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Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

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ABSTRACT

A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

No MeSH data available.


Synthesis of hexadentate enterobactin analogues 7a–c (L1–3H6) and 5a–c (L7–9H2).
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f1: Synthesis of hexadentate enterobactin analogues 7a–c (L1–3H6) and 5a–c (L7–9H2).

Mentions: The preparation of hexadentate enterobactin analogues 7a–c (L1–3H6) is shown in Fig. 1. 2,3-bis(dibenzyloxy)benzonic acid 2 (80%) was generated from commercially available 2,3-bis(hydroxyl)benzonic acid 128. Aminoalcohol 3a–c and 2 were condensed using HOBt/DCC to obtain the desired benzamides (4a–c) with up to 90% yield29. 1,3,5-Benzenetricarbonyl trichloride was then added to benzamides 4a–c in the presence of Et3N in anhydrous CH2Cl2. The reaction generated benzyl-protected derivatives 6a–c with up to 71% yield. Deprotection of the hydroxyl groups under typical catalytic hydrogenation conditions with removal of the benzyl group (room temperature, 130 mL/min H2, atmospheric pressure, and Pd/C in THF) produced 5a–c (L7–9H2) and 7a–c (L1–3H6) with up to 99% yield.


Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies
Synthesis of hexadentate enterobactin analogues 7a–c (L1–3H6) and 5a–c (L7–9H2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037427&req=5

f1: Synthesis of hexadentate enterobactin analogues 7a–c (L1–3H6) and 5a–c (L7–9H2).
Mentions: The preparation of hexadentate enterobactin analogues 7a–c (L1–3H6) is shown in Fig. 1. 2,3-bis(dibenzyloxy)benzonic acid 2 (80%) was generated from commercially available 2,3-bis(hydroxyl)benzonic acid 128. Aminoalcohol 3a–c and 2 were condensed using HOBt/DCC to obtain the desired benzamides (4a–c) with up to 90% yield29. 1,3,5-Benzenetricarbonyl trichloride was then added to benzamides 4a–c in the presence of Et3N in anhydrous CH2Cl2. The reaction generated benzyl-protected derivatives 6a–c with up to 71% yield. Deprotection of the hydroxyl groups under typical catalytic hydrogenation conditions with removal of the benzyl group (room temperature, 130 mL/min H2, atmospheric pressure, and Pd/C in THF) produced 5a–c (L7–9H2) and 7a–c (L1–3H6) with up to 99% yield.

View Article: PubMed Central - PubMed

ABSTRACT

A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

No MeSH data available.