Axial Ligand Exchange of <i>N</i>‑heterocyclic Cobalt(III) Schiff Base Complexes: Molecular Structure and NMR Solution Dynamics

The kinetic and thermodynamic ligand exchange dynamics are important considerations in the rational design of metal-based therapeutics and therefore, require detailed investigation. Co­(III) Schiff base complex derivatives of bis­(acetylacetone)­ethylenediimine [acacen] have been found to be potent enzyme and transcription factor inhibitors. These complexes undergo solution exchange of labile axial ligands. Upon dissociation, Co­(III) irreversibly interacts with specific histidine residues of a protein, and consequently alters structure and causes inhibition. To guide the rational design of next generation agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the pD- and temperature-dependent axial ligand substitution dynamics of a series of <i>N</i>-heterocyclic [Co­(acacen)­(X)₂]⁺ complexes [where X = 2-methylimidazole (2MeIm), 4-methylimidazole (4MeIm), ammine (NH₃), <i>N</i>-methylimidazole (NMeIm), and pyridine (Py)] were characterized by NMR spectroscopy. The pD stability was shown to be closely related to the nature of the axial ligand with the following trend toward aquation: 2MeIm > NH₃ ≫ 4MeIm > Py > Im > NMeIm. Reaction of each [Co­(III)­(acacen)­(X)₂]⁺ derivative with 4MeIm showed formation of a mixed ligand Co­(III) intermediate via a dissociative ligand exchange mechanism. The stability of the mixed ligand adduct was directly correlated to the pD-dependent stability of the starting Co­(III) Schiff base with respect to [Co­(acacen)­(4MeIm)₂]⁺. Crystal structure analysis of the [Co­(acacen)­(X)₂]⁺ derivatives confirmed the trends in stability observed by NMR spectroscopy. Bond distances between the Co­(III) and the axial nitrogen atoms were longest in the 2MeIm derivative as a result of distortion in the planar tetradentate ligand, and this was directly correlated to axial ligand lability and propensity toward exchange

Axial Ligand Exchange of <i>N</i>‑heterocyclic Cobalt(III) Schiff Base Complexes: Molecular Structure and NMR Solution Dynamics

The kinetic and thermodynamic ligand exchange dynamics are important considerations in the rational design of metal-based therapeutics and therefore, require detailed investigation. Co­(III) Schiff base complex derivatives of bis­(acetylacetone)­ethylenediimine [acacen] have been found to be potent enzyme and transcription factor inhibitors. These complexes undergo solution exchange of labile axial ligands. Upon dissociation, Co­(III) irreversibly interacts with specific histidine residues of a protein, and consequently alters structure and causes inhibition. To guide the rational design of next generation agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the pD- and temperature-dependent axial ligand substitution dynamics of a series of <i>N</i>-heterocyclic [Co­(acacen)­(X)₂]⁺ complexes [where X = 2-methylimidazole (2MeIm), 4-methylimidazole (4MeIm), ammine (NH₃), <i>N</i>-methylimidazole (NMeIm), and pyridine (Py)] were characterized by NMR spectroscopy. The pD stability was shown to be closely related to the nature of the axial ligand with the following trend toward aquation: 2MeIm > NH₃ ≫ 4MeIm > Py > Im > NMeIm. Reaction of each [Co­(III)­(acacen)­(X)₂]⁺ derivative with 4MeIm showed formation of a mixed ligand Co­(III) intermediate via a dissociative ligand exchange mechanism. The stability of the mixed ligand adduct was directly correlated to the pD-dependent stability of the starting Co­(III) Schiff base with respect to [Co­(acacen)­(4MeIm)₂]⁺. Crystal structure analysis of the [Co­(acacen)­(X)₂]⁺ derivatives confirmed the trends in stability observed by NMR spectroscopy. Bond distances between the Co­(III) and the axial nitrogen atoms were longest in the 2MeIm derivative as a result of distortion in the planar tetradentate ligand, and this was directly correlated to axial ligand lability and propensity toward exchange

Nanodiamond–Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field

The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond–gadolinium­(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium­(III) [Gd­(III)]–nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd­(III) compared to that of clinical Gd­(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG-labeled flank tumors by <i>T</i>₁- and <i>T</i>₂-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities

Graphene Oxide Enhances Cellular Delivery of Hydrophilic Small Molecules by Co-incubation

The delivery of bioactive molecules into cells has broad applications in biology and medicine. Polymer-modified graphene oxide (GO) has recently emerged as a <i>de facto</i> noncovalent vehicle for hydrophobic drugs. Here, we investigate a different approach using native GO to deliver hydrophilic molecules by co-incubation in culture. GO adsorption and delivery were systematically studied with a library of 15 molecules synthesized with Gd(III) labels to enable quantitation. Amines were revealed to be a key chemical group for adsorption, while delivery was shown to be quantitatively predictable by molecular adsorption, GO sedimentation, and GO size. GO co-incubation was shown to enhance delivery by up to 13-fold and allowed for a 100-fold increase in molecular incubation concentration compared to the alternative of nanoconjugation. When tested in the application of Gd(III) cellular MRI, these advantages led to a nearly 10-fold improvement in sensitivity over the state-of-the-art. GO co-incubation is an effective method of cellular delivery that is easily adoptable by researchers across all fields

Mechanisms of Gadographene-Mediated Proton Spin Relaxation

Gd­(III) associated with carbon nanomaterials relaxes water proton spins at an effectiveness that approaches or exceeds the theoretical limit for a single bound water molecule. These Gd­(III)-labeled materials represent a potential breakthrough in sensitivity for Gd­(III)-based contrast agents used for magnetic resonance imaging (MRI). However, their mechanism of action remains unclear. A gadographene library encompassing GdCl₃, two different Gd­(III) complexes, graphene oxide (GO), and graphene suspended by two different surfactants and subjected to varying degrees of sonication was prepared and characterized for their relaxometric properties. Gadographene was found to perform comparably to other Gd­(III)–carbon nanomaterials; its longitudinal (<i>r</i>₁) and transverse (<i>r</i>₂) relaxivity are modulated between 12–85 mM^–1 s^–1 and 24–115 mM^–1 s^–1, respectively, depending on the Gd­(III)–carbon backbone combination. The unusually large relaxivity and its variance can be understood under the modified Florence model incorporating the Lipari–Szabo approach. Changes in hydration number (<i>q</i>), water residence time (τ_M), molecular tumbling rate (τ_R), and local motion (τ_fast) sufficiently explain most of the measured relaxivities. Furthermore, results implicated the coupling between graphene and Gd­(III) as a minor contributor to proton spin relaxation