Synthesis and Unprecedented Complexation Properties of β-Cyclodextrin-Based Ligand for Lanthanide Ions

Abstract

Here, we report the synthesis and detailed studies on the coordination chemistry of a novel chemically modified polyaminocarboxylate (5) based on β-cyclodextrin (CD) scaffold for lanthanides. The target ligand is prepared in a highly efficient manner (seven total steps) from β-CD using the readily available iminodiacetic acid as a starting material. A propargyl group is attached to the iminodiacetate via N-alkylation, and the obtained derivative is efficiently conjugated to the β-CD scaffold via the copper(I)-mediated 1,3-dipolar cycloaddition. The generated 1,2,3-triazolmethyl residues advantageously provide a competent chelating group while displacing the metal coordination center away from the primary rim of β-CD, to afford the required conformational flexibility. The functional groups from each of the two adjacent glucopyranosyl units of β-CD complete a uniquely created octavalent coordination sphere for lanthanides while still sparing one site for dynamic water coordination. To help study the coordination chemistry of CD ligand 5, we also design a relevant maltoside ligand 6, which faithfully represents one submetal-binding section of ligand 5. Thanks to HRMS and NMR studies, we successfully elucidate the coordination chemistries of synthesized ligands. The octavalent coordination sphere of ligand 5 shows strong binding affinity to lanthanides. By potentiometric titration experiments, ligand 5 is found to bind gadolinium(III), forming 1:1, 1:2, and 1:3 multinuclear complexes with lanthanides, thus possessing great capacity for catalyzing the dynamic water-exchange. Further NMR studies also reveal that the formed ligand 5/Gd(III) complexes show significantly better abilities to alter T1 relaxivities of coordinated water than DOTA-Gd(III) and also some of the synthetic CD probes reported in the literature.

Gd3+ Complexes Conjugated to Cyclodextrins: Hydroxyl Functions Influence the Relaxation Properties

“…This suggests that at the lower temperatures slow water exchange starts to become the limiting parameter, rather than fast rotational dynamics. In order to better decipher the relaxivity dependence, we performed 17 O NMR measurements on the different 1-3 complexes.…”

“…Variable temperature 17 O T 2 measurements give access to the water exchange rate, k ex . The reduced 17 O transverse relaxation rates for 1-3 are presented in Figure 4.…”

“…Thus, a large number of bulkier ligands coordinating the Gd 3+ ion was developed to create more efficient MRI contrast agents. Gd 3+ complexes were therefore incorporated into macromolecular systems such as proteins [12][13][14][15], dendrimers [16], cyclodextrins [17], polyrotaxanes [18][19][20], etc. However, the relaxivity enhancements has been often less than those expected, due to the flexibility of the macromolecule which implies faster local motion for Gd 3+ than the overall slow motion of the entire macromolecule.…”

Synthesis of Single Isomeric Complexes with Dissymmetric Structures Using Macrocyclic Homooligomers

“…They also reported a β‐cyclodextrin derivative with seven bpy groups introduced via a flexible linkage, but the discussion on the resulting isomers upon metal complexation was not made [22] . As shown by this example and other macrocyclic derivatives with multiple metal binding units, [23–26] it is a formidable challenge to demonstrate the formation of a single product when the number of total valences in the ligands and metals is mismatched. The cyclodextrin derivatives in this study can form many possible isomers upon metal complexation.…”

Synthesis of Single Isomeric Complexes with Dissymmetric Structures Using Macrocyclic Homooligomers

“…[19][20][21] They also reported a b-cyclodextrin derivative with seven bpy groups introduced via af lexible linkage,b ut the discussion on the resulting isomers upon metal complexation was not made. [22] As shown by this example and other macrocyclic derivatives with multiple metal binding units, [23][24][25][26] it is af ormidable challenge to demonstrate the formation of as ingle product when the number of total valences in the ligands and metals is mismatched. Thec yclodextrin derivatives in this study can form many possible isomers upon metal complexation.…”