Aqua ligands can undergo rapid internal rotation about the M-O bond. For magnetic resonance contrast agents, this rotation results in diminished relaxivity. Here we show that an intramolecular hydrogen bond to the aqua ligand can reduce this internal rotation and increase relaxivity. Molecular modeling was used to design a series of four Gd complexes capable of forming an intramolecular H-bond to the coordinated water ligand, and these complexes had anomalously high relaxivities compared to similar complexes lacking a H-bond acceptor. Molecular dynamics simulations supported the formation of a stable intramolecular H-bond while alternative hypotheses that could explain the higher relaxivity were systematically ruled out. Intramolecular H-bonding represents a useful strategy to limit internal water rotational motion and increase relaxivity of Gd complexes.
The synthesis of two bifunctional chelates, 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) conjugates of benzothiazoles (H3L3a and H3L3b), and the corresponding gadolinium complexes (GdL3a and GdL3b) was achieved. The intracellular and tumor‐specific nature of GdL3a and GdL3b were confirmed by magnetic resonance images of the cytosols and nuclei of various cell lines. The two complexes displayed antitumor activities with varying degrees of growth‐inhibition and total‐growth‐inhibition values depending on the types of tumor cells. They caused morphological changes in tumor cell lines at much lower concentrations of gadolinium ([Gd] ≥ 50 μM) than their predecessors, DO3A–(p‐aniline benzothiazole) conjugates (H3L1), and its GdIII complex (GdL1) required concentrations that were almost four times as high ([Gd] ≥ 200 μM).
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