Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Abstract

Iron chelators have been shown to control the growth of cancer cells in culture by sequestering exogenous iron in the media. Thus, the ligands prevent cellular access to the metal. However, because transferrin provides iron to tumor cells in animals, chelators have not been effective antitumor agents. Polyamine chelator conjugates in which the polyamine vectored ligands into cells were far more active than the free chelators themselves. However, the free ligands were not released from the vector once in the cell. The current study focuses on the synthesis and preliminary evaluation of a polyamine chelator conjugate capable of releasing the free ligand intracellularly via a nonspecific esterase.

Figure 1

Polyamine analogue DENSPM (1), chelators 2 and 6, and polyamine analogue chelator conjugates 3,4,5,7

Scheme 1

Reagents and conditions: (a) mesitylenesulfonyl chloride, aq 1 N NaOH, CH₂Cl₂, 67%; (b) 4-(tert-butoxycarbonyl)benzyl bromide, 60% NaH, DMF, 70 °C, 70%; (c) 30% HBr in AcOH, PhOH, CH₂Cl₂, 84%; (d) BOC₂O, aq THF, Et₃N, 85%; (e) EDAC, DMAP, CH₂Cl₂, 55%; (f) TFA, CH₂Cl₂, ion exchange, aq 1 N HCl, quantitative.