The synthesis and iron(III) coordination properties of three tripodal ligands (L 1 , L 2 , and L 3 ) possessing hydroxamate coordination cavities are examined by various methods (ESMS, UV−vis, CD). The ligands rely on a trisamine as anchor, which is extended by an alternating sequence of variable spacers and hydroxamates as ion binding groups. This modular strategy of design is adopted for the compounds' preparation and enables modifications of each structural element independently. The coordination properties of these iron binding molecules and particularly the presence of allosteric effects are examined by classical spectrophotometric titrations in combination with electrospray mass spectrometric measurements (ESMS). A good match between these two methods is observed, as both indicate the formation of three species in thermodynamic equilibrium: mononuclear, binuclear, and trinuclear ferric complexes. The respective stability constants are determined at p[H] = 6.5 ± 0.1 in methanol, and the corresponding distribution curves clearly illustrate the variations from ligand to ligand. These findings demonstrate that subtle structural changes have a pronounced effect on these compounds' coordination properties. Moreover, among the binders studied representatives of opposite cooperative behavior is identified. The observed dependence of the ligands' coordination properties on their structural features are rationalized.
This study shows that Pseudomonas putida possesses active uptake systems for Fe3+-ferrioxamine B (FOB) and Fe3+-coprogen B (Cop. B). These systems were characterized using natural and synthetic siderophores as structural probes. The synthetic analogues p178, p191, p239, p254 and p271 are a family of systematically modified linear retro-trishydroxamates that have shorter links between the ion binding groups relative to the natural compounds and possess chiral centres. They form a lower number of isomeric Fe3+ complexes relative to the natural compounds, and may be regarded as their specific conformers. Growth promotion and facilitated 55Fe3+ uptake using both natural and synthetic siderophores were studied. The results obtained, along with those from competition experiments between the natural and the synthetic analogues demonstrate that: (i) the FOB and Cop. B uptake systems share common transport determinants; (ii) FOB and Cop. B make use of separate receptors; (iii) the Cop. B receptor is conformationally more demanding than the FOB receptor; and (iv) the FOB receptor has preference for the &cis configuration although the natural siderophore is achiral. These results also demonstrate the usefulness of the synthetic analogues as structural probes. Some of these analogues simulate the natural counterparts as Fe3+ carriers, while others merely inhibit the action of the natural compounds by competing for the respective siderophore receptor.
Molecular recognition by microbial receptors for siderophores [natural iron(II1) carriers] is examined with synthetic iron(II1) carriers as structural probes. The iron(II1) carriers have been designed to reproduce the two essential features of the natural siderophores: the capability to form octahedral iron(II1) bindmg cavities and to fit specific membrane receptors. Specifically, analogs of tripodal femchrome and linear ferrioxamines have been prepared and examined. The femchrome analogs rely on C,-symmetric binders that are assembled from triscarboxylates as anchors, amino acids as bridges, and terminal hydroxamate groups as binding sites. The femoxamine analogs are based on linear assemblies of three identical monomers, each derived from a chiral amino acid. The deliberate use of animo acid residues as variable buildmg blocks enables us to systematically modify the molecules' envelopes and the preferred absolute configuration of the iron(II1) complexes until optimal performance is reached. Examination of the synthetic analogs in Pseudomonas putida demonstrates that the domains around the iron(II1) center and their chiral sense dictate the extent of recognition by the membrane receptors. It is also shown that the synthetic siderophore analogs may be designed to either exert a broader, or a more narrow range of microbial activity than the natural siderophores. The implications of these findings are discussed in relation to the possible design of species-specific antimicrobial agents. KEY WORDS: synthetic siderophore analogs, hydroxamates, ferrichrome, ferrioxamine, coprogen, Pseudomonas putidu, membrane receptors, transport proteins, growth promotion, growth inhibition Chral recognition has traditionally been studied by exploring the performance of natural and synthetic enzymes, and by examining binding of chiral ammonium salts and amino acids to artificial receptors.Enzyme performance depends on substrate binding to often unknown recognition sites, and on the extent to which the active sites stabilize the reactions' transition states. ' 3 Therefore, analysis of the molecular interactions occurring in these systems poses inherent difficulties. The design of artificial receptors for chiral ammonium ions relied mostly on strong interactions between the positively charged organic guest ions and the electron-rich host molecules. 1,2 This approach led to the synthesis of structures that exhibit high chiral discrimination and are suitable for the separation of racemic mixtures. However, the interactions of the flexible guest molecules with the host molecules are often difficult to interpret. We adopted an alternative approach for the study of chiral recognition and concentrated on chiral metal complexes and on probing the interactions of these complexes with siderophore receptors of microbial origin. The selection of this route was based on two major considerations. First, metal complexes are conformationally more restricted than most organic substrates as they may be considered as polycyclic derivatives of io...
Linear hydroxamate derivatives, possessing chiral alpha-amino acid moieties, were synthesized and their iron transport activities were studied in bacteria and fungi. No growth-promoting activity could be detected in the Gram-positive hydroxamate-auxotroph Aureobacterium flavescens JG9. However, Gram-negative enterobacteria, such as Escherichia coli, Pantoea agglomerans and Hafnia alvei were able to utilize iron from these analogues. Uptake of 55Fe-labeled analogues was inhibited by sodium azide, suggesting an active transport process. The receptors involved during uptake in enterobacteria were identified by using appropriate indicator organisms which are defective in the transport of either ferrioxamines (P. agglomerans FM13), coprogens (H. alvei), or both of these siderophore classes (E. coli fhuE). Our data suggest that the chiral hydroxamates are recognized by the ferrioxamine receptor (FoxA) and the coprogen receptor (FhuE) at a ratio which depends on the optical lambda/delta isomer fraction and the nature of side chains. Transport was also observed in the fungus Neurospora crassa, known to take up coprogen rather than ferrioxamines, suggesting that in this fungus the synthetic analogues behave like coprogen.
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