title: Octadentate Zirconium(IV)-Loaded Macrocycles with Varied Stoichiometry Assembled From Hydroxamic Acid Monomers using Metal-Templated Synthesis.
abstract: The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT1)] ([M + H]+calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an additional methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT1)] ([M + H]+calc 943.4, obs 943.1). A second, well-resolved peak in the liquid chromatogram from the for-PPH MTS system also characterized as a species with [M + H]+943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT1D)2]. Treatment of for-[Zr(PPDFOT1)] or for-[Zr(PPDFOT1D)2] with EDTA at pH 4.0 gave the respective hydroxamic acid macrocycles as free ligands: octadentate PPDFOT1or two equivalents of tetradentate PPDFOT1D(homobisucaberin, HBC). At pH values closer to physiological, EDTA treatment of for-[Zr(DFOT1)], for-[Zr(PPDFOT1)], or Zr(IV) complexes with related linear tri- or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomography (PET) imaging of cancer.
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney , New South Wales 2006, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Tieu
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney , New South Wales 2006, Australia.
authors.forename: Tulip
authors.initials: T
authors.lastname: Lifa
authors.affiliation: Department of Molecular Imaging, Royal Prince Alfred Hospital , Camperdown, New South Wales 2050, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Katsifis
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney , New South Wales 2006, Australia.
authors.forename: Rachel
authors.identifier: http://orcid.org/0000-0002-2703-883X
authors.initials: R
authors.lastname: Codd
mesh_terms: D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D015040:Zirconium / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D056831:Coordination Complexes; D006877:Hydroxamic Acids; D008024:Ligands; D047028:Macrocyclic Compounds; D015040:Zirconium