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 microb ial iron(III) uptake systems by forming conformationally unique comple xes with iron(III). This target is achieved by (i) prohibiting the for mation of trans isomers due to shortened bridges between the hydroxama te groups and (ii) imposing preferentially either the DELTA-cis or DEL TA-cis configuration due to the presence of chiral centers. The prepar ation of these analogs is realized by oligomerization of three identic al monomers via the Merrifield method of synthesis. Each monomer is co mposed of an amino acid (L-ala, L-leu, L-asp, L-glu, D-glu) and N-hydr oxy-3-aminopropionic acid that are linked together through the formati on of a hydroxamate ion binding group. Some of these analogs, 1-3, hav e been found to substitute ferrioxamine B as growth promoter and iron( III) carrier, while others, 4 and 5, inhibit ferrioxamine B mediated i ron(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 transpo rt of the siderophore-iron(III) complex across the membrane, and (iii) iron(III) release. In an attempt to determine which of these three pa rameters dictate the compounds' microbial activity, we compare their c oordination properties in vitro with their overall effectiveness in vi vo. Specifically, we examine the complexes' iron(III) release kinetics with CDTA as sensitive indicators of their coordination properties. I ron(III) release is shown to occur by two rate-limiting processes: a b imolecular 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). Th e bulkier the side chain and longer the chain length, the slower the d issociation and iron(III) exchange rates. These observations are ratio nalized in terms of electronic and stereochemical effects and compared with the data of the natural counterpart. They also enable us to inte rpret the compounds' activities in vivo, indicate that transport of th e siderophore complexes across the membrane is the decisive parameter, and demonstrate the role of conformational subtleties.