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endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis


Brown, Christopher J M; Gotsbacher, Michael P; Holland, Jason P; Codd, Rachel (2019). endo-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis. Inorganic Chemistry, 58(20):13591-13603.

Abstract

An expedited synthesis of endo-hydroxamic acid aminocarboxylic acid (endo-HXA) compounds has been developed. These monomeric ligands are relevant to the synthesis of metal–macrocycle complexes using metal-templated synthesis (MTS), and the downstream production of apomacrocycles. Macrocycles can display useful drug properties and be used as ligands for radiometals in medical imaging applications, which supports methodological advances in accessing this class of molecule. Six endo-HXA ligands were prepared that contained methylene groups, ether atoms, or thioether atoms in different regions of the monomer (1–6). MTS using a 1:2 Fe(III)/ligand ratio furnished six dimeric hydroxamic acid macrocycles complexed with Fe(III) (1a–6a). The corresponding apomacrocycles (1b–6b) were produced upon treatment with diethylenetriaminepentaacetic acid (DTPA). Constitutional isomers of the apomacrocycles that contained one ether oxygen atom in the diamine-containing (2b) or dicarboxylic acid-containing (3b) region were well resolved by reverse-phase high-performance liquid chromatography (RP-HPLC). Density functional theory calculations were used to compute the structures and solvated molecular properties of 1b–6b and showed that the orientation of the amide bonds relative to the pseudo-C2 axis was close to parallel in 1b, 2b, and 4b–6b but tended toward perpendicular in 3b. This conformational constraint in 3b reduced the polarity compared with 2b, consistent with the experimental trend in polarity observed using RP-HPLC. The improved synthesis of endo-HXA ligands allows expanded structural diversity in MTS-derived macrocycles and the ability to modulate macrocycle properties.

Abstract

An expedited synthesis of endo-hydroxamic acid aminocarboxylic acid (endo-HXA) compounds has been developed. These monomeric ligands are relevant to the synthesis of metal–macrocycle complexes using metal-templated synthesis (MTS), and the downstream production of apomacrocycles. Macrocycles can display useful drug properties and be used as ligands for radiometals in medical imaging applications, which supports methodological advances in accessing this class of molecule. Six endo-HXA ligands were prepared that contained methylene groups, ether atoms, or thioether atoms in different regions of the monomer (1–6). MTS using a 1:2 Fe(III)/ligand ratio furnished six dimeric hydroxamic acid macrocycles complexed with Fe(III) (1a–6a). The corresponding apomacrocycles (1b–6b) were produced upon treatment with diethylenetriaminepentaacetic acid (DTPA). Constitutional isomers of the apomacrocycles that contained one ether oxygen atom in the diamine-containing (2b) or dicarboxylic acid-containing (3b) region were well resolved by reverse-phase high-performance liquid chromatography (RP-HPLC). Density functional theory calculations were used to compute the structures and solvated molecular properties of 1b–6b and showed that the orientation of the amide bonds relative to the pseudo-C2 axis was close to parallel in 1b, 2b, and 4b–6b but tended toward perpendicular in 3b. This conformational constraint in 3b reduced the polarity compared with 2b, consistent with the experimental trend in polarity observed using RP-HPLC. The improved synthesis of endo-HXA ligands allows expanded structural diversity in MTS-derived macrocycles and the ability to modulate macrocycle properties.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:21 October 2019
Deposited On:07 Feb 2020 15:42
Last Modified:07 Feb 2020 15:47
Publisher:American Chemical Society (ACS)
ISSN:0020-1669
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.inorgchem.9b00878
Project Information:
  • : FunderAustralian Research Council
  • : Grant IDDP140100092
  • : Project Title

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