CHIRAL SIDEROPHORE ANALOGS - FERRICHROME

Two novel families of chiral trishydroxamate binders are described. These compounds have been modeled after the natural siderophore ferrichrome in an attempt to mimic its biological properties as iron(III) carrier and growth promoter. In these analogs the hydroxamate binding sites and tripodal topology of ferrichrome are retained, but the chiral hexapeptide anchor of the natural siderophore is replaced by C3-symmetric tricarboxylates of two homologous types (m = 1, type 1; m = 2, type 2). The resulting loss of chirality is compensated by symmetric extension of these anchors with natural amino acids (Figure 1). In this design two elements are of particular importance: (i) the amino acid bridges that induce chirality, stabilize specific conformations of the free ligands, and allow systematic modifications and (ii) the use of two homologous anchors that dictate the conformations of the metal complexes. Type 2 binders proved to either simulate the performance of the natural ferrichrome and act as growth promoters or to inhibit the action of ferrichrome and function as growth inhibitors. On the other hand, none of the type 1 binders proved active. In an attempt to establish the origin of these differences, the structures of the two types of compounds and of their octahedral metal complexes are examined by a combination of IR, NMR, UV/vis, CD, and NMR spectroscopy. Little differences were observed in the conformations of the free ligands as both types adopt propeller-like arrangements that are stabilized by intramolecular H-bonds. Both types of complexes also predominantly assume the LAMBDA-cis configuration when L-amino acids are used. However, pronounced differences were observed in the conformations of the metal complexes: while in type 1 complexes the amides are positioned tangentially to the molecules cross section, in type 2 complexes they are oriented radially with the amide-NH pointing inward. In the latter arrangement the amide-NH groups become fit to form intramolecular H-bonds. These findings allowed us to interpret the in vivo performance of these compounds and to identify the structural requirements for obtaining growth promoters or growth inhibitors, respectively. The systematically modified ligands allowed us to examine the effect of intramolecular interactions, specifically H-bond networks and van der Waals forces, on the complexes' stoichiometry and isomeric and optical purity. The presence of either of the two intramolecular forces is sufficient to obtain monomeric complexes of 1 : 1 stoichiometry, while the absence of both like in the glycine derivative of type 1 ligand, 1G, causes the formation of polymeric complexes.