (CP254) provide the optimum coordination interactions with iron (III) to form highly stable complexes [72,73]. Similar approaches using polymers modified with various iron-chelating motifs were reported and shown in vivo iron-binding capability in rats when given orally [74,75]. This strategy has also been extended to other metals such as aluminum, cadmium, and lead [54,76–78].…”