Complexes Formed in Solution Between Vanadium(IV)/(V) and the Cyclic Dihydroxamic Acid Putrebactin or Linear Suberodihydroxamic Acid

The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues to generate interest in the poten-tial applications of these bioligands in the environment and medicine.13 Siderophores produced by terrestrial and marin

Metal-templated synthesis of forward and reverse Fe(III)- or Ga(III)-desferrioxamine E and ringexpanded macrocycles

Desferrioxamine E (DFOE) is a macrocyclic trihydroxamic acid-based siderophore that is produced by Streptomyces species for Fe acquisition. Macrocyclic molecules of this class have applications in biomedicine and imaging. This study aimed to synthesize metal-loaded DFOE and analogs using a metal-templated synthesis (MTS) approach from the cognate monomeric fragments. Chapter 2 described the synthesis of forward and retro hydroxamic acids as characterized by NMR, LC-MS and ESI-MS. These hydroxamic acids were subjected to metal templation and cyclization chemistry to synthesize metal-loaded DFOE and analogs. Chapter 3 and 4 described the synthesis of metal-loaded DFOE and ring-expanded macrocyclic analogs as determined by LC-MS and ESI-MS. The LC-MS results suggested that the metal-loaded retro analogs were more lipophilic than the forward isomers. This provides one rational for the predominance in nature of forward hydroxamic acids as effective Fe(III) solubilization agents. Chapter 5 described the synthesis of biotinylated desferrioxamine B (DFOB) using a new form of solid phase organic phase (SPOS) and solution phase chemistry as determined by NMR, LC-MS and ESI-MS. The thesis in total describes new synthetic methodologies to generate macrocyclic siderophore derivatives, and other siderophore adducts

Foward and reverse (retro) iron(III) or gallium (III) desferrioxamine E and ring-expanded analogues prepared using metal-templated synthesis from endo-hydroxamic acid monomers

A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)-propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H+]+, m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded analogues of for-[Fe(DFOE)] and ret-[Fe(DFOE)] were prepared from endo-hydroxamic acid monomers with one additional methylene unit in the amine-containing region, 4-[(6-aminohexyl)(hydroxy)amino]-4-oxobutanoic acid ( for-HBH) or 3-(7-amino-N-hydroxyheptanamido)propanoic acid (ret-HBH), to give the corresponding tris(homoferrioxamine E) macrocycles, for-[Fe(HHDFOE)] or ret-[Fe(HHDFOE)] ([M + H+]+, m/zcalc 696.3, m/zobs 696.4). The MTS reaction using a constitutional isomer of for-HBH that transposed the methylene unit to the carboxylic acid containing region, 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (for-PPH), gave the macrocycle for-[Fe(HPDFOE)] in a yield significantly less than that for for-[Fe(HHDFOE)], with the gallium(III) analogue for-[Ga(HPDFOE)] unable to be detected. The work demonstrates the utility and limits of MTS for the assembly of macrocyclic siderophores from endo-hydroxamic acid monomers. Indirect measures (RP-HPLC order of elution, c log P values, molecular mechanics, and density functional theory calculations) of the relative water solubility of the ligands, the iron(III) macrocycles, and the apomacrocycles were consistent in identifying for-DFOE as the most water-soluble macrocycle from for-DFOE, ret-DFOE, for-HHDFOE, ret-HHDFOE, and for-HPDFOE. From this group, only for-DFOE is known in nature, which could suggest that water solubility is an important trait in its natural selection