CHIRAL SIDEROPHORE ANALOGS - FERRIOXAMINES AND THEIR IRON(III) COORDINATION PROPERTIES

This article describes a new family of linear ferrioxamine B analogs. These analogs have been designed to serve as chemical probes of microbial iron(III) uptake systems by forming conformationally unique complexes with iron(III). This target is achieved by (i) prohibiting the formation of trans isomers due to shortened bridges between the hydroxamate groups and (ii) imposing preferentially either the DELTA-cis or DELTA-cis configuration due to the presence of chiral centers. The preparation of these analogs is realized by oligomerization of three identical monomers via the Merrifield method of synthesis. Each monomer is composed of an amino acid (L-ala, L-leu, L-asp, L-glu, D-glu) and N-hydroxy-3-aminopropionic acid that are linked together through the formation of a hydroxamate ion binding group. Some of these analogs, 1-3, have been found to substitute ferrioxamine B as growth promoter and iron(III) carrier, while others, 4 and 5, inhibit ferrioxamine B mediated iron(III) uptake. A priori, three parameters may be taken into account when siderophore-mediated microbial iron(III) uptake is considered: (i) iron(III) binding to the siderophore, (ii) the efficiency of transport of the siderophore-iron(III) complex across the membrane, and (iii) iron(III) release. In an attempt to determine which of these three parameters dictate the compounds' microbial activity, we compare their coordination properties in vitro with their overall effectiveness in vivo. Specifically, we examine the complexes' iron(III) release kinetics with CDTA as sensitive indicators of their coordination properties. Iron(III) release is shown to occur by two rate-limiting processes: a bimolecular ligand exchange step and a monomolecular one which measures the inertness of the complex under the given acidic conditions. Both processes show pronounced dependence on the nature of the amino acid (namely its substituents CH3, i-Bu, and CH2CONEt2 and chain length). The bulkier the side chain and longer the chain length, the slower the dissociation and iron(III) exchange rates. These observations are rationalized in terms of electronic and stereochemical effects and compared with the data of the natural counterpart. They also enable us to interpret the compounds' activities in vivo, indicate that transport of the siderophore complexes across the membrane is the decisive parameter, and demonstrate the role of conformational subtleties.