Convergent Synthesis of Macrocyclic and Linear Desferrioxamines

Abstract

Polyhydroxamate desferrioxamines (DFO) are nontoxic siderophores endowed with high potential for development of therapeutic chelating agents. Herein, we report a modular and convergent strategy for diverse synthesis of macrocyclic and linear DFOs. The strategy employed orthogonally protected N-hydroxy-N-succinylcadaverine building blocks, which allowed bidirectional extension of the DFO structure. The efficiency of the new strategy was demonstrated by the total synthesis of 44-membered macrocyclic DFO-T-1, as well as four related DFO compounds in 11-13 linear steps and 2.1 %-10 % overall yields. Comparison of the iron binding affinity of the DFOs revealed DFO-E as the best chelator.